David J. Fisher

<h3>Importance</h3> Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. <h3>Objective</h3> To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. <h3>Design, Setting, and Participants</h3> Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the<i>I2</i>statistic. The primary analysis was an inverse variance–weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance–weighted fixed-effect analysis using risk ratios. <h3>Exposures</h3> Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). <h3>Main Outcomes and Measures</h3> The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. <h3>Results</h3> A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82];<i>P</i> &lt; .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (<i>I2</i> = 15.6%;<i>P</i> = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01;<i>P</i> = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82;<i>P</i> &lt; .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12;<i>P</i> = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87;<i>P</i> = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo. <h3>Conclusions and Relevance</h3> In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

To assess the association between infant size or growth and subsequent obesity and to determine if any association has been stable over time.Systematic review.Medline, Embase, bibliographies of included studies, contact with first authors of included studies and other experts.Studies that assessed the relation between infant size or growth during the first two years of life and subsequent obesity.Obesity at any age after infancy.24 studies met the inclusion criteria (22 cohort and two case-control studies). Of these, 18 assessed the relation between infant size and subsequent obesity, most showing that infants who were defined as "obese" or who were at the highest end of the distribution for weight or body mass index were at increased risk of obesity. Compared with non-obese infants, in those who had been obese odds ratios or relative risks for subsequent obesity ranged from 1.35 to 9.38. Ten studies assessed the relation of infant growth with subsequent obesity and most showed that infants who grew more rapidly were at increased risk of obesity. Compared with other infants, in infants with rapid growth odds ratios and relative risks of later obesity ranged from 1.17 to 5.70. Associations were consistent for obesity at different ages and for people born over a period from 1927 to 1994.Infants who are at the highest end of the distribution for weight or body mass index or who grow rapidly during infancy are at increased risk of subsequent obesity.

In this paper, a general framework is proposed to relate tip radius, interface undercooling and primary arm spacing in alloy dendrite growth. All the growth morphologies (pox, cells, dendrites) developed between the limiting morphology at low and at high velocity: the plane front, are described to a first approximation, using an ellipsoid of revolution. In order to keep the model tractable and the solutions analytic, substantial simplifications are made. It seems nevertheless that this still permits a semi-quantitative prediction of the above-mentioned characteristics for alloy growth in a positive temperature gradient (as in the case of columnar growth or directional solidification). Dans ce travail, un cadre général est proposé pour établir des relations entre rayon de pointe, surfusion et espacement primaire des dendrites dans un alliage. Toutes les morphologies de croissance (front plan, cellules, dendrites) sont décrites en première approximation par un ellipsoide. Pour obtenir des solutions analytiques, des simplifications substantielles ont été faites. Malgré ces simplifications, le calcul des grandeurs caractéristiques pour la croissance des dendrites des alliages dans un gradient de température positif est possible; comme dans le cas de la solidification colonnaire d'une coulée ou de la solidification orientée. Es wird ein allgemeiner Rahmen vorgeschlagen, der für Legierungsdendriten eine Lösung der Zusammenhänge zwischen Spitzenradius, Unterkühlung und Primärabstand ermöglicht. Die Wachstumsformen (ebene Front, Zellen, Dendriten) werden in erster Näherung durch ein Ellipsoid beschrieben. Aufgrund starker Vereinfachungen im Modell können analytische Lösungen angegeben werden. Trotz dieser Vereinfachungen scheint es, dass halbquantitative Voraussagen zum Dendriten wachstum in Legierungen im positiven Temperaturgradienten (transkristalline, bzw. gerichtete Erstarrung) gegeben werden können.

BackgroundIn the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.MethodsIn this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.Findings1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3–29·2] in the control group vs 17·0 months [9·4–30·1] in the cetuximab group; HR 1·04, 95% CI 0·87–1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0–12·5] in the control group vs 8·6 months [5·1–13·8] in the cetuximab group; HR 0·96, 0·82–1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5–27·4); KRAS mutant, 14·4 months (8·5–24·0); all wild-type, 20·1 months (11·5–31·7).InterpretationThis trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.FundingCancer Research UK, Cancer Research Wales, UK Medical Research Council, Merck KGgA.

Raised maternal plasma total homocysteine (tHcy) concentrations predict small size at birth, which is a risk factor for type 2 diabetes mellitus. We studied the association between maternal vitamin B12, folate and tHcy status during pregnancy, and offspring adiposity and insulin resistance at 6 years.In the Pune Maternal Nutrition Study we studied 700 consecutive eligible pregnant women in six villages. We measured maternal nutritional intake and circulating concentrations of folate, vitamin B12, tHcy and methylmalonic acid (MMA) at 18 and 28 weeks of gestation. These were correlated with offspring anthropometry, body composition (dual-energy X-ray absorptiometry scan) and insulin resistance (homeostatic model assessment of insulin resistance [HOMA-R]) at 6 years.Two-thirds of mothers had low vitamin B12 (<150 pmol/l), 90% had high MMA (>0.26 micromol/l) and 30% had raised tHcy concentrations (>10 micromol/l); only one had a low erythrocyte folate concentration. Although short and thin (BMI), the 6-year-old children were relatively adipose compared with the UK standards (skinfold thicknesses). Higher maternal erythrocyte folate concentrations at 28 weeks predicted higher offspring adiposity and higher HOMA-R (both p < 0.01). Low maternal vitamin B12 (18 weeks; p = 0.03) predicted higher HOMA-R in the children. The offspring of mothers with a combination of high folate and low vitamin B12 concentrations were the most insulin resistant.Low maternal vitamin B12 and high folate status may contribute to the epidemic of adiposity and type 2 diabetes in India.

Abstract Purpose: To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAFMT) status in metastatic colorectal cancer (mCRC). Experimental Design: A pooled analysis of four phase III studies in first-line treatment of mCRC (CAIRO, CAIRO2, COIN, and FOCUS) was performed. Primary outcome parameter was the hazard ratio (HR) for median progression-free survival (PFS) and overall survival (OS) in relation to MMR and BRAF. For the pooled analysis, Cox regression analysis was performed on individual patient data. Results: The primary tumors of 3,063 patients were analyzed, of which 153 (5.0%) exhibited deficient MMR (dMMR) and 250 (8.2%) a BRAFMT. BRAFMT was observed in 53 (34.6%) of patients with dMMR tumors compared with 197 (6.8%) of patients with proficient MMR (pMMR) tumors (P &amp;lt; 0.001). In the pooled dataset, median PFS and OS were significantly worse for patients with dMMR compared with pMMR tumors [HR, 1.33; 95% confidence interval (CI), 1.12–1.57 and HR, 1.35; 95% CI, 1.13–1.61, respectively), and for patients with BRAFMT compared with BRAF wild-type (BRAFWT) tumors (HR, 1.34; 95% CI, 1.17–1.54 and HR, 1.91; 95% CI, 1.66–2.19, respectively). PFS and OS were significantly decreased for patients with BRAFMT within the group of patients with pMMR, but not for BRAF status within dMMR, or MMR status within BRAFWT or BRAFMT. Conclusions: Prevalence of dMMR and BRAFMT in patients with mCRC is low and both biomarkers confer an inferior prognosis. Our data suggest that the poor prognosis of dMMR is driven by the BRAFMT status. Clin Cancer Res; 20(20); 5322–30. ©2014 AACR.

Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis.For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel).We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68-0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5-14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58-0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12-19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69-1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61-0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5-10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79-0·98]; p=0·025), which translates to 5% (1-8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83-1·07]; p=0·323), which translates to an absolute improvement in survival of 2% (-3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 [66%] of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 [0·89-1·18]; p=0·724) or zoledronic acid (0·98 [0·82-1·16]; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials.The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small.Medical Research Council UK.

Background It is unclear whether adjuvant or early salvage radiotherapy following radical prostatectomy is more appropriate for men who present with localised or locally advanced prostate cancer. We aimed to prospectively plan a systematic review of randomised controlled trials (RCTs) comparing these radiotherapy approaches. Methods We used a prospective framework for adaptive meta-analysis (FAME), starting the review process while eligible trials were ongoing. RCTs were eligible if they aimed to compare immediate adjuvant radiotherapy versus early salvage radiotherapy, following radical prostatectomy in men (age ≥18 years) with intermediate-risk or high-risk, localised or locally advanced prostate cancer. We searched trial registers and conference proceedings until July 8, 2020, to identify eligible RCTs. By establishing the ARTISTIC collaboration with relevant trialists, we were able to anticipate when eligible trial results would emerge, and we developed and registered a protocol with PROSPERO before knowledge of the trial results (CRD42019132669). We used a harmonised definition of event-free survival, as the time from randomisation until the first evidence of either biochemical progression (prostate-specific antigen [PSA] ≥0·4 ng/mL and rising after completion of any postoperative radiotherapy), clinical or radiological progression, initiation of a non-trial treatment, death from prostate cancer, or a PSA level of at least 2·0 ng/mL at any time after randomisation. We predicted when we would have sufficient power to assess whether adjuvant radiotherapy was superior to early salvage radiotherapy. Investigators supplied results for event-free survival, both overall and within predefined patient subgroups. Hazard ratios (HRs) for the effects of radiotherapy timing on event-free survival and subgroup interactions were combined using fixed-effect meta-analysis. Findings We identified three eligible trials and were able to obtain updated results for event-free survival for 2153 patients recruited between November, 2007, and December, 2016. Median follow-up ranged from 60 months to 78 months, with a maximum follow-up of 132 months. 1075 patients were randomly assigned to receive adjuvant radiotherapy and 1078 to a policy of early salvage radiotherapy, of whom 421 (39·1%) had commenced treatment at the time of analysis. Patient characteristics were balanced within trials and overall. Median age was similar between trials at 64 or 65 years (with IQRs ranging from 59 to 68 years) across the three trials and most patients (1671 [77·6%]) had a Gleason score of 7. All trials were assessed as having low risk of bias. Based on 270 events, the meta-analysis showed no evidence that event-free survival was improved with adjuvant radiotherapy compared with early salvage radiotherapy (HR 0·95, 95% CI 0·75–1·21; p=0·70), with only a 1 percentage point (95% CI −2 to 3) change in 5-year event-free survival (89% vs 88%). Results were consistent across trials (heterogeneity p=0·18; I2=42%). Interpretation This collaborative and prospectively designed systematic review and meta-analysis suggests that adjuvant radiotherapy does not improve event-free survival in men with localised or locally advanced prostate cancer. Until data on long-term outcomes are available, early salvage treatment would seem the preferable treatment policy as it offers the opportunity to spare many men radiotherapy and its associated side-effects. Funding UK Medical Research Council.

BackgroundWhen cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim.MethodsCOIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448.Findings1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4–26·1) in arm A and 14·4 months (8·0–24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008–1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0–28·1) in arm A and 18·0 months (12·1–29·3) in arm C (HR 1·087, 0·986–1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80–1·15, p=0·66), versus 1·54 (1·17–2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand–foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment.InterpretationAlthough this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break.FundingCancer Research UK.

The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels.We analysed individual patients' data from 15,071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints.In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ(2)=0.83, 95% CI 0.83-0.83 in trials without radiotherapy, and 0.87, 0.87-0.87 in trials with radiotherapy) and excellent at trial level (R(2)=0.92, 95% CI 0.88-0.95 in trials without radiotherapy and 0.99, 0.98-1.00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ(2) range 0.77-0.85, dependent on the regimen being assessed) and trial level (R(2) range 0.89-0.97). In studies with data on locoregional control, individual-level correlations were good (ρ(2)=0.71, 95% CI 0.71-0.71 for concurrent chemotherapy and ρ(2)=0.61, 0.61-0.61 for modified vs standard radiotherapy) and trial-level correlations very good (R(2)=0.85, 95% CI 0.77-0.92 for concurrent chemotherapy and R(2)=0.95, 0.91-0.98 for modified vs standard radiotherapy).We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted.Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.

Many trials are evaluating therapies for men with metastatic hormone-sensitive prostate cancer (mHSPC).To systematically review trials of prostate radiotherapy.Using a prospective framework (framework for adaptive meta-analysis [FAME]), we prespecified methods before any trial results were known. We searched extensively for eligible trials and asked investigators when results would be available. We could then anticipate that a definitive meta-analysis of the effects of prostate radiotherapy was possible. We obtained prepublication, unpublished, and harmonised results from investigators.We included trials that randomised men to prostate radiotherapy and androgen deprivation therapy (ADT) or ADT only.Hazard ratios (HRs) for the effects of prostate radiotherapy on survival, progression-free survival (PFS), failure-free survival (FFS), biochemical progression, and subgroup interactions were combined using fixed-effect meta-analysis.We identified one ongoing (PEACE-1) and two completed (HORRAD and STAMPEDE) eligible trials. Pooled results of the latter (2126 men; 90% of those eligible) showed no overall improvement in survival (HR=0.92, 95% confidence interval [CI] 0.81-1.04, p=0.195) or PFS (HR=0.94, 95% CI 0.84-1.05, p=0.238) with prostate radiotherapy. There was an overall improvement in biochemical progression (HR=0.74, 95% CI 0.67-0.82, p=0.94×10-8) and FFS (HR=0.76, 95% CI 0.69-0.84, p=0.64×10-7), equivalent to ∼10% benefit at 3yr. The effect of prostate radiotherapy varied by metastatic burden-a pattern consistent across trials and outcome measures, including survival (<5, ≥5; interaction HR=1.47, 95% CI 1.11-1.94, p=0.007). There was 7% improvement in 3-yr survival in men with fewer than five bone metastases.Prostate radiotherapy should be considered for men with mHSPC with a low metastatic burden.Prostate cancer that has spread to other parts of the body (metastases) is usually treated with hormone therapy. In men with fewer than five bone metastases, addition of prostate radiotherapy helped them live longer and should be considered.

Identifying which individuals benefit most from particular treatments or other interventions underpins so-called personalised or stratified medicine. However, single trials are typically underpowered for exploring whether participant characteristics, such as age or disease severity, determine an individual’s response to treatment. A meta-analysis of multiple trials, particularly one where individual participant data (IPD) are available, provides greater power to investigate interactions between participant characteristics (covariates) and treatment effects. We use a published IPD meta-analysis to illustrate three broad approaches used for testing such interactions. Based on another systematic review of recently published IPD meta-analyses, we also show that all three approaches can be applied to aggregate data as well as IPD. We also summarise which methods of analysing and presenting interactions are in current use, and describe their advantages and disadvantages. We recommend that testing for interactions using within-trials information alone (the deft approach) becomes standard practice, alongside graphical presentation that directly visualises this.

