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Abstract Polycystic ovary syndrome (PCOS) is a heterogeneous condition, defined by oligo-/anovulation, hyper-androgenism and/or polycystic ovaries. Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes, which severely compromise the clinical course of affected women. Yet, therapeutic options remain mostly symptomatic and of limited efficacy for the metabolic and reproductive alterations of PCOS. We report here the hormonal, metabolic and gonadal responses to the glucagon-like peptide-1 (GLP1)-based multi-agonists, GLP1/Estrogen (GLP1/E), GLP1/gastric inhibitory peptide (GLP1/GIP) and GLP1/GIP/Glucagon, in two mouse PCOS models, with variable penetrance of metabolic and reproductive traits, and their comparison with metformin. Our data illustrate the superior efficacy of GLP1/E vs. other multi-agonists and metformin in the management of metabolic complications of PCOS; GLP1/E ameliorates also ovarian cyclicity in an ovulatory model of PCOS, without direct estrogenic uterotrophic effects. In keeping with GLP1-mediated brain targeting, quantitative proteomics reveals changes in common and distinct hypothalamic pathways in response to GLP1/E between the two PCOS models, as basis for differential efficiency. Altogether, our data set the basis for the use of GLP1-based multi-agonists, and particularly GLP1/E, in the personalized management of PCOS.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Abstract CETP inhibitors are a class of lipid-lowering drugs in development for treatment of coronary heart disease (CHD). Genetic studies in East Asian ancestry have interpreted the lack of CETP signal with low-density lipoprotein cholesterol (LDL-C) and lack of drug target Mendelian randomization (MR) effect on CHD as evidence that CETP inhibitors might not be effective in East Asian participants. Capitalizing on recent increases in sample size of East Asian genetic studies, we conducted a drug target MR analysis, scaled to a standard deviation increase in high-density lipoprotein cholesterol. Despite finding evidence for possible neutral effects of lower CETP levels on LDL-C, systolic blood pressure and pulse pressure in East Asians (interaction p-values < 1.6 × 10−3), effects on cardiovascular outcomes were similarly protective in both ancestry groups. In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries.

Abstract An electroanalytical methodology was developed by direct differential pulse voltammetric (DPV) measurement of Levodopa (LD), Carbidopa (CD) and Entacapone (ENT) mixture using bare glassy carbon electrode (GCE) in Britton Robinson (BR) buffer (pH = 2.0). A multivariate calibration model was then applied to the exported preprocessed voltammetric data using partial least square (PLS) as a chemometric tool. Additionally, the model was cross-validated and the number of latent variables (LVs) were determined to produce a reliable model for simultaneous quantitation of the three drugs either in their synthetic mixtures or in their marketed pharmaceutical formulation with high accuracy and precision. Data preprocessing was used to tackle the problem of lacking bi-linearity which is commonly found in electrochemical data. The proposed chemometric model was able to provide fast and reliable technique for quantitative determination of antiparkinson drugs in their dosage forms. This was successfully achieved by utilizing sixteen mixtures as calibration set and nine mixtures as validation set. The percent recoveries for LD, CD and ENT were found to be 100.05% ± 1.28%, 100.04% ± 0.53% and 99.99% ± 1.25%, respectively. The obtained results of the proposed method were statistically compared to those of a previously reported High Performance Liquid Chromatography (HPLC) methodology. Finally, the presented analytical method strongly supports green analytical chemistry regarding the minimization of potentially dangerous chemicals and solvents, as well as reducing energy utilization and waste generation.

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH-wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contributed to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures were often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, d-2-hydroxyglutarate, rapidly synchronized neuronal spike firing in a seizure-like manner, but only when non-neoplastic glial cells were present. In vitro and in vivo models recapitulated IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibited seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

