Konstantinos Manolopoulos

<h2>Summary</h2> Nicotinamide adenine dinucleotide (NAD⁺) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD⁺ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD⁺ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.

Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined.To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS.Cross-sectional study.14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016).1305 prospectively recruited persons with benign adrenal tumors.Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry.Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased.Cross-sectional design; possible selection bias.A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes.Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Upper- and lower-body fat depots exhibit opposing associations with obesity-related metabolic disease. We defined the relationship between DEXA-quantified fat depots and diabetes/cardiovascular risk factors in a healthy population-based cohort (n = 3,399). Gynoid fat mass correlated negatively with insulin resistance after total fat mass adjustment, whereas the opposite was seen for abdominal fat. Paired transcriptomic analysis of gluteal subcutaneous adipose tissue (GSAT) and abdominal subcutaneous adipose tissue (ASAT) was performed across the BMI spectrum (n = 49; 21.4-45.5 kg/m(2)). In both depots, energy-generating metabolic genes were negatively associated and inflammatory genes were positively associated with obesity. However, associations were significantly weaker in GSAT. At the systemic level, arteriovenous release of the proinflammatory cytokine interleukin-6 (n = 34) was lower from GSAT than ASAT. Isolated preadipocytes retained a depot-specific transcriptional "memory" of embryonic developmental genes and exhibited differential promoter DNA methylation of selected genes (HOTAIR, TBX5) between GSAT and ASAT. Short hairpin RNA-mediated silencing identified TBX5 as a regulator of preadipocyte proliferation and adipogenic differentiation in ASAT. In conclusion, intrinsic differences in the expression of developmental genes in regional adipocytes provide a mechanistic basis for diversity in adipose tissue (AT) function. The less inflammatory nature of lower-body AT offers insight into the opposing metabolic disease risk associations between upper- and lower-body obesity.

Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder occurring in up to 10% of women of reproductive age. PCOS is associated with insulin resistance and cardiovascular risk. Androgen excess is a defining feature of PCOS and has been suggested as causally associated with insulin resistance; however, mechanistic evidence linking both is lacking. We hypothesized that adipose tissue is an important site linking androgen activation and metabolic dysfunction in PCOS.We performed a human deep metabolic in vivo phenotyping study examining the systemic and intra-adipose effects of acute and chronic androgen exposure in 10 PCOS women, in comparison with 10 body mass index-matched healthy controls, complemented by in vitro experiments.PCOS women had increased intra-adipose concentrations of testosterone (P = 0.0006) and dihydrotestosterone (P = 0.01), with increased expression of the androgen-activating enzyme aldo-ketoreductase type 1 C3 (AKR1C3) (P = 0.04) in subcutaneous adipose tissue. Adipose glycerol levels in subcutaneous adipose tissue microdialysate supported in vivo suppression of lipolysis after acute androgen exposure in PCOS (P = 0.04). Mirroring this, nontargeted serum metabolomics revealed prolipogenic effects of androgens in PCOS women only. In vitro studies showed that insulin increased adipose AKR1C3 expression and activity, whereas androgen exposure increased adipocyte de novo lipid synthesis. Pharmacologic AKR1C3 inhibition in vitro decreased de novo lipogenesis.These findings define an intra-adipose mechanism of androgen activation that contributes to adipose remodeling and a systemic lipotoxic metabolome, with intra-adipose androgens driving lipid accumulation and insulin resistance in PCOS. AKR1C3 represents a promising therapeutic target in PCOS.

Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), which affects 10% of women and represents a lifelong metabolic disorder, with increased risk of type 2 diabetes, hypertension, and cardiovascular events. Previous studies have suggested an increased risk of nonalcoholic fatty liver disease (NAFLD) in individuals with PCOS and implicated androgen excess as a potential driver.We carried out a retrospective longitudinal cohort study utilizing a large primary care database in the United Kingdom, evaluating NAFLD rates in 63,120 women with PCOS and 121,064 age-, body mass index (BMI)-, and location-matched control women registered from January 2000 to May 2016. In 2 independent cohorts, we also determined the rate of NAFLD in women with a measurement of serum testosterone (n = 71,061) and sex hormone-binding globulin (SHBG; n = 49,625). We used multivariate Cox models to estimate the hazard ratio (HR) for NAFLD and found that women with PCOS had an increased rate of NAFLD (HR = 2.23, 95% CI 1.86-2.66, p < 0.001), also after adjusting for BMI or dysglycemia. Serum testosterone >3.0 nmol/L was associated with an increase in NAFLD (HR = 2.30, 95% CI 1.16-4.53, p = 0.017 for 3-3.49 nmol/L and HR = 2.40, 95% CI 1.24-4.66, p = 0.009 for >3.5 nmol/L). Mirroring this finding, SHBG <30 nmol/L was associated with increased NAFLD hazard (HR = 4.75, 95% CI 2.44-9.25, p < 0.001 for 20-29.99 nmol/L and HR = 4.98, 95% CI 2.45-10.11, p < 0.001 for <20 nmol/L). Limitations of this study include its retrospective nature, absence of detailed information on criteria used to diagnosis PCOS and NAFLD, and absence of data on laboratory assays used to measure serum androgens.We found that women with PCOS have an increased rate of NAFLD. In addition to increased BMI and dysglycemia, androgen excess contributes to the development of NAFLD in women with PCOS. In women with PCOS-related androgen excess, systematic NAFLD screening should be considered.

Abstract Obesity is a complex disorder of excessive adiposity, and is associated with adverse health effects such as cardiometabolic complications, which are to a large extent attributable to dysfunctional white adipose tissue. Adipose tissue dysfunction is characterized by adipocyte hypertrophy, impaired adipokine secretion, a chronic low‐grade inflammatory status, hormonal resistance and altered metabolic responses, together contributing to insulin resistance and related chronic diseases. Adipose tissue hypoxia, defined as a relative oxygen deficit, in obesity has been proposed as a potential contributor to adipose tissue dysfunction, but studies in humans have yielded conflicting results. Here, we will review the role of adipose tissue oxygenation in the pathophysiology of obesity‐related complications, with a specific focus on human studies. We will provide an overview of the determinants of adipose tissue oxygenation, as well as the role of adipose tissue oxygenation in glucose homeostasis, lipid metabolism and inflammation. Finally, we will discuss the putative effects of physiological and experimental hypoxia on adipose tissue biology and whole‐body metabolism in humans. We conclude that several lines of evidence suggest that alteration of adipose tissue oxygenation may impact metabolic homeostasis, thereby providing a novel strategy to combat chronic metabolic diseases in obese humans.

Brown adipose tissue (BAT) is a thermogenic organ with substantial metabolic capacity and has important roles in the maintenance of body weight and metabolism. Regulation of BAT is primarily mediated through the β-adrenoceptor (β-AR) pathway. The in vivo endocrine regulation of this pathway in humans is unknown. The objective of our study was to assess the in vivo BAT temperature responses to acute glucocorticoid administration.We studied 8 healthy male volunteers, not pre-selected for BAT presence or activity and without prior BAT cold-activation, on two occasions, following an infusion with hydrocortisone (0.2mg.kg-1.min-1 for 14h) and saline, respectively. Infusions were given in a randomized double-blind order. They underwent assessment of supraclavicular BAT temperature using infrared thermography following a mixed meal, and during β-AR stimulation with isoprenaline (25ng.kg fat-free mass-1.min-1 for 60min) in the fasting state.During hydrocortisone infusion, BAT temperature increased both under fasting basal conditions and during β-AR stimulation. We observed a BAT temperature threshold, which was not exceeded despite maximal β-AR activation. We conclude that BAT thermogenesis is present in humans under near-normal conditions. Glucocorticoids modulate BAT function, representing important physiological endocrine regulation of body temperature at times of acute stress.

Abstract Objective To assess the association of ethnicity and birthplace on emotional and psychosexual well‐being in women with polycystic ovary syndrome (PCOS). Design Cross‐sectional study. Setting Community recruitment via social media campaigns. Population Women with PCOS completing an online questionnaire in September–October 2020 (UK) and May–June 2021 (India). Methods The survey has five components, with a baseline information and sociodemographic section followed by four validated questionnaires: Hospital Anxiety and Depression Scale (HADS); Body Image Concern Inventory (BICI); Beliefs About Obese Persons Scale (BAOP); and Female Sexual Function Index (FSFI). Main outcome measures We used adjusted linear and logistic regression models, adjusting for age, education, marital status and parity, to evaluate the impact of ethnicity and birthplace on questionnaire scores and outcomes (anxiety and/or depression, HADS ≥ 11; body dysmorphic disorder (BDD), BICI ≥ 72). Results A total of 1008 women with PCOS were included. Women of non‐white ethnicity (613/1008) reported higher rates of depression (OR 1.96, 95% CI 1.41–2.73) and lower BDD (OR 0.57, 95% CI 0.41–0.79) than white women (395/1008). Women born in India (453/1008) had higher anxiety (OR 1.57, 95% CI 1.00–2.46) and depression (OR 2.20, 95% CI 1.52–3.18) but lower BDD rates (OR 0.42, 95% CI 0.29–0.61) than women born in the UK (437/1008). All sexual domains, excluding desire, scored lower for non‐white women and women born in India. Conclusions Non‐white women and women born in India reported higher emotional and sexual dysfunction, whereas white women and women born in the UK reported higher body image concerns and weight stigma. Ethnicity and birthplace need to be considered for tailored, multidisciplinary care.

11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) is a therapeutic target in metabolic syndrome because it catalyses reductase regeneration of cortisol from cortisone in adipose and liver. 11βHSD1 can also catalyze the reverse dehydrogenase reaction in vitro (e.g., if cofactor is limited). We used stable isotope tracers to test the hypothesis that both 11βHSD1-reductase and -dehydrogenase activities occur in human metabolic tissues in vivo. 1,2-[2H]2-Cortisone (d2-cortisone) was validated as a tracer for 11β-dehydrogenase activity and its inhibition by licorice. d2-Cortisone and 9,11,12,12-[2H]4-cortisol (d4-cortisol) (to measure 11β-reductase activity) were coinfused and venous samples obtained from skeletal muscle, subcutaneous adipose (n = 6), and liver (n = 4). Steroids were measured by liquid chromatography–tandem mass spectrometry and arteriovenous differences adjusted for blood flow. Data are means ± SEM. 11β-Reductase and -dehydrogenase activities were detected in muscle (cortisol release 19.7 ± 4.1 pmol/100 mL/min, d3-cortisol 5.9 ± 1.8 pmol/100 mL/min, and cortisone 15.2 ± 5.8 pmol/100 mL/min) and splanchnic (cortisol 64.0 ± 11.4 nmol/min, d3-cortisol 12.9 ± 2.1 nmol/min, and cortisone 19.5 ± 2.8 nmol/min) circulations. In adipose, dehydrogenase was more readily detected than reductase (cortisone release 38.7 ± 5.8 pmol/100 g/min). Active recycling between cortisol and cortisone in metabolic tissues in vivo may facilitate dynamic control of intracellular cortisol but makes consequences of dysregulation of 11βHSD1 transcription in obesity and diabetes unpredictable. Disappointing efficacy of 11βHSD1 inhibitors in phase II studies could be explained by lack of selectivity for 11β-reductase.