This is the first account of the history of our understanding of, and ability to model, solidification microstructures. Its objective is to retrace the scientific steps made, from the earliest observations of the eighteenth century to our present-day understanding of dendrites and eutectics. Because of the abundance of information, especially that added during the present century, sub-division was essential: this being the first of three articles. They cover dendrites and cells from 1700 to 2000, and then from 2001 to 2015 and finally eutectics and peritectics from 1700 to 2015. The authors have striven always to identify the genesis of every advance made, being aware that such a compact history must leave many worthy contributions by the wayside; others will doubtless complete the history. This review shows how cross-fertilisation between theory and experiment, and basic and applied research led to both the posing and answering of challenging fundamental questions, thus rewarding society with beneficial results.

Our prior systematic review and meta-analysis of individual participant data (IPD) suggesting a benefit of adjuvant chemotherapy for muscle-invasive bladder cancer was limited by the number and size of included randomised trials. We have updated results to include additional trials, providing the most up-to-date and reliable evidence of the effects of this treatment.To investigate the role of adjuvant cisplatin-based chemotherapy in the treatment of muscle-invasive bladder cancer.Published and unpublished trials were sought via searches of bibliographic databases, trials registers, conference proceedings, and hand searching. Updated IPD were centrally collected, checked, and analysed. Results from individual randomised controlled trials (RCTs) were combined using a two-stage fixed-effect model. Prespecified analyses explored any variation in effect by trial and participant characteristics.Analyses of ten RCTs (1183 participants) demonstrated a benefit of cisplatin-based adjuvant chemotherapy on overall survival (hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70-0.96, p = 0.02). This represents an absolute improvement in survival of 6% at 5 yr, from 50% to 56%, and a 9% absolute benefit when adjusted for age, sex, pT stage, and pN category (HR = 0.77, 95% CI = 0.65-0.92, p = 0.004). There was no clear evidence that the effect varied by trial or participant characteristics. Adjuvant chemotherapy was also shown to improve recurrence-free survival (HR = 0.71, 95% CI = 0.60-0.83, p < 0.001), locoregional recurrence-free survival (HR = 0.68, 95% CI = 0.55-0.85, p < 0.001), and metastasis-free survival (HR = 0.79, 95% CI = 0.65-0.95, p = 0.01), with absolute benefits of 11%, 11%, and 8%, respectively.This systematic review and meta-analysis demonstrates that cisplatin-based adjuvant chemotherapy is a valid option for improving outcomes for muscle-invasive bladder cancer.We looked at the effect of cisplatin-based chemotherapy on outcomes in participants with muscle-invasive bladder cancer. We gathered this information from eligible randomised controlled trials. We demonstrated that cisplatin-based chemotherapy is a valid option for improving outcomes of muscle-invasive bladder cancer.

Background/Objectives: Vitamin D is required for bone growth and normal insulin secretion. Maternal hypovitaminosis D may impair fetal growth and increase the risk of gestational diabetes. We have related maternal vitamin D status in pregnancy to maternal and newborn glucose and insulin concentrations, and newborn size, in a South Indian population. Subjects/Methods: Serum 25 hydroxy vitamin D (25(OH)D) concentrations, glucose tolerance, and plasma insulin, proinsulin and 32–33 split proinsulin concentrations were measured at 30 weeks gestation in 559 women who delivered at the Holdsworth Memorial Hospital, Mysore. The babies' anthropometry and cord plasma glucose, insulin and insulin precursor concentrations were measured. Results: In total 66% of women had hypovitaminosis D (25(OH)D concentrations <50 nmol l−1) and 31% were below 28 nmol l−1. There was seasonal variation in 25(OH)D concentrations (P<0.0001). There was no association between maternal 25(OH)D and gestational diabetes (incidence 7% in women with and without hypovitaminosis D). Maternal 25(OH)D concentrations were unrelated to newborn anthropometry or cord plasma variables. In mothers with hypovitaminosis D, higher 25(OH)D concentrations were associated with lower 30-min glucose concentrations (P=0.03) and higher fasting proinsulin concentrations (P=0.04). Conclusions: Hypovitaminosis D at 30 weeks gestation is common in Mysore mothers. It is not associated with an increased risk of gestational diabetes, impaired fetal growth or altered neonatal cord plasma insulin secretory profile.

It has long been recognised that irregular eutectics, such as AlSi or FeC are characterised by large average phase spacings, compared to those of regular eutectics growing at the same rate and by large interfacial undercoolings. More recently, experimental evidence has accumulated to show that both spacings and undercoolings are decreased upon increasing the imposed temperature gradient in steadystate unidirectional growth. None of the existing models of eutectic growth explain any of these facts. In the present paper, some new results are presented which clarify the mode of growth of irregular eutectics. On the basis of these, a first attempt is made to incorporate the various disparate facts, concerning their growth, into a coherent growth model. In particular, the usual, minimum undercooling criterion is abandoned in favour of one based on the morphological instability and branching of the phases. Despite numerous approximations, the correct order of magnitude of spacing and undercooling is predicted, as is the effect of the imposed temperature gradient. On s'est aperçu depuis longtemps que les eutectiques irréguliers, tels que AlSi ou FeC sont caractérisés par un grand espacement moyen des phases, en comparaison avec celui des eutectiques réguliers croissant à la même vitesse, et par une forte surfusion à l'interface. Plus récemment des résultats expérimentaux ont montré qu'en régime permanent de croissance unidirectionelle l'espacement et la surfusion diminuent lorsqu'on augmente le gradient de température imposé. Les modèles de croissance des eutectiques n'expliquent aucun de ces faits expérimentaux. Les résultats expérimentaux présentés dans cet article clarifient le mode de croissance des eutectiques irréguliers. Divers résultats expérimentaux disparates ont été incorporés dans un modèle cohérent de croissance. Un nouveau critère, reposant sur l'instabilité morphologique et te branchement des phases, remplace dans le présent modèle l'habituel critère de la surfusion minimale. Malgré de nombreuses approximations, nous pouvons prévoir l'ordre de grandeur correct de l'espacement et de la surfusion, ainsi que l'effet d'un gradient de température imposé. Irreguläre Eutektika wie z.B. AlSi oder FeC weisen, verglichen mit regulären mit gleicher Geschwindigkeit gewachsenen eutektischen Legierungen, grosse mittlere Phasenabstände und grosse Grenzflächenunterkühlung auf. Neuere experimentelle Arbeiten zeigten, dass Abstände und Unterkühlung abnehmen, wenn der Temperaturgradient bei stationärer gerichteter Erstarrung zunimmt. Diese Ergebnisse können durch keine der vorliegenden Wachstumstheorien erklärt werden. In der vorliegenden Arbeit werden neue Ergebnisse beschrieben, die die Art des Wachstums irregulärer Eutektika aufklären. Auf dieser Grundlage wird versucht, die verschiedenen unvereinbaren Tatsachen in ein zusammenhängendes Wachstumsmodell aufzunehmen. Insbesondere wird das übliche Kriterium einer minimalen Unterkühlung zugunsten eines Kriteriums, das auf der morphologischen Instabilität und dem Verzweigen der Phasen aufbaut, aufgegeben. Trotz vieler Näherungen wird die richtige Grössenordnung der Abstände und der Unterkühlung erhalten, ebenso der Einfluss des eingestellten Temperaturgradienten.

Background Multiple micronutrient deficiencies are common among women in low-income countries and may adversely affect pregnancy outcomes. Objective This meta-analysis reports the effects on newborn size and duration of gestation of multiple micronutrient supplementation mainly compared with iron plus folic acid during pregnancy in recent randomized, controlled trials. Methods Original data from 12 randomized, controlled trials in Bangladesh, Burkina Faso, China, GuineaBissau, Indonesia, Mexico, Nepal, Niger, Pakistan, and Zimbabwe, all providing approximately 1 recommended dietary allowance (RDA) of multiple micronutrients to presumed HIV-negative women, were included. Outcomes included birthweight, other birth measurements, gestation, and incidence of low birthweight (LBW) (&lt; 2,500 g), small-for-gestational age birth (SGA, birthweight below the within-each-population 10th percentile), large-for-gestational age birth (LGA, birthweight above the within-each-population 90th percentile), and preterm delivery (&lt; 37 weeks). Results Compared with control supplementation (mainly with iron–folic acid), multiple micronutrient supplementation was associated with an increase in mean birthweight (pooled estimate: +22.4 g [95% CI, 8.3 to 36.4 g]; p = .002), a reduction in the prevalence of LBW (pooled OR = 0.89 [95% CI, 0.81 to 0.97]; p = .01) and SGA birth (pooled OR = 0.90 [95% CI, 0.82 to 0.99]; p = .03), and an increase in the prevalence of LGA birth (pooled OR = 1.13 [95% CI, 1.00 to 1.28]; p = .04). In most studies, the effects on birthweight were greater in mothers with higher body mass index (BMI). In the pooled analysis, the positive effect of multiple micronutrients on birthweight increased by 7.6 g (95% CI, 1.9 to 13.3 g) per unit increase in maternal BMI (p for interaction = .009). The intervention effect relative to the control group was + 39.0 g (95% CI, +22.0 to +56.1 g) in mothers with BMI of 20 kg/m 2 or higher compared with −6.0 g (95% CI, −8.8 to +16.8 g) in mothers with BMI under 20 kg/m 2 . There were no significant effects of multiple micronutrient supplementation on birth length or head circumference nor on the duration of gestation (pooled effect: +0.17 day [95% CI, −0.35 to +0.70 day]; p = .51) or the incidence of preterm birth (pooled OR = 1.00 [95% CI, 0.93 to 1.09]; p = .92). Conclusions Compared with iron–folic acid supplementation alone, maternal supplementation with multiple micronutrients during pregnancy in low-income countries resulted in a small increase in birthweight and a reduction in the prevalence of LBW of about 10%. The effect was greater among women with higher BMI.

Pulmonary hypertension may occur in the fetus in the presence of constriction of the ductus arteriosus. The feasibility of detection and quantitation of fetal ductal constriction by Doppler echocardiography was assessed in an animal preparation in which ductal constriction was created in the fetal lamb with a variable ligature causing varying degrees of fetal pulmonary hypertension (fetal pulmonary arterial systolic pressure 57 to 97 mm Hg and ductal gradient 9 to 42 mm Hg). Comparison of blinded, continuous-wave peak Doppler velocity (V) measurements of the ductal gradient with the modified Bernoulli assumption (gradient = 4V2) compared well with direct catheter measurements of instantaneous peak systolic gradient (r = .99, catheter = 0.95 X Doppler + 0.6), peak-to-peak gradient (r = .97), and mid-diastolic gradient (r = .85). Ductal constriction was characterized by an increase in the peak systolic and diastolic velocities. The normal human fetal ductus arteriosus blood flow velocity pattern was assessed by pulsed Doppler techniques in 25 normal human fetuses after 20 weeks gestation. The peak systolic flow velocity in the ductus arteriosus measured by image-directed pulsed Doppler echocardiography ranged from 50 to 141 cm/sec (mean 80 cm/sec) and increased with gestational age (r = .50). Diastolic velocity in the ductus arteriosus was consistently directed toward the descending aorta and ranged from 6 to 30 cm/sec. The ductal systolic velocities were the highest blood flow velocities in the fetal cardiovascular system. Application of these techniques to fetuses whose mothers were receiving indomethacin for treatment of premature labor at 30 to 31 weeks gestation confirmed this method to be sensitive for detection of fetal ductal constriction, which developed in three fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective Treatments may be more effective in some patients than others, and individual participant data (IPD) meta-analysis of randomized trials provides perhaps the best method of investigating treatment-covariate interactions. Various methods are used; we provide a comprehensive critique and develop guidance on method selection. Study Design and Setting We searched MEDLINE to identify all frequentist methods and appraised them for simplicity, risk of bias, and power. IPD data sets were reanalyzed. Results Four methodological categories were identified: PWT: pooling of within-trial covariate interactions; OSM: “one-stage” model with a treatment-covariate interaction term; TDCS: testing for difference between covariate subgroups in their pooled treatment effects; and CWA: combining PWT with meta-regression. Distinguishing across- and within-trial information is important, as the former may be subject to ecological bias. A strategy is proposed for method selection in different circumstances; PWT or CWA are natural first steps. The OSM method allows for more complex analyses; TDCS should be avoided. Our reanalysis shows that different methods can lead to substantively different findings. Conclusion The choice of method for investigating interactions in IPD meta-analysis is driven mainly by whether across-trial information is considered for inclusion, a decision, which depends on balancing possible improvement in power with an increased risk of bias.

To improve strategies for the treatment of BRAF-mutant advanced colorectal cancer (aCRC) patients, we examined individual data from patients treated with chemotherapy alone in three randomised trials to identify points on the treatment pathway where outcomes differ from BRAF wild-types.2530 aCRC patients were assessed from three randomised trials. End-points were progression-free survival, response rate, disease control rate, post-progression survival (P-PS) and overall survival. Treatments included first-line oxaliplatin/fluorouracil (OxFU) and second-line irinotecan. Clinicians were unaware of BRAF-status.231 patients (9.1%) had BRAF-mutant tumours. BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic. Compared with wild-type, BRAF-mutant patients treated with first-line OxFU had similar DCR (59.2% versus 72%; adjusted OR = 0.76, P = 0.24) and PFS (5.7 versus 6.3 months; adjusted HR = 1.14, P = 0.26). Following progression on first-line chemotherapy, BRAF-mutant patients had a markedly shorter P-PS (4.2 versus 9.2 months, adjusted HR = 1.69, P < 0.001). Fewer BRAF-mutant patients received second-line treatment (33% versus 51%, P < 0.001), but BRAF-mutation was not associated with inferior second-line outcomes (RR adjusted OR = 0.56, P = 0.45; PFS adjusted HR = 1.01, P = 0.93). Significant clinical heterogeneity within the BRAF-mutant population was observed: a proportion (24.3%) had good first-line PFS and P-PS (both >6 months; OS = 24.0 months); however, 36.5% progressed rapidly through first-line chemotherapy and thereafter, with OS = 4.7 months.BRAF-mutant aCRC confers a markedly worse prognosis independent of associated clinicopathological features. Chemotherapy provides meaningful improvements in outcome throughout treatment lines. Post-progression survival is markedly worse and vigilance is required to ensure appropriate delivery of treatment after first-line progression.