AbstractSleep loss heightens pain sensitivity, but the pathways underlying this association are not known. Given that experimental sleep disruption induces increases in cellular inflammation as well as selective loss of slow wave, N3 sleep, this study examined whether these mechanisms contribute to pain sensitivity following sleep loss in healthy adults. This assessor-blinded, cross-over sleep condition, single-site, randomized clinical trial enrolled 95 healthy adults (mean [SD] age, 27.8 [6.4]; female, 44 [53.7%]). The 2 sleep conditions were 2 nights of undisturbed sleep (US) and 2 nights of sleep disruption or forced awakening (FA, 8 pseudorandomly distributed awakenings and 200 minutes wake time during the 8-hour sleep opportunity), administered in a cross-over design after 2 weeks of washout and in a random order (FA-US; US-FA). Primary outcome was heat pain threshold (hPTH). Sleep architecture was assessed by polysomnography, and morning levels of cellular inflammation were evaluated by Toll-like receptor-4 stimulated monocyte intracellular proinflammatory cytokine production. As compared with US, FA was associated with decreases in the amount of slow wave or N3 sleep ( P < 0.001), increases in Toll-like receptor-4 stimulated production of interleukin-6 and tumor necrosis factor-α ( P = 0.03), and decreases in hPTH ( P = 0.02). A comprehensive causal mediation analysis found that FA had an indirect effect on hPTH by decreases in N3 sleep and subsequent increases in inflammation (estimate=-0.15; 95% confidence interval, -0.30 to -0.03; P < 0.05) with the proportion mediated 34.9%. Differential loss of slow wave, N3 sleep, and increases in cellular inflammation are important drivers of pain sensitivity after sleep disruption.Clinical Trials Registration: NCT01794689.

Abstract In this paper, we looked at the collaboration publishing patterns for groups of Global South countries (Latin America, Africa, ASEAN, Asian, BRICS), as well as publishing parameters. We looked at financing and the relationships between these groups and the Global North. Data from 2002 to 2021 was collected from InCites ® (Web of Science, Clarivate Analytics) and SciVal® (Scopus Elsevier). The impact was lower for BRICS, while Latin America and Asean countries tended to have a higher Field Weighted Citation Impact. Good Health and well-being (SDG 3) dominates South-South Collaborations. Asian countries showed a higher percentage of Affordable and Clean Energy (SDG7), while Africa and Latin America had a higher rate of Zero Hunger (SDG1). Each region shows different production profiles, but collaboration with the Global North is necessary for all regions. Intra-regional shows a lower impact than inter-regional financing, calling attention to the increasing influence of China in all regions, except for Latin America. The data analysed can be used for orienting South-South scientific Collaboration programs, focusing on pre-existent synergies and on where policy changes and results can be maximised.

Digital engineering and digital twins are increasingly being used in nuclear energy projects with important impacts. At Idaho National Laboratory, these approaches have been applied in a variety of nuclear energy research, development, and demonstration projects, with key lessons and evolutions occurring for each. In this paper, we describe the use of digital engineering and digital twins in the Versatile Test Reactor design, National Reactor Innovation Center test beds, and nonproliferation analysis of the AGN-201 reactor design. We share key lessons learned for these projects related to tool selection, adoption and training, and working with existing assets versus beginning at the design phase. We also share highlights of future potential uses of digital twins and digital engineering, including using artificial intelligence to perform repetitive design tasks and digital twins to move towards semiautonomous nuclear power plant operations.

The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral Aβ amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis-Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10−3), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10−5) and plasma tau concentration (0.06 log2(ng l−1) 95%CI 0.03; 0.08, p = 4.55 × 10−6). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.

Summary: Background: Drug development for atrial fibrillation (AF) has failed to yield new approved compounds. We sought to identify and prioritise potential druggable targets with support from human genetics, by integrating the available evidence with bioinformatics sources relevant for AF drug development. Methods: Genetic hits for AF and related traits were identified through structured search of MEDLINE. Genes derived from each paper were cross-referenced with the OpenTargets platform for drug interactions. Confirmation/validation was demonstrated through structured searches and review of evidence on MEDLINE and ClinialTrials.gov for each drug and its association with AF. Findings: 613 unique drugs were identified, with 21 already included in AF Guidelines. Cardiovascular drugs from classes not currently used for AF (e.g. ranolazine and carperitide) and anti-inflammatory drugs (e.g. dexamethasone and mehylprednisolone) had evidence of potential benefit. Further targets were considered druggable but remain open for drug development. Interpretation: Our systematic approach, combining evidence from different bioinformatics platforms, identified drug repurposing opportunities and druggable targets for AF. Funding: KK is supported by Barts Charity grant G-002089 and is mentored on the AFGen 2023-24 Fellowship funded by the AFGen NIH/NHLBI grant R01HL092577. RP is supported by the UCL BHF Research Accelerator AA/18/6/34223 and NIHR grant NIHR129463. AFS is supported by the BHF grants PG/18/5033837, PG/22/10989 and UCL BHF Accelerator AA/18/6/34223 as well as the UK Research and Innovation (UKRI) under the UK government’s Horizon Europe funding guarantee EP/Z000211/1 and by the UKRI-NIHR grant MR/V033867/1 for the Multimorbidity Mechanism and Therapeutics Research Collaboration. AF is supported by UCL BHF Accelerator AA/18/6/34223. CF is supported by UCL BHF Accelerator AA/18/6/34223.

