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Background: Circulating insulin and insulin-like growth factor-1 (IGF-1) concentrations are positively correlated with adiposity. However, the causal effects of insulin and IGF-1 on adiposity are unclear., Methods: We performed two-sample Mendelian randomization analyses to estimate the likely causal effects of fasting insulin and IGF-1 on relative childhood adiposity and adult body mass index (BMI). To improve accuracy and biological interpretation, we applied Steiger filtering (to avoid reverse causality) and 'biological effect' filtering of fasting insulin and IGF-1 associated variants., Results: Fasting insulin-increasing alleles (35 variants also associated with higher fasting glucose, indicative of insulin resistance) were associated with lower relative childhood adiposity (P = 3.8 × 10 -3 ) and lower adult BMI (P = 1.4 × 10 -5 ). IGF-1-increasing alleles also associated with taller childhood height (351 variants indicative of greater IGF-1 bioaction) showed no association with relative childhood adiposity (P = 0.077) or adult BMI (P = 0.562). Conversely, IGF-1-increasing alleles also associated with shorter childhood height (306 variants indicative of IGF-1 resistance) were associated with lower relative childhood adiposity (P = 6.7 × 10 -3 ), but effects on adult BMI were inconclusive., Conclusions: Genetic causal modelling indicates negative effects of insulin resistance on childhood and adult adiposity, and negative effects of IGF-1 resistance on childhood adiposity. Our findings demonstrate the need to distinguish between bioaction and resistance when modelling variants associated with biomarker concentrations., (© 2024. The Author(s).)

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care., Competing Interests: Declaration of interests I.S.F. has consulted for a number of companies developing weight loss drugs (including Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals) and investors (Goldman Sachs, SV Health). I.S.F. is a member of the Advisory Board of Cell. J.R.B.P. is an employee and shareholder of Insmed, receives research funding from GSK, and is a paid consultant for WW International. K.W.W. holds shares in Novo Nordisk and Eli Lilly., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Many variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation., (© 2024. The Author(s).)

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease., (© 2024. The Author(s).)

Corynebacterium striatum is an emerging nosocomial pathogen. This is the first report showing the presence of three distinct multidrug resistant lineages of C. striatum among patients in a UK hospital. The presence of ErmX, Tet(W), Bla and AmpC proteins, and mutations in gyrA gene are associated with the resistance to clindamycin, doxycycline, penicillin and moxifloxacin, respectively. These strains are equipped with several corynebacterial virulence genes including two SpaDEF-type and a novel pilus gene cluster, which needs further molecular characterisation. This study highlights a need of developing an active surveillance strategy for routine monitoring and preventing potential cross-transmission among susceptible patients., (© 2024. The Author(s).)

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals 1,2 , but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet (HFD) in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and overexpression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased HFD intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced HFD intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dearden et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and multiple interconnected underlying biological mechanisms. Mosaic loss of chromosome Y (mLOY) is one of the most common forms of acquired chromosome abnormality in men, which has been reported to be associated with increased risk of various chronic progressive diseases including fibrotic diseases. However, the exact role of mLOY in the development of PF remains elusive and to be elucidated., Methods: We adopted three complementary approaches to explore the role of mLOY in the pathogenesis of PF. We used copy number on chromosome Y to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. We performed Mendelian randomisation to examine the causal relationship between mLOY, IPF, and telomere length., Results: The genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (P = 0.0032). mLOY is related to age (P = 0.00021) and shorter telomere length (P = 0.0081) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells and appears to be related to presence and severity of fibrosis. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY., Conclusion: Our study confirms the existence of mLOY in PF patients and suggests that mLOY is not a major driver of IPF. The combined evidence suggests a triangulation model where telomere shortening leads to both IPF and mLOY.