There is a pressing need for more-efficient trial designs for biomarker-stratified clinical trials. We suggest a new approach to trial design that links novel treatment evaluation with the concurrent evaluation of a biomarker within a confirmatory phase II/III trial setting. We describe a new protocol using this approach in advanced colorectal cancer called FOCUS4. The protocol will ultimately answer three research questions for a number of treatments and biomarkers: (1) After a period of first-line chemotherapy, do targeted novel therapies provide signals of activity in different biomarker-defined populations? (2) If so, do these definitively improve outcomes? (3) Is evidence of activity restricted to the biomarker-defined groups? The protocol randomizes novel agents against placebo concurrently across a number of different biomarker-defined population-enriched cohorts: BRAF mutation; activated AKT pathway: PI3K mutation/absolute PTEN loss tumors; KRAS and NRAS mutations; and wild type at all the mentioned genes. Within each biomarker-defined population, the trial uses a multistaged approach with flexibility to adapt in response to planned interim analyses for lack of activity. FOCUS4 is the first test of a protocol that assigns all patients with metastatic colorectal cancer to one of a number of parallel population-enriched, biomarker-stratified randomized trials. Using this approach allows questions regarding efficacy and safety of multiple novel therapies to be answered in a relatively quick and efficient manner, while also allowing for the assessment of biomarkers to help target treatment.

<h2>Summary</h2><h3>Background</h3> Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy. <h3>Methods</h3> COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested <i>BRAF</i> and <i>NRAS</i> status retrospectively. The trial was registered, ISRCTN38375681. <h3>Findings</h3> We registered 401 patients, 226 of whom were enrolled. Results for 169 with <i>KRAS</i> wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients <i>vs</i> 20 [22%] of 92 patients), neutropenia (22 [29%] <i>vs</i> 30 [33%]), diarrhoea (14 [18%] <i>vs</i> 23 [25%]), and lethargy (20 [26%] <i>vs</i> 19 [21%]). <h3>Interpretation</h3> Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials. <h3>Funding</h3> UK Medical Research Council, Merck KGaA.

Randomised controlled trials (RCTs) of anti-EGFR monoclonal antibodies (MAb) in patients with advanced colorectal cancer (aCRC) have reported conflicting results.A systematic review of RCTs comparing standard treatments±anti-EGFR MAbs was conducted. Hazard ratios (HR) for progression-free (PFS) and overall survival (OS) were derived for patients with wild-type (WT) and mutant KRAS. Prespecified analyses were conducted for line of treatment, MAb used, chemotherapy regimen, and choice of fluouropyrimidine. Trials using bevacizumab on both arms were included in a sensitivity analysis.Fourteen eligible RCTs were identified, with results by KRAS status available for ten RCTs. For third line treatment, the effect of anti-EGFR MAbs depended on KRAS status (interaction p<0.00001), with a PFS benefit for patients with WT KRAS only (HR=0.43, 95% CI 0.35-0.52, p<0.00001). For first and second line treatment, the effect also appeared to depend on KRAS status (interaction p=0.0003), again with the PFS benefit only for patients with WT KRAS (HR=0.83, 95% CI 0.76-0.90, p<0.0001). Differences between trial results (heterogeneity p=0.02, I(2)=62%) were best explained by the fluouropyrimidine used, with PFS benefits confined to trials combining MAbs alongside 5FU-based chemotherapy (HR=0.77, 95% CI 0.70-0.85, p<0.00001). There was no evidence of a PFS benefit when MAbs were given with bevacizumab.For aCRC patients with WT KRAS, there are clear benefits of anti-EGFR MAbs in the third line and in the first and second line, when used alongside infusional 5FU-based regimens. However, there is no benefit for patients with KRAS mutations.

Abstract Purpose: To study the somatic molecular profile of the EGF receptor (EGFR) pathway in advanced colorectal cancer, its relationship to prognosis, the site of the primary and metastases, and response to cetuximab. Experimental Design: We used Sequenom and Pyrosequencing for high-throughput somatic profiling of the EGFR pathway in 1,976 tumors from patients with advanced colorectal cancer from the COIN trial (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). Correlations between mutations, clinicopathologic, response, and survival data were carried out. Results: Sequenom and Pyrosequencing had 99.0% (9,961/10,063) genotype concordance. We identified 13 different KRAS mutations in 42.3% of advanced colorectal cancers, 2 BRAF mutations in 9.0%, 4 NRAS mutations in 3.6%, and 5 PIK3CA mutations in 12.7%. 4.2% of advanced colorectal cancers had microsatellite instability (MSI). KRAS and PIK3CA exon 9, but not exon 20, mutations cooccurred (P = 8.9 × 10−4) as did MSI and BRAF mutations (P = 5.3 × 10−10). KRAS mutations were associated with right colon cancers (P = 5.2 × 10−5) and BRAF mutations with right (P = 7.2 × 10−5) and transverse colon (P = 9.8 × 10−6) cancers. KRAS mutations were associated with lung-only metastases (P = 2.3 × 10−4), BRAF mutations with peritoneal (P = 9.2 × 10−4) and nodal-only (P = 3.7 × 10−5) metastases, and MSI (BRAFWT) with nodal-only metastases (P = 2.9 × 10−4). MSI (BRAFWT) was associated with worse survival (HR = 1.89, 95% CI 1.30–2.76, P = 8.5 × 10−4). No mutations, subsets of mutations, or MSI status were associated with response to cetuximab. Conclusions: Our data support a functional cooperation between KRAS and PIK3CA in colorectal tumorigenesis and link somatic profiles to the sites of metastases. MSI was associated with poor prognosis in advanced disease, and no individual somatic profile was associated with response to cetuximab in COIN. Clin Cancer Res; 19(15); 4104–13. ©2013 AACR.

Precision medicine research often searches for treatment-covariate interactions, which refers to when a treatment effect (eg, measured as a mean difference, odds ratio, hazard ratio) changes across values of a participant-level covariate (eg, age, gender, biomarker). Single trials do not usually have sufficient power to detect genuine treatment-covariate interactions, which motivate the sharing of individual participant data (IPD) from multiple trials for meta-analysis. Here, we provide statistical recommendations for conducting and planning an IPD meta-analysis of randomized trials to examine treatment-covariate interactions. For conduct, two-stage and one-stage statistical models are described, and we recommend: (i) interactions should be estimated directly, and not by calculating differences in meta-analysis results for subgroups; (ii) interaction estimates should be based solely on within-study information; (iii) continuous covariates and outcomes should be analyzed on their continuous scale; (iv) nonlinear relationships should be examined for continuous covariates, using a multivariate meta-analysis of the trend (eg, using restricted cubic spline functions); and (v) translation of interactions into clinical practice is nontrivial, requiring individualized treatment effect prediction. For planning, we describe first why the decision to initiate an IPD meta-analysis project should not be based on between-study heterogeneity in the overall treatment effect; and second, how to calculate the power of a potential IPD meta-analysis project in advance of IPD collection, conditional on characteristics (eg, number of participants, standard deviation of covariates) of the trials (potentially) promising their IPD. Real IPD meta-analysis projects are used for illustration throughout.

In this article, I describe a command, ipdmetan, that facilitates two-stage individual participant data meta-analysis of any measure of effect and its standard error by fitting a specified model to data from each study. The command can estimate random effects and heterogeneity statistics and include additional covariates and interactions. If individual participant data are available for certain studies and aggregate data for others, ipdmetan allows them to be combined in one analysis. This command can produce detailed and flexible forest plots, including ones outside the context of formal meta-analysis.

While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk.We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels.Risk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65-0.92, P = 3.9 × 10-3; ORPOA = 0.36, 95% CI: 0.15-0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93-0.98, P = 3.7 × 10-4; ORAA = 1.05, 95% CI: 1.02-1.07, P = 1.7 × 10-4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01-1.35, P = 0.041).Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk.

Background The role of postoperative radiotherapy (PORT) in the treatment of patients with completely resected non‐small cell lung cancer (NSCLC) was not clear. A systematic review and individual participant data meta‐analysis was undertaken to evaluate available evidence from randomised controlled trials (RCTs). These results were first published in Lung Cancer in 2013. Objectives To evaluate the effects of PORT on survival and recurrence in patients with completely resected NSCLC. To investigate whether predefined patient subgroups benefit more or less from PORT. Search methods We supplemented MEDLINE and CANCERLIT searches (1965 to 8 July 2016) with information from trial registers, handsearching of relevant meeting proceedings and discussion with trialists and organisations. Selection criteria We included trials of surgery versus surgery plus radiotherapy, provided they randomised participants with NSCLC using a method that precluded prior knowledge of treatment assignment. Data collection and analysis We carried out a quantitative meta‐analysis using updated information from individual participants from all randomised trials. We sought data on all participants from those responsible for the trial. We obtained updated individual participant data (IPD) on survival and date of last follow‐up, as well as details on treatment allocation, date of randomisation, age, sex, histological cell type, stage, nodal status and performance status. To avoid potential bias, we requested information on all randomised participants, including those excluded from investigators' original analyses. We conducted all analyses on intention‐to‐treat on the endpoint of survival. Main results We identified 14 trials evaluating surgery versus surgery plus radiotherapy. Individual participant data were available for 11 of these trials, and our analyses are based on 2343 participants (1511 deaths). Results show a significant adverse effect of PORT on survival, with a hazard ratio of 1.18, or an 18% relative increase in risk of death. This is equivalent to an absolute detriment of 5% at two years (95% confidence interval (CI) 2% to 9%), reducing overall survival from 58% to 53%. Subgroup analyses showed no differences in effects of PORT by any participant subgroup covariate. We did not undertake analysis of the effects of PORT on quality of life and adverse events. Investigators did not routinely collect quality of life information during these trials, and it was unlikely that any benefit of PORT would offset the observed survival disadvantage. We considered risk of bias in the included trials to be low. Authors' conclusions Results from 11 trials and 2343 participants show that PORT is detrimental to those with completely resected non‐small cell lung cancer and should not be used in the routine treatment of such patients. Results of ongoing RCTs will clarify the effects of modern radiotherapy in patients with N2 tumours.

PURPOSE Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition. METHODS Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level. RESULTS FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%). CONCLUSION In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Further testing is required in this sizable population of unmet need.

Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours.The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591.We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55-85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9-11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (pinteraction=0·0019), higher volume of metastases (pinteraction=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (pinteraction=0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (-1%, 95% CI -15 to 12, for progression-free survival; 0%, -10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival).The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes.UK Medical Research Council and Prostate Cancer UK.

Existing clinical trials of cognitive behavioural therapies with a trauma focus (CBTs-TF) are underpowered to examine key variables that might moderate treatment effects. We aimed to determine the efficacy of CBTs-TF for young people, relative to passive and active control conditions, and elucidate putative individual-level and treatment-level moderators.This was an individual participant data meta-analysis of published and unpublished randomised studies in young people aged 6-18 years exposed to trauma. We included studies identified by the latest UK National Institute of Health and Care Excellence guidelines (completed on Jan 29, 2018) and updated their search. The search strategy included database searches restricted to publications between Jan 1, 2018, and Nov 12, 2019; grey literature search of trial registries ClinicalTrials.gov and ISRCTN; preprint archives PsyArXiv and bioRxiv; and use of social media and emails to key authors to identify any unpublished datasets. The primary outcome was post-traumatic stress symptoms after treatment (<1 month after the final session). Predominantly, one-stage random-effects models were fitted. This study is registered with PROSPERO, CRD42019151954.We identified 38 studies; 25 studies provided individual participant data, comprising 1686 young people (mean age 13·65 years [SD 3·01]), with 802 receiving CBTs-TF and 884 a control condition. The risk-of-bias assessment indicated five studies as low risk and 20 studies with some concerns. Participants who received CBTs-TF had lower mean post-traumatic stress symptoms after treatment than those who received the control conditions, after adjusting for post-traumatic stress symptoms before treatment (b=-13·17, 95% CI -17·84 to -8·50, p<0·001, τ2=103·72). Moderation analysis indicated that this effect of CBTs-TF on post-traumatic stress symptoms post-treatment increased by 0·15 units (b=-0·15, 95% CI -0·29 to -0·01, p=0·041, τ2=0·03) for each unit increase in pre-treatment post-traumatic stress symptoms.This is the first individual participant data meta-analysis of young people exposed to trauma. Our findings support CBTs-TF as the first-line treatment, irrespective of age, gender, trauma characteristics, or carer involvement in treatment, with particular benefits for those with higher initial distress.Swiss National Science Foundation.

Context/Objective: Bone mass is influenced by genetic and environmental factors. Recent studies have highlighted associations between maternal nutritional status during pregnancy and bone mass in the offspring. We hypothesized that maternal calcium intakes and circulating micronutrients during pregnancy are related to bone mass in Indian children. Design/Setting/Participants/Main Outcome Measures: Nutritional status was measured at 18 and 28 wk gestation in 797 pregnant rural Indian women. Measurements included anthropometry, dietary intakes (24-h recall and food frequency questionnaire), physical workload (questionnaire), and circulating micronutrients (red cell folate and plasma ferritin, vitamin B12, and vitamin C). Six years postnatally, total body and total spine bone mineral content and bone mineral density (BMD) were measured using dual-energy x-ray absorptiometry (DXA) in the children (n = 698 of 762 live births) and both parents. Results: Both parents’ DXA measurements were positively correlated with the equivalent measurements in the children (P < 0.001 for all). The strength of these correlations was similar for fathers and mothers. Children of mothers who had a higher frequency of intake of calcium-rich foods during pregnancy (milk, milk products, pulses, nonvegetarian foods, green leafy vegetables, fruit) had higher total and spine bone mineral content and BMD, and children of mothers with higher folate status at 28 wk gestation had higher total and spine BMD, independent of parental size and DXA measurements. Conclusions: Modifiable maternal nutritional factors may influence bone health in the offspring. Fathers play a role in determining their child’s bone mass, possibly through genetic mechanisms or through shared environment.