Glucocorticoids increase adipocyte proliferation and differentiation, a process underpinned by the local reactivation of inactive cortisone to active cortisol within adipocytes catalyzed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The adrenal sex steroid precursor dehydroepiandrosterone (DHEA) has been shown to inhibit 11β-HSD1 in murine adipocytes; however, rodent adrenals do not produce DHEA physiologically. Here, we aimed to determine the effects and underlying mechanisms of the potential antiglucocorticoid action of DHEA and its sulfate ester DHEAS in human preadipocytes. Utilizing a human subcutaneous preadipocyte cell line, Chub-S7, we examined the metabolism and effects of DHEA in human adipocytes, including adipocyte proliferation, differentiation, 11β-HSD1 expression, and activity and glucose uptake. DHEA, but not DHEAS, significantly inhibited preadipocyte proliferation via cell cycle arrest in the G1 phase independent of sex steroid and glucocorticoid receptor activation. 11β-HSD1 oxoreductase activity in differentiated adipocytes was inhibited by DHEA. DHEA coincubated with cortisone significantly inhibited preadipocyte differentiation, which was assessed by the expression of markers of early (LPL) and terminal (G3PDH) adipocyte differentiation. Coincubation with cortisol, negating the requirement for 11β-HSD1 oxoreductase activity, diminished the inhibitory effect of DHEA. Further consistent with glucocorticoid-opposing effects of DHEA, insulin-independent glucose uptake was significantly enhanced by DHEA treatment. DHEA increases basal glucose uptake and inhibits human preadipocyte proliferation and differentiation, thereby exerting an antiglucocorticoid action. DHEA inhibition of the amplification of glucocorticoid action mediated by 11β-HSD1 contributes to the inhibitory effect of DHEA on human preadipocyte differentiation.

Idiopathic intracranial hypertension (IIH) is strongly associated with obesity. We aimed to utilise dual-energy X-ray absorptiometry (DEXA) to characterise fat distribution, and to evaluate change in fat mass and distribution following weight loss. IIH patients (n = 24) had a similar fat distribution to body mass index (BMI)- and gender-matched obese controls (n = 47). In the IIH cohort, truncal fat mass correlated with lumbar puncture pressure. Weight loss in IIH patients resulted in a significant reduction in disease activity and fat mass, predominantly from the truncal region (-4.40 ± 1.6%; p = 0.008) compared with the limbs (+0.79 ± 6.5%; p = 0.71). These results indicate that, contrary to previous studies using waist-hip ratios, IIH adiposity is centripetal, similar to simple obesity. Future studies should establish the risk of the metabolic syndrome and the role of adipose tissue depot-specific function in IIH.

Summary Objective Previous studies suggest that androgens have a sexually dimorphic impact on metabolic dysfunction. However, the sex‐specific link between circulating androgens and risk of type 2 diabetes mellitus (T2DM) has not been examined in a large scale, longitudinal cohort, a task we undertook in this study. Design A retrospective cohort study in a UK primary care database. Patients We included men and women with available serum testosterone and sex hormone‐binding globulin (SHBG) results. Measurements We categorized serum concentrations according to clinically relevant cut‐off points and calculated crude and adjusted T2DM Incidence Rate Ratios (IRRs and aIRRs). Results Serum testosterone concentrations were available in 70 541 men and 81 889 women; serum SHBG was available in 15 907 men and 42 034 women. In comparison to a reference cohort with serum testosterone ≥20 nmol/L, men with lower serum testosterone had a significantly increased risk of T2DM, with the highest risk in those with serum testosterone &lt;7 nmol/L (aIRR 2.71, 95% CI 2.34‐3.14, P &lt; 0.001). In women, the risk of T2DM started to increase significantly when serum testosterone concentrations exceeded 1.5 nmol/L, with the highest risk in women with serum testosterone ≥3.5 nmol/L (aIRR 1.98, 95% CI 1.55‐2.52, P &lt; 0.001). These observations were verified in a continuous rather than categorized analysis. The risk of T2DM increased in men and women with serum SHBG &lt;40 and &lt;50 nmol/L, respectively. Conclusions/Interpretation In this longitudinal study, we found sexually dimorphic associations between serum testosterone and risk of incident T2DM. Androgen deficiency and excess should be considered important risk factors for diabetes in men and women, respectively.

Vitamin D is lipophilic and accumulates substantially in adipose tissue. Even without supplementation, the amount of vitamin D in the adipose of a typical adult is equivalent to several months of the daily reference nutrient intake (RNI). Paradoxically, despite the large amounts of vitamin D located in adipose tissue, individuals with obesity are often vitamin D deficient according to consensus measures of vitamin D status (serum 25-hydroxyvitamin D concentrations). Thus, it appears that vitamin D can become 'trapped' in adipose tissue, potentially due to insufficient lipolytic stimulation and/or due to tissue dysfunction/adaptation resulting from adipose expansion. Emerging evidence suggests that exercise may mobilise vitamin D from adipose (even in the absence of weight loss). If exercise helps to mobilise vitamin D from adipose tissue, then this could have important ramifications for practitioners and policymakers regarding the management of low circulating levels of vitamin D, as well as chronically low levels of physical activity, obesity and associated health conditions. This perspective led us to design a study to examine the impact of exercise on vitamin D status, vitamin D turnover and adipose tissue vitamin D content (the VitaDEx project). The VitaDEx project will determine whether increasing physical activity (via exercise) represents a potentially useful strategy to mobilise vitamin D from adipose tissue.

Abstract Background Poor recovery from periods of disuse accelerates age‐related muscle loss, predisposing individuals to the development of secondary adverse health outcomes. Exercise prior to disuse (prehabilitation) may prevent muscle deterioration during subsequent unloading. The present study aimed to investigate the effect of short‐term resistance exercise training (RET) prehabilitation on muscle morphology and regulatory mechanisms during 5 days of bed rest in older men. Methods Ten healthy older men aged 65–80 years underwent four bouts of high‐volume unilateral leg RET over 7 days prior to 5 days of inpatient bed rest. Physical activity and step‐count were monitored over the course of RET prehabilitation and bed rest, whilst dietary intake was recorded throughout. Prior to and following bed rest, quadriceps cross‐sectional area (CSA), and hormone/lipid profiles were determined. Serial muscle biopsies and dual‐stable isotope tracers were used to determine integrated myofibrillar protein synthesis (iMyoPS) over RET prehabilitation and bed rest phases, and acute postabsorptive and postprandial myofibrillar protein synthesis (aMyoPS) rates at the end of bed rest. Results During bed rest, daily step‐count and light and moderate physical activity time decreased, whilst sedentary time increased when compared with habitual levels ( P &lt; 0.001 for all). Dietary protein and fibre intake during bed rest were lower than habitual values ( P &lt; 0.01 for both). iMyoPS rates were significantly greater in the exercised leg (EX) compared with the non‐exercised control leg (CTL) over prehabilitation (1.76 ± 0.37%/day vs. 1.36 ± 0.18%/day, respectively; P = 0.007). iMyoPS rates decreased similarly in EX and CTL during bed rest (CTL, 1.07 ± 0.22%/day; EX, 1.30 ± 0.38%/day; P = 0.037 and 0.002, respectively). Postprandial aMyoPS rates increased above postabsorptive values in EX only ( P = 0.018), with no difference in delta postprandial aMyoPS stimulation between legs. Quadriceps CSA at 40%, 60%, and 80% of muscle length decreased significantly in EX and CTL over bed rest (0.69%, 3.5%, and 2.8%, respectively; P &lt; 0.01 for all), with no differences between legs. No differences in fibre‐type CSA were observed between legs or with bed rest. Plasma insulin and serum lipids did not change with bed rest. Conclusions Short‐term resistance exercise prehabilitation augmented iMyoPS rates in older men but did not offset the relative decline in iMyoPS and muscle mass during bed rest.

Introduction Upper and lower body fat accumulation poses an opposing obesity-related cardiometabolic disease risk. Depot-differences in subcutaneous adipose tissue (SAT) function may underlie these associations. We aimed to investigate the inflammatory signatures of abdominal (ABD) and femoral (FEM) SAT in postmenopausal women with normal weight or obesity. Methods We included 23 postmenopausal women with normal weight (n = 13) or obesity (n = 10). In vivo secretion of adipokines from ABD and FEM SAT was measured using the arterio-venous balance technique. Adipokine gene expression and adipocyte morphology were examined in ABD and FEM SAT. Furthermore, adipokine expression and secretion were investigated in vitro using differentiated human primary ABD and FEM subcutaneous adipocytes derived from the study participants. Results Plasma leptin and plasminogen activator inhibitor (PAI)-1 concentrations were higher, and ABD and FEM adipocytes were larger in women with obesity than normal weight. No differences in adipocyte size and blood flow were apparent between ABD and FEM SAT. We found significant release of leptin and monocyte chemoattractant protein (MCP)-1 from ABD and FEM SAT, with higher fractional release of MCP-1 from ABD than FEM SAT. Gene expression of leptin, PAI-1, and tumor necrosis factor-α was lower in ABD than FEM SAT and higher in women with obesity than normal weight. In ABD adipocytes, interleukin-6, PAI-1, and leptin gene expression were higher, while adiponectin and dipeptidyl-peptidase-4 gene expression were lower than in FEM adipocytes. Finally, ABD adipocytes secreted less MCP-1 compared to FEM adipocytes. Discussion These findings demonstrate that upper and lower body SAT and adipocytes are characterized by distinct inflammatory signatures in postmenopausal women, which seem independent of adipocyte size.

Abstract Context Pre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness. Objective To assess acute and chronic effects of exercise performed before versus after nutrient ingestion on whole-body and intramuscular lipid utilization and postprandial glucose metabolism. Design (1) Acute, randomized, crossover design (Acute Study); (2) 6-week, randomized, controlled design (Training Study). Setting General community. Participants Men with overweight/obesity (mean ± standard deviation, body mass index: 30.2 ± 3.5 kg⋅m-2 for Acute Study, 30.9 ± 4.5 kg⋅m-2 for Training Study). Interventions Moderate-intensity cycling performed before versus after mixed-macronutrient breakfast (Acute Study) or carbohydrate (Training Study) ingestion. Results Acute Study—exercise before versus after breakfast consumption increased net intramuscular lipid utilization in type I (net change: –3.44 ± 2.63% versus 1.44 ± 4.18% area lipid staining, P &amp;lt; 0.01) and type II fibers (–1.89 ± 2.48% versus 1.83 ± 1.92% area lipid staining, P &amp;lt; 0.05). Training Study—postprandial glycemia was not differentially affected by 6 weeks of exercise training performed before versus after carbohydrate intake (P &amp;gt; 0.05). However, postprandial insulinemia was reduced with exercise training performed before but not after carbohydrate ingestion (P = 0.03). This resulted in increased oral glucose insulin sensitivity (25 ± 38 vs –21 ± 32 mL⋅min-1⋅m-2; P = 0.01), associated with increased lipid utilization during exercise (r = 0.50, P = 0.02). Regular exercise before nutrient provision also augmented remodeling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 (P &amp;lt; 0.05). Conclusions Experiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (ie, in the fasted state) may exert beneficial effects on lipid utilization and reduce postprandial insulinemia.