Background: The role of metabolism in the variation of age at menarche (AAM) and age at natural menopause (ANM) in the female population is not entirely known. We aimed to investigate the causal role of circulating metabolites in AAM and ANM using Mendelian randomization (MR)., Methods: We combined MR with genetic colocalization to investigate potential causal associations between 658 metabolites and AAM and between 684 metabolites and ANM. We extracted genetic instruments for our exposures from four genome-wide association studies (GWAS) on circulating metabolites and queried the effects of these variants on the outcomes in two large GWAS from the ReproGen consortium. Additionally, we assessed the mediating role of the body mass index (BMI) in these associations, identified metabolic pathways implicated in AAM and ANM, and sought validation for selected metabolites in the Avon Longitudinal Study of Parents and Children (ALSPAC)., Results: Our analysis identified 10 candidate metabolites for AAM, but none of them colocalized with AAM. For ANM, 76 metabolites were prioritized (FDR-adjusted MR P-value ≤ 0.05), with 17 colocalizing, primarily in the glycerophosphocholines class, including the omega-3 fatty acid and phosphatidylcholine (PC) categories. Pathway analyses and validation in ALSPAC mothers also highlighted the role of omega and polyunsaturated fatty acids levels in delaying age at menopause., Conclusions: Our study suggests that metabolites from the glycerophosphocholine and fatty acid families play a causal role in the timing of both menarche and menopause. This underscores the significance of specific metabolic pathways in the biology of female reproductive longevity., (© 2024. The Author(s).)

The clinical imaging and pathology of a rare case of immature teratoma of the placenta is presented with a discussion of controversies related to classification and clinical suggestions for therapy and follow-up., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

Approximately 1 in 4 people worldwide have non-alcoholic fatty liver disease (NAFLD); however, there are currently no medications to treat this condition. This study investigated the role of adiposity-associated orphan G protein-coupled receptor 75 (GPR75) in liver lipid accumulation. We profiled Gpr75 expression and report that it is most abundant in the brain. Next, we generated the first single-cell-level analysis of Gpr75 and identified a subpopulation co-expressed with key appetite-regulating hypothalamic neurons. CRISPR-Cas9-deleted Gpr75 mice fed a palatable western diet high in fat adjusted caloric intake to remain in energy balance, thereby preventing NAFLD. Consistent with mouse results, analysis of whole-exome sequencing data from 428,719 individuals (UK Biobank) revealed that variants in GPR75 are associated with a reduced likelihood of hepatic steatosis. Here, we provide a significant advance in understanding of the expression and function of GPR75, demonstrating that it is a promising pharmaceutical target for NAFLD treatment., Competing Interests: Declaration of interests E.J.G. and J.R.B.P. are employees of and hold shares in Adrestia Therapeutics., (Copyright © 2024. Published by Elsevier Inc.)

Although whistleblowing is thought to represent an effective mechanism for detecting and uncovering doping in sport, it has yet to become a widely adopted practice. Understanding the factors that encourage or discourage whistleblowing is of vital importance for the promotion of this practice and the development of pedagogical material to enhance the likelihood of whistleblowing. The current study employed a qualitative methodology to explore the personal and organisational factors that underpin intentions to blow the whistle or that may lead to engagement in whistleblowing behaviours in sport. Thirty-three competitive athletes across a range of sports took part in a semi-structured interview which sought to explore what they would do should they encounter a doping scenario. Content analysis revealed that whistleblowing is a dynamic process characterised by the interaction of a range of personal and organisational factors in determining the intention to report PED use. These factors included moral reasoning, a desire to keep the matter "in-house", perceived personal costs, institutional attitudes to doping, and social support. Analysis revealed a number of "intervening events", including a perceived lack of organisational protection (e.g., ethical leadership) within some sporting sub-cultures, which present an important obstacle to whistleblowing. The intention to report doping was underpinned by a "fairness-loyalty trade-off" which involved athletes choosing to adhere to either fairness norms (which relate to a sense that all people and groups are treated equally) or loyalty norms (which reflect preferential treatment towards an in-group) when deciding whether they would blow the whistle. The promotion of fairness norms that emphasise a group's collective interests might encourage athletes to view whistleblowing as a means of increasing group cohesiveness and effectiveness and thereby increase the likelihood of this practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Toner, Jones, Fairs, Mantis, Barkoukis, Daroglou, Perry, Micle, Theodorou, Shakhverdieva, Stoicescu, Pompiliu-Nicolae, Vesic, Dikic, Andjelkovic, Revilla, García-Grimau, Martínez, Amigo, Schomöller and Nicholls.)

Carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter spp. represent major threats and have few approved therapeutic options. Non-‍fermenting Gram-negative isolates were collected from hospitalized inpatients from 49 sites in 6 European countries between 01 January 2020 and 31 December 2020 and underwent susceptibility testing against cefiderocol and β-lactam/β-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L), cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-resistant isolates were analyzed by whole-genome sequencing to identify resistance mechanisms. Overall, 1,451 (950 P . aeruginosa ; 501 Acinetobacter spp.) isolates were collected, commonly from the respiratory tract (42.0% and 39.3%, respectively). Cefiderocol susceptibility was higher than ‍β‍-‍l‍a‍c‍t‍a‍m‍/‍β‍-‍l‍a‍c‍t‍a‍mase‍ inhibitor combinations against P. aeruginosa (98.9% vs 83.3%-91.4%), and P. ‍aeruginosa resistant to meropenem ( n = 139; 97.8% vs 12.2%-59.7%), β-lactam/β-lactamase inhibitor combinations (93.6%-98.1% vs 10.7%-71.8%), and both meropenem and ceftazidime-avibactam (96.7% vs 5.0%-‍‍45.0%) or ‍ceftolozane-tazobactam (98.4% vs 8.1%-54.8%), respectively. Cefiderocol and sulbactam-durlobactam susceptibilities were high against Acinetobacter spp. (92.4% and 97.0%) and meropenem-resistant Acineto‍bacter ‍spp. ( n = 227; 85.0% and 93.8%) but lower against sulbactam-durlobactam- ( n ‍= 15; 13.3%) and cefiderocol- ( n = 38; 65.8%) resistant isolates, respectively. Among meropenem-resistant P. aeruginosa and Acinetobacter spp., the most common β-‍‍lactamase genes were metallo-β-lactamases [30/139; bla VIM-2 (15/139)] and oxacillinases [215/227; bla OXA-23 (194/227)], respectively. Acquired β-lactamase genes were identified in 1/10 and 32/38 of cefiderocol-resistant P. aeruginosa and Acinetobacter spp., and pirA -like or piuA mutations in 10/10 and 37/38, respectively. Conclusion: cefiderocol susceptibility was high against P. aeruginosa and Acinetobacter spp., including meropenem-resistant isolates and those resistant to recent β-lactam/β-lactamase inhibitor combinations common in first-line treatment of European non-fermenters., Importance: This was the first study in which the in vitro activity of cefiderocol and non-licensed β-lactam/β-lactamase inhibitor combinations were directly compared against Pseudomonas aeruginosa and Acinetobacter spp., including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates. A notably large number of European isolates were collected. Meropenem resistance was defined according to the MIC breakpoint for high-dose meropenem, ensuring that data reflect antibiotic activity against isolates that would remain meropenem resistant in the clinic. Cefiderocol susceptibility was high against non-fermenters, and there was no apparent cross resistance between cefiderocol and β-lactam/β-lactamase inhibitor combinations, with the exception of sulbactam-durlobactam. These results provide insights into therapeutic options for infections due to resistant P. aeruginosa and Acinetobacter spp. and indicate how early susceptibility testing of cefiderocol in parallel with β-lactam/β-lactamase inhibitor combinations will allow clinicians to choose the effective treatment(s) from all available options. This is particularly important as current treatment options against non-fermenters are limited., Competing Interests: A.S.H. is an employee of Maxel Consulting ApS, Jyllinge, Denmark and is a contract employee of Shionogi B.V. Both K.J. and A.O. declare honoraria and grants from Shionogi, Pfizer, and MSD. I.M. is an employee of Antimicrobial Focus Ltd and was involved with the reporting of the study data by IHMA. C.L. is an employee of Shionogi B.V. J.D.P., M.W.P., and S.S. have no relevant conflicts of interest to disclose.

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity., (© 2024. The Author(s).)

The aim of this study was to assess the utility of CHROMID ® Colistin R for direct detection of colistin-resistant Gram-negative bacteria from positive blood cultures. A total of 390 blood cultures from hospitalised patients containing Gram-negative bacteria were included in this study. These blood cultures were referred to clinical laboratories in the United Kingdom and Türkiye. A further 16 simulated positive blood culture bottles were included that contained a range of colistin-resistant strains as well as susceptible control strains. Fluid from each positive blood culture was diluted 1/200 in saline and 10 µL aliquots cultured onto cystine-lactose-electrolyte-deficient agar and CHROMID ® Colistin R. All recovered bacteria were identified, and for Gram-negative bacteria, their minimum inhibitory concentration of colistin was measured using the broth microdilution method. From a total of 443 Gram-negative isolates, 57 colistin-resistant isolates were recovered, of which 53 (93%) grew on CHROMID ® Colistin R within 18 h. Of the 377 isolates determined to be colistin-susceptible, only 9 isolates were able to grow, including 6 isolates of Pseudomonas aeruginosa . For positive blood cultures that are shown to contain Gram-negative bacteria, culture on CHROMID ® Colistin R is a useful diagnostic tool to detect susceptibility or resistance to colistin within 18 h.

Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT-β-catenin pathway. The increase in PFKP elevates energy metabolic activities and, as a consequence, enhances the sensitivity of LSCs to chemotherapeutic agents. Moreover, the upregulation of PFKP promotes MYC degradation and, consequently, reduces the immune evasion abilities of LSCs. Overall, our study demonstrates that targeting SHP-1 disrupts the metabolic balance in LSCs, thereby increasing their vulnerability to chemotherapy and immunosurveillance. This approach offers a promising strategy to overcome LSC resistance in acute myeloid leukaemia., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

An individual's nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra's trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions., (© 2023. Springer Nature Limited.)

Background: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank., Results: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation., Conclusion: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern., (© 2023. The Author(s).)

Age at menarche (AAM) and age at natural menopause (ANM) are highly heritable traits and have been linked to various health outcomes. We aimed to identify circulating proteins associated with altered ANM and AAM using an unbiased two-sample Mendelian randomization (MR) and colocalization approach. By testing causal effects of 1,271 proteins on AAM, we identified 22 proteins causally associated with AAM in MR, among which 13 proteins (GCKR, FOXO3, SEMA3G, PATE4, AZGP1, NEGR1, LHB, DLK1, ANXA2, YWHAB, DNAJB12, RMDN1 and HPGDS) colocalized. Among 1,349 proteins tested for causal association with ANM using MR, we identified 19 causal proteins among which 7 proteins (CPNE1, TYMP, DNER, ADAMTS13, LCT, ARL and PLXNA1) colocalized. Follow-up pathway and gene enrichment analyses demonstrated links between AAM-related proteins and obesity and diabetes, and between AAM and ANM-related proteins and various types of cancer. In conclusion, we identified proteomic signatures of reproductive ageing in women, highlighting biological processes at both ends of the reproductive lifespan., (© 2024. The Author(s).)

Study Question: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins?, Summary Answer: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3., What Is Known Already: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures., Study Design, Size, Duration: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls)., Participants/materials, Setting, Methods: Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation., Main Results and the Role of Chance: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle., Large Scale Data: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/)., Limitations, Reasons for Caution: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility., Wider Implications of the Findings: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility., Study Funding/competing Interest(s): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Skłodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Loss-of-function of DDX3X is a leading cause of neurodevelopmental disorders (NDD) in females. DDX3X is also a somatically mutated cancer driver gene proposed to have tumour promoting and suppressing effects. We perform saturation genome editing of DDX3X, testing in vitro the functional impact of 12,776 nucleotide variants. We identify 3432 functionally abnormal variants, in three distinct classes. We train a machine learning classifier to identify functionally abnormal variants of NDD-relevance. This classifier has at least 97% sensitivity and 99% specificity to detect variants pathogenic for NDD, substantially out-performing in silico predictors, and resolving up to 93% of variants of uncertain significance. Moreover, functionally-abnormal variants can account for almost all of the excess nonsynonymous DDX3X somatic mutations seen in DDX3X-driven cancers. Systematic maps of variant effects generated in experimentally tractable cell types have the potential to transform clinical interpretation of both germline and somatic disease-associated variation., (© 2023. The Author(s).)

Context: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown., Objective: This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH)., Methods: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort., Results: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07)., Conclusion: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Clonal hematopoiesis (CH)-age-related expansion of mutated hematopoietic clones-can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk., (© 2023. Springer Nature Limited.)

Two experiments investigated whether mental toughness (MT) is associated with the ability to respond to and/or overcome unwanted information during real-time sport performance. Participants were male snooker players ranging from club to professional level, and MT was measured using the MTQ48 (Clough et al., 2002). In experiment 1, players performed five break-off shots and received deceptive feedback (either positive or negative) from the researcher about their performance relative to other players. Then they performed another five break-offs. Results showed a significant decline in performance following feedback, but no interaction with the nature of feedback or MT variables. In experiment 2, feedback was delivered by a coach and yielded a significant effect on performance. Specifically, negative feedback improved performance while positive feedback impaired performance. The Life Control subscale of the MTQ48 was a significant covariate. The results suggest that negative feedback, delivered constructively by a respected figure, may act as a catalyst for performance enhancement in snooker and that this is moderated by MT., Competing Interests: Declaration of competing interest There are no conflicts of interest regarding this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10 -6 ): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10 -4 . Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small., (© 2023. The Author(s).)