In phase II and III trials of gadoteridol (Gd-HP-D03A), a new nonionic, low-osmolar contrast agent, 40 patients with intracranial neoplasms underwent magnetic resonance (MR) imaging with experimental doses of 0.05-0.3 mmol/kg. Fifteen patients also underwent contrast studies with the standard dose (0.1 mmol/kg) of gadopentetate dimeglumine. Both gadopentetate dimeglumine and gadoteridol appear to have a similar effect when given in equal doses (0.1 mmol/kg, n = 5). Lesion enhancement and delineation were better at higher experimental doses (0.2 or 0.3 mmol/kg, n = 7) and worse at a lower experimental dose (0.05 mmol/kg, n = 3). Quantitative analysis of 10 lesions examined with identical imaging protocols revealed a directly proportional relationship (r = .975) between lesion contrast ratio and dose over a range of 0.05-0.3 mmol/kg. Phantom experiments support the clinical results. Improved enhancement, detection, and delineation of central nervous system (CNS) neoplasms resulting from increased injected doses of gadoteridol have the potential to be clinically significant and may justify the possibly higher cost of increased contrast material dosage. Lower doses may not be adequate for the evaluation of most CNS tumors.

We measured myocardial oxygen, glucose, lactate, and pyruvate consumption in chronically instrumented fetal and adult sheep. Although ascending aortic blood concentration of oxygen was significantly lower in fetuses, myocardial consumption of oxygen was similar in the two groups. This was accomplished by a significantly greater myocardial blood flow in the fetuses. Although ascending aortic blood glucose concentration was significantly lower in fetuses, myocardial consumption of glucose was significantly greater in fetuses. Complete oxidative combustion of all glucose consumed by the fetal heart would supply only one-third of myocardial energy demands, as measured by oxygen consumption. Ascending aortic blood concentration of lactate was similar in fetuses and adults, but myocardial consumption of lactate was significantly greater in fetuses. Complete oxidative combustion of all lactate consumed by fetal hearts would supply almost 60% of myocardial energy demands. Small, but significant, amounts of pyruvate are consumed by both fetuses and adults. Our data indicate that fetal lamb myocardium requires substrates other than glucose alone. The large amount of lactate consumed indicates that there is oxidative metabolism in addition to glycolysis and that lactate is of equal, or perhaps greater, importance as a myocardial energy substrate.

The synthesis of sterically hindered anilines has been a significant challenge in organic chemistry. Here we report a Cu-catalyzed radical addition with in situ-generated nitroso compounds to prepare sterically hindered amines directly from readily available materials. The transformation is conducted at room temperature, uses abundant copper salts, and is tolerant of a range of functional groups.

Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies.Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed.We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability).Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Background and Purpose Transcranial near-infrared laser therapy (TLT) is a promising and novel method to promote neuroprotection and clinical improvement in both acute and chronic neurodegenerative diseases such as acute ischemic stroke (AIS), traumatic brain injury (TBI), and Alzheimer's disease (AD) patients based upon efficacy in translational animal models. However, there is limited information in the peer-reviewed literature pertaining to transcranial near-infrared laser transmission (NILT) profiles in various species. Thus, in the present study we systematically evaluated NILT characteristics through the skull of 4 different species: mouse, rat, rabbit and human. Results Using dehydrated skulls from 3 animal species, using a wavelength of 800nm and a surface power density of 700 mW/cm2, NILT decreased from 40.10% (mouse) to 21.24% (rat) to 11.36% (rabbit) as skull thickness measured at bregma increased from 0.44 mm in mouse to 0.83 mm in rat and then 2.11 mm in rabbit. NILT also significantly increased (p<0.05) when animal skulls were hydrated (i.e. compared to dehydrated); but there was no measurable change in thickness due to hydration. In human calvaria, where mean thickness ranged from 7.19 mm at bregma to 5.91 mm in the parietal skull, only 4.18% and 4.24% of applied near-infrared light was transmitted through the skull. There was a slight (9.2-13.4%), but insignificant effect of hydration state on NILT transmission of human skulls, but there was a significant positive correlation between NILT and thickness at bregma and parietal skull, in both hydrated and dehydrated states. Conclusion This is the first systematic study to demonstrate differential NILT through the skulls of 4 different species; with an inverse relationship between NILT and skull thickness. With animal skulls, transmission profiles are dependent upon the hydration state of the skull, with significantly greater penetration through hydrated skulls compared to dehydrated skulls. Using human skulls, we demonstrate a significant correlation between thickness and penetration, but there was no correlation with skull density. The results suggest that TLT should be optimized in animals using novel approaches incorporating human skull characteristics, because of significant variance of NILT profiles directly related to skull thickness.

The phase III COntinuous or INtermittent (COIN) trial failed to show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in overall survival (OS). The present analysis evaluated whether the derived neutrophil to lymphocyte ratio (dNLR) could predict the effect of intermittent vs continuous chemotherapy on OS in patients with advanced colorectal cancer. A post hoc exploratory analysis of COIN arms A and C was performed. Landmark analysis was conducted on all patients with available WBC and neutrophils data. The dNLR was calculated using a formula which has previously demonstrated predictive power in cancer patients: dNLR=ANC/(WBC−ANC). A high dNLR was defined using a cut-off value of ⩾2.22. Derived neutrophil to lymphocyte ratio was then correlated with clinical outcomes. Survival curves were generated based on dNLR using the Kaplan–Meier method. Comparison between groups was performed using Cox regression. A total of 1630 patients were assigned to the continuous (N=815) or intermittent (N=815) arms. There was a strong association between dNLR level and OS. The median survival times in the ITT population were 18.6 months and 12.5 months for patients with low and high dNLR, respectively (HR=1.70; 95% CI=1.52–1.90; P<0.001). The estimate of the hazard ratio did not alter substantially (HR=1.54) after adjusting for treatment, tumour status, number of metastatic sites, alkaline phosphate and platelet count. Derived neutrophil to lymphocyte ratio is strongly prognostic for survival in the COIN intermittent vs continuous treatment arms. Derived neutrophil to lymphocyte ratio does not predict for detrimental survival in patients treated with intermittent therapy.

Abstract Because of potential reduced cost and improved retained conductivity, high viscosity friction reducers (HVFRs) are becoming increasingly popular in hydraulic fracturing stages where linear or crosslinked guar gels are traditionally used. However, concerns remain regarding the proppant transport capability of HVFRs relative to that of traditional linear gels. To address these concerns, the proppant transport capability of a polyacrylamide-based HVFR is compared with that of linear guar at cost-parity concentrations. Correlation between the proppant transport capability and rheological properties of the fluids, including viscosity and elasticity, is also discussed. A slot flow device was used to visualize the proppant transport performance of each fluid. The fluid concentrations ranged from 2.25 to 4.5 gpt (gallons per thousand gallons) for the HVFRs and 15# to 30# (pounds per thousand gallons) for guar, which were matched to achieve cost-parity between the two classes of fluids. The proppants used were 30/50, 20/40, and 12/20 mesh sand at 2 ppg (pounds per gallon) loading. Comprehensive rheological properties of the carrier fluids were characterized under steady-state and oscillatory shear and correlated with the observed proppant transport behavior. At least two sand transport mechanisms were observable in the slot flow tests. Small sand particles remained suspended in the fluid and were transported by convection. Large sand particles settled quickly, but top layers of the settled particles crept forward at a slower speed. The HVFR showed significantly better sand transport efficiency than guar at cost-parity concentrations despite the fact that the HVFR had a lower viscosity at high shear rates. The improved sand transport performance may be attributed to two factors: first, sand particles were suspended for a longer time in the HVFR because of its elevated viscosity at lower shear rates in the center of the slot; second, the HVFR's increased elasticity in the high shear regime near the wall further enhanced sand suspension by providing an elastic lifting force to hinder sand settling. The elastic effect on sand settling is estimated to be much larger than the viscous effect for the HVFR investigated herein but is neglibile in guar. Field results validated the capability of the HVFR to carry proppants, including 20/40 mesh coarse sand, in situations where traditional slickwater FRs and linear guar gel failed. This study demonstrated that the HVFR has superior proppant transport capability, relative to guar, at cost-parity concentrations despite having lower viscosity at high shear rates. The results indicate that the proppant transport performance of fracturing fluids correlates better with their elasticity and low shear viscosity than the high shear viscosity. Additionally, the findings provide much needed proppant transport data for field engineers to make rational choices for the selection of fracturing fluids.

Background It remains unclear when standard systematic reviews and meta-analyses that rely on published aggregate data (AD) can provide robust clinical conclusions. We aimed to compare the results from a large cohort of systematic reviews and meta-analyses based on individual participant data (IPD) with meta-analyses of published AD, to establish when the latter are most likely to be reliable and when the IPD approach might be required. Methods and findings We used 18 cancer systematic reviews that included IPD meta-analyses: all of those completed and published by the Meta-analysis Group of the MRC Clinical Trials Unit from 1991 to 2010. We extracted or estimated hazard ratios (HRs) and standard errors (SEs) for survival from trial reports and compared these with IPD equivalents at both the trial and meta-analysis level. We also extracted or estimated the number of events. We used paired t tests to assess whether HRs and SEs from published AD differed on average from those from IPD. We assessed agreement, and whether this was associated with trial or meta-analysis characteristics, using the approach of Bland and Altman. The 18 systematic reviews comprised 238 unique trials or trial comparisons, including 37,082 participants. A HR and SE could be generated for 127 trials, representing 53% of the trials and approximately 79% of eligible participants. On average, trial HRs derived from published AD were slightly more in favour of the research interventions than those from IPD (HRAD to HRIPD ratio = 0.95, p = 0.007), but the limits of agreement show that for individual trials, the HRs could deviate substantially. These limits narrowed with an increasing number of participants (p < 0.001) or a greater number (p < 0.001) or proportion (p < 0.001) of events in the AD. On average, meta-analysis HRs from published AD slightly tended to favour the research interventions whether based on fixed-effect (HRAD to HRIPD ratio = 0.97, p = 0.088) or random-effects (HRAD to HRIPD ratio = 0.96, p = 0.044) models, but the limits of agreement show that for individual meta-analyses, agreement was much more variable. These limits tended to narrow with an increasing number (p = 0.077) or proportion of events (p = 0.11) in the AD. However, even when the information size of the AD was large, individual meta-analysis HRs could still differ from their IPD equivalents by a relative 10% in favour of the research intervention to 5% in favour of control. We utilised the results to construct a decision tree for assessing whether an AD meta-analysis includes sufficient information, and when estimates of effects are most likely to be reliable. A lack of power at the meta-analysis level may have prevented us identifying additional factors associated with the reliability of AD meta-analyses, and we cannot be sure that our results are generalisable to all outcomes and effect measures. Conclusions In this study we found that HRs from published AD were most likely to agree with those from IPD when the information size was large. Based on these findings, we provide guidance for determining systematically when standard AD meta-analysis will likely generate robust clinical conclusions, and when the IPD approach will add considerable value.

Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy.Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology.Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II-IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47-2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry (P = 0.0009), which may mediate disease progression through common biology (KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression).Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials.

A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence.Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomisation were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence.One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0·82 [0·71-0·95, p = 0·008]] and sarilumab [0·80 [0·61-1·04, p = 0·09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 [95%CI 0·81-1·32, p = 0·80]. The p-value for the global test of inconsistency was 0·28.Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.

By 2050 more than 1.6 billion women worldwide will be of post-reproductive age, with >75% reporting severe menopausal symptoms. The last few years saw a gradual uplift in public awareness reaffirming the health needs of women with menopause. Still, effective translation of available evidence on menopause treatments is hindered by several methodological limitations and poor research conduct. We argue that a paradigm shift is required in menopause research to address the remaining knowledge gap and guide safe evidence-based care provision. A critical misconception across studies on menopause is the assumption that women represent a homogeneous group who respond similarly to a particular therapy irrespective of their exposure and individual risk factors. We highlight potential solutions to optimize the quality of future research in menopause including adopting robust trial methodology, standardize outcome reporting to capture quality-of-life measures, and improve lay patient and public involvement in future research.

Injuries to the atlanto-occipital region, which range from complete atlanto-occipital or atlantoaxial dislocation to nondisplaced occipital condyle avulsion fractures, are usually of critical clinical importance. At initial cross-table lateral radiography, measurement of the basion-dens and basion-posterior axial line intervals and comparison with normal measurements may help detect injury. Computed tomography (CT) with sagittal and coronal reformatted images permits optimal detection and evaluation of fracture and luxation. CT findings that may suggest atlanto-occipital injury include joint incongruity, focal hematomas, vertebral artery injury, capsular swelling, and, rarely, fractures through cranial nerve canals. Magnetic resonance (MR) imaging of the cervical spine with fat-suppressed gradient-echo T2-weighted or short-inversion-time inversion recovery sequences can demonstrate increased signal intensity in the atlantoaxial and atlanto-occipital joints, craniocervical ligaments, prevertebral soft tissues, and spinal cord. Axial gradient-echo MR images may be particularly useful in assessing the integrity of the transverse atlantal ligament. All imaging studies should be conducted with special attention to bone integrity and the possibility of soft-tissue injury. Atlanto-occipital injuries are now recognized as potentially survivable, although commonly with substantial morbidity. Swift diagnosis by the trauma radiologist is crucial for ensuring prompt, effective treatment and preventing delayed neurologic deficits in patients who survive such injuries.