Polycystic ovary syndrome (PCOS) has been traditionally perceived as a reproductive disorder due to its most common presentation with menstrual dysfunction and infertility. However, it is now clear that women with PCOS are at increased risk of metabolic dysfunction, from impaired glucose tolerance and type 2 diabetes mellitus to nonalcoholic fatty liver disease and cardiovascular disease. PCOS is characterised by androgen excess, with cross-sectional data showing that hyperandrogenism is directly complicit in the development of metabolic complications. Recent studies have also shown that C11-oxy C19 androgens are emerging to be clinically and biochemically significant in PCOS, thus emphasising the importance of understanding the impact of both classic and C11-oxy C19 androgens on women’s health. Here we discuss androgen metabolism in the context of PCOS, and dissect the role played by androgens in the development of metabolic disease through their effects on metabolic target tissues in women.

Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative AT failure in a monogenic obese cohort, a finding supported by observations in a novel conditional mouse model (Almsflin/flin) and ALMS1-silenced human primary adipocytes, whereas selective reactivation of ALMS1 gene in AT of an ALMS conditional knockdown mouse model (Almsflin/flin; Adipo-Cre+/−) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative AT failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte-driven IR may assist development of AT-targeted therapeutic strategies for diabetes.

Following the evolution of COVID-19 pandemic, reports pointed on a high prevalence of thyroiditis-related thyrotoxicosis. Interpretation of thyroid tests during illness, however, is hampered by changes occurring in the context of non-thyroidal illness syndrome (NTIS). In order to elucidate these findings, we studied thyroid function in carefully selected cohorts of COVID-19 positive and negative patients.Cohort observational study.We measured TSH, FT4, T3 within 24 h of admission in 196 patients without thyroid disease and/or confounding medications. In this study, 102 patients were SARS-CoV-2 positive; 41 admitted in the ICU, 46 in the ward and 15 outpatients. Controls consisted of 94 SARS-CoV-2 negative patients; 39 in the ICU and 55 in the ward. We designated the thyroid hormone patterns as consistent with NTIS, thyrotoxicosis and hypothyroidism.A NTIS pattern was encountered in 60% of ICU and 36% of ward patients, with similar frequencies between SARS-CoV-2 positive and negative patients (46.0% vs 46.8%, P = NS). A thyrotoxicosis pattern was observed in 14.6% SARS-CoV-2 ICU patients vs 7.7% in ICU negative (P = NS) and, overall in 8.8% of SARS-CoV-2 positive vs 7.4% of negative patients. In these patients, thyroglobulin levels were similar to those with normal thyroid function or NTIS. The hypothyroidism pattern was rare.NTIS pattern is common and relates to the severity of disease rather than SARS-CoV-2 infection. A thyrotoxicosis pattern is less frequently observed with similar frequency between patients with and without COVID-19. It is suggested that thyroid hormone monitoring in COVID-19 should not differ from other critically ill patients.

Abstract Background/Objectives Intranasal (IN) administration of insulin decreases appetite in humans, but the underlying mechanisms are unclear, and it is unknown whether IN insulin affects the food intake of women with obesity. Subjects/Methods In a double-blind, placebo-controlled, crossover design, participants (35 lean women and 17 women with obesity) were randomized to receive 160 IU/1.6 mL of IN insulin or placebo in a counterbalanced order in the post prandial state. The effects of IN insulin on cookie intake, appetite, mood, food reward, cognition and neural activity were assessed. Results IN insulin in the post prandial state reduced cookie intake, appetite and food reward relative to placebo and these effects were more pronounced for women with obesity compared with lean women. IN insulin also improved mood in women with obesity. In both BMI groups, IN insulin increased neural activity in the insula when viewing food pictures. IN insulin did not affect cognitive function. Conclusions These results suggest that IN insulin decreases palatable food intake when satiated by reducing food reward and that women with obesity may be more sensitive to this effect than lean women. Further investigation of the therapeutic potential of IN insulin for weight management in women with obesity is warranted.

Tissue cortisol exposure is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). 11β-HSD1 in vivo, acts as an oxoreductase converting inactive cortisone to active cortisol. We hypothesized that 11β-HSD1 activity is dysregulated in obesity and alters following bariatric surgery induced weight loss in different tissues.We recruited 21 patients prior to undergoing bariatric surgery and performed cortisol generation profiles (following oral cortisone administration), urinary corticosteroid metabolite analysis, adipose tissue microdialysis, and tissue gene expression before and after weight loss, following bariatric surgery. Archived tissue samples from 20 previous bariatric surgery patients were also used for tissue gene expression studies.Gene expression showed a positive correlation with 11β-HSD1 and BMI in omental adipose tissue (OM) (r = +0.52, P = .0001) but not sc adipose tissue (r = +0.28, P = .17). 11β-HSD1 expression in liver negatively correlated with body mass index (BMI) (r = -0.37, P = .04). 11β-HSD1 expression in sc adipose tissue was significantly reduced after weight loss (0.41 ± 0.28 vs 0.17 ± 0.1 arbitrary units, P = .02). Following weight loss, serum cortisol generation increased during a cortisol generation profile (area under the curve 26 768 ± 16 880 vs 47 579 ± 16 086 nmol/L/minute, P ≤ .0001.) Urinary corticosteroid metabolites demonstrated a significant reduction in total cortisol metabolites after bariatric surgery (15 224 ± 6595 vs 8814 ± 4824 μg/24 h, P = .01). Microdialysis of sc adipose tissue showed a threefold reduction in cortisol/cortisone ratio after weight loss.This study highlights the differences in tissue specific regulation of cortisol metabolism in obesity and after weight loss. Following bariatric surgery hepatic 11β-HSD1 activity increases, sc adipose tissue 11β-HSD1 activity is reduced and total urinary cortisol metabolites are reduced indicating a possible reduction in hypothalamic pituitary adrenal axis drive. 11β-HSD1 expression correlates positively with BMI in omental adipose tissue and negatively within hepatic tissue. 11β-HSD1 expression is reduced in sc adipose tissue after weight loss.

A new tracking detector is under development for use by the CMS experiment at the High-Luminosity LHC (HL-LHC). A crucial requirement of this upgrade is to provide the ability to reconstruct all charged particle tracks with transverse momentum above 2–3 GeV within 4 μs so they can be used in the Level-1 trigger decision. A concept for an FPGA-based track finder using a fully time-multiplexed architecture is presented, where track candidates are reconstructed using a projective binning algorithm based on the Hough Transform, followed by a combinatorial Kalman Filter. A hardware demonstrator using MP7 processing boards has been assembled to prove the entire system functionality, from the output of the tracker readout boards to the reconstruction of tracks with fitted helix parameters. It successfully operates on one eighth of the tracker solid angle acceptance at a time, processing events taken at 40 MHz, each with up to an average of 200 superimposed proton-proton interactions, whilst satisfying the latency requirement. The demonstrated track-reconstruction system, the chosen architecture, the achievements to date and future options for such a system will be discussed.

The biguanide derivative metformin is a potent anti-diabetic drug widely used in the treatment of type 2 diabetes mellitus. Its major effect on glucose metabolism consists in the inhibition of hepatic glucose production. Since the mechanisms of metformin action are only partially understood at the molecular level, we studied the regulation of the gene promoter activity of glucose-6-phosphatase (G6Pase), the central hepatic gluconeogenic enzyme, by this drug. We have found that both metformin and insulin inhibit the basal and dexamethasone/cAMP-stimulated G6Pase promoter activity in hepatoma cells. Since one of the pharmacological targets of metformin is AMP-activated protein kinase (AMPK) and activation of AMPK is known to inhibit hepatic glucose production by the suppression of G6Pase gene transcription, we studied the effect of AMPK in this context. Under nonstimulated conditions, the inhibitory effect of both insulin and metformin was partially counteracted to a similar extent by treatment with compound C, a specific inhibitor of AMPK. In contrast, under conditions of stimulation with dexamethasone and cAMP, treatment with compound C reversed the inhibitory effect of metformin on G6Pase promoter activity to a similar extent as compared to nonstimulated conditions, whereas the effect of insulin was almost resistant to treatment with the AMPK-antagonist. These data indicate a differential AMPK-dependent regulation of G6Pase gene expression by insulin and metformin under basal and dexamethasone/cAMP-stimulated conditions.

A 64-year-old woman with osteogenesis imperfecta type 4 was commenced on iv bisphosphonates after a low-trauma fracture of her ankle. After having received pamidronate for 3 years and zoledronic acid for 2 years, she complained of a 10-month history of right lateral thigh and groin pain. She was able to bear weight with only minimal discomfort, and there was no limitation of movement. Plain radiographs demonstrated an incomplete subtrochanteric fracture of the lateral cortex of the right femur (Figure 1A) and a similar finding at the mid-diaphysis on the left (Figure 1B). Nuclear medicine bone scanning with single photon emission computed tomography (CT) combined with CT revealed intense uptake in the regions corresponding to those identified on the plain x-rays (Figure 1, C and D). Further bisphosphonate treatment was withheld. Teriparatide, a bone anabolic agent, was commenced to promote fracture healing. Osteogenesis imperfecta is typically associated with frequent fractures in childhood and adolescence, but, with age-associated decline in bone density, patients may enter a second period of heightened fracture risk. Our patient had a genetic predisposition to fractures and was treated with bisphosphonates to ameliorate fracture risk (1, 2). Paradoxically, in this case, such treatment is linked to the evolution of bilateral incomplete subtrochanteric fractures (3, 4). Even in patients with unequivocally increased fracture risk (such as in osteogenesis imperfecta), close clinical scrutiny and follow-up are required when using iv bisphosphonates to provide individualized treatment. Careful and sequential reassessments of risks and benefits must be made when managing all patients with bisphosphonates.

Manolopoulos, E, Katis, A, Manolopoulos, K, Kalapotharakos, V, and Kellis, E. Effects of a 10-week resistance exercise program on soccer kick biomechanics and muscle strength. J Strength Cond Res 27(12): 3391–3401, 2013—The purpose of the study was to examine the effects of a resistance exercise program on soccer kick biomechanics. Twenty male amateur soccer players were divided in the experimental group (EG) and the control group (CG), each consisting of 10 players. The EG followed a 10-week resistance exercise program mainly for the lower limb muscles. Maximal instep kick kinematics, electromyography, and ground reaction forces (GRFs) as well as maximum isometric leg strength were recorded before and after training. A 2-way analysis of variance showed significantly higher ball speed values only for the EG (26.14 ± 1.17 m·s−1 vs. 27.59 ± 1.49 m·s−1 before and after training, respectively), whereas no significant differences were observed for the CG. The EG showed a decline in joint angular velocities and an increase in biceps femoris electromyography of the swinging leg during the backswing phase followed by a significant increase in segmental and joint velocities and muscle activation of the same leg during the forward swing phase (p < 0.05). The EG also showed significantly higher vertical GRFs and rectus femoris and gastrocnemius activation of the support leg (p < 0.05). Similarly, maximum and explosive isometric force significantly increased after training only for the EG (p < 0.05). These results suggest that increases in soccer kicking performance after a 10-week resistance training program were accompanied by increases in maximum strength and an altered soccer kick movement pattern, characterized by a more explosive backward-forward swinging movement and higher muscle activation during the final kicking phase.

