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Crohn's disease and ulcerative colitis are chronic inflammatory diseases of the gastrointestinal tract. In addition to bowel symptoms, patients may also have oral manifestations. This thesis investigated potential associations between disease activity in the gut, oral health, salivary gland function, and saliva composition. Patients with Crohn's disease had a significantly higher DMFT index, but showed no difference in periodontal diseases compared to a healthy control group. The saliva composition in patients with active bowel disease differed from that in patients with inactive bowel disease, suggesting that saliva analysis could potentially be used in the future to determine the degree and severity of bowel disease. The knowledge of gastroenterologists and dentists regarding oral manifestations of bowel diseases was found to be limited. Gastroenterologists and dentists valued interdisciplinary patient consultation as very useful, but the frequency of consultation was considered insufficient.

Background: Outpatient parenteral antimicrobial treatment (OPAT) is a safe and effective therapy used in several settings across Australia. As OPAT services expand their inclusion criteria to include complex patient populations, there is an increased need for selecting appropriate patients to receive either healthcare-administered OPAT (H-OPAT) or self-administered OPAT (S-OPAT)., Aims: To describe patient demographics, diagnosis, microbiology and outcomes of patients treated by H-OPAT and S-OPAT within the Sunshine Coast Hospital and Health Service, Australia., Methods: Data on demographics, diagnoses, treatment and outcomes on all patients treated by H-OPAT and S-OPAT from March 2017 to December 2019 were collected retrospectively., Results: One hundred and sixty-five patients (62.26%) were enrolled in H-OPAT and 100 patients (37.74%) in S-OPAT. S-OPAT patients were significantly younger. H-OPAT patients were more comorbid. Bone and joint infections were the most treated infections and were more likely to be treated by S-OPAT. There was no difference in treatment duration, cure and complication rates between S-OPAT and H-OPAT. Longer duration of therapy was associated with more complications. Treatment failure was associated with infections due to multiple organisms, number of comorbidities and treatment of surgical site, skin and soft tissue infections., Conclusions: There were significant differences in demographics between H-OPAT and S-OPAT without any difference in outcomes. Overall failure and complication rates were low. Higher rates of treatment failure were predicted by the diagnosis, number of comorbidities and number of organisms treated., (© 2024 Royal Australasian College of Physicians.)