Objective: The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). Methods: Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice. Results: Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the β-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice. Conclusions: GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism.

Research illustrating the adverse impact of discrimination and the increasing ethnic and racial diversity in the United States has resulted in a substantial body of work examining risk and protective factors for marginalized and ethnic and racial minority individuals. One factor that has received considerable attention over the past several decades is "ethnic-racial socialization" (ERS). Extant empirical research on ERS has heavily focused on parents, especially mothers, as socialization agents. What is noticeably missing from this literature is the potentially important roles of siblings as salient ERS agents. After briefly illustrating the focus of past research on parents as ERS agents, we review the theoretical justification for studying siblings in the ERS process and the very limited research on siblings' role in ERS-related processes. We close with a discussion of the important considerations for future researchers investigating sibling ERS.

Abstract Adenoid cystic carcinoma (ACC) is a rare form of adenocarcinoma that usually begins in the oral cavity, with most cases arising from the salivary glands. Owing to its low incidence, the precise clinical and pathological features, including therapeutic strategy and survival data have not been conclusively reported. ACCs are typically characterized by slow growth, perineural invasion with local and often late recurrence after initial diagnosis. However, some cases demonstrate unusual aggressive biologic behaviour. Herein we describe our experience of two patients with a diagnosis of ACC. These cases highlight the spectrum of the disease with individualized treatment strategies.

Time perspective is conceptualized as a multidimensional construct that assesses individuals' feelings and thoughts about the past, present, and future. The current study examined relationships between feelings (time attitudes) and thoughts (time orientation) about time and substance use behaviors across three adolescent samples. Participants included a high-risk sample of adjudicated youth (N=124; M age =15.54, SD=1.69; 51.61% female) and two general population school samples (N=777; M age =15.82, SD=1.23; 53.41% female; N=1873; M age =15.87, SD=1.28; 52.22% female). Cross-sectional survey data were collected from samples in schools during 2010, 2016, and 2011, respectively. Poisson and negative binomial regression analyses indicated that overall, more positive feelings about time were associated with fewer substances used and, conversely, more negative feelings about time were associated with more substances used. These findings were particularly salient for participants with stronger positive and negative feelings toward the past and present time periods. Further, across the three samples, adolescents with a balanced time orientation (i.e., equal emphasis on all three time periods) generally reported less substance use than individuals who emphasized only one or two time periods. Findings highlight relationships between time perspective dimensions and substance use across diverse samples and illustrate opportunities for adapting time perspective-based substance use interventions for adolescents.

Human induced pluripotent stem cell (hiPSC)-derived cells can reproduce human-specific pathophysiology, patient-specific vulnerability, and gene-environment interactions in neurological disease. Human in vitro models of neurotrauma therefore have great potential to advance the field. However, this potential cannot be realized until important biomaterials challenges are addressed. Status quo stretch injury models of neurotrauma culture cells on sheets of polydimethylsiloxane (PDMS) that are incompatible with long-term monoculture of hiPSC-derived neurons. Here, we overcame this challenge in an established human in vitro neurotrauma model by replacing PDMS with a highly biocompatible form of polyurethane (PU). This substitution allowed long-term monoculture of hiPSC-derived neurons. It also changed the biomechanics of stretch injury. We quantified these changes experimentally using high-speed videography and digital image correlation. We used finite element modeling to quantify the influence of the culture substrate's thickness, stiffness, and coefficient of friction on membrane stretch and concluded that the coefficient of friction explained most of the observed biomechanical changes. Despite these changes, we demonstrated that the modified model produced a robust, dose-dependent trauma phenotype in hiPSC-derived neuron monocultures. In summary, the introduction of this PU film makes it possible to maintain hiPSC-derived neurons in monoculture for long periods in a human in vitro neurotrauma model. In doing so, it opens new horizons in the field of neurotrauma by enabling the unique experimental paradigms (e.g., isogenic models) associated with hiPSC-derived neurons.