The purpose of the study was to investigate the effects of resistance training (RT) and sensorimotor training combined with RT (SM-RT) on balance, 1 repetition maximum (RM), rate of force development (RFD), and squat jump (SJ) height. Twenty amateur soccer players were equally divided into 2 groups assigned as SM-RT group (age: 22 ± 1.7 years, body mass: 79.9 ± 6.3 kg, body height: 1.81 ± 0.06 m) and RT group (age: 21.3 ± 1.3 years, body mass: 77.4 ± 9.3 kg, body height: 1.78 ± 0.04 m). Both groups were trained over a 6-week period with 2 session units per week. SM-RT group performed sensorimotor training (balance on balance board) followed by a high-intensity RT at 8-5RM leg press. The RT group performed the resistance program only. Both groups showed significantly increased 1RM leg press strength, RFD, SJ height, and balance abilities (p ≤ 0.05), whereas no significant between-group differences were observed in any of the outcome variables (p > 0.05). It was concluded that SM-RT was not superior compared with RT for both balance and strength enhancement. These findings have implications in time management during training for soccer players.

Objectives To investigate the association of birthweight percentile with cord blood glucose, lipids, and insulin levels. Study design Data obtained from 1522 newborns were included in the Born in Guangzhou Cohort study. The generalized additive model and multivariable linear regression model were used to explore the nonlinear and linear relationships between birthweight and cord blood metabolic measures, and to evaluate the differences of metabolic measures Z-scores among small for gestational age, appropriate for gestational age, and large for gestational age babies. Results Birthweight Z-score was linearly associated with increased cord blood insulin Z-score (adjusted β = 0.30; 95% CI, 0.22-0.37). Compared with appropriate for gestational age babies, neonates born small for gestational age had significantly higher cord blood triglycerides Z-score (adjusted mean difference [MDadj], 0.60; 95% CI, 0.40-0.79) and lower cord blood insulin (MDadj, −0.37; 95% CI, −0.57 to −0.16), high-density lipoprotein cholesterol (MDadj, −0.34; 95% CI, −0.55 to −0.13), total cholesterol (MDadj, −0.26; 95% CI, −0.47 to −0.05), and low-density lipoprotein (MDadj, −0.23; 95% CI, −0.43 to −0.02) Z-scores, and neonates born large for gestational age had higher cord blood insulin Z-score (MDadj, 0.31; 95% CI, 0.09 to 0.52). Conclusions Our findings support the hypothesis that babies born small for gestational age and large for gestational age are exposed to different intrauterine environments, which may contribute to altered fat accumulation patterns with implications for the risk of metabolic dysfunction later in life. There is a need to consider the development of tailored intervention strategies to prevent metabolic dysfunction in adult life for these babies. To investigate the association of birthweight percentile with cord blood glucose, lipids, and insulin levels. Data obtained from 1522 newborns were included in the Born in Guangzhou Cohort study. The generalized additive model and multivariable linear regression model were used to explore the nonlinear and linear relationships between birthweight and cord blood metabolic measures, and to evaluate the differences of metabolic measures Z-scores among small for gestational age, appropriate for gestational age, and large for gestational age babies. Birthweight Z-score was linearly associated with increased cord blood insulin Z-score (adjusted β = 0.30; 95% CI, 0.22-0.37). Compared with appropriate for gestational age babies, neonates born small for gestational age had significantly higher cord blood triglycerides Z-score (adjusted mean difference [MDadj], 0.60; 95% CI, 0.40-0.79) and lower cord blood insulin (MDadj, −0.37; 95% CI, −0.57 to −0.16), high-density lipoprotein cholesterol (MDadj, −0.34; 95% CI, −0.55 to −0.13), total cholesterol (MDadj, −0.26; 95% CI, −0.47 to −0.05), and low-density lipoprotein (MDadj, −0.23; 95% CI, −0.43 to −0.02) Z-scores, and neonates born large for gestational age had higher cord blood insulin Z-score (MDadj, 0.31; 95% CI, 0.09 to 0.52). Our findings support the hypothesis that babies born small for gestational age and large for gestational age are exposed to different intrauterine environments, which may contribute to altered fat accumulation patterns with implications for the risk of metabolic dysfunction later in life. There is a need to consider the development of tailored intervention strategies to prevent metabolic dysfunction in adult life for these babies.

Gluteofemoral adipose tissue (AT) has interesting positive associations with metabolic health, yet little is known of its metabolic physiology. Here, we describe a technique for cannulation of a vein draining the femoral fat depot. Using ultrasound guidance, a cannula was introduced into a superficial branch of the great saphenous vein. We also obtained arterialized blood and, for comparison, blood representing drainage from forearm muscle and from subcutaneous abdominal AT. We measured appropriate biomarkers of skeletal muscle (creatinine) and AT (nonesterified fatty acids (NEFAs), glycerol, leptin) drainage. Blood obtained in this way from the saphenous vein did not show creatinine release (creatinine concentration 100.5 +/- 0.4%, mean +/- s.e.m., of that in arterialized blood), whereas creatinine concentrations in blood draining forearm muscle averaged 121 +/- 1% of those in arterialized blood. Fatty acid release from the tissue drained was suppressed after feeding and increased during beta-adrenergic stimulation. We also demonstrated leptin secretion. These findings suggest that blood so obtained is representative of AT drainage with little apparent contribution of skeletal muscle. We believe this technique will facilitate physiological studies of a lower-body fat depot in humans.

Adipose tissue (AT) inflammation may increase obesity-related cardiometabolic complications. Altered AT oxygen partial pressure (pO2) may impact the adipocyte inflammatory phenotype. Here, we investigated the effects of physiological pO2 levels on the inflammatory phenotype of abdominal (ABD) and femoral (FEM) adipocytes derived from postmenopausal women with normal weight (NW) or obesity (OB). Biopsies were collected from ABD and FEM subcutaneous AT in eighteen postmenopausal women (aged 50-65 years) with NW (BMI 18-25 kg/m2, n = 9) or OB (BMI 30-40 kg/m2, n = 9). We compared the effects of prolonged exposure to different physiological pO2 levels on adipokine expression and secretion in differentiated human multipotent adipose-derived stem cells. Low physiological pO2 (5% O2) significantly increased leptin gene expression/secretion in ABD and FEM adipocytes derived from individuals with NW and OB compared with high physiological pO2 (10% O2) and standard laboratory conditions (21% O2). Gene expression/secretion of IL-6, DPP-4, and MCP-1 was reduced in differentiated ABD and FEM adipocytes from individuals with OB but not NW following exposure to low compared with high physiological pO2 levels. Low physiological pO2 decreases gene expression and secretion of several proinflammatory factors in ABD and FEM adipocytes derived from individuals with OB but not NW.

Abdominal obesity is associated with increased cardiometabolic disease risk, while lower body fat seems to confer protection against obesity-related complications. The functional differences between upper and lower body adipose tissue (AT) remain poorly understood.We aimed to examine whether mitochondrial respiration is impaired in abdominal as compared to femoral differentiated human multipotent adipose-derived stem cells (hMADS; primary outcome) and AT in postmenopausal women.In this cross-sectional study, 23 postmenopausal women with normal weight or obesity were recruited at the University of Birmingham/Queen Elizabeth Hospital Birmingham (Birmingham, UK). We collected abdominal and femoral subcutaneous AT biopsies to determine mitochondrial oxygen consumption rates in differentiated abdominal and femoral hMADS. Furthermore, we assessed OXPHOS protein expression and mtDNA content in abdominal and femoral AT as well as hMADS. Finally, we explored in vivo fractional oxygen extraction and carbon dioxide release across abdominal and femoral subcutaneous AT in a subgroup of the same individuals with normal weight or obesity.We found lower basal and maximal uncoupled mitochondrial oxygen consumption rates in abdominal compared to femoral hMADS. In line, in vivo fractional oxygen extraction and carbon dioxide release were lower across abdominal than femoral AT. OXPHOS protein expression and mtDNA content did not significantly differ between abdominal and femoral differentiated hMADS and AT.The present findings demonstrate that in vitro mitochondrial respiration and in vivo oxygen fractional extraction are lower in upper compared to lower body differentiated hMADS and AT, respectively, in postmenopausal women.

Multiply-Add Fused (MAF) units play a key role in the processor's performance for a variety of applications. Aiming at improving the MAF functionality this paper presents a dual-mode MAF architecture, which is able to perform either one double-precision or two single-precision operations in parallel. The design attains low latency by following a dual-path approach and by combining final addition with rounding. The organization performs a MAF instruction in three cycles, while single floating-point addition in two cycles. The design has been validated and implemented with TSMC 0.13um.

The current paper presents a multi-mode floating point multiplier operating efficiently with every precision format specified by the IEEE 754-2008 standard. The design performs one quadruple precision multiplication, or two double precision multiplications in parallel, or four single precision multiplications in parallel. The proposed multiplier is pipelined to achieve execution of one quadruple multiplication in 3 cycles and either two double precision operations in parallel or four single precision operations in parallel in only 2 cycles. The proposed design improves the throughput by a factor of two compared to a double precision multiplier and by four compared to a single precision multiplication. An example implementation on VLSI verifies the design and it achieves a maximum operating frequency of 505 MHz.

Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti-inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS. This is a Phase 2, single-centre, single-arm, open-label trial. A total of 18 patients with ALMS will be enrolled to receive PBI-4050 at a total daily oral dose of 800 mg for an initial 24 weeks with continuation for an additional 36 or 48 weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests. This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality. The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217 , February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015–001625-16, Sept 2015).

Multiply-Add Fused (MAF) units play a key role in the processor׳s performance for a variety of applications. The objective of this paper is to present a multi-functional, multiple precision floating-point Multiply-Add Fused (MAF) unit. The proposed MAF is reconfigurable and able to execute a quadruple precision MAF instruction, or two double precision instructions, or four single precision instructions in parallel. The MAF architecture features a dual-path organization reducing the latency of the floating-point add (FADD) instruction and utilizes the minimum number of operating components to keep the area low. The proposed MAF design was implemented on a 65 nm silicon process achieving a maximum operating frequency of 293.5 MHz at 381 mW power.

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future. The global incidence of GDM is difficult to estimate, due to lack of uniform diagnostic criteria. Various diagnostic criteria have been proposed. The benefit of treating GDM has also been controversial. The clinical significance of treating maternal hyperglycemia was made evident in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. The HAPO study demonstrated that there is a continuous association of maternal glucose levels with adverse pregnancy outcomes and served as the basis for a new set of diagnostic criteria, proposed in 2010 by the International Association of Diabetes and Pregnancy Groups (IADPSG). According to these criteria the diagnosis of GDM is made if there is at least one abnormal value (≥92, 180 and 153 mg/dl for fasting, one-hour and two-hour plasma glucose concentration respectively), after a 75 g oral glucose tolerance test (OGTT).

A new tracking system is under development for operation in the CMS experiment at the High Luminosity LHC. It includes an outer tracker which will construct stubs, built by correlating clusters in two closely spaced sensor layers for the rejection of hits from low transverse momentum tracks, and transmit them off-detector at 40 MHz. If tracker data is to contribute to keeping the Level-1 trigger rate at around 750 kHz under increased luminosity, a crucial component of the upgrade will be the ability to identify tracks with transverse momentum above 3 GeV/c by building tracks out of stubs. A concept for an FPGA-based track finder using a fully time-multiplexed architecture is presented, where track candidates are identified using a projective binning algorithm based on the Hough Transform. A hardware system based on the MP7 MicroTCA processing card has been assembled, demonstrating a realistic slice of the track finder in order to help gauge the performance and requirements for a full system. This paper outlines the system architecture and algorithms employed, highlighting some of the first results from the hardware demonstrator and discusses the prospects and performance of the completed track finder.