Usefulness of turbo spin-echo MR imaging in the evaluation of meniscal tears: comparison with a conventional spin-echo sequence.E M Escobedo, J C Hunter, G C Zink-Brody, A J Wilson, S D Harrison and D J FisherAudio Available | Share

PURPOSE To study MR patterns of venous sinus occlusive disease and to relate them to the underlying pathophysiology by comparing the appearance and pathophysiologic features of venous sinus occlusive disease with those of arterial ischemic disease. METHODS The clinical data and MR examinations of 26 patients with venous sinus occlusive disease were retrospectively reviewed with special attention to mass effect, hemorrhage, and T2-weighted image abnormalities as well as to abnormal parenchymal, venous, or arterial enhancement after intravenous gadopentetate dimeglumine administration. Follow-up studies when available were evaluated for atrophy, infarction, chronic mass effect, and hemorrhage. RESULTS Mass effect was present in 25 of 26 patients. Eleven of the 26 had mass effect without abnormal signal on T2-weighted images. Fifteen patients had abnormal signal on T2-weighted images, but this was much less extensive than the degree of brain swelling in all cases. No patient showed abnormal parenchymal or arterial enhancement. Abnormal venous enhancement was seen in 10 of 13 patients who had contrast-enhanced studies. Intraparenchymal hemorrhage was seen in nine patients with high signal on T2-weighted images predominantly peripheral to the hematoma in eight. Three overall MR patterns were observed in acute sinus thrombosis: 1) mass effect without associated abnormal signal on T2-weighted images, 2) mass effect with associated abnormal signal on T2-weighted images and/or ventricular dilatation that may be reversible, and 3) intraparenchymal hematoma with surrounding edema. CONCLUSION MR findings of venous sinus occlusive disease are different from those of arterial ischemia and may reflect different underlying pathophysiology. In venous sinus occlusive disease, the breakdown of the blood-brain barrier (vasogenic edema and abnormal parenchymal enhancement) does not always occur, and brain swelling can persist up to 2 years with or without abnormal signal on T2-weighted images. Abnormal signal on T2-weighted images may be reversible and does not always indicate infarction.

We measured blood flow to the myocardium of the left ventricular free wall, and blood glucose, lactate, pyruvate, and oxygen concentrations simultaneously in the aorta and coronary sinus 13 times in seven previously instrumented newborn sheep, 4 to 25 days after birth. We calculated arteriovenous difference and consumption of oxygen, glucose, lactate, and pyruvate by the newborn myocardium. Results were compared with recently obtained measurements in the myocardium of fetal and adult sheep (6). Myocardial consumption of oxygen in the newborn (577 +/- 38 microM.min-1.100 g LV-1) was higher than in either the fetuses or the adults. This was associated with a greater myocardial blood flow (201 +/- 21 mm.min-1.100 g LV-1) in the newborns. However, the increased myocardial oxygen consumption in the newborns was commensurate with their increased cardiac work as compared with both the fetuses and adults. Although there is an abrupt postnatal increase in arterial glucose concentration, there was no significant difference in either the myocardial consumption of glucose or the contribution of glucose to the total myocardial energy supply among fetal, newborn or adult sheep. Postnatal decreases in myocardial consumption of lactate and pyruvate are not compensated for by an increase in glucose consumption. In newborn sheep, carbohydrates including glucose, lactate, and pyruvate supply the substrate for no more than approximately one-fourth of the total myocardial energy demands (carbohydrate/oxygen quotient was 0.26).

Abstract Objective To evaluate the effect of disease‐modifying antirheumatic drugs (DMARDs) on the likelihood of patients with rheumatoid arthritis (RA) developing septic arthritis (SA). Methods The United Kingdom General Practice Research Database (GPRD) was used to identify adults with RA, and age‐, sex‐, and practice‐matched control subjects. Subjects were studied between 1987 and 2002. The risk of developing SA (excluding infected joint replacements) for individuals with RA was calculated and the effect of DMARD use determined. Results A total of 136,977 subjects (34,250 patients with RA, 102,747 controls) were identified. SA was identified in 345 subjects, of which 321 (236 in patients with RA, 85 in controls) cases occurred during the study period. The incidence rate of SA was 12.9 times higher in subjects with RA than in those without (95% confidence interval [95% CI] 10.1–16.5, P &lt; 0.001). The incident rate ratios (IRRs) for developing SA while receiving DMARDs compared with receiving no DMARDs were different for different medications. Penicillamine (adjusted IRR 2.51, 95% CI 1.29–4.89, P = 0.004), sulfasalazine (adjusted IRR 1.74, 95% CI 1.04–2.91, P = 0.03), and prednisolone (adjusted IRR 2.94, 95% CI 1.93–4.46, P &lt; 0.001) were associated with an increased incidence of SA when compared with not receiving any DMARD. The use of other DMARDs including methotrexate showed no such effect. Conclusion Individuals with RA have an increased risk of developing SA. This increased risk can be attributed to both the disease process and the use of DMARDs.

Background Multiple micronutrient deficiencies are common among women in low-income countries and may adversely affect pregnancy outcomes Objective To conduct a meta-analysis of the effects on stillbirths and on early and late neonatal mortality of supplementation during pregnancy with multiple micronutrients compared with iron–folic acid in recent randomized, controlled trials. Methods Twelve randomized, controlled trials were included in the analysis (Bangladesh; Burkina Faso; China; Guinea-Bissau; Indramayu and Lombok, Indonesia; Mexico; Sarlahi and Janakur, Nepal; Niger; Pakistan; and Zimbabwe), all providing approximately 1 recommended dietary allowance (RDA) of multiple micronutrients or iron–folic acid to presumed HIV-negative women. Results Supplementation providing approximately 1 RDA of multiple micronutrients did not decrease the risk of stillbirth (OR = 1.01; 95% CI, 0.88 to 1.16), early neonatal mortality (OR = 1.23; 95% CI, 0.95 to 1.59), late neonatal mortality (OR = 0.94; 95% CI, 0.73 to 1.23), or perinatal mortality (OR = 1.11; 95% CI, 0.93 to 1.33). Conclusions Our meta-analysis provides consistent evidence that supplementation providing approximately 1 RDA of multiple micronutrients during pregnancy does not result in any reduction in stillbirths or in early or late neonatal deaths compared with iron–folic acid alone.

Abstract The mechanisms of action against Botrytis cinerea of the dicarboximide fungicides vinclozolin ( I ), procyrnidone ( II ), iprodione ( III ) and the less closely related compound prochloraza ( IV ) have been compared. They all inhibited mycelial growth much more than spore germination. None of the compounds affected respiration, membrane permeability or RNA production but III inhibited DNA synthesis and IV inhibited protein synthesis. Although chitin biosynthesis was inhibited by all the fungicides it was barely affected at the ED 50 concentrations (the concentration required to reduce the growth or germination of the test species by 50%) and is thus unlikely to be the primary target. The fungicides altered fungal lipid composition. I and II inhibited triglyceride production but III had no effect on it; III and IV reduced sterol biosynthesis. No common primary mode of action was found.

We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin-fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatin+capecitabine (Xelox, 41%), 102 received OxMdG+cetuximab (OxMdG+C, 13%) and 166 Xelox+cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdG+C and Xelox+C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xelox+cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P=0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P=0.012). The excess toxicity observed in the oxaliplatin-, capecitabine-, cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen.

Electrophoretic mobility refers to measure of the movement of a particle in a solution when subjected to an externally applied electric field. The direction and rate of this movement depends on the polarity and density of the surface charges. Many surfaces acquire a charge in aqueous media, measurements of electrophoretic mobility can provide useful information regarding the composition of surfaces and the physical behavior of suspended particles. Surface properties can play an important role in the behavior of microorganisms and gene expression can also be modified by responses of the surface to changes in environment. The external surfaces of microorganisms vary widely in structure and composition. Bacterial and fungal spores often have a layered wall structure and a complex surface morphology. Ionic surface groups can be identified by studying pH-mobility curves of cells before and after treatment with specific chemical reagents or enzymes. This chapter deals with the practical applications of the electrophoretic mobility technique to the study of various microorganisms.

BackgroundA substantial change in trial methodology for solid tumours has taken place, in response to increased understanding of cancer biology. FOCUS4 is a phase 2–3 trial programme testing targeted agents in patients with advanced colorectal cancer in molecularly stratified cohorts. Here, we aimed to test the hypothesis that combined inhibition of EGFR, HER2, and HER3 signalling with the tyrosine kinase inhibitor AZD8931 will control growth of all wild-type tumours.MethodsIn FOCUS4-D, we included patients from 18 hospitals in the UK with newly diagnosed advanced or metastatic colorectal cancer whose tumour was wild-type for BRAF, PIK3CA, KRAS, and NRAS. After 16 weeks of first-line therapy, patients with stable or responding tumours were randomised to oral AZD8931 (40 mg twice a day) or placebo. Randomisation was done by minimisation with a random element of 20%, minimisation by hospital site, site of primary tumour, WHO performance status, 16-week CT scan result, number of metastatic sites, and first-line chemotherapy regimen. The primary outcome was progression-free-survival. CT scans were assessed by local radiologists according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Preplanned interim analyses were assessed per protocol and were agreed using multiarm multistage (MAMS) trial design methodology triggered by occurrence of progression-free survival events in the placebo group. The final analysis was assessed by intention to treat. This trial is registered at controlled-trials.com, ISRCTN 90061546.FindingsBetween July 7, 2014, and March 7, 2016, 32 patients were randomised to study treatment, 16 to AZD8931 and 16 to placebo. At the first preplanned interim analysis (March, 2016), the independent data monitoring committee (IDMC) recommended closure of FOCUS4-D because of a lack of activity. At the final analysis (Aug 1, 2016), 31 patients had had a progression-free survival event (15 with AZD8931 and 16 with placebo). Median progression-free survival was 3·48 months (95% CI 1·51–5·09) in the placebo group and 2·96 months (1·94–5·62) in the AZD8931 group. No progression-free survival benefit of AZD8931 compared with placebo was noted (hazard ratio [HR] 1·10, 95% CI 0·47–3·57; p=0·95). The most common grade 3 adverse event in the AZD8931 group was skin rash (three [20%] of 15 patients with available data vs none of 16 patients in the placebo group), and in the placebo group it was diarrhoea (one [7%] vs one [6%]). No grade 4 adverse events were recorded and no treatment-related deaths were reported.InterpretationThe MAMS trial design for FOCUS4 has shown efficiency and effectiveness in trial outcome delivery, informing the decision to proceed or stop clinical evaluation of a targeted treatment within a molecularly defined cohort of patients. The overarching FOCUS4 trial is now aiming to open a replacement arm in the cohort with all wild-type tumours.FundingMedical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme, Cancer Research UK, NIHR Clinical Trials Research Network, Health and Care Research Wales, and AstraZeneca.

Clinical staging of non-small cell lung cancer (NSCLC) helps determine the prognosis and treatment of patients; few data exist on the accuracy of clinical staging and the impact on treatment and survival of patients. We assessed whether participant or trial characteristics were associated with clinical staging accuracy as well as impact on survival.We used individual participant data from randomized controlled trials (RCTs), supplied for a meta-analysis of preoperative chemotherapy (± radiotherapy) vs surgery alone (± radiotherapy) in NSCLC. We assessed agreement between clinical TNM (cTNM) stage at randomization and pathologic TNM (pTNM) stage, for participants in the control group.Results are based on 698 patients who received surgery alone (± radiotherapy) with data for cTNM and pTNM stage. Forty-six percent of cases were cTNM stage I, 23% were cTNM stage II, and 31% were cTNM stage IIIa. cTNM stage disagreed with pTNM stage in 48% of cases, with 34% clinically understaged and 14% clinically overstaged. Agreement was not associated with age (P = .12), sex (P = .62), histology (P = .82), staging method (P = .32), or year of randomization (P = .98). Poorer survival in understaged patients was explained by the underlying pTNM stage. Clinical staging failed to detect T4 disease in 10% of cases and misclassified nodal disease in 38%.This study demonstrates suboptimal agreement between clinical and pathologic staging. Discrepancies between clinical and pathologic T and N staging could have led to different treatment decisions in 10% and 38% of cases, respectively. There is therefore a need for further research into improving staging accuracy for patients with stage I-IIIa NSCLC.

Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy.FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability.Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups.Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy.

5070 Background: Adding docetaxel to androgen deprivation therapy(ADT) improves survival in metastatic, hormone-sensitive prostate cancer (mHSPC), but uncertainty remains about who benefits most. To investigate this thoroughly and reliably, the STOPCAP M1 collaborationconducted a meta-analysis of individual participant data (IPD) from relevant trials. Methods: Methods were included in a registered protocol ( CRD42019140591 ). Updated IPD from the GETUG-15, CHAARTED and STAMPEDE trials were harmonised and checked. The main outcomes were overall survival (OS), progression-free survival (PFS) and failure-free survival (FFS). Overall pooled effects were estimated using intention-to-treat, 2-stage, fixed-effect meta-analysis, adjusted for age, PSA, Gleason sum score, performance status, and timing of metastatic disease (missing covariate values imputed), with 1-stage and random-effects sensitivity analyses. We assessed subgroup effects using 2-stage, fixed-effect meta-analysis of within-trial interactions, adjusted for the same covariates. We based these on PFS to maximise power, and OS whenever interactions were found. To explore multiple subgroup interactions, and to derive subgroup-specific absolute treatment effects, we used 1-stage, flexible parametric modelling and standardisation. Results: We obtained IPD for all 2261 men randomised, with median FU of 6 years (all patients). There were clear relative benefits of docetaxel on OS (HR = 0.79, 95% CI 0.70 to 0.88, p&lt;0.0001), PFS (HR = 0.70, 95% CI 0.63 to 0.77, p&lt;0.0001) and FFS (HR = 0.64, 95% CI 0.58 to 0.71, p&lt;0.0001). With evidence of non-proportional hazards, we also estimated 5-year absolute differences: OS 10% (95% CI 6 to 15%), PFS 9% (95% CI 5 to 13%) and FFS 9% (95% CI 6 to 12%). The relative effect of docetaxel on PFS differed by volume of metastases (interaction p=0.027; high volume HR = 0.60, 95% CI 0.52 to 0.68; low volume HR = 0.78, 95% CI 0.64 to 0.94), and timing of metastatic disease (interaction p=0.077; synchronous HR = 0.67, 95% CI 0.60 to 0.75; metachronous HR = 0.89, 95% CI 0.67 to 1.18). OS results were similar. When metastatic disease volume and timing were combined, docetaxel appeared to improve PFS and OS for all men, except those with low volume, metachronous disease (Table). Conclusions: This IPD meta-analysis provides the most detailed assessment of the effects of docetaxel for mHSPC, and suggests that men with low volume, metachronous disease should be managed differently to those with other types of metastatic disease. [Table: see text]

PURPOSE To evaluate the effect of MR contrast dose versus delayed imaging time on the detection of metastatic brain lesions based on lesion size. METHODS Contrast MR examinations with gadoteridol were obtained in 45 patients with brain metastases. The patients were divided into two groups: 16 received cumulative standard dose (0.1 mmol/kg) and 29 received cumulative triple dose (0.3 mmol/kg). Both groups were evaluated at two dose levels (lower dose and higher dose) with two separate injections. Each patient received an initial bolus injection of either 0.05 (cumulative standard dose) or 0.1 (cumulative triple dose) mmol/kg of gadoteridol to reach the lower-dose level and underwent imaging immediately and 10 and 20 minutes later. Thirty minutes after injection, an additional bolus injection of 0.05 (cumulative standard dose) or 0.2 (cumulative triple dose) mmol/kg was administered to reach the cumulative higher-dose level (cumulative standard dose, 0.1 mmol/kg; cumulative triple dose, 0.3 mmol). Images were acquired immediately. RESULTS There was no difference in the detection rate for lesions larger than 10 mm among T2-weighted, lower-dose immediate and delayed, or immediate higher-dose images in both study groups. Lesions smaller than 10 mm had improved detection with delayed imaging in both study groups; however, the immediate higher-dose studies still had the highest detection rate. CONCLUSION In the evaluation of small central nervous system metastases, either delayed imaging after the injection of standard contrast dose or higher contrast dose may improve their detection, and therefore affect clinical management. Higher contrast dose (cumulative triple dose) studies appear to be more effective than delayed imaging with standard dose.