Abstract Background Agonism at the receptor for the glucose-dependent insulinotropic polypeptide (GIPR) is a key component of the novel unimolecular GIPR:GLP-1R co-agonists, which are among the most promising drugs in clinical development for the treatment of obesity and type 2 diabetes. The therapeutic effect of chronic GIPR agonism to treat dyslipidemia and thus to reduce the cardiovascular disease risk independently of body weight loss has not been explored yet. Methods After 8 weeks on western diet, LDL receptor knockout (LDLR-/-) male mice were treated with daily subcutaneous injections of long-acting acylated GIP analog (acyl-GIP; 10nmol/kg body weight) for 28 days. Body weight, food intake, whole-body composition were monitored throughout the study. Fasting blood glucose and intraperitoneal glucose tolerance test (ipGTT) were determined on day 21 of the study. Circulating lipid levels, lipoprotein profiles and atherosclerotic lesion size was assessed at the end of the study. Acyl-GIP effects on fat depots were determined by histology and transcriptomics. Results Herein we found that treatment with acyl-GIP reduced dyslipidemia and atherogenesis in male LDLR-/- mice. Acyl-GIP administration resulted in smaller adipocytes within the inguinal fat depot and RNAseq analysis of the latter revealed that acyl-GIP may improve dyslipidemia by directly modulating lipid metabolism in this fat depot. Conclusions This study identified an unanticipated efficacy of chronic GIPR agonism to improve dyslipidemia and cardiovascular disease independently of body weight loss, indicating that treatment with acyl-GIP may be a novel approach to alleviate cardiometabolic disease.

This paper serves as a companion paper to the Economic Development and Institutions’ (EDI) White Paper “At the Intersection: A Review of Institutions in Economic Development” (Dal Bó and Finan, 2016). The White Paper reviewed nearly 200 publications from economics and political science on the role of institutions in development, drawing from experimental and quasi-experimental evidence whenever possible. The goal of the White Paper was threefold: (i) to present a framework for reviewing and synthesizing the existing evidence on how legal and political institutions affect development outcomes; (ii) to distill lessons learned from the literature; and (iii) to present open questions in each topic that defined the research frontier at that time. This Green Paper revisits the themes and research priorities identified by the White Paper five years later. The purpose is to assess how the research funded by the EDI program contributes to our knowledge of how institutions affect development, and where the research frontier lies today. Whenever possible, we synthesize lessons across funded studies in cross-cutting analytic themes to identify the mechanisms that underlie observed effects. This paper illustrates the substantial progress we have made in our understanding of the role of institutions in development and growth. While this new evidence sheds light on many of the open questions originally raised in the White Paper, often it also raises new questions and pushes the research frontier forward. It is clear that this is an active area of research where our knowledge should, and hopefully will, continue to evolve over time.

Parkinson's disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson's disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson's disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson's disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson's disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson's disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson's disease drug development.

This paper serves as a companion paper to the Economic Development and Institutions’ (EDI) White Paper “At the Intersection: A Review of Institutions in Economic Development” (Dal Bó and Finan, 2016). The White Paper reviewed nearly 200 publications from economics and political science on the role of institutions in development, drawing from experimental and quasi-experimental evidence whenever possible. The goal of the White Paper was threefold: (i) to present a framework for reviewing and synthesizing the existing evidence on how legal and political institutions affect development outcomes; (ii) to distill lessons learned from the literature; and (iii) to present open questions in each topic that defined the research frontier at that time.

Using interpretative phenomenology analysis, this study explored the lived experiences of eight Latinx and Asian trainees. Four superordinate themes were identified: illuminating hegemonic structures, identity challenges, increasing competence through awareness, and varying connections. Implications related to cross-cultural counseling and counselor education and future research are discussed.

BackgroundWe analyzed the prevalence of active infection with common curable sexually transmitted infections (STIs) including N. gonorrhea, C. trachomatis, T. vaginalis, and T. pallidum, as well as active infection with HPV, herpes simplex virus types I (HSV-1) and II (HSV-2), M. hominis, M. genitalium, C. albicans, and Ureaplasma in 351 Lebanese women.MethodsA cross-sectional study, involving 351 sexually active women, 40 years or younger, who were recruited from outpatient Obstetrics and Gynecology clinic attendees between September 2016 and November 2017.ResultsThe prevalence of active infection was low at 0.3% for N. gonorrhea, 0.6% for HSV-2, 2.8% for C. trachomatis, and 2.9% for any curable STIs. Prevalence of active HPV infection was high assessed at 15.7% for high-risk and 12.2% for low-risk genotypes. Furthermore, the prevalence was 2.0% for M. genitalium, 6.8% for ureaplasma, 13.7% for Candida albicans, and 20.5% for M. hominis. No active infections with T. vaginalis, T. pallidum, or HSV-1 were observed. Significant age differences were noted in the prevalence of high-risk and low-risk HPV genotypes, but no such differences were noted in the prevalence of other infections. No appreciable variations were identified in the prevalence of key STIs based on smoking, marital status, or the number of sexual partners.ConclusionsThe study documented active infection with substantial prevalence for multiple STIs among women attending outpatient gynecology and obstetrics clinics in Lebanon. These findings underscore the importance of strengthening STI surveillance, linkage to care, and prevention interventions in reducing STI incidence among women.