Combat sports require participants to engage in potentially dangerous forms of contact-based competition. Pressure to succeed, coupled with the risk of severe injury can induce significant levels of anxiety, which if uncontrolled, can negatively impact performance and possibly promote unsporting conduct. The present study examined competitive anxiety levels of combat sports athletes and determined whether self-reported scores were associated with mental toughness and Sportspersonship attitudes. A cross-sectional survey design was used whereby participants ( N = 194) completed a battery of questionnaires measuring competitive combat sport experiences, demographic details, Sportspersonship traits (compliance towards rules, respect for opponents, and game perspective), and competition anxiety (somatic, cognitive, and self-confidence; reported retrospectively). Results suggest that mentally tough athletes experience lower levels of cognitive and somatic anxiety, and higher self-confidence, prior to competitions. Findings also found that athletes endorsing more altruistic and respectful attitudes in sport (Sportspersonship) reported higher levels of competition anxiety. The findings demonstrate that mental toughness is allied to positive attributes and could potentially be operationalized to improve both the retention and performance of combat sports athletes. Thus, the authors advocate the use of mental toughness coaching interventions within combat sports.

Infective endocarditis (IE) remains a difficult condition to diagnose and treat and is an infection of high consequence for patients, causing long hospital stays, life-changing complications and high mortality. A new multidisciplinary, multiprofessional, British Society for Antimicrobial Chemotherapy (BSAC)-ledWorking Party was convened to undertake a focused systematical review of the literature and to update the previous BSAC guidelines relating delivery of services for patients with IE. A scoping exercise identified new questions concerning optimal delivery of care, and the systematic review identified 16 231 papers of which 20 met the inclusion criteria. Recommendations relating to endocarditis teams, infrastructure and support, endocarditis referral processes, patient follow-up and patient information, and governance are made as well as research recommendations. This is a report of a joint Working Party of the BSAC, British Cardiovascular Society, British Heart Valve Society, British Society of Echocardiography, Society of Cardiothoracic Surgeons of Great Britain and Ireland, British Congenital Cardiac Association and British Infection Association., Competing Interests: Competing interests: The British Society for Antimicrobial Chemotherapy provided funds for literature search, administrative support and meeting space. JATS (JS) received research funding from the National Institute for Health Research, the Medical Research Council, Welcome Trust, Engineering and Physical Sciences Council, and Jon Moulton Charity Trust. JS received consulting fees from Tillotts Pharma and Medtron. BDP and JBC are on the Editorial Board for BMJ Heart. BDP received consulting fees from Anteris and Microport, honoraria from Medtronic, Abbott, Edwards Lifesciences and Anteris and is on the data safety monitoring committee of Colibri. He is a board member of PCR and has received writing fees from Edwards Lifesciences., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Obesity contributes substantially to the global burden of disease and has a significant heritable component. Recent large-scale exome sequencing studies identified several genes in which rare, protein-coding variants have large effects on adult body mass index (BMI). Here we extended such work by performing sex-stratified associations in the UK Biobank study (N∼420,000). We identified genes in which rare heterozygous loss-of-function increases adult BMI in women ( DIDO1, PTPRG, and SLC12A5 ) and in men ( SLTM ), with effect sizes up to ∼8 kg/m 2 . This is complemented by analyses implicating rare variants in OBSCN and MADD for recalled childhood adiposity. The known functions of these genes, as well as findings of common variant genome-wide pathway enrichment analyses, suggest a role for neuron death, apoptosis, and DNA damage response mechanisms in the susceptibility to obesity across the life-course. These findings highlight the importance of considering sex-specific and life-course effects in the genetic regulation of obesity., Competing Interests: E.J.G., S.P.J., and J.R.B.P. are employees and shareholders of Adrestia Therapeutics Ltd., (© 2023 The Authors.)