We describe a novel wave-front sensor comprising a distorted diffraction grating, simple optics, and a single camera. A noniterative phase-diversity algorithm is used for wave-front reconstruction. The sensor concept and practical implementation are described in detail, and performance is validated against different Zernike modes and a representative atmospheric phase map.

PURPOSE To assess the effectiveness and safety of higher doses of gadoteridol in the MR evaluation of patients with brain metastases. MATERIALS AND METHODS Thirty-one patients with a clinical suspicion of brain metastases were studied prospectively with gadoteridol, a new, nonionic, low-osmolality contrast agent. Each patient received an initial injection of 0.1 mmol/kg and an additional dose of 0.2 mmol/kg 30 minutes later. Images were obtained before, immediately after, and 10 and 20 minutes after the initial dose. Images also were acquired immediately after the additional dose of gadoteridol. RESULTS No adverse effects were attributed to the injection of gadoteridol. Four patients9 examinations were excluded from analysis because of machine malfunction (two patients) and excessive motion artifact (two patients). Four patients had no detectable metastases. After the additional dose of gadoteridol, there was a marked qualitative improvement in lesion conspicuity and detection. The conspicuity of 80 of 81 lesions was increased in the high-dose studies, and 46 new lesions were detected in 19 of 27 patients. Quantitative image analysis demonstrated a significant increase in normalized mean lesion contrast between the initial-dose and high-dose studies (35 lesions identified in 13 patients, P less than .0001). The additional information gained by high-dose examinations contributed to a potential modification of the treatment in 10 of 27 patients. High-dose examinations increased flow-related artifact in the posterior fossa in 12 of 27 patients. CONCLUSION Based on our preliminary results, high-dose gadolinium-enhanced MR examinations may have advantages over 0.1 mmol/kg examinations in detecting early and/or small metastases. This may be significant in the management of patients with cerebral metastases.

Abstract The systemic fungicides furalaxyl, metalaxyl and ofurace, Ofurace is the proposed BSI and ISO common name for α‐(2‐chloro‐ N ‐2,6‐xylylacetamido)‐γ‐butyrolactone. used to control diseases caused by phycomycetes, were extremely active in vitro against Pythium ultimum, Phytophthora nicotianae and Phytophthora palmivora . Sporangia production was reduced more than mycelial growth but germination of sporangia and zoospores was relatively unaffected. Less than 1% of the metalaxyl or furalaxyl, present in media at the ED 50 for hyphal growth, was firmly absorbed by Phyt. palmivora mycelium; uptake was against a concentration gradient and was characterised by a rapid accumulation followed by a more gradual release. Respiration and wall synthesis were not inhibited, whilst membrane permeability was unaffected. Lipid patterns were altered but these changes were probably of secondary importance. The fungicides inhibited protein and nucleic acid synthesis; RNA production was particularly affected. There was some evidence of a reduction in nuclear division. The primary effect of furalaxyl and metalaxyl probably involves impaired biosynthesis of RNA so that mitosis is inhibited; ofurace may act in the same way.

To elucidate the determinants of arrhythmias during acute myocardial ischemia, a 25-minute coronary artery occlusion was performed in 101 open-chest dogs. Heart rate correlated positively with the number of premature ventricular complexes (PVCs) and the occurrence of ventricular tachycardia (VT) and fibrillation (VF). The size of the occluded coronary bed was positively correlated with the occurrence of VF, but exhibited only a weak association with PVCs and VT. Coronary collateral flow exhibited a strong negative correlation with all forms of arrhythmias. Importantly, a sensitive coupling was present, whereby small differences in flow were associated with large differences in rhythm disorders. VT occurred in all ranges of occluded bed size examined, but within any given range, its incidence was inversely related to collateral flow. Thus, VT is relatively independent of occluded bed size, and is determined primarily by the degree of myocardial hypoperfusion. In contrast, even in the presence of low flows, VF did not develop with occluded beds less than 28% of left ventricular mass; above this critical occluded bed size, the incidence of VF was inversely related to collateral perfusion. VF is therefore determined by the association of a large occluded bed with a poor collateral function. This study identifies and systematically analyzes three major determinants of arrhythmias during acute myocardial ischemia: the heart rate, the amount of ischemic myocardium, and the severity of myocardial flow reduction. The finding that these factors account for most of the variability in the occurrence of malignant tachyarrhythmias has important methodological and clinical implications.

SUMMARY: Microelectrophoresis has shown surface lipid to be present on conidia of Alternaria tenuis, Botrytis fabae and Neurospora crassa and on sporangiospores of Rhizopus stolonifer. Surface lipid is absent from conidia of Erysiphe cichoracearum, E. graminis, Nectria galligena, Penicillium expansum and Verticillium albo-atrum and sporangiospores of Mucor rouxii. The compositions of the fatty acid and hydrocarbon fractions of the surface and wall lipids from the same organisms are different. The fatty acids are mainly straight-chain and even carbon-numbered. Palmitic and stearic acids predominate. Polyunsaturated acids were absent. Surface hydrocarbons consist almost entirely of n-alkanes but wall fractions are more complex. An equal distribution of odd and even carbon-numbered alkanes occurs in both the surface and wall lipid fractions.

Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10(-10) and HR = 1.8, P = 3.7×10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest.

4-Hydroxycyclopentenones represent a privileged scaffold in chemical synthesis. A dysprosium(III) trifluoromethanesulfonate catalyzed rearrangement of furylcarbinols to 4-hydroxycyclopentenones via a 4π electrocyclization has been developed. The catalytic Piancatelli rearrangement affords a single trans-diastereomer from both aryl and alkyl substituted furylcarbinols.

The role of postoperative radiotherapy (PORT) in the treatment of patients with completely resected non-small cell lung cancer (NSCLC) was not clear. A systematic review and individual participant data meta-analysis was undertaken to evaluate available evidence from randomised controlled trials (RCTs). These results were first published in Lung Cancer in 2013.To evaluate the effects of PORT on survival and recurrence in patients with completely resected NSCLC. To investigate whether predefined patient subgroups benefit more or less from PORT.We supplemented MEDLINE and CANCERLIT searches (1965 to 8 July 2016) with information from trial registers, handsearching of relevant meeting proceedings and discussion with trialists and organisations.We included trials of surgery versus surgery plus radiotherapy, provided they randomised participants with NSCLC using a method that precluded prior knowledge of treatment assignment.We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. We sought data on all participants from those responsible for the trial. We obtained updated individual participant data (IPD) on survival and date of last follow-up, as well as details on treatment allocation, date of randomisation, age, sex, histological cell type, stage, nodal status and performance status. To avoid potential bias, we requested information on all randomised participants, including those excluded from investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival.We identified 14 trials evaluating surgery versus surgery plus radiotherapy. Individual participant data were available for 11 of these trials, and our analyses are based on 2343 participants (1511 deaths). Results show a significant adverse effect of PORT on survival, with a hazard ratio of 1.18, or an 18% relative increase in risk of death. This is equivalent to an absolute detriment of 5% at two years (95% confidence interval (CI) 2% to 9%), reducing overall survival from 58% to 53%. Subgroup analyses showed no differences in effects of PORT by any participant subgroup covariate.We did not undertake analysis of the effects of PORT on quality of life and adverse events. Investigators did not routinely collect quality of life information during these trials, and it was unlikely that any benefit of PORT would offset the observed survival disadvantage. We considered risk of bias in the included trials to be low.Results from 11 trials and 2343 participants show that PORT is detrimental to those with completely resected non-small cell lung cancer and should not be used in the routine treatment of such patients. Results of ongoing RCTs will clarify the effects of modern radiotherapy in patients with N2 tumours.

SUMMARY: Hydrogenasesfrom Azotobacter vinelandii and Clostridium pasteurianum reduced methylene blue, ferricyanide, benzyl- and methyl-viologens when hydrogen was the donor. Methylene blue was the most effective acceptor. Hughes press preparations of either organism in tris (2-amino-2-hydroxymethyl propane-1:3-diol) buffer (pH 8·0) resulted in the best extraction of the enzyme. Hydrogenase from C. pasteurianum was readily inactivated by traces of oxygen but this could be prevented by sodium dithionite. Pyridine nucleotides and cytochrome c. are reduced by hydrogenase, but in extracts of Azotobacter, however, the addition of iron was required to couple DPNH to cytochrome c. The mechanism appears to involve the reduction of Fe3+ to Fe2+ enzymically and the Fe2+ is oxidized by cytochrome c non-enzymically. The effect of pH value and nature of buffer on this system was examined. Mo5+ did not reduce cytochrome c, with or without hydrogenase. Metal-deficiency experiments, inhibitor studies, activation of dialysed preparations, and the results of radioactive tracer assays of purified protein fractions, showed that iron is the main metal constituent of hydrogenase. Molybdenum, however, is required for the fixation of nitrogen.

Background: The optimal timing of RT after RP for prostate cancer (PCa) is uncertain.RADICALS-RT compared the efficacy and safety of adjuvant RT (aRT) versus an observation policy with salvage RT for PSA failure (ObsþsRT).Methods: Patients with post-op PSA0.2ng/ml and 1 risk factor (pT3/4, Gleason 7-10, positive margins or pre-op PSA10ng/ml) were randomised 22wk after surgery to aRT or ObsþsRT for PSA failure (PSA0.1ng/mlor 3 consecutive rises).

One of the biggest challenges for network meta‐analysis is inconsistency, which occurs when the direct and indirect evidence conflict. Inconsistency causes problems for the estimation and interpretation of treatment effects and treatment contrasts. Krahn and colleagues proposed the net heat approach as a graphical tool for identifying and locating inconsistency within a network of randomized controlled trials. For networks with a treatment loop, the net heat plot displays statistics calculated by temporarily removing each design one at a time, in turn, and assessing the contribution of each remaining design to the inconsistency. The net heat plot takes the form of a matrix which is displayed graphically with coloring indicating the degree of inconsistency in the network. Applied to a network of individual participant data assessing overall survival in 7531 patients with lung cancer, we were surprised to find no evidence of important inconsistency from the net heat approach; this contradicted other approaches for assessing inconsistency such as the Bucher approach, Cochran's Q statistic, node‐splitting, and the inconsistency parameter approach, which all suggested evidence of inconsistency within the network at the 5% level. Further theoretical work shows that the calculations underlying the net heat plot constitute an arbitrary weighting of the direct and indirect evidence which may be misleading. We illustrate this further using a simulation study and a network meta‐analysis of 10 treatments for diabetes. We conclude that the net heat plot does not reliably signal inconsistency or identify designs that cause inconsistency.

The vast majority of systematic reviews are planned retrospectively, once most eligible trials have completed and reported, and are based on aggregate data that can be extracted from publications. Prior knowledge of trial results can introduce bias into both review and meta-analysis methods, and the omission of unpublished data can lead to reporting biases. We present a collaborative framework for prospective, adaptive meta-analysis (FAME) of aggregate data to provide results that are less prone to bias. Also, with FAME, we monitor how evidence from trials is accumulating, to anticipate the earliest opportunity for a potentially definitive meta-analysis.We developed and piloted FAME alongside 4 systematic reviews in prostate cancer, which allowed us to refine the key principles. These are to: (1) start the systematic review process early, while trials are ongoing or yet to report; (2) liaise with trial investigators to develop a detailed picture of all eligible trials; (3) prospectively assess the earliest possible timing for reliable meta-analysis based on the accumulating aggregate data; (4) develop and register (or publish) the systematic review protocol before trials produce results and seek appropriate aggregate data; (5) interpret meta-analysis results taking account of both available and unavailable data; and (6) assess the value of updating the systematic review and meta-analysis. These principles are illustrated via a hypothetical review and their application to 3 published systematic reviews.FAME can reduce the potential for bias, and produce more timely, thorough and reliable systematic reviews of aggregate data.

Background Anti-EGFR antibodies plus doublet chemotherapy is the standard of care in RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No phase-3 level of evidence is available to guide treatment de-escalation after anti-EGFR-based first-line. Several randomised clinical trials investigated de-intensification strategies with 5-fluorouracil/leucovorin (5-FU/LV) and/or anti-EGFR. Methods We performed an individual patient data pooled analysis of Valentino, Panama, MACRO-2, COIN-B trials including RAS wild-type mCRC patients who received first-line therapy with FOLFOX plus panitumumab or cetuximab followed by pre-specified maintenance strategy. Only patients who started maintenance according to the assigned arm were included. Patients were categorised by type of maintenance (i.e. 5-FU/LV, anti-EGFR or 5-FU/LV + anti-EGFR). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of maintenance; toxicity was evaluated for the maintenance treatment period. Results A total of 518 patients were included in the pooled analysis. Overall, 123, 185 and 210 patients received maintenance with 5-FU/LV, anti-EGFR, 5-FU/LV + anti-EGFR, respectively. Median PFS was 5.6, 6.0 and 9.0 (P = 0.009) and OS was 25.7, 24.0 and 28.0 months (P = 0.134) in 5-FU/LV, anti-EGFR and 5-FU/LV + anti-EGFR arms, respectively. Monotherapy maintenance (either 5-FU/LV or anti-EGFR) was inferior to combination in terms of PFS (hazard ratios [HR] 1.26, P = 0.016) and non-significantly trending also in OS (HR 1.20, P = 0.111). An increase of overall any grade and grade ≥ 3 AEs and selected AEs was reported in combination compared to either 5-FU/LV or anti-EGFR arms. Conclusions This pooled analysis including four randomised phase II supports the use of 5-FU/LV plus anti-EGFR as the preferred maintenance regimen. Data provide rational for a more individualised maintenance treatment approach based on tumour and patients features.