Background Most people with autosomal dominant familial hypercholesterolaemia (FH) remain undetected, which represents a missed opportunity for coronary heart disease prevention.Objective To evaluate the performance of two-stage adult population screening for FH.Design Using data from UK Biobank, we estimated the screening performance of different low-density lipoprotein cholesterol (LDL-C) cut-offs (stage 1) to select adults for DNA sequencing (stage 2) to identify individuals with FH-causing variants in LDLR, APOB, PCSK9 and APOE. We estimated the number of additional FH cases detected by cascade testing of first-degree relatives of index cases and compared the overall approach with screening in childhood.Setting UK Biobank.Participants 140 439 unrelated participants of European ancestry from UK Biobank with information on circulating LDL-C concentration and exome sequence.Main outcome measures For different LDL-C cut-offs, we estimated the detection and false-positive rate, the proportion of individuals who would be referred for DNA sequencing (stage 1 screen positive rate), and the number of FH cases identified by population screening followed by cascade testing.Results We identified 488 individuals with an FH-causing variant and 139 951 without (prevalence 1 in 288). An LDL-C cut-off of >4.8 mmol/L had a stage 1 detection rate (sensitivity) of 40% (95% CI 36 to 44%) for a false-positive rate of 10% (95% CI 10 to 11%). Detection rate increased at lower LDL-C cut-offs but at the expense of higher false-positive and screen positive rates, and vice versa. Two-stage screening of 100 000 adults using an LDL-C cut-off of 4.8 mmol/L would generate 10 398 stage 1 screen positives for sequencing, detect 138 FH cases and miss 209. Up to 207 additional cases could be detected through two-generation cascade testing of first-degree relatives. By comparison, based on previously published data, childhood screening followed by cascade testing was estimated to detect nearly three times as many affected individuals for around half the sequencing burden.Conclusions Two-stage adult population screening for FH could help achieve the 25% FH case detection target set in the National Health Service Long Term Plan, but less efficiently than childhood screening and with a greater sequencing requirement.

Abstract We look at Brazilian collaboration in Scientific papers based on SciVal and Incites regarding the Sustainable Development Goals (SDGs) of the United Nations. Data were collected from InCites® and SciVal® (2012-2021). Groups of Global South countries were formed (ASEAN, Asia, Africa, BRICS, Caribbean, Central and Latin America). Analyses included Cluster (Author position, impact/citations, open access, journal quartil), principal component, path and analysis of variance to see the effect of region and SDGs in Brazilian publishing. Scopus data were analysed in Vosviewer® for creating country networks through publication, citation and bibliographic coupling, as well as keyword analysis. SDG 3 (Good Health and Well-Being) dominates all Brazilian scientific collaborations with the various country groups. While gender equality shows greater importance in ASEAN and African countries, Life Below Water (SDG14), on Land (SDG15), and Climate Action (SDG13), are important in all regions. SDGs 1, 8, 10, 12, and 16 show less importance in this collaboration overall. Brazil is relatively more active in Zero Hunger (SDG2) and Life on Land (SDG15) than worldwide. Brazil South-South collaboration in published documents shows higher impact than North South in some areas. Collaboration priorities vary by region and triangulation with countries is high depending on language and region.

Abstract. Introduction:. Patients with chronic pain experience a high prevalence of comorbid insomnia, which is associated with functional impairment. Recent advances in sleep electroencephalography (sleep-EEG) may clarify the mechanisms that link sleep and chronic pain. In this clinical update, we outline current advancements in sleep-EEG assessments for pain and provide research recommendations. Results:. Promising preliminary work suggests that sleep-EEG spectral bands, particularly beta, gamma, alpha, and delta power, may create candidate neurophysiological signatures of pain, and macro-architectural parameters (e.g., total sleep time, arousals, and sleep continuity) may facilitate EEG-derived sleep phenotyping and may enable future stratification in the treatment of pain. Conclusion:. Integration of measures obtained through sleep-EEG represent feasible and scalable approaches that could be adopted in the future. We provide research recommendations to progress the field towards a deeper understanding of their utility and potential future applications in clinical practice.