Adipose tissue blood flow (ATBF) is an important determinant of adipose tissue (AT) function. 133Xenon wash-out technique is considered the gold-standard for human ATBF measurements. However, decreasing 133Xenon clinical use and costly production and preservation, make alternative (non-invasive) methods necessary. Here, we explored percutaneous Doppler ultrasound as a proxy method to quantify intravascular subcutaneous abdominal and femoral ATBF in humans (n= 17). Both fasting ATBF and the postprandial increase in ATBF were significantly higher in abdominal compared to femoral AT. Although anatomical variations in vein location and depot thickness may impact feasibility, we demonstrate that Doppler ultrasound detects the expected depot-differences and postprandial increase in ATBF in healthy individuals. This method warrants further investigation in other populations and metabolic conditions.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive syndromic obesity of childhood onset among many other features. To date, the excess risk of metabolic complications of severe early-onset obesity in BBS remains controversial. In-depth investigation of adipose tissue structure and function with detailed metabolic phenotype has not been investigated yet.To investigate adipose tissue function in BBS.A prospective cross-sectional study.To determine if there are differences in insulin resistance, metabolic profile, adipose tissue function and gene expression in patients with BBS compared to BMI-matched polygenic obese controls.9 adults with BBS and 10 controls were recruited from the national centre for BBS, Birmingham, UK. An in-depth study of adipose tissue structure and function along with insulin sensitivity was performed using hyperinsulinemic-euglycemic clamp studies, adipose tissue microdialysis, histology and RNA sequencing, and measurement of circulating adipokines and inflammatory biomarkers.Adipose tissue structure, gene expression and in vivo functional analysis between BBS and polygenic obesity cohorts were similar. Using hyperinsulinemic-euglycemic clamp and surrogate markers of insulin resistance, we found no significant differences in insulin sensitivity between BBS and obese controls. Furthermore, no significant changes were noted in an array of adipokines, cytokines, pro-inflammatory markers and adipose tissue RNA transcriptomic.Although childhood-onset extreme obesity is a feature of BBS, detailed studies of insulin sensitivity and adipose tissue structure and function are similar to common polygenic obesity. This study adds to the literature by suggesting that it is the quality and quantity of adiposity not the duration that drives the metabolic phenotype.

This pilot study aimed to compare the effects of eight weeks of concurrent resistance training (RT) and high-intensity interval training (HIIT) vs. RT alone on muscle performance, mass and quality in adults with type 2 diabetes (T2DM). Twelve T2DM adults were randomly allocated to the RT + HIIT (n = 5) or RT (n = 7) group. Before and after training, maximal oxygen uptake (VO2max), muscle strength and power were evaluated by calorimetry, dynamometry and one-repetition maximum (1RM) test. Quadriceps muscle volume was determined by MRI, and muscle quality was estimated. After RT, VO2max (+12%), knee muscle power (+20%), quadriceps muscle volume (+5.9%) and quality (leg extension, +65.4%; leg step-up, +223%) and 1RM at leg extension (+66.4%), leg step-up (+267%), lat pulldown (+60.9%) and chest press (+61.2%) significantly increased. The RT + HIIT group improved on VO2max (+27%), muscle volume (+6%), muscle power (+9%) and 1RM at lat pulldown (+47%). No other differences were detected. Among groups, changes in muscle quality at leg step-up and leg extension and VO2max were significantly different. The combination of RT and HIIT effectively improves muscle function and size and increases cardiorespiratory fitness in adults with T2DM. However, HIIT combined with RT may interfere with the development of muscle quality.

Abstract Context: Glucocorticoids have pleiotropic metabolic functions, and acute glucocorticoid excess affects fatty acid metabolism, increasing systemic lipolysis. Whether glucocorticoids exert adipose tissue depot-specific effects remains unclear. Objective: To provide an in vivo assessment of femoral and abdominal adipose tissue responses to acute glucocorticoid administration. Design and Outcome Measures: Nine healthy male volunteers were studied on two occasions, after a hydrocortisone infusion (0.2 mg/kg/min for 14 hours) and a saline infusion, respectively, given in randomized double-blind order. The subjects were studied in the fasting state and after a 75-g glucose drink with an in vivo assessment of femoral adipose tissue blood flow (ATBF) using radioactive xenon washout and of lipolysis and glucose uptake using the arteriovenous difference technique. In a separate study (same infusion design), eight additional healthy male subjects underwent assessment of fasting abdominal ATBF and lipolysis only. Lipolysis was assessed as the net release of nonesterified fatty acids (NEFAs) from femoral and abdominal subcutaneous adipose tissue. Results: Acute hypercortisolemia significantly increased basal and postprandial ATBF in femoral adipose tissue, but the femoral net NEFA release did not change. In abdominal adipose tissue, hypercortisolemia induced substantial increases in basal ATBF and NEFA release. Conclusions: Acute hypercortisolemia induces differential lipolysis and ATBF responses in abdominal and femoral adipose tissue, suggesting depot-specific glucocorticoid effects. Abdominal, but not femoral, adipose tissue contributes to the hypercortisolemia-induced systemic NEFA increase, with likely contributions from other adipose tissue sources and intravascular triglyceride hydrolysis.

SUMMARY NAD + is modulated by conditions of metabolic stress and has been reported to decline with aging, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD + metabolome, and questioned if tissue NAD + levels are depressed with aging. We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD + metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways. NR also depressed levels of circulating inflammatory cytokines. In an additional study, 31 P magnetic resonance spectroscopy-based NAD + measurement in muscle and brain showed no difference between young and aged individuals. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD + decline is not associated with chronological aging per se in human muscle or brain.

An apple-shaped fat distribution is associated with an adverse cardiometabolic phenotype. Hypercortisolaemia (Cushing's syndrome) is characterised by abdominal fat accumulation and gluteofemoral fat loss. The mechanisms underpinning this redistribution of fat mass are unknown. Since adipose tissue blood flow (ATBF) is an important determinant of lipolytic rate in vivo, we hypothesised that hypercortisolaemia might lead to differential abdominal and femoral ATBF.Six healthy male volunteers (median age 25 years [IQR 20-50], median body-mass index 27·0 kg/m(2) [24·4-29·1]) were recruited. Abdominal and femoral ATBF were studied in vivo by use of the radioactive xenon washout technique after a hydrocortisone infusion (2 mg/kg per min for 16 h) or saline (control). Infusions were given in a randomised double-blind manner. On each of 2 study days ATBF was studied in the fasting state and after a 75 g glucose drink.Under control conditions, there was no difference between fasting or postprandial abdominal and femoral ATBF. Hypercortisolaemia increased fasting femoral ATBF (time-averaged area under the curve, from a median of 1·6 mL/min per 100 g tissue [IQR 1·2-4·4] to 4·3 [2·7-5·9], Wilcoxon signed rank test p=0·08), increased postprandial femoral ATBF (2·4 [1·6-4·0] to 6·9 [3·4-8·7], p=0·046), increased abdominal fasting ATBF (2·2 [1·8-6·2] to 3·0 [1·7-7·5], p=0·465), and increased abdominal postprandial ATBF (3·5 [1·9-4·2] to 4·7 [2·1-9·0], p=0·225). Total ATBF time-averaged area under the curve response to hypercortisolaemia showed a strong negative correlation with waist to hip ratio (Spearman's r abdomen -0·986, p<0·0001; femoral -0·928, p=0·008).We showed that hypercortisolaemia increases ATBF, most strikingly in the gluteofemoral depot, an effect further augmented in the postprandial state. This finding might point to depot specificity of glucocorticoid responses and insulin interactions. Depot-specific responses might lead to differential fatty acid fluxes in the abdominal and gluteofemoral depot, resulting in the fat distribution changes associated with Cushing's syndrome.Society for Endocrinology, Wellcome Trust Institutional Strategic Support Fund.

High performance VLSI-based FFT architectures are key to signal processing and telecommunication systems since they meet the hard real-time constraints at low silicon area and low power compared to CPU-based solutions. In order to meet these goals, this paper presents a novel VLSI FFT architecture based on combining three consecutive radix-4 stages to result in a 64-point FFT engine. Cascading these 64-point FFT engines consequences an improved architecture design featuring certain characteristics. First, it can efficiently accommodate large input data sets in real time. It also simplifies processing requirements due to the radix-4 calculations. Finally, it reduces memory requirements and latency to one third compared to the fully unfolded radix-4 architecture. Two different implementations are utilized in order to validate the architecture efficiency: a FPGA implementation of a 4096-point FFT achieving a throughput of 4096 point/20.48 usec, and a VLSI implementation sustaining a throughput of 4096 point/3.89 usec.

This work presents a detailed case study in customizing a configurable, extensible, 32-bit RISC processor with vector/SIMD instruction extensions for the efficient execution of block-based video-coding algorithms utilizing a proprietary co-design environment. In addition to the default Full-Search motion estimation of the MPEG-2 Test Model 5, fourteen fast ME algorithms were implemented in both scalar and vector form. Results demonstrate a reduction of up to 68% in the dynamic instruction count of the full search-based encoder whereas the fast motion estimation algorithms achieved a reduction in instruction count of nearly 90%, both accelerated via three 128-bit vector/SIMD instructions when compared to the scalar, reference implementation of the standard. We address in detail the profiling, vectorization and the development of these vector instruction set extensions, discuss in depth the implementation of a parametric vector accelerator that implements these instructions and show the introduction of that accelerator into a 32-bit RISC processor pipeline, in a closely-coupled configuration.

Recent evidence indicates that adipose tissue macrophages and lymphocytes have a major role in the pathophysiology of obesity. The arterio-venous (A–V) difference technique has been used very effectively to understand adipose tissue metabolism in humans in vivo, and we set out to investigate whether it is possible to apply and use this technique to determine A–V differences for peripheral blood mononuclear cells (PBMCs) across human adipose tissue. We used flow-cytometric analysis of arterial blood and venous blood draining upper- (abdominal) and lower-body (femoral) adipose tissue depots in middle-aged volunteers (age 45±8 years, BMI 25.9±4.1 kg m−2). We determined A–V differences for various PBMCs. In basal conditions, there was evidence of modest retention of some PBMCs in adipose tissue, whereas the infusion of low-dose (physiological) adrenaline led to a marked release of many PBMCs (with little evidence of depot-specific differences). In addition to the demonstration that this approach is technically feasible, these results also indicate that physiological stimuli that change adrenaline concentrations and/or adipose tissue blood flow (such as physical activity) provoke the release of PBMCs from femoral and abdominal adipose depots.

Targeting to improving the efficiency of real-time Fourier transform computations with large input data sets, this paper presents the design and the VLSI implementation of 16 K, 64 K and 265 K complex points fast Fourier transform (FFT) systolic architectures. These organizations are deeply pipelined to maximize the operating frequency and follow the approach of decomposing the transforms into 64 -point FFT computations to minimize the buffer size between consecutive stages. The resulting organizations achieve real time performance on testing and observation applications. They include simple processing elements and they are scalable with respect to the operating frequency and data width. Validation on FPGA showed operation at 250 MHz and 125 MHz for the 16 K and the 64 K architectures with throughput lGs/s and 500 Ms/s respectively. The VLSI implementations of the proposed 16 K, 64 K and 265 K architectures achieve post-route clock frequencies of 352, 256.5, and 188 MHz respectively and they can sustain throughputs of 1.4 Gs/s, lGs/s and 188 Ms/s.