To determine whether increased cerebrospinal fluid (CSF) signal intensity is seen on fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) images in patients under general anesthesia and to investigate the cause of these changes.MR images from nine examinations performed in eight patients under general anesthesia were reviewed retrospectively. In phantom experiments, T1 measurements obtained with several inhaled anesthetic agents and propofol dissolved in saline were compared with those obtained with either 100% O2 or room air. To confirm phantom experiment results, a healthy volunteer underwent sequential FLAIR imaging while breathing high-flow 100% O2.Of the nine examinations performed with patients under general anesthesia, eight had resultant images that showed increased CSF signal intensity within the basal cisterns and sulci over the cerebral convexities. Anesthetic phantom measurements showed T1 shortening only when the agent was administered with high concentrations of oxygen. In the healthy volunteer, images obtained before and during administration of 100% O2 demonstrated increased CSF signal intensity after O2 administration; this was identical to the changes observed in patients under anesthesia.The paramagnetic effects of supplemental O2 administration result in shortened CSF T1. Radiologists should be aware of this phenomenon to avoid attributing increased CSF signal intensity on FLAIR images to abnormal CSF properties such as hemorrhage or elevated protein content.

Objectives. To describe the use of disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA) and changing trends in their use.

Previous studies have demonstrated that myocardial function changes during mammalian perinatal development. The purpose of this study was to evaluate the subcellular basis underlying the slower relaxation in the developing heart by examining perinatal changes in sarcoplasmic reticulum (SR) function, and in SR Ca2+ pump protein and mRNA abundance. We measured Ca2+ uptake and ATPase rates in isolated fetal, newborn, and adult rabbit cardiac SR membranes. In fetal and adult SR membranes, we estimated the active Ca2+ pump protein content by measuring the steady state Ca(2+)-dependent phosphoenzyme content; the total Ca2+ pump protein content was estimated by Western analysis of the immunoreactive Ca2+ pumps. We isolated RNA from fetal and adult hearts and estimated the SR Ca2+ pump mRNA content by Northern analysis. Ca2+ uptake and ATPase rates were significantly lower in the fetal and newborn SR membranes compared with the adult. The contents of active and total Ca2+ pump protein and of Ca2+ pump mRNA were 52-63% lower in the fetus than in the adult. These results indicate that a great deal of the slower sarcoplasmic reticulum Ca2+ uptake and ATPase rates in the fetal rabbit heart can be related to lower Ca2+ pump mRNA and protein contents. It is evident that transcriptional and/or posttranscriptional regulation of the SR Ca2+ pump may form an important part of the subcellular basis of the perinatal change in mammalian cardiac relaxation.

Background Slower rates of infant growth are associated with increased rates of death from ischaemic heart disease (IHD) in later life. We carried out a systematic review to assess the association between infant size or growth and leading causes of adult burden of disease to contribute to the debate on the potential of the promotion of infant growth to prevent ischaemic heart disease. Methods We searched Medline, Embase, CINAHL, PsycINFO, and bibliographies of included studies. First authors of included studies and other experts were contacted to locate unpublished analyses. Outcome measures for the review were leading causes of adult burden of disease selected from the Global Burden of Disease study. We included studies that assessed the relationship between infant size or growth during the first 2 years and the leading causes of adult burden of disease. Results Nineteen studies relating to 10 causes of burden of disease met inclusion criteria. Most studies reported data on infant size. Larger size in infancy was associated with increased risk of insulin-dependent diabetes. Larger infant size was associated with reduced rates of IHD in men but not in women. There were considerable gaps in the evidence and many conditions that account for a high burden of disease, such as cancer, mental illness, stroke, chronic obstructive pulmonary disease, and non-insulin-dependent diabetes, had few or no studies associating them with infant size or growth. Conclusions Our findings suggest that there is no single optimal pattern of infant growth that is associated with beneficial adult health outcomes. There is insufficient evidence to recommend prevention of adult disease through strategies to alter infant growth.

It has been suggested that vasodilation distal to a stenosis may cause a profound decrease in perfusion pressure and adversely affect regional left ventricular function. This phenomenon could explain the clinical concept of reversal of regional dysfunction by coronary revascularization. To evaluate the hypothesis that regional myocardial function parallels regional coronary blood pressure in the absence of changes in coronary flow, dogs chronically instrumented with left circumflex coronary artery flow probes, cuff occluders, pressure catheters and segmental function sonomicrometers were studied. By decreasing regional coronary vascular resistance with selective intracoronary dipyridamole and controlling blood flow with a proximal coronary cuff occluder, the mean left circumflex artery pressure was reduced from 83 ± 3 to 38 ± 2 mm Hg while circumflex coronary blood flow was maintained constant. Regional contractile function as measured by circumflex sonomicrometers was unchanged at constant circumflex subendocardial blood flow as measured by radioactive microspheres. These findings suggest that regional contractile function is dependent on subendocardial blood flow and is independent of coronary perfusion pressure.

The clinical spectrum of neonatal endocarditis, including bacterial and nonbactenal types, is examined in five case reports that were drawn from nursery experiences over a recent 2-year period. In contrast to previous reports of 100% mortality from neonatal endocarditis, one patient survived. Changing heart murmur and hematuria were most frequently associated with bacterial and nonbacterial endocarditis in four of the five cases. Pulmonary hypertension, thrombocytopenia, and coagulopathy were also associated with nonbacterial endocarditis. Echocardiograms were performed on four of the patients; only one was suggestive of endocarditis. Staphylococcus aureus was isolated from both cases of bacterial endocarditis, including the single survivor. Thus, it is suggested that the initial antibiotic coverage of any neonate with the clinical syndrome of sepsis, hematuria, and a heart murmur include antistaphylococcal coverage for the possibility of bacterial endocarditis.

COIN compared first-line continuous chemotherapy with the same chemotherapy given intermittently or with cetuximab in advanced colorectal cancer (aCRC).Choice between oxaliplatin/capecitabine (OxCap) and oxaliplatin/leucovorin (LV)/infusional 5-FU (OxFU) was by physician and patient choice and switching regimen was allowed. We compared OxCap with OxFU and OxCap+cetuximab with OxFU+cetuximab retrospectively in patients and examined efficacy, toxicity profiles and the effect of mild renal impairment.In total, 64% of 2397 patients received OxCap(± cetuximab). Overall survival, progression free survival and overall response rate were similar between OxCap and OxFU but rate of radical surgeries was higher for OxFU. Progression free survival was longer for OxFU+cetuximab compared with OxCap+cetuximab but other efficacy measures were similar. Oxaliplatin/LV/infusional 5-FU (± cetuximab) was associated with more mucositis and infection whereas OxCap(± cetuximab) caused more gastrointestinal toxicities and palmar-plantar erythema. In total, 118 patients switched regimen, mainly due to toxicity; only 16% came off their second regimen due to intolerance. Patients with creatinine clearance (CrCl) 50-80 ml min(-1) on OxCap(± cetuximab) or OxFU+cetuximab had more dose modifications than those with better renal function.Overall, OxFU and OxCap are equally effective in treating aCRC. However, the toxicity profiles differ and switching from one regimen to the other for poor tolerance is a reasonable option. Patients with CrCl 50-80 ml min(-1) on both regimens require close toxicity monitoring.

Quantitative evidence synthesis through meta‐analysis is central to evidence‐based medicine. For well‐documented reasons, the meta‐analysis of individual patient data is held in higher regard than aggregate data. With access to individual patient data, the analysis is not restricted to a “two‐stage” approach (combining estimates and standard errors) but can estimate parameters of interest by fitting a single model to all of the data, a so‐called “one‐stage” analysis. There has been debate about the merits of one‐ and two‐stage analysis. Arguments for one‐stage analysis have typically noted that a wider range of models can be fitted and overall estimates may be more precise. The two‐stage side has emphasised that the models that can be fitted in two stages are sufficient to answer the relevant questions, with less scope for mistakes because there are fewer modelling choices to be made in the two‐stage approach. For Gaussian data, we consider the statistical arguments for flexibility and precision in small‐sample settings. Regarding flexibility, several of the models that can be fitted only in one stage may not be of serious interest to most meta‐analysis practitioners. Regarding precision, we consider fixed‐ and random‐effects meta‐analysis and see that, for a model making certain assumptions, the number of stages used to fit this model is irrelevant; the precision will be approximately equal. Meta‐analysts should choose modelling assumptions carefully. Sometimes relevant models can only be fitted in one stage. Otherwise, meta‐analysts are free to use whichever procedure is most convenient to fit the identified model.

Background National targets for timely diagnosis and management of a potential cancer are driven in part by the perceived risk of disease progression during avoidable delays. However, it is unclear to what extent time-to-treatment impacts prognosis for patients with non-small cell lung cancer, with previous reviews reporting mixed or apparently paradoxical associations. This systematic review focuses on potential confounders in order to identify particular patient groups which may benefit most from timely delivery of care. Methods Medline, EMBASE and Cochrane databases were searched for publications between January 2012 and October 2020, correlating timeliness in secondary care pathways to patient outcomes. The protocol is registered with PROSPERO (the International Prospective Register of Systematic Reviews; ID 99239). Prespecified factors (demographics, performance status, histology, stage and treatment) are examined through narrative synthesis. Results Thirty-seven articles were included. All but two were observational. Timely care was generally associated with a worse prognosis in those with advanced stage disease (6/8 studies) but with better outcomes for patients with early-stage disease treated surgically (9/12 studies). In one study, patients with squamous cell carcinoma referred for stereotactic ablative radiotherapy benefited more from timely care, compared with patients with adenocarcinoma. One randomised controlled trial supported timeliness as being advantageous in those with stage I–IIIA disease. Conclusion There are limitations to the available evidence, but observed trends suggest timeliness to be of particular importance in surgical candidates. In more advanced disease, survival trends are likely outweighed by symptom burden, performance status or clinical urgency dictating timeliness of treatment.

The purpose of this study was to assess the MR and CT appearance of brain infection after bone marrow transplantation and to correlate the appearances with laboratory and pathologic findings.We retrospectively reviewed the records of seven bone marrow transplant recipients with radiologic evidence of brain infection.Forty-one lesions were detected in seven patients with proved infectious foci outside the brain before brain infection was suspected clinically. Six patients had low total WBC or lymphocyte counts and one patient had normal total WBC and lymphocyte counts. Most lesions in patients with low total WBC or lymphocyte counts showed no appreciable edema or contrast enhancement. However, all lesions detected in the patient with normal total WBC and lymphocyte counts showed marked vasogenic edema and ring enhancement.Brain infection in bone marrow transplant recipients during immunosuppression exhibited MR characteristics different from those typically seen in immunocompetent patients. This appearance may be related to a diminished immunologic/inflammatory response.

One of the compensatory hemodynamic mechanisms seen in the anemic human fetus is an increased cardiac output. With Doppler techniques, cardiac output was measured in 21 fetuses before and immediately after 38 intrauterine transfusions for severe red cell alloimmunization. Umbilical venous pressures were measured before and after transfusion; amniotic fluid pressure was also quantitated. After subtraction of amniotic pressure, umbilical venous pressure increased by 1.7 +/- 2.8 mm Hg (p less than 0.01). Left and right ventricular output declined by 19% and 22%, respectively (p less than 0.001). Four factors are known to affect cardiac output: heart rate, cardiac contractility, preload, and afterload. Fetal heart rate and mean acceleration, a measure of myocardial contractility, were unchanged after transfusion. A calculated mean increase in the fetoplacental volume of 18% in conjunction with an increase in umbilical venous pressure would indicate that cardiac preload was increased. We propose that intravascular intrauterine transfusion leads to an increased cardiac afterload, possibly by increasing blood viscosity. The fetal heart responds to the increased afterload by a decrease in stroke volume, leading to a fall in cardiac output.

Two days after catheter placement we measured the heart rate, arterial blood pressure, myocardial blood flow, and the myocardial consumption of oxygen, glucose, lactate, and pyruvate in 11 fetal sheep in utero. We then administered 8-10% oxygen to the ewe, producing a 50% decrease in oxygen content in the fetal ascending aortic blood. After 15 min of hypoxemia we repeated the measurements. Oxygen content in the fetal coronary sinus blood decreased significantly, but the arteriovenous difference of oxygen across the left ventricle also decreased during hypoxemia. Fetal myocardial blood flow increased 160% above the control level, and the myocardial oxygen consumption did not change. The systolic arterial blood pressure increased and the heart rate decreased, but cardiac work, as estimated by the rate-pressure product, was unchanged. As both fetal myocardial oxygen consumption and cardiac work did not change, myocardial oxygenation, the relationship between oxygen consumption and cardiac work, appears to be unchanged during this degree of hypoxemia. Although arterial blood glucose, lactate, and pyruvate concentrations increased significantly during hypoxemia, only the myocardial consumption of pyruvate increased; the arteriovenous difference of glucose and lactate decreased in proportion to the increase in myocardial blood flow. During hypoxemia, glucose consumption did not change, and lactate continued to be consumed rather than produced; thus it is apparent that fetal myocardial metabolism continued to be aerobic during this degree of hypoxemia. Complete oxidative combustion of the quantities of carbohydrates that were consumed would supply all of the substrate necessary to meet fetal myocardial energy demands both at rest and during hypoxemia.

This paper reports on the methods and characteristics of 12 studies from developing countries included in a meta-analysis of the impact of antenatal supplements of multiple micronutrients compared with iron–folic acid on micronutrient status, maternal nutritional status, birth outcomes, and neonatal survival.

