Showing papers by "University of Lorraine published in 2021"

Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.

Abstract: Summary Background Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. Methods We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18–75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0–1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1–14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov ( NCT01804790 ) and is now complete. Findings Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4–61·6), 3-year disease-free survival rates were 76% (95% CI 69–81) in the neoadjuvant chemotherapy group and 69% (62–74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49–0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3–4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3–4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3–4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one ( Interpretation Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. Funding Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

Abstract: Background The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect ...

Towards the sustainable discovery and development of new antibiotics

Abstract: An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children.

Abstract: Importance Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown Objective To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C Design, Setting, and Participants Retrospective cohort study drawn from a national surveillance system with propensity score–matched analysis All cases with suspected MIS-C were reported to the French National Public Health Agency Confirmed MIS-C cases fulfilling the World Health Organization definition were included The study started on April 1, 2020, and follow-up ended on January 6, 2021 Exposures IVIG and methylprednisolone vs IVIG alone Main Outcomes and Measures The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit The primary analysis involved propensity score matching with a minimum caliper of 01 Results Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 86 years [interquartile range, 47 to 121]) Five children did not receive either treatment Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, −028 [95% CI, −048 to −008]; odds ratio [OR], 025 [95% CI, 009 to 070];P = 008) IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, −022 [95% CI, −040 to −004]; OR, 019 [95% CI, 006 to 061];P = 004), hemodynamic support (absolute risk difference, −017 [95% CI, −034 to −0004]; OR, 021 [95% CI, 006 to 076]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, −018 [95% CI, −035 to −001]; OR, 020 [95% CI, 006 to 066]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, −24 [95% CI, −40 to −07]) Conclusions and Relevance Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course Study interpretation is limited by the observational design

Assessment of WHO antibiotic consumption and access targets in 76 countries, 2000-15: an analysis of pharmaceutical sales data.

Abstract: Summary Background The WHO Access, Watch, and Reserve (AWaRe) antibiotic classification framework aims to balance appropriate access to antibiotics and stewardship. We aimed to identify how patterns of antibiotic consumption in each of the AWaRe categories changed across countries over 15 years. Methods Antibiotic consumption was classified into Access, Watch, and Reserve categories for 76 countries between 2000, and 2015, using quarterly national sample survey data obtained from IQVIA. We measured the proportion of antibiotic use in each category, and calculated the ratio of Access antibiotics to Watch antibiotics (access-to-watch index), for each country. Findings Between 2000, and 2015, global per-capita consumption of Watch antibiotics increased by 90·9% (from 3·3 to 6·3 defined daily doses per 1000 inhabitants per day [DIDs]) compared with an increase of 26·2% (from 8·4 to 10·6 DIDs) in Access antibiotics. The increase in Watch antibiotic consumption was greater in low-income and middle-income countries (LMICs; 165·0%; from 2·0 to 5·3 DIDs) than in high-income countries (HICs; 27·9%; from 6·1 to 7·8 DIDs). The access-to-watch index decreased by 38·5% over the study period globally (from 2·6 to 1·6); 46·7% decrease in LMICs (from 3·0 to 1·6) and 16·7% decrease in HICs (from 1·8 to 1·5), and 37 (90%) of 41 LMICs had a decrease in their relative access-to-watch consumption. The proportion of countries in which Access antibiotics represented at least 60% of their total antibiotic consumption (the WHO national-level target) decreased from 50 (76%) of 66 countries in 2000, to 42 (55%) of 76 countries in 2015. Interpretation Rapid increases in Watch antibiotic consumption, particularly in LMICs, reflect challenges in antibiotic stewardship. Without policy changes, the WHO national-level target of at least 60% of total antibiotic consumption being in the Access category by 2023, will be difficult to achieve. The AWaRe framework is an important measure of the effort to combat antimicrobial resistance and to ensure equal access to effective antibiotics between countries. Funding US Centers for Disease Control and Prevention.

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial.

Abstract: Background: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but...

Recent advances in cellulose-based piezoelectric and triboelectric nanogenerators for energy harvesting: a review

Abstract: Cellulose is the most earth-abundant natural polymer resource, which with combined eco-friendly and extraordinary sustainable properties such as renewability, biodegradability, low cost and excellent biocompatibility has been widely used by humans for thousands of years. In the past few years, many novel cellulosic materials and their unique applications have been developed including the recent research focus on energy harvesting. The high crystallization and plentiful polar hydroxyl groups endow cellulose with a large number of dipoles and strong electron donating capacity, resulting in a promising potential of piezoelectric and triboelectric effects. However, there is no review about cellulose-based nanogenerators until now. In this paper, the most recent developments of designing, modification, processing and integration of cellulose-based piezoelectric nanogenerators (PENGs), triboelectric nanogenerators (TENGs) and hybrid piezo/triboelectric nanogenerators (PTENGs) for energy harvesting and other applications are reviewed in detail. For cellulose-based PENGs, representative basic piezoelectric cellulose and recent research on PENG devices are discussed. For cellulose-based TENGs, several effective strategies including rough modification of contact surface, addition of electronic functional fillers and chemical modification for improving the output performance are further summarized. Meanwhile, the latest cellulose-based hybrid PTENG is also introduced from the fundamental design to the investigations on enhanced strategies. The opportunities and challenges of these cellulose-based nanogenerator devices are put forward in the final part, which could enable this up-to-date and state-of-the-art review to be an effective guidance for the future research on cellulose-based nanogenerators in energy harvesting.

Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights From EMPEROR-Reduced.

Abstract: Background: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin reduced cardiovascular death or heart failure (HF) ...

Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis.

Abstract: Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.

Accurate crystal structures and chemical properties from NoSpherA2

Abstract: The relationship between the structure and the properties of a drug or material is a key concept of chemistry. Knowledge of the three-dimensional structure is considered to be of such importance that almost every report of a new chemical compound is accompanied by an X-ray crystal structure – at least since the 1970s when diffraction equipment became widely available. Crystallographic software of that time was restricted to very limited computing power, and therefore drastic simplifications had to be made. It is these simplifications that make the determination of the correct structure, especially when it comes to hydrogen atoms, virtually impossible. We have devised a robust and fast system where modern chemical structure models replace the old assumptions, leading to correct structures from the model refinement against standard in-house diffraction data using no more than widely available software and desktop computing power. We call this system NoSpherA2 (Non-Spherical Atoms in Olex2). We explain the theoretical background of this technique and demonstrate the far-reaching effects that the improved structure quality that is now routinely available can have on the interpretation of chemical problems exemplified by five selected examples.

Nanostructured electrodes for electrocatalytic advanced oxidation processes: From materials preparation to mechanisms understanding and wastewater treatment applications

Abstract: The implementation of nanostructured materials in electrochemistry implied the enhancement of conversion yield in fuel cell, in electrosynthesis of oxidants and electrolytic treatment for environmental protection, while it allowed reducing the detection limit in electroanalysis. Nanostructured materials are becoming a hot topic of research, especially in electrochemical treatment for environmental applications that is strongly related to the rise of graphene and subsequent 2D materials that emerged in the last ten years. Nano-structuration allows bringing new properties of the materials such as number of active sites and conductivity improvement. It can therefore enhance the heterogeneous catalysis mechanism at electrode surface. This is primordial since it makes increase the rate of electrochemical reactions that can be the rate limiting steps in electrocatalytic treatment. Such advanced materials contribute to make advanced electrochemical processes as “greener” processes than the conventional ones. This paper aims to be a comprehensive, critical, and accessible review of general interest. The literature covers mainly the last ten years’ period due to the recent topic, especially the last five years with the considerable increase of number of publications in this period. The contents particularly devote efforts to establish links between the nanostructured-based electrode properties and electrochemical treatment efficiency through the mechanisms involved. The perspectives about mechanisms understanding and electrodes stability improvement are especially discussed.

Safety and efficacy of intensive blood pressure lowering after successful endovascular therapy in acute ischaemic stroke (BP-TARGET): a multicentre, open-label, randomised controlled trial.

Abstract: Summary Background High systolic blood pressure after successful endovascular therapy for acute ischaemic stroke is associated with increased risk of intraparenchymal haemorrhage. However, no randomised controlled trials are available to guide optimal management. We therefore aimed to assess whether an intensive systolic blood pressure target resulted in reduced rates of intraparenchymal haemorrhage compared with a standard systolic blood pressure target. Methods We did a multicentre, open-label, randomised controlled trial at four academic hospital centres in France. Eligible individuals were adults (aged ≥18 years) with an acute ischaemic stroke due to a large-vessel occlusion that was successfully treated with endovascular therapy. Patients were randomly assigned (1:1) to either an intensive systolic blood pressure target group (100–129 mm Hg) or a standard care systolic blood pressure target group (130–185 mm Hg), by means of a central web-based procedure, stratified by centre and intravenous thrombolysis use before endovascular therapy. In both groups, the target systolic blood pressure had to be achieved within 1 h after randomisation and maintained for 24 h with intravenous blood pressure lowering treatments. The primary outcome was the rate of radiographic intraparenchymal haemorrhage at 24–36 h and the primary safety outcome was the occurrence of hypotension. Analyses were done on an intention-to-treat basis. BP-TARGET is registered with ClinicalTrials.gov , number NCT03160677 , and the trial is closed at all participating sites. Findings Between June 21, 2017, and Sept 27, 2019, 324 patients were enrolled in the four participating stroke centres: 162 patients were randomly assigned to the intensive target group and 162 to the standard target group. Four (2%) of 162 patients were excluded from the intensive target group and two (1%) of 162 from the standard target group for withdrawal of consent or legal reasons. The mean systolic blood pressure during the first 24 h after reperfusion was 128 mm Hg (SD 11) in the intensive target group and 138 mm Hg (17) in the standard target group. The primary outcome was observed in 65 (42%) of 154 patients in the intensive target group and 68 (43%) of 157 in the standard target group on brain CT within 24–36 h after reperfusion] (adjusted odds ratio 0·96, 95% CI 0·60–1·51; p=0·84). Hypotensive events were not significantly different between both groups and occurred in 12 (8%) of 158 patients in the intensive target and five (3%) of 160 in the standard target group. Mortality within the first week after randomisation occurred in 11 (7%) of 158 patients in the intensive target group and in seven (4%) of 160 in the standard target group. Interpretation An intensive systolic blood pressure target of 100–129 mm Hg after successful endovascular therapy did not reduce radiographic intraparenchymal haemorrhage rates at 24–36 h as compared with a standard care systolic blood pressure target of 130–185 mm Hg. Notably, these results are applicable to patients with successful reperfusion and systolic blood pressures of more than 130 mm Hg at the end of procedure. Further studies are needed to understand the association between blood pressure and outcomes after reperfusion. Funding French Health Ministry.