A readout system suitable for a large number of synchronized photo-detection units has been designed. Each unit embeds a specifically designed fully integrated communicating system based on Xilinx FPGA SoC technology. It runs the VxWorks real-time OS and a custom data acquisition software designed within the Ice middleware framework, resulting in a highly flexible, controllable and scalable distributed application. Clock distribution and delay calibration over customized fixed latency gigabit Ethernet links enable synchronous time-stamping of events with nanosecond precision. The implementation of this readout system on several data-collecting units as well as its performances are described.

Abstract Background The female fat distribution pattern of gluteofemoral fat mass accumulation is associated with protection from cardiovascular disease and diabetes. Furthermore, women are known to have higher systemic leptin concentrations than men. Differential adipokine secretion from subcutaneous adipose tissue depots may be responsible for these differences. We aimed to study the physiological release of leptin and interleukin (IL) 6, a pro-inflammatory adipokine, from abdominal and femoral adipose tissue in vivo. Methods Depot-specific leptin and IL-6 release were measured in 42 healthy volunteers (23 men and 19 women), matched for age and body-mass index (mean 25·4 kg/m 2 ). Measurements were carried out after an overnight fast. Leptin and IL-6 release were studied with the arteriovenous difference technique across abdominal and femoral adipose tissue. Findings Leptin release showed a strong sex dichotomy with 3·5-fold higher systemic plasma concentrations (p r =0·54, p Interpretation Adipose tissue is characterised by differential adipokine secretion between sexes and subcutaneous fat depots. The widely observed higher systemic leptin concentration in women is a result of a high leptin production rate and large gluteofemoral fat mass compared with men. Femoral adipose tissue is characterised by a lower IL-6 release rate, which may suggest that gluteofemoral fat is resistant to low-grade inflammation. Funding Higher Education Funding Council for England.

KM3NeT is a deep-sea neutrino telescope of very large scale (several km3) to be deployed and operated in the Mediterranean Sea. Neutrino-induced charged particles are detected by measuring their Cherenkov light in sea-water, using Photomultiplier Tubes inside transparent, pressure resistant spherical enclosures. The aim is to instrument several km3 of sea volume with tens of thousands of optical sensors, connected to the shore through electro-optical cables up to 100km. The KM3NeT collaboration has successfully developed an optical sensor, the Digital Optical Module, by placing 31, 3-inch Photomultiplier Tubes in a 17-inch glass sphere along with the readout electronics. Each Digital Optical Module is supplied power through a high voltage (400VDC) line, converted to low voltage (12VDC) in a breakout box before entering the Digital Optical Module. The Power Converter Board, situated inside the Digital Optical Module, is used to produce seven voltage rails as required by the Digital Optical Module electronic modules. This paper summarizes the design considerations and implementation of the Power Converter Board and the results of the trial runs so far. Technology and Instrumentation in Particle Physics 2014, 2-6 June, 2014 Amsterdam, the Netherlands

The Compact Muon Solenoid (CMS) experiment at CERN is scheduled for a major upgrade in the next decade in order to meet the demands of the new High Luminosity Large Hadron Collider.Amongst others, a new tracking system is under development including an outer tracker capable of rejecting low transverse momentum particles by looking at the coincidences of hits (stubs) in two closely spaced sensor layers in the same tracker module.Accepted stubs are transmitted off-detector for further processing at 40 MHz.In order to maintain under the increased luminosity the Level-1 trigger rate at 750 kHz, tracker data need to be included in the decision making process.For this purpose, a system architecture has to be developed that will be able to identify particles with transverse momentum above 3 GeV/c by building tracks out of stubs, while achieving an overall processing latency of maximum 4us.Targeting these requirements the current paper presents an FPGA-based track finding architecture that identifies track candidates in real-time and bases its functionality on a fully time-multiplexed approach.As a proof of concept, a hardware system has been assembled targeting the MP7 MicroTCA processing card that features a Xilinx Virtex-7 FPGA, demonstrating a realistic slice of the track finder.The paper discusses the algorithms' implementation and the efficient utilisation of the available FPGA resources, it outlines the system architecture, and presents some of the hardware demonstrator results.

Abstract Study question Is it feasible to carry out a large-scale multi-national Assisted Reproductive Technology Real World Data (RWD) collection prospectively, encompassing collected patient and treatment cycle information? Summary answer The creation of an international database collecting RWD is feasible. The quality and quantity of the data allow them to be used for research purposes. What is known already Real World Evidence (RWE) may help to answer clinical research questions that are relevant to a broad population of patients. For 40 years, Assisted Reproductive Technology (ART) treatment cycle data have been collected in national registries. The aggregated national data are further collated on an international level. These data are useful for describing secular trends in ART utilization and associated outcomes. However, registries often fall short in providing patient-level and treatment-cycle-level information for data collation and analysis. Furthermore, national registries may restrict access of raw data for open research, for political, infrastructural, or legal reasons. Study design, size, duration In a first phase, the OPERA database (Observational retrospective ProjEct for a Research database for ART procedures) included data from cycles recorded between January 2016 and December 2020 in eighteen clinics, providing a robust sample size for Real World Data analyses. Fondazione per la Ricerca Ospedale di Bergamo (FROM), together with expert clinicians in the ART field, promoted the OPERA project with the financial support from two pharmaceutical companies (Merck KGaA, IBSA SA). Participants/materials, setting, methods The Eighteen clinics located in Germany and Italy joining the OPERA data collection, have proven expertise in ART procedures and use MedITEX® DB. The study protocol was reviewed by the competent Ethic Committees and Data Protection Officers. Among the outcomes collected were the mean number of cycles, the pregnancy and birth rate per Embryo Transfer, and the pregnancy and birth rates as a function of female age. The first extraction was scheduled for December 2022. Main results and the role of chance Around 75,000 ART cycles were collected from the first ten participating centers. Among the around 45,000 cycles that have available fertilization information , 11,553 (25.7%) were the In-Vitro Fertilization treatments (IVF), 31,202 (69.3%) Intracytoplasmic Sperm Injection treatments (ICSI), and 2,282 (5.1%) a combination of the two techniques. Of the adopted stimulation protocols, 38.43% (10,538) of the total were with variable antagonists, 31.27% (8,574) were with a single antagonist, 24.31% (6,665) were with a long agonist, 5.51% (1,511) were with a short agonist, and 0.35% (96) were with fixed antagonists. The average number of oocytes retrieved is 11.28, with a median of 10.0. The average number of 2 Pronuclear Oocytes (2PN) obtained is 3.7, with a median of 3.0. Moreover, the average number of 8 cell embryos at day 3 is 2.0, with a median of 2.0. It was also recorded the rate of unsuccessful cycles with no oocytes retrieved (4.8%). Among the cycles collected, 2.9% of the total were from frozen oocytes. Most of the ET (40.0%) were performed 5 days after the oocyte retrieval. Limitations, reasons for caution Amassing ART cycle information does not compensate for the well-known insufficiencies of primary data quality, of information on confounders and of access to patient level data. Moreover, the technical risk of this project is the potential loss of participant confidentiality, mitigated through a full anonymization. Wider implications of the findings The OPERA project may facilitate the transition of ART surveillance from a national aggregate level to a large-scale individual patient and treatment cycle level. Furthermore, as an evolutionary path, the OPERA project may help building large and longitudinal databases, suitable for appropriate epidemiological research in ART. Trial registration number not applicable

Abstract Disclosure: C.S. Pan: None. E. Melson: None. T. Ogiliev: None. D. Zhou: None. S.Y. Ng: None. F. Rezai: None. Z. Olateju: None. E. Radcliffe: None. P. Balendran: None. A. Radcliffe: None. G.M. Lau: None. J. Sheikh: None. H. Kaur: None. C. Cooper: None. F. Abdelhameed: None. F. Pang: None. S. Bhatt: None. D. Shabbir: None. M. Davitadze: None. A. Prete: None. C.L. Ronchi: None. I. Bancos: None. V. Chortis: None. J.D. Newell-Price: None. H.L. Simpson: None. H. Gleeson: None. K. Manolopoulos: None. J. Chu: None. M.W. O'Reilly: None. W. Arlt: None. C. Gillett: None. P. Kempegowda: None. O. SIMBA team: None. Introduction: Simulation via Instant Messaging - Birmingham Advance (SIMBA) is an effective educational platform in increasing clinicians’ confidence in managing various endocrine conditions (Melson, 2020). However, it has lacked input from the patients living with these conditions. We hypothesize that engaging patients and members of the public can inform clinicians to better tailor management to suit the concerns and expectations of patients. Methods: Two virtual simulation sessions covering topics related to Polycystic Ovary Syndrome (PPI-PCOS) and Adrenal conditions (PPI-Adrenal) were organized for clinicians. Nine cases were simulated using anonymized real-life patient data. Members of the general public living with PCOS or Adrenal conditions were recruited from several support groups to undergo a workshop-style discussion to provide their opinions on how representative the cases were and how the management of the condition could be improved. At the end of the simulations, all clinicians and patients were invited to a panel discussion led by expert consultants over Zoom incorporating the summaries from the workshops. Pre- and post-simulation surveys were distributed to measure the change in clinicians’ confidence using Wilcoxon signed-rank test. Thematic analysis was used to identify gaps in knowledge and expectations between clinicians and patients with PCOS or Adrenal conditions. Results: Self-reported confidence by clinicians in the management of PCOS (n=25) and Adrenal conditions (n=23) increased post-simulation (PPI-PCOS simulated:+41.0%, p&amp;lt;0.001; non-simulated:+40.0%, p&amp;lt;0.001. PPI-Adrenal simulated:+22.5% (p=0.0001); non-simulated:+24.0% (p=0.0005)). 90% and 100% of patients agreed PPI-PCOS benefits patients to understand their condition better, and helps clinicians and patients understand each other’s perspectives respectively, whereas this is true for 80% of patients from PPI-Adrenal regarding both aspects. Recurring themes identified through thematic analysis included approach to handling complexities resulting in delayed diagnosis or management, the need for personalized care, lack of information provided to patients with regards to the progression of symptoms, complications or treatment received. Conclusion: PPI-PCOS and PPI-Adrenal were effective in increasing the knowledge and understanding of PCOS and Adrenal conditions for both members of the general public and healthcare professionals. They also helped narrow the gap in knowledge and expectations by exchanging perspectives through a common dialogue. Presentation: Thursday, June 15, 2023