Background: Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype., Methods: In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation., Findings: Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6&#95;Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36&#95;37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice., Interpretation: We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process., Funding: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Aim: During the COVID-19 pandemic, health workers' facial exposure to pathogens has been brought into focus. In this study, we aimed to determine the occurrence and degree of facial contamination to both endoscopists and their assistants during endoscopic procedures to help inform future safety measures., Methods: Non-sterile visors worn by endoscopist, assistant and room control visors from 50 procedures were swabbed post procedure for culture. Procedure type, therapy, duration and evidence of visible visor contamination were recorded. After 48-hour incubation, all bacterial colonies were identified using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry. Organisms were classified into skin/environmental, oronasal and enteric., Results: A total of 104 visors were available for assessment (93 staff; 11 control). In worn visors, skin/environmental flora were isolated from 70, oronasal flora from 8, and enteric flora from 3 with an average colony count of >9.5. Notably, bacteria of enteric origin ( Escherichia coli and Enterobacter cloacae ) were isolated from three worn visors. In room control, skin/environmental flora were isolated from seven and oronasal flora from one with average colony count of five. No room control visors grew enteric flora. Overall, 9.1% room control and 10.8% worn visors were contaminated with organisms that could possibly have originated from patients. However, enteric flora were only obtained from worn visors. No visors were visibly contaminated., Conclusion: This pilot study demonstrates risk of contamination to faces of endoscopists and assistants. Larger studies are required to determine degree of risk and to give guidance on facial protection during gastrointestinal endoscopy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

A series of [2-(nitroaryl)ethenyl]pyridinium and quinolinium derivatives have been synthesised as potential indicators of microbial nitroreductase activity. When assessed against a selection of 20 clinically important pathogenic microorganisms, microbial colonies of various colours (yellow, green, red, brown, black) were produced and attributed to nitroreductase activity. Most substrates elicited colour responses with Gram-negative microorganisms. In contrast, the growth of several species of Gram-positive microorganisms and yeasts was often inhibited by the substrates and hence coloured responses were not seen.

Higher cardiorespiratory fitness is associated with lower risk of type 2 diabetes. However, the causality of this relationship and the biological mechanisms that underlie it are unclear. Here, we examine genetic determinants of cardiorespiratory fitness in 450k European-ancestry individuals in UK Biobank, by leveraging the genetic overlap between fitness measured by an exercise test and resting heart rate. We identified 160 fitness-associated loci which we validated in an independent cohort, the Fenland study. Gene-based analyses prioritised candidate genes, such as CACNA1C, SCN10A, MYH11 and MYH6, that are enriched in biological processes related to cardiac muscle development and muscle contractility. In a Mendelian Randomisation framework, we demonstrate that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity. Integration with proteomic data identified N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein and sex hormone-binding globulin as potential mediators of this relationship. Collectively, our findings provide insights into the biological mechanisms underpinning cardiorespiratory fitness and highlight the importance of improving fitness for diabetes prevention., (© 2023. The Author(s).)

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10 -6 ) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10 -4 ). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: This observational study investigated the relationship between malocclusion and smiling., Methods: Adolescents and young adults (n = 72; aged 16-25 years) were identified according to their Dental Aesthetic Index (DAI) and allocated to 3 groups: (1) malocclusion group (n = 24; DAI ≥31), (2) retention group (n = 24; pretreatment DAI ≥31) with a prior malocclusion that had been corrected by orthodontic treatment, (3) control group with no-to-minor malocclusion (n = 24; DAI ≤25). Participants were requested to watch an amusing video. Based on the Facial Action Coding System, automated pattern recognition was used to detect smile episodes and assess their frequency, duration, genuineness, intensity, and extent of tooth show. Demographics, Big Five personality dimensions, and self-perceived smile esthetics-related quality of life were collected from all participants via questionnaires. Data were analyzed by mixed-model analysis and adjusted for possible confounders., Results: Patients from the malocclusion and retention groups smiled significantly less than participants from the control group, with the duration of smiles and smiling time being around half those of control subjects. Smile genuineness, smile intensity, and teeth shown did not differ across groups. Personality traits did not differ significantly among the 3 groups, whereas the malocclusion group scored around 30% less for dental self-confidence than the other 2 groups., Conclusions: Patients with severe malocclusion tend to smile less, but the features of their smiles are similar to those without malocclusion. A lower propensity to smile in patients with a corrected malocclusion may persist after orthodontic treatment., (Copyright © 2023 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Lobular neoplasia (LN) involves proliferative changes within the breast lobules. LN is divided into lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH). LCIS can be further subdivided into three subtypes: classic LCIS, pleomorphic LCIS, and LCIS with necrosis (florid type). Because classic LCIS is now considered as a benign etiology, current guidelines recommend close follow-up with imaging versus surgical excision. The goal of our study was to determine if the diagnosis of classic LN on core needle biopsy (CNB) merits surgical excision. This is a retrospective, observational study conducted at Mount Auburn Hospital, Cambridge, MA, from May 17, 2017, through June 30, 2020. We reviewed the data of breast biopsies conducted at our hospital over this period and included patients who were diagnosed with classic LN (LCIS and/or ALH) and excluded patients having any other atypical lesions on CNB. All known cancer patients were excluded. Of the 2707 CNBs performed during the study period, we identified 68 women who were diagnosed with ALH or LCIS on CNB. CNB was performed for an abnormal mammogram in the majority of patients (60; 88%) while 7(10.3%) had an abnormal breast magnetic resonance imaging study (MRI), and 1 had an abnormal ultrasound (US). A total of 58 patients (85%) underwent excisional biopsy, of which 3 (5.2%) showed malignancy, including 2 cases of DCIS and 1 invasive carcinoma. In addition, there was 1 case (1.7%) with pleomorphic LCIS and 11 cases with ADH (15.5%). The management of LN found on core biopsy is evolving, with some advocating surgical excision and others recommending observation. Our data show a change in diagnosis with excisional biopsy in 13 (22.4%) of patients with 2 cases of DCIS, 1 invasive carcinoma, 1 pleomorphic LCIS, and 9 cases of ADH, diagnosed on excisional biopsy. While ALH and classic LCIS are considered benign, the choice of ongoing surveillance versus excisional biopsy should be made with shared decision making with the patient, with consideration of personal and family history, as well as patient preferences., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Chinmay Jani et al.)