Recent advances in flexible PVDF based piezoelectric polymer devices for energy harvesting applications

Abstract: Energy harvesting is one of the most promising research areas to produce sustainable power sources from the ambient environment. Which found applications to attain the extensive lifetime self-power...

Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

Abstract: Aims: We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction.Methods and results: The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45-0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66-0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated.Conclusion: The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.

ASVspoof 2019: Spoofing Countermeasures for the Detection of Synthesized, Converted and Replayed Speech

Abstract: The ASVspoof initiative was conceived to spearhead research in anti-spoofing for automatic speaker verification (ASV). This paper describes the third in a series of bi-annual challenges: ASVspoof 2019. With the challenge database and protocols being described elsewhere, the focus of this paper is on results and the top performing single and ensemble system submissions from 62 teams, all of which out-perform the two baseline systems, often by a substantial margin. Deeper analyses shows that performance is dominated by specific conditions involving either specific spoofing attacks or specific acoustic environments. While fusion is shown to be particularly effective for the logical access scenario involving speech synthesis and voice conversion attacks, participants largely struggled to apply fusion successfully for the physical access scenario involving simulated replay attacks. This is likely the result of a lack of system complementarity, while oracle fusion experiments show clear potential to improve performance. Furthermore, while results for simulated data are promising, experiments with real replay data show a substantial gap, most likely due to the presence of additive noise in the latter. This finding, among others, leads to a number of ideas for further research and directions for future editions of the ASVspoof challenge.

Factors Associated With Severe SARS-CoV-2 Infection.

Abstract: BACKGROUND: Initial reports on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in children suggested that very young age and comorbidities may increase risk of severe evolution, but these findings remained to be confirmed. We aimed to analyze the clinical spectrum of hospitalized pediatric SARS-CoV-2 infection and predictors of severe disease evolution. METHODS: We conducted a French national prospective surveillance of children hospitalized with SARS-CoV-2 infection. We included all children with confirmed SARS-CoV-2 infection in 60 hospitals during February 15 to June 1, 2020. The main outcome was the proportion of children with severe disease, defined by hemodynamic or ventilatory (invasive or not) support requirement. RESULTS: We included 397 hospitalized children with SARS-CoV-2 infection. We identified several clinical patterns, ranging from paucisymptomatic children, admitted for surveillance, to lower respiratory tract infection or multisystem inflammatory syndrome in children. Children CONCLUSIONS: In contrast with preliminary reports, young age was not an independent factor associated with severe SARS-CoV-2 infection, and children

Turgor - a limiting factor for radial growth in mature conifers along an elevational gradient.

Abstract: A valid representation of intra-annual wood formation processes in global vegetation models is vital for assessing climate change impacts on the forest carbon stock. Yet, wood formation is generally modelled with photosynthesis, despite mounting evidence that cambial activity is rather directly constrained by limiting environmental factors. Here, we apply a state-of-the-art turgor-driven growth model to simulate 4 yr of hourly stem radial increment fromPicea abies(L.) Karst. andLarix deciduaMill. growing along an elevational gradient. For the first time, wood formation observations were used to validate weekly to annual stem radial increment simulations, while environmental measurements were used to assess the climatic constraints on turgor-driven growth. Model simulations matched the observed timing and dynamics of wood formation. Using the detailed model outputs, we identified a strict environmental regulation on stem growth (air temperature > 2 degrees C and soil water potential > -0.6 MPa). Warmer and drier summers reduced the growth rate as a result of turgor limitation despite warmer temperatures being favourable for cambial activity. These findings suggest that turgor is a central driver of the forest carbon sink and should be considered in next-generation vegetation models, particularly in the context of global warming and increasing frequency of droughts.

Flotation of Fine Particles: A Review

Abstract: Literature shows that flotation is highly size dependent and processing both coarse and fine size fractions is problematic. The latter is the subject of the current paper. Fine particles have a rel...

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.