We would like to draw attention to circumstances that could explain the absence of a functional genetic effect of the ADRB2 Arg16Gly polymorphism in the LARGE trial (Nov 21, p 1754).1Wechsler ME Kunselman SJ Chinchilli VM et al.Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial.Lancet. 2009; 374: 1754-1764Summary Full Text Full Text PDF PubMed Scopus (204) Google Scholar The ADRB2 gene is highly polymorphic and several single nucleotide polymorphisms (SNPs) are known to affect β2-receptor affinity, signal transduction, and cellular trafficking in vitro.2Green SA Turki J Innis M Liggett SB Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties.Biochemistry. 1994; 33: 9414-9419Crossref PubMed Scopus (717) Google Scholar, 3Green SA Cole G Jacinto M Innis M Liggett SB A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor.J Biol Chem. 1993; 268: 23116-23121Summary Full Text PDF PubMed Google Scholar The synergistic effect of SNPs in haplotypic combination is linked with the striking differences in the physiology of β2 adrenoreceptors in vivo.4Drysdale CM McGraw DW Stack CB et al.Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness.Proc Natl Acad Sci USA. 2000; 97: 10483-10488Crossref PubMed Scopus (905) Google Scholar The haplotype structure is straightforward in the ADRB2 gene, where three common haplotypes are seen (arbitrarily named 2, 4, and 6). The ADRB2 haplotypes are associated with differential β2-adrenoreceptor sensitivity, as shown in bronchodilation response and in lipolytic regulation.4Drysdale CM McGraw DW Stack CB et al.Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness.Proc Natl Acad Sci USA. 2000; 97: 10483-10488Crossref PubMed Scopus (905) Google Scholar, 5Eriksson P Dahlman I Ryden M Hoffstedt J Arner P Relationship between beta-2 adrenoceptor gene haplotypes and adipocyte lipolysis in women.Int J Obes. 2004; 28: 185-190Google Scholar Although the ADRB2 Arg16Gly SNP is likely to be functional (differences in β2-adrenoreceptor trafficking resulting in differential agonist-promoted downregulation of the receptor have been seen),2Green SA Turki J Innis M Liggett SB Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties.Biochemistry. 1994; 33: 9414-9419Crossref PubMed Scopus (717) Google Scholar, 4Drysdale CM McGraw DW Stack CB et al.Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness.Proc Natl Acad Sci USA. 2000; 97: 10483-10488Crossref PubMed Scopus (905) Google Scholar it is shared between the 2 and 4 ADRB2 haplotypes, each of which contains unique and putatively functional variants in their own right. The participants in the LARGE trial were recruited according to ADRB2 Arg16Gly carrier status. In white people, the Arg versus Gly stratification leads to the pooling of carriers of haplotypes 2 (associated with normal receptor sensitivity) and 6 (increased receptor sensitivity). In African-Americans, who make up 20% of the LARGE study population, haplotype 6 is more common than is haplotype 2. In summary, the absence of effect seen in the LARGE trial, and the conflicting results often reported in relation to ADRB2 SNPs, could be explained by lack of recognition of the importance of the ADRB2 haplotypes in β2-adrenoreceptor function. We declare that we have no conflicts of interest. ADRB2 Arg16Gly polymorphism in the LARGE trial – Authors' replyA pharmacogenomic effect was seen in the LARGE trial: by contrast with B16 Gly/Gly patients, B16 Arg/Arg patients treated with salmeterol in LARGE did not have better methacholine responsiveness than did those on placebo. Although we agree that differences in haplotype may have a role in determining phenotypic differences between individuals, the lack of genotype-specific effect on morning peak expiratory flow in our white population—by contrast with previous studies1,2—was unlikely to be due to haplotypic differences, since about 94% of white Arg/Arg are in haplotype 4. Full-Text PDF

Abstract Context Pre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness. We hypothesised that in men with overweight/obesity, acute exercise before versus after nutrient ingestion would increase whole-body and intramuscular lipid utilization, translating into greater increases in oral glucose insulin sensitivity over 6-weeks of training. Design and Participants We showed in men with overweight/obesity (mean±SD for BMI: 30.2±3.5 kg×m -2 for acute, crossover study, 30.9±4.5 kg×m -2 for randomized, controlled, training study) a single exercise bout before versus after nutrient provision increased lipid utilisation at the whole-body level, but also in both type I ( p&lt; 0.01) and type II muscle fibres ( p= 0.02). We then used a 6-week training intervention to show sustained, 2-fold increases in lipid utilisation with exercise before versus after nutrient provision ( p&lt; 0.01). Main Outcome Measures Postprandial glycemia was not differentially affected by exercise training before vs after nutrient provision ( p&gt; 0.05), yet plasma was reduced with exercise training before, but not after nutrient provision ( p= 0.03), resulting in increased oral glucose insulin sensitivity when training was performed before versus after nutrient provision (25±38 vs −21±32 mL×min -1 ×m -2 ; p= 0.01) and this was associated with increased lipid utilisation during exercise ( r =0.50, p= 0.02). Regular exercise prior to nutrient provision augmented remodelling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 ( p&lt; 0.05). Conclusions Experiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (i.e., in the fasted state) may exert beneficial effects on lipid utilisation and reduce postprandial insulinemia. Précis Exercise in the fasted- versus fed-state increased intramuscular and whole-body lipid use, translating into increased muscle adaptation and insulin sensitivity when regularly performed over 6 weeks.

The CMS collaboration is preparing a major upgrade of its detector, so it can operate during the high luminosity run of the LHC from 2026. The upgraded tracker electronics will reconstruct the trajectories of charged particles within a latency of a few microseconds, so that they can be used by the level-1 trigger. An emulation framework, CIDAF, has been developed to provide a reference for a proposed FPGA-based implementation of this track finder, which employs a Time-Multiplexed (TM) technique for data processing.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The "metabolic syndrome" consists of some common risk factors for cardiovascular diseases: central obesity, diabetes mellitus, hyperlipidaemia and hypertension. The metabolic syndrome (MTS) leads to increased morbidity and mortality and to higher direct and indirect healthcare costs. The MTS can be diagnosed using the NCEP/ATP III criteria. The prevalence of the MTS in Germany is estimated at 23.8% and is expected to rise further, due to increasing obesity among children and adolescents. Studies have shown that the MTS leads to increased cardiovascular and total mortality and thus to a decreased life expectancy. Studies estimating the total costs of MTS are missing, but after addition of the costs for all the risk factors it is assumed that MTS costs amount to 5% of total healthcare costs. This is the result of the more frequent demand of health services and longer hospitalisation of patients with MTS. Even moderate weight loss can decrease the rates of morbidity and healthcare costs.

The KM3NeT readout concept is based on a point-to-point optical network connecting the 10,000 optical modules in the deep-sea neutrino telescope with the shore station. The numerous fiber optic channels arriving at the shore station will be concentrated on the shore electronics systems, which will receive, merge and time order the data, and send them to the DAQ system. Although the network functionality is bi-directional, the physical channel allocation is asymmetric; most channels are assigned to the data reception and only a few channels are used for control with data transport from shore to the telescope. We will discuss the FPGA based platform systems for the shore station and the appropriate firmware implementation for the data gathering and broadcast demands of a neutrino telescope. We will present our experiences based on FPGA evaluation platforms suitable to build a demonstrator of the KM3NeT shore station.

In the KM3NeT neutrino telescope design the readout concept is based on a point-to-point network connecting tenthousands of optical modules in the deep sea through a photonic network with the shore station. The time-over-threshold data from each Photo Multiplier Tube (PMT) of each optical module will be send to shore over fibres using dedicated wavelengths. Nanosecond timing accuracy will be schieved using a clock signal embedded in the data stream and measuring the roundtrip time from the shore to each optical module individually. The DAQ software architecture based on the Internet Communications Engine (ICE) will provide a common and uniform software framework for the control of each optical module and the data acquisition of the whole neutrino telescope.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

University of Oxford (K.N.M.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford OX3 7LJ, United Kingdom; Medizinische Klinik und Poliklinik III (A.B.), Technische Universitat Dresden, Universitatsklinikum Carl Gustav Carus, 01307 Dresden, Germany; Endokrinologikum Ruhr (A.B.), Alter Markt 4, 44866 Bochum, Germany; and University of Bochum, University Hospital Bergmannsheil, Departments of Radiology (V.N.) and Internal Medicine, Diabetology and Endocrinology (K.N.M., H.H.K., S.H.), 44789 Bochum, Germany

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The efficiency of fused multiply add units plays a key role in the processor's performance for a variety of applications. A design keeping the advantages of the FMA regarding the latency and the hardware utilization and also improving the result's accuracy in both normalized and denormalized numbers is the subject of this work. The FMA unit has configurable latency and it is integrated in a VLIW processor. The VLSI TSMC 0.13 implementation achieved an operating frequency of 232.6 MHz and a final post-routed area of 121900.478 um <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> .

The aim of the present work was to assess the acute and chronic effects of manipulating nutrient-exercise timing on lipid metabolism, skeletal muscle adaptation, and oral glucose insulin sensitivity in overweight and obese men. This project comprised two experiments. We first assessed the acute metabolic and mRNA responses to manipulating nutrient-exercise timing (Acute Study), followed by a 6-week randomized controlled trial to assess the longer-term adaptations in response to nutrient-exercise timing (Training Study). We showed that in overweight/obese, but otherwise healthy men (mean±SD for age: 30 ± 10 years for acute study, 35 ± 9 years for training study and BMI: 30.2±3.5 kg/m-2 for acute study, 30.9±4.5 kg/m-2 for training study) a single exercise bout before versus after nutrient provision increased lipid utilization at the whole-body level, but also in both type I (p<0.01) and type II muscle fibers (p=0.02). We then used a 6-week intervention to show sustained, 2-fold increases in lipid utilization with exercise training before versus after nutrient provision (p<0.01). An oral glucose-derived estimate of peripheral insulin sensitivity (OGIS index) increased when training was performed before versus after nutrient provision (25±38 vs -21±32 mL/min/m-2; p=0.01) and this was associated with increased lipid utilization during exercise (r=0.50, p=0.02). Regular exercise prior to nutrient provision augmented remodelling of skeletal muscle phospholipids and muscle expression of the glucose transport protein GLUT4 (p<0.05). These responses were observed despite similar changes in body mass, waist-to-hip ratio, and oxidative capacity. Therefore: 1) experiments investigating exercise training and metabolic health need to control for nutrient-exercise timing; 2) exercise performed before versus after nutrient intake may exert beneficial effects on lipid utilization and oral glucose insulin sensitivity.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

GRBNeT is a Gamma Ray Burst Neutrino Telescope made of autonomously operated arrays of deep-sea light detectors, anchored to the sea-bed without any cabled connection to the shore. This paper presents the digital and analog electronics that we have designed and developed for the GRBNeT prototype. We describe the requirements for these electronics and present their design and functionality. We present low-power analog electronics for the PMTs utilized in the GRBNeT prototype and the FPGA based digital system for data selection and storage. We conclude with preliminary performance measurements of the electronics systems for the GRBNeT prototype.

GRBNeT is a project aiming at the detection of ultra–high energy neutrinos, for example neutrinos originating from Gamma Ray Bursts. The goal is to design, construct and deploy a prototype unit of an autonomous (data/energy–wise) neutrino detector. Being autonomous is crucial since for the detection of ultra–high energy neutrinos a very large volume of water is required. Large scale facilities such as IceCube and KM3NeT are designed to be more sensitive to galactic and diffuse flux neutrinos rather than extragalactic ultra–high energy neutrinos. However, their sensitivity to such neutrinos could be increased by placing around and at larger distances detectors such as the one of the GRBNeT project. This extension would increase the instrumented volume of neutrino telescopes to several cubic kilometres. In addition to that, as no cable connection to the shore is required, GRBNeT detection units cost significantly less than regular detection units and can become a cost effective extension of large scale facilities. For the GRBNeT prototype unit ultra low power electronics have been developed. The response to high energy neutrinos from GRBs and to the atmospheric muon background has been simulated.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

ResultsISO infusion resulted in significant ß-adrenergic mediated increases in heart rate (47 ±4 bpm) peaking at 45 min (Figure 2a).ISO infusion resulted in a highly localized increase in local temperature within the supraclavicular region compared to baseline (Δ 0.54 ±0.08°C, P=0.001 [Figure 2c,d]) HC resulted in a lesser increase in BAT temperature during ISO infusion (Δ 0.51 ± 0.09°C, P=0.01 [Figure 2c,d]).Further, basal BAT temperature is increased in HC compared to saline (Figure 2b). Conclusionsß-adrenergic stimulation induced dynamic changes in BAT activity that was measurable by IT.This confirms IT as a simple, noninvasive method for assessment of real-time BAT function.Acute hypercortisolaemia resulted in blunting of the adrenergicmediated increase in BAT activity, possibly due to glucocorticoiddependent BAT pre-activation.Future studies should focus on the effects of chronic glucocorticoid excess on human BAT function, and whether tissue-specific inhibition of glucocorticoid activity/generation can contribute to increased BAT thermogenesis.