Objective: Growth hormone insensitivity (GHI) encompasses growth restriction, normal/elevated growth hormone (GH), and low insulin-like growth factor I (IGF1). "Nonclassical" GHI is poorly characterized and is rarely caused by heterozygous dominant-negative (DN) variants located in the intracellular or transmembrane domains of the GH receptor (GHR). We sought to determine the molecular mechanisms underpinning the growth restriction in 2 GHI cases., Methods and Design: A custom-made genetic investigative pipeline was exploited to identify the genetic cause of growth restriction in patients with GHI. Nanoluc binary technology (NanoBiT), in vitro splicing assays, western blotting, and flow cytometry, characterized the novel GHR variants., Results: Novel heterozygous GHR variants were identified in 2 unrelated patients with GHI. In vitro splicing assays indicated both variants activated the same alternative splice acceptor site resulting in aberrant splicing and exclusion of 26 base pairs of GHR exon 9. The GHR variants produced truncated receptors and impaired GH-induced GHR signaling. NanoBiT complementation and flow cytometry showed increased cell surface expression of variant GHR homo/heterodimers compared to wild-type (WT) homodimers and increased recombinant human GH binding to variant GHR homo/heterodimers and GH binding protein (GHBP) cleaved from the variant GHRs. The findings demonstrated increased variant GHR dimers and GHBP with resultant GH sequestration., Conclusion: We identified and characterized 2 novel, naturally occurring truncated GHR gene variants. Intriguingly, these DN GHR variants act via the same cryptic splice acceptor site, highlighting impairing GH binding to excess GHBP as a potential therapeutic approach., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology.)

Objectives: To evaluate effects of worsening surgically induced chronic kidney disease (CKD-S) on oncological and non-oncological survival outcomes in renal cell carcinoma (RCC)., Patients and Methods: We performed a retrospective analysis of patients who underwent partial (PN) or radical nephrectomy (RN) and were free of preoperative CKD (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m 2 ). Patients were stratified by CKD stage at last follow-up: no CKD-S (eGFR ≥60 mL/min/1.73 m 2 ), de novo CKD-S 3a (eGFR 45-59 mL/min/1.73 m 2 ), CKD-S 3b (eGFR <45 and ≥30 mL/min/1.73 m 2 ) and CKD-S 4 (eGFR <30 and ≥15 mL/min/1.73 m 2 ). The primary outcome was all-cause mortality (ACM). Secondary outcomes included non-cancer mortality (NCM), cancer-specific mortality (CSM) and de novo CKD-S Stage 3/4. Multivariable analysis (MVA) was utilised to identify risk factors for outcomes. Kaplan-Meier analysis (KMA) was utilised to evaluate overall (OS), non-cancer (NCS), and cancer-specific survival with respect to CKD-S categories., Results: We analysed 3239 patients. The mean preoperative and last-follow-up eGFRs were 87.4 and 69.5 mL/min/1.73 m 2 , respectively. On last follow-up, 57.9% (n = 1876) had no CKD-S, 18.7% (n = 606) had CKD-S 3a, 15.1% (n = 489) had CKD-S 3b and 8.3% (n = 268) had CKD-S 4. On MVA, de novo CKD-S 3b and 4 were independently associated with ACM (hazard ratios [HRs] 1.3-2.1, P = 0.003-0.001) and NCM (HRs 1.5-2.8, P = 0.021-0.001), but not CSM (P = 0.219-0.909); de novo CKD-S 3a was not predictive for any mortality outcomes (P = 0.102-0.81). RN was independently associated with CKD-S 3-4 (HRs 1.78-1.99, P < 0.001-0.035). Comparing no CKD-S, CKD-S 3a, CKD-S 3b and CKD-S 4, KMA demonstrated worsening outcomes with progressive CKD-S stage: 5-year OS 84% vs 78% vs 71% vs 60% (P < 0.001) and 5-year NCS 93% vs 87% vs 83% vs 72% (P < 0.001)., Conclusion: Development of CKD-S Stage 3b and 4, but not 3a, was associated with worsened ACM and NCM. The decision to proceed with nephron preservation via PN should be individualised based on oncological risk and risk of functional decline to CKD-S 3b or 4, and not CKD-S 3a., (© 2022 BJU International.)