SUMMARY The electrophoretic mobilities of conidia of Alternaria tenuis, Botrytis fabae, Penicillium expansum, Erysiphe graminis, Podosphaera leucotricha and Venturia inaequalis, basidiospores of Stereum purpureum, sporangia and encysted zoospores of Phytophthora infestans were determined in solution at various pH values. The spores all had characteristic and distinct pH-mobility curves. The zero mobility of P. infestans sporangia over the range pH 2 to 11 is consistent with a cellulose surface free from ionizable groups. The mobility of basidiospores of S. purpureum depended entirely on the presence of carboxyl groups. Chemical and enzymic treatments showed both amino and carboxyl groups on A. tenuis and B. fabae; phosphate was present in addition on P. expansum. The amino groups of ϵ-lysine, histidine and leucine contributed to the surface charge of B. fabae; amino acids and tyrosine were detected on A. tenuis. The surface of P. expansum was protein-free and the amino groups present were probably derived from a glucosamine or galactosamine polymer. Washed cell walls and intact conidia of B. fabae were electrophoretically similar but cell walls of P. expansum, unlike normal conidia, were phosphate-free. Mycelial ‘protoplasts’ of A. tenuis and Neurospora crassa and conidial ‘protoplasts’ of B. fabae had pH-mobility curves characteristic of a protein surface.

Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients’ tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

SUMMARY: Conidia of Penicillium expansum are covered with a surface layer of polyphosphate when grown on a high phosphate medium. The composition of this polyphosphate layer, which appears 2 days after conidial initiation, is dependent on the phosphate content of the growth medium; the layer is absent from conidia grown on a low phosphate medium. The rodlet layer which lies beneath the polyphosphate is free of cutin and does not consist of a unique protein. The amino acid composition of the surface protein is, however, different from that of the total wall protein. The rodlet layer appears to be an integral part of the spore wall. The pH--mobility curves of Penicillium conidia are constant and species-specific when the fungi are grown on defined media.

Background Inherited genetic variants may influence response to, and side-effects from, chemotherapy. We sought to generate a comprehensive inherited pharmacogenetic profile for oxaliplatin and 5FU/capecitabine therapy in advanced colorectal cancer (aCRC). Methods We analysed more than 200 potentially functional, common, inherited variants in genes within the 5FU, capecitabine, oxaliplatin and DNA repair pathways, together with four rare dihydropyrimidine dehydrogenase (DPYD) variants, in 2183 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy with, or without, cetuximab (from MRC COIN and COIN-B trials). Primary end-points were response, any toxicity and peripheral neuropathy. We had >85% power to detect odds ratios (ORs) = 1.3 for variants with minor allele frequencies >20%. Results Variants in DNA repair genes (Asn279Ser in EXO1 and Arg399Gln in XRCC1) were most associated with response (OR 1.9, 95% confidence interval [CI] 1.2–2.9, P = 0.004, and OR 0.7, 95% CI 0.5–0.9, P = 0.003, respectively). Common variants in DPYD (Cys29Arg and Val732Ile) were most associated with toxicity (OR 0.8, 95% CI 0.7–1.0, P = 0.008, and OR 1.6, 95% CI 1.1–2.1, P = 0.006, respectively). Two rare DPYD variants were associated with increased toxicity (Asp949Val with neutropenia, nausea and vomiting, diarrhoea and infection; IVS14+1G>A with lethargy, diarrhoea, stomatitis, hand-foot syndrome and infection; all ORs > 3). Asp317His in DCLRE1A was most associated with peripheral neuropathy (OR 1.3, 95% CI 1.1–1.6, P = 0.003). No common variant associations remained significant after Bonferroni correction. Conclusions DNA repair genes may play a significant role in the pharmacogenetics of aCRC. Our data suggest that both common and rare DPYD variants may be associated with toxicity to fluoropyrimidine-based chemotherapy.

Abstract Purpose: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer. Experimental Design: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer. Results: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer. Conclusions: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.

Chapter 25 Meta-Analysis in Stata David J. Fisher, David J. FisherSearch for more papers by this authorMarcel Zwahlen, Marcel ZwahlenSearch for more papers by this authorMatthias Egger, Matthias EggerSearch for more papers by this authorJulian P.T. Higgins, Julian P.T. HigginsSearch for more papers by this author David J. Fisher, David J. FisherSearch for more papers by this authorMarcel Zwahlen, Marcel ZwahlenSearch for more papers by this authorMatthias Egger, Matthias EggerSearch for more papers by this authorJulian P.T. Higgins, Julian P.T. HigginsSearch for more papers by this author Book Editor(s):Matthias Egger, Matthias Egger Professor of Epidemiology and Public Health Institute for Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland Centre for Infectious Diseases Epidemiology and Research, University of Cape Town, South AfricaSearch for more papers by this authorJulian P.T. Higgins, Julian P.T. Higgins Professor of Evidence Synthesis Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UKSearch for more papers by this authorGeorge Davey Smith, George Davey Smith Professor of Clinical Epidemiology and Director of the MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UKSearch for more papers by this author First published: 22 April 2022 https://doi.org/10.1002/9781119099369.ch25 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onFacebookTwitterLinked InRedditWechat Summary Stata is a commercial general-purpose, programmable statistical package. A comprehensive set of commands are available for meta-analysis of different types of studies and data. Meta-analysis of studies comparing two treatments can be performed for binary (relative risk, odds ratio, risk difference) or continuous outcomes (difference in means, standardized difference in means). Meta-analysis of proportions or of generic effect estimates can also be performed. All widely used fixed-effect (inverse-variance method, Mantel–Haenszel method and Peto's method) and random-effects (DerSimonian and Laird, restricted maximum likelihood [REML], and many more) models are available. Forest plots, funnel plots, and other type of plots can be obtained, and statistical tests for funnel plot asymmetry computed. Additional commands are available for meta-analysis of specific applications such as diagnostic test accuracy and dose–response, as well as generalizations such as meta-regression, multivariate meta-analysis, and network meta-analysis. These additional commands also include tailor-made plotting options. Further details on meta-analysis in Stata are available from a dedicated book published by Stata Press (2016), although the information presented in this chapter is more up to date. Systematic Reviews in Health Research: Meta-Analysis in Context, Third Edition RelatedInformation

We sought to identify age-related differences in the ventricular response of patients after bidirectional cavopulmonary anastomosis (CPA) and to compare changes in the ventricular response among children <3 years of age who underwent CPA with that of age-matched control subjects who had a systemic to pulmonary artery shunt alone. Pre-Fontan CPA has been advocated over a systemic to pulmonary artery shunt alone in patients with a single ventricle to facilitate ventricular volume unloading and minimize risk of the Fontan operation. Our study evaluated 23 patients who initially received a systemic to pulmonary artery shunt as an initial procedure before subsequent Fontan palliation. In eight of these patients (group I), bidirectional CPA was performed before age 3 years, and in four (group II), it was performed after age 10 years. The remaining 11 patients (group III, age and weight control group for group I) were maintained with their initial shunt until they underwent Fontan palliation. Serial echocardiographic analysis was used retrospectively to evaluate left ventricular volume and mass and systolic pump function (ejection fraction) before and after bidirectional CPA. Through 10 months of follow-up, group I patients showed significant decreases in indexed end-diastolic volume both after CPA (120 ml/m1.5 body surface area vs. 78 ml/m1.5, p = 0.001) and in comparison with values in patients in groups II and III, who showed no changes in end-diastolic volume (p < 0.001). Indexed ventricular mass decreased moderately after bidirectional CPA in group I (from 228 g/m1.5 body surface area to 148 g/m1.5) but remained unchanged in groups II and III. The differences in trends between groups I and III were significant (p = 0.03). Ejection fraction decreased significantly in group II versus group I patients (0.48 to 0.27 vs. 0.51 to 0.52, p < 0.05) after CPA. Oxygen saturation measurements before and after bidirectional CPA revealed a significant increase in group I (73% to 86%, p < 0.001) and a decrease in group II (82% to 73%, p < 0.01). Bidirectional CPA facilitates ventricular volume unloading and promotes regression of left ventricular mass in younger children (<3 years) in preparation for a Fontan operation. In contrast, bidirectional CPA is of questionable value in older children as a staging procedure for Fontan palliation.

PURPOSE To assess the efficacy and safety profile of high-dose (0.3 mmol/kg cumulative dose) gadoteridol in patients with suspected central nervous system metastatic disease. METHODS We studied 67 patients using an incremental-dose technique. Patient monitoring included a medical history, physical examination, vital signs, and extensive laboratory tests within 24 hours before and after the MR examination. Precontrast T1- and T2-weighted spin-echo studies were performed, followed by intravenous injection of 0.1 mmol/kg of gadoteridol. T1-weighted images were acquired immediately after and at 10 and 20 minutes after injection. At 30 minutes an additional 0.2 mmol/kg of gadoteridol was administered (0.3-mmol/kg cumulative dose), and T1-weighted images were acquired. Cases demonstrating abnormal MR findings were assessed for efficacy by unblinded and blinded reviewers and were analyzed quantitatively. RESULTS Three adverse effects in two patients were considered to be related to gadoteridol administration. No adverse effects were serious; all self-resolved. Forty-nine cases showed abnormal MR findings and were included in the efficacy analysis. A significantly greater number of lesions was seen on the high-dose as opposed to the standard-dose images. Blinded and unblinded readers identified 5 and 8 patients, respectively, with solitary lesions on standard-dose examination and multiple lesions on high-dose examination. Two patients who had normal standard-dose findings had lesions identified on high-dose studies. Quantitative analysis of 133 lesions in 45 patients demonstrated significant increases in lesion signal intensity on high-dose studies when compared with standard-dose studies. CONCLUSION Gadoteridol can be safely administered up to a cumulative dose of 0.3 mmol/kg. High-dose contrast studies provide improved lesion detectability and additional diagnostic information over studies performed in the same patients with a 0.1-mmol/kg dose and aid in patient diagnosis and treatment. High-dose gadoteridol study may facilitate the care of patients with suspected central nervous system metastasis.

We measured and calculated their product, regional myocardial oxygen delivery, in unanesthetized, previously instrumented fetal, newborn, and adult sheep. In the fetus, blood flow and oxygen delivery were greater to the right ventricular free wall than to the left ventricular free wall. In the left ventricular free wall oxygen delivery increased significantly after birth and later decreased to a level in the adult that was similar to that of the fetus. There was a progressive decrease in oxygen delivery to the right ventricular free wall during the developmental period that we studied. Although the inner-to-outer blood flow ratio was significantly lower for the left and right ventricular free walls of the fetuses as compared with the newborns and adults, the ratio was greater than one in all three groups for both of the ventricular free walls. These data demonstrate that the changes that occur in the circulation after birth are associated with significant alterations in right and left ventricular myocardial blood flow and oxygen delivery, which most likely reflect changes in regional myocardial metabolic demands. In addition, there are further significant changes in regional myocardial blood flow during the transition from the newborn to adult hemodynamics.

AbstractAbstractCasting alloys of eutectic composition are of great practical importance. Good microstructural control of these alloys is essential in obtaining the required properties in the cast state. Primary phases present in a eutectic matrix may have either a beneficial or a detrimental effect on these properties. Therefore, their appearance must be carefully controlled. In this review the authors describe the fundamentals and recent advances in the understanding of the extent of eutectic growth – the coupled zone. Because of the inherent difficulties and the present inapplicability of stability analyses to predicting eutectic to eutectic plus dendrite transitions, the simpler 'competitive growth' approach is presented in this review. As this involves separate consideration of eutectic and dendrite growth, the theory of these growth forms for temperature gradients is first reviewed. The competitivegrowth principle is then applied, i.e. the principle that the morphologies appearing in the microstructure, under given conditions, will be those having the highest interface temperature or the highest growth rate (depending on whether growth rate or undercooling is the controlled variable). On the basis of this theory, a modified classification of eutectics is proposed. Mter discussion of the experimental techniques available for determining the form and extent of the coupled zone, the experimental results are compared with theory. Conclusions are drawn concerning the reasons for the various forms of coupled zone.

Surface charges on flocculent and non-flocculent yeast cells have been measured by micro-electrophoresis. Yeasts were grown both in calcium deficient and in complete medium and particular attention was paid to changes as cells passed from a logarithimic to a stationary phase of growth. Many of the ionogenic groups contributing to surface charge are situated well within the cell wall; charges on cells from the calcium-deficient medium were higher than on cells from the complete medium. A pH-dependent rearrangement of an underlying surface protein layer is postulated for the flocculent yeast Saccharomyces cerevisiae Strain NCYC 1109. No evidence of a similar rearrangement was found with other flocculent strains examined. The results are discussed in relation to ‘calcium bridge’ formation.

Genome-wide association studies have identified numerous loci associated with colorectal cancer risk. Several of these have also been associated with patient survival, although none have been validated. Here, we used large independent training and validation cohorts to identify robust prognostic biomarkers for colorectal cancer.In our training phase, we analyzed 20 colorectal cancer-risk SNPs from 14 genome-wide associated loci, for their effects on survival in 2,083 patients with advanced colorectal cancer. A Cox survival model was used, stratified for treatment, adjusted for known prognostic factors, and corrected for multiple testing. Three SNPs were subsequently analyzed in an independent validation cohort of 5,552 colorectal cancer patients. A validated SNP was analyzed by disease stage and response to treatment.Three variants associated with survival in the training phase; however, only rs9929218 at 16q22 (intron 2 of CDH1, encoding E-cadherin) was significant in the validation phase. Patients homozygous for the minor allele (AA genotype) had worse survival (training phase HR, 1.43; 95% confidence intervals; CI, 1.20-1.71, P = 5.8 × 10(-5); validation phase HR, 1.18; 95% CI, 1.01-1.37, P = 3.2 × 10(-2); combined HR, 1.28; 95% CI, 1.14-1.43, P = 2.2 × 10(-5)). This effect was independent of known prognostic factors, and was significant amongst patients with stage IV disease (P = 2.7 × 10(-5)). rs9929218 was also associated with poor response to chemotherapy (P = 3.9 × 10(-4)).We demonstrate the potential of common inherited genetic variants to inform patient outcome and show that rs9929218 identifies approximately 8% of colorectal cancer patients with poor prognosis. rs9929218 may affect CDH1 expression and E-cadherin plays a role in epithelial-to-mesenchymal transition providing a mechanism underlying its prognostic potential. Clin Cancer Res; 21(15); 3453-61. ©2015 AACR.