The XG-PON standard for Passive Optical Networks (PONs) imposes requirements for high performance network equipment architectures.Especially, the 10G receiver of the ONU/ONT becomes quite demanding.The current paper proposes an efficient architecture for the synchronization and the calibration processing blocks of the ONU/ONT receiver.The proposed architecture process in parallel words of 64 bits and it achieves the calibration of the receiver in 2ms.The design uses fragments of 16 bits for comparison with the synchronization pattern (Psync) to improve the combination of hardware resource utilization and time response.This work verifies the performance of the design on a Xilinx Virtex 7.

A valuable functionality for sensor networks, distributed in large volumes is the capability to characterize and analyze the data traffic at wire speed and monitor the data prior to committing to permanent storage. As a demonstrator we use a reconfigurable hardware router for real-time monitoring of data before their transmission to further processing and storage. The reconfigurable hardware router is based on the NetFPGA platform. In this study we report on the hardware implementation to monitor web-based network applications and compare our results with a software based network analyzer.

The recent evolution of deep-sea observatories has provided the infrastructure for studying rare phenomena in astroparticle physics, extended phenomena in physical oceanography and environmental monitoring for climate modeling and civic alert systems. The observatories involve sets of sensors distributed in the deep-sea, which transmit data through Gbit electro-optical lines to a shore station for real-time processing. Each set of sensors communicates data and control with the shore station through a readout system. Targeting the improvement of the observatory, the current paper proposes a readout system with enhanced functionality, which includes the ability to reconfigure the communication channels, provide statistic measurements of the communicated data and efficient data filtering. The design of the architecture is suited for FPGA implementation and the instantiation on the Xilinx ML605 board validates the results.

Introduction: An increased gluteofemoral adipose tissue (AT) mass is associated with a protective cardiovascular and metabolic risk profile, and effective fatty acid retention in femoral AT has been proposed as a possible mechanism. Catecholamines are important regulators of AT lipolysis and blood flow (ATBF). The aim of the thesis was to investigate regional differences in the adrenergic regulation of fatty acid release and ATBF between abdominal and femoral AT in vivo . Furthermore, in vivo regional fatty acid trafficking was studied in a physiological setting over 24 h. Methods: Regional fatty acid trafficking, along with the measurement of ATBF, was studied with the arterio-venous difference technique and stable isotope tracers in healthy volunteers. Adrenergic agonists (isoprenaline, adrenaline) were infused either locally by microinfusion, or systemically. Local microinfusion of adrenoreceptor antagonists (propranolol, phentolamine) was used to characterize specific adrenoreceptor subtype effects. The trafficking of dietary fatty acids was studied over a 24 h period involving three meals containing stable isotope-labelled fatty acids along with intravenous infusions of another labelled fatty acid. Results: Femoral ATBF and lipolysis was less responsive to adrenergic stimulation with adrenaline compared to abdominal AT. This was due to increased femoral α-adrenoreceptor responsiveness. When studied over 24 h, femoral AT showed a lower lipolysis rate compared to abdominal AT, while dietary fatty acids were extracted more avidly by abdominal AT. Uptake of non-dietary fatty acids (derived from very-low-density lipoproteins or unbound non-esterified fatty acids) was comparable between abdominal and femoral AT. Conclusion: There are fundamental differences in response to adrenergic stimuli between abdominal and gluteofemoral tissues and the ability of femoral AT to trap non-dietary fatty acids may provide protection of other tissues from ectopic fatty acid deposition.

We thank Dr Janiszewski and Dr Kuk for their thoughtful comments.1 These comments highlight the complexity of the relationships between different fat depots and metabolic health. The protective effects of the gluteofemoral fat depot are independent of other body fat depots. However, in any cross-sectional study there are strong positive correlations between gluteofemoral fat mass and total and abdominal fat mass. For instance, in our own cohort of 1500 randomly selected healthy individuals, waist circumference is significantly correlated to hip circumference (r=0.79 in women, r=0.82 in men, P<0.001). Hence, the protective effects of gluteofemoral fat are only seen after appropriate statistical adjustment for other fat depots. In obese individuals, the deleterious effects of their increased waist circumference may override any protection that the gluteofemoral fat depot provides. Weight loss, as studied by Janiszewski et al.,1 results in the reduction of total fat mass, abdominal fat mass and, concomitantly, gluteofemoral fat mass. Thus, physiological gluteofemoral fat loss through diet and exercise is closely linked to the decrease in abdominal fat mass and its associated beneficial effects, and indeed in their study reductions in lower-body subcutaneous fat were not related to metabolic health improvements after adjustment for changes in other fat depots. In contrast, the isolated gluteofemoral fat mass loss observed in diseases like Cushing's syndrome and lipodystrophy is clearly associated with deleterious metabolic effects.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract Context Bardet–Biedl syndrome (BBS) is a rare autosomal recessive syndromic obesity of childhood onset among many other features. To date, the excess risk of metabolic complications of severe early-onset obesity in BBS remains controversial. In-depth investigation of adipose tissue structure and function in link with detailed metabolic phenotype has not been investigated yet. Objective To investigate adipose tissue function in BBS Design A prospective cross-sectional study. Main outcome measure To determine if there are differences in insulin resistance, metabolic profile, adipose tissue function and gene expression in patients with BBS compared to BMI-matched polygenic obese controls. Method 9 adults with BBS and 10 controls were recruited from the national centre for BBS, Birmingham, UK. An in-depth study of adipose tissue structure and function along with insulin sensitivity was performed using hyperinsulinemic-euglycemic clamp studies, adipose tissue microdialysis, histology and RNA sequencing, and measurement of circulating adipokines and inflammatory biomarkers. Results Adipose tissue structure, gene expression and in-vivo functional analysis between BBS and polygenic obesity cohorts were similar. Using hyperinsulinemic-euglycemic clamp and surrogate markers of insulin resistance, we found no significant differences in insulin sensitivity between BBS and obese controls. Furthermore, no significant changes were noted in an array of adipokines, cytokines and pro-inflammatory markers. Conclusion Although childhood-onset extreme obesity is a feature of BBS, detailed studies of insulin sensitivity and adipose tissue structure and function are similar to common polygenic obesity. This study adds to the literature by suggesting that it is the quality and quantity of adiposity not the duration that drives the metabolic phenotype.

This work focuses on speeding up MPEG-2 and MPEG-4 encoding by using thread parallelism for shared-memory, System-on-Chip (SoC) multiprocessors. Improving the performance of the MPEG encoders is shown by reducing the dynamic instruction count at multiple processor contexts and then mapping onto a configurable SoC multiprocessor. The resulting reduction in the dynamic instruction count of the parallelized MPEG-2 TM5 encoder for 32 processor contexts reaches a maximum of 95% and that of the MPEG-4 XViD a maximum of 83% for 16 processor contexts, both compared to the sequential encoder. To realize the parallelized encoders we present a configurable, N-way, extensible, bus-based, cache-coherent SoC multiprocessor, augmented with data-parallel coprocessors, and we give the VLSI implementation for the 2-way and 4-way configurations.

A new tracking detector is under development for use by the CMS experiment at the High-Luminosity LHC (HL-LHC).A crucial component of this upgrade will be the ability to reconstruct within a few microseconds all charged particle tracks with transverse momentum above 3 GeV, so they can be used in the Level-1 trigger decision.A concept for an FPGA-based track finder using a fully time-multiplexed architecture is presented, where track candidates are reconstructed using a projective binning algorithm based on the Hough Transform followed by a track fitting based on the linear regression technique.A hardware demonstrator using MP7 processing boards has been assembled to prove the entire system, from the output of the tracker readout boards to the reconstruction of tracks with fitted helix parameters.It successfully operates on one eighth of the tracker solid angle at a time, processing events taken at 40 MHz, each with up to 200 superimposed proton-proton interactions, whilst satisfying latency constraints.The demonstrated track-reconstruction system, the chosen architecture, the achievements to date and future options for such a system will be discussed.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

BACKGROUND: Adrenal incidentalomas (AI) are frequently associated with mild autonomous cortisol excess (MACE). The 1mg-dexamethasone suppression test (1mg-DST) differentiates MACE into MACE-1 (possible MACE; post-Dex cortisol 50-138 nmol/L) and MACE-2 (definitive MACE; post-Dex cortisol >138 nmol/L). MACE patients do not show clinically overt signs of hypercortisolism but are thought to carry a higher metabolic risk than nonfunctioning (NF) AIs. However, large-scale data about the metabolic impact of MACE are lacking. METHODS: We included 1208 patients with benign AIs and 1mg-DST results prospectively recruited as part of the ENSAT EURINE-ACT study. Clinical information and 24-h urines were available for all patients. Results of mass spectrometry-based urinary steroid profiling were compared to 162 healthy controls and 56 patients with overt adrenal Cushing’s syndrome (CUSH), using a sex- and age-adjusted linear regression model. RESULTS: MACE was found in 48% of adrenal incidentaloma patients (MACE-1 37%, MACE-2 11%), predominantly affecting women (NF 64%, MACE-1 67%, MACE-2 77%). MACE patients were significantly older than those with NF (p<0.001). MACE AIs were larger (median 32mm vs. 22mm in NF) and more often bilateral (31% vs. 17% in NF). The presence and grade of MACE were significantly linked to metabolic risk as assessed by prevalence of hypertension (NF 64%, MACE-1 75%, MACE-2 78%), type 2 diabetes (NF 20%, MACE-1 27%, MACE-2 30%), use of lipid-lowering medications (NF 40%, MACE-1 54%, MACE-2 52%), and osteopenia/osteoporosis (NF 37%, MACE-1 50%, MACE-2 56%) (all p<0.01 by Fisher’s exact test). Patients with MACE and type 2 diabetes more frequently required insulin treatment (31% vs. 15% in NF; p<0.01), and those with hypertension more often needed ≥3 medications (42% vs. 35% in NF; p<0.01). Urinary steroid metabolome analysis of MACE urines revealed a profile characterized by decreased androgen metabolites and increased glucocorticoid metabolites, resembling the profile of CUSH patients, with the latter also showing significantly increased mineralocorticoid precursor excretion (corticosterone and 11- deoxycorticosterone metabolites) (all p<0.001 vs. controls). CONCLUSIONS: MACE is highly prevalent in AIs and associated with an increased burden of metabolic co-morbidities. In addition, the similarities between the MACE and CUSH steroid metabolomes suggests that MACE is both a highly relevant clinical and biochemical entity.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)