Objectives: This report aims to review the management and outcomes of Brucella -associated mycotic aortic aneurysms., Methods: This is a retrospective chart review at a tertiary-level healthcare system. IRB approval was waived per policy., Results: We describe a case of Brucella aortitis acquired from habitual contact with wild hogs. Clinical presentation included lower back pain and elevated white blood cell count. Diagnosis was confirmed with imaging showing an infrarenal abdominal aortic aneurysm and serology revealing elevated Brucella antibodies titers. The patient was initially managed with endovascular aortic repair and combined oral and intravenous antibiotics therapy. He then underwent explanation and extra-anatomical bypass due to symptomatic periaortic infection and interval development of type I endoleak. The patient was asymptomatic after his final operation at 24 months of follow-up and remained on suppressive oral antibiotic therapy., Conclusions: An aortic aneurysm secondary to Brucella is a rare entity. A detailed history of long-term exposure to animals may be a clue to obtain serologic testing. Operative debridement and re-establishing of reliable blood flow combined with long-term antibiotic suppression are the mainstay of treatment.

Hematopoietic stem cells (HSCs) are the source for all blood cells, including immune cells, and they interact dynamically with the immune system. This chapter will explore the nature of stem cells, particularly HSCs, in the context of their immune microenvironment. The dynamic interactions between stem cells and the immune system can have profound implications for current and future therapies, particularly regarding a potential "immune-privileged" HSC microenvironment. Immune/stem cell interactions change during times of stress and injury. Recent advances in cancer immunotherapy have overturned the long-standing belief that, being derived from the self, cancer cells should be immunotolerant. Instead, an immunosurveillance system recognizes and eliminates emergent pre-cancerous cells. Only in the context of a failing immunosurveillance system does cancer fully develop. Combined with the knowledge that stem cells or their unique properties can be critically important for cancer initiation, persistence, and resistance to therapy, understanding the unique immune properties of stem cells will be critical for the development of future cancer therapies. Accordingly, the therapeutic implications for leukemic stem cells (LSCs) inheriting an immune-privileged state from HSCs will be discussed. Through their dynamic interactions with a diverse immune system, stem cells serve as the light and dark root of cancer prevention vs. development., (© 2023. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.)

T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy with poor prognosis, but a decisive marker and effective treatment for leukaemia stem cells (LSCs) remain unclear. Here, using lineage tracing, limiting dilution assays and in vivo live imaging approaches, we identify rare inhibitory receptor programmed cell death 1 (PD-1)-expressing cells that reside at the apex of leukaemia hierarchy for initiation and relapse in T-ALL. Ablation of PD-1-expressing cells, deletion of PD-1 in T-ALL cells or blockade of PD-1 or PD-1 ligand 1 significantly eradicated LSCs and suppressed disease progression. Combination therapy using PD-1 blockade and chemotherapy substantially extended the survival of mice engrafted with mouse or human T-ALL cells. Mechanistically, PD-1 + LSCs had high NOTCH1-MYC activity for disease initiation. Furthermore, PD-1 signalling maintained quiescence and protected LSCs against T cell receptor-signal-induced apoptosis. Overall, our data highlight the hierarchy of leukaemia by identifying PD-1 + LSCs and provide a therapeutic approach for the elimination of LSCs through PD-1 blockade in T-ALL., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)