The main aim of the current study was to find biomarkers of health in calves transported at different ages. The selected blood parameters were total cholesterol, insulin, and IGF-1, and the longitudinal study investigated whether or not these concentrations were different between calves that were transported from the dairy farm to the veal farm at 14 or 28 d of age. Relationships between these blood variables and health characteristics of veal calves were investigated. In a 34-wk study period, a total of 683 calves originating from 13 Dutch dairy farms were transported at an age of 14 or 28 d to 8 Dutch veal farms. Calves were blood sampled the first week after birth (mean and SD: 4.4 ± 2.1 d), 1 d before transport (mean and SD: 25.8 ± 7.3 d), and in wk 2 post-transport (mean and SD: 36.7 ± 12.2 d). In these samples, insulin, IGF-1, and total cholesterol were determined and analyzed with a linear mixed model (LMM). Individual medical treatments were recorded from birth until the day of transport at the dairy farm, and from the moment of arrival at the veal farm until slaughter, and analyzed as a binary response variable (calf treated or not) with a generalized LMM. Fecal (calf with or without loose or liquid manure) and navel (calves with or without swollen and inflamed navel) scores measured during a single visit in wk 2 post-transport were also analyzed as binary response variables, whereas carcass weights at slaughter age were analyzed with a LMM. Cholesterol, insulin, and IGF-1 were included as covariates in the previous models to test their relationships with the likelihood of calves being medically treated, fecal and navel scores, and carcass weights. One day before transport 28-d-old calves had higher blood cholesterol (Δ = 0.40 mmol/L) and IGF-1 (Δ = 53.6 ng/mL) concentrations, and evidence of higher insulin (Δ = 12.2 µU/mL) compared with 14-d-old calves. In wk 2 post-transport, 28-d-old calves had higher blood IGF-1 (Δ = 21.1 ng/mL), with evidence of higher insulin (Δ = 12.2 µU/mL) concentrations compared with 14-d-old calves. Cholesterol concentration measured 1 d before transport and in wk 2 post-transport had a positive relationship with carcass weight at slaughter (regression coefficients [β] = 4.8 and 7.7 kg/mmol per liter, respectively). Blood cholesterol concentration in wk 2 post-transport was negatively associated with the fecal score measured at the same sampling moment (β = -0.55/mmol/L), with the likelihood of a calf of being treated with antibiotics (β = -0.36/mmol/L) and other medicines (β = -0.45/mmol/L) at the veal farm. Blood IGF-1 concentration in wk 2 post-transport was negatively associated with the likelihood of a calf of being treated with antibiotics and other medicines (both β = -0.01/ng/mL) at the veal farm, and with fecal score recorded in wk 2 post-transport (β = -0.004/ng/mL). When looking at the blood indicators, it appeared that calves transported at 28 d of age were more developed compared with 14-d-old calves, thus transport at an older age might be more beneficial for the animals. It can be concluded that both blood cholesterol and IGF-1 concentrations seemed to be valuable biomarkers of health and energy availability in veal calves., (© 2024, The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Introduction: Effective diabetes management relies mainly on an individual's ability to perform self-care tasks. However, this process is influenced by a complex interplay of factors. This study explores the multifaceted influences on Diabetes Self-Management (DSM), examining both factors influencing and affecting DSM. Understanding these influences is crucial for developing targeted Digital Health Interventions that empower individuals with diabetes to achieve successful self-management., Objectives: To identify problems faced by Type 2 Diabetes Mellitus (T2DM) individuals in self-managing diabetes and leveraging mHealth technology, with need-based solutions to Empower Self-Management in T2DM., Methodology: In-depth semi-structured interviews were conducted among ten patients with T2DM visiting the outpatient department of a tertiary care hospital in coastal Karnataka. Additionally, six healthcare professionals (HCPs) working closely with T2DM patients were interviewed to understand their perspectives on using mHealth to manage T2DM effectively. The themes for the solutions described were analyzed using ATLAS-TI software., Results: Our research examined certain factors that might have influenced effective diabetes self-management and investigated patient perspectives on using digital health solutions in diabetes self-management. This study found that technology skills, duration of diabetes, knowledge, and personal beliefs were all significant factors affecting self-management in participants with T2DM. Additionally, socioeconomic factors were also seen to influence effective diabetes self-management. The Google search engine was used by 50% of the participants interviewed to learn about T2DM. Diet management through Google searches was used by a minority (30%) of the patients. None of the participants had previously used any mobile health applications (mHealth apps) to manage T2DM. 20% of the participants expressed limited knowledge about using smartphones or wearables to track health parameters. The study also identified potential non-technological barriers to mHealth adoption. To address these concerns, researchers used an empathy map to develop solutions that promote mHealth use., Conclusion: Several challenges and need-based mHealth solutions were identified to empower diabetes self-management education among T2DM patients. Implementing need-based mHealth solutions such as data tracking, personalized feedback, and access to educational resources can lead to better disease control and a higher quality of life for those with T2DM. Further research and development in mHealth interventions, and collaborative efforts among healthcare providers, patients, and technology developers, hold a promising future for the healthcare sector in providing efficient, effective, and accessible care., (© 2024. The Author(s).)

Purpose: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs)., Methods: We coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations., Results: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses., Conclusion: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies., (Copyright © 2024. Published by Elsevier Inc.)

High-throughput omics technologies have become valuable tools for systems science research and clinical management of sepsis. This article analyzes sepsis research using omics technologies in the European Union (EU) and the United Kingdom from 1990 to May 2023 using bibliometric data from the Web of Science database. Using VOSviewer for network analysis, we examined the distribution patterns, funding characteristics, and collaborations among the states, noting trends of convergence and divergence. The analysis included 2078 articles, revealing an increasing rate of publications on sepsis research using omics approaches. The United Kingdom's research output is notably high, contributing 28.3% of the total research from the EU and United Kingdom combined. Germany, France, the Netherlands, and Italy together account for 56.9% of the publications from the EU member states. The United States is the leading international collaborator, particularly with the United Kingdom, followed by Germany and France. The EU-15 countries have significantly more publication outputs in this domain with growing but limited inclusion of the newer members of the EU. We suggest that the role of EU member states and the United Kingdom in sepsis research using omics technologies can be advanced by facilitating high-value, technology-driven health research, fostering collaboration, convergence, and equity in global health and biomedical research.

Underrepresented populations are often excluded from genomic studies owing in part to a lack of resources supporting their analyses. The 1000 Genomes Project (1kGP) and Human Genome Diversity Project (HGDP), which have recently been sequenced to high coverage, are valuable genomic resources because of the global diversity they capture and their open data sharing policies. Here, we harmonized a high-quality set of 4094 whole genomes from 80 populations in the HGDP and 1kGP with data from the Genome Aggregation Database (gnomAD) and identified over 153 million high-quality SNVs, indels, and SVs. We performed a detailed ancestry analysis of this cohort, characterizing population structure and patterns of admixture across populations, analyzing site frequency spectra, and measuring variant counts at global and subcontinental levels. We also show substantial added value from this data set compared with the prior versions of the component resources, typically combined via liftOver and variant intersection; for example, we catalog millions of new genetic variants, mostly rare, compared with previous releases. In addition to unrestricted individual-level public release, we provide detailed tutorials for conducting many of the most common quality-control steps and analyses with these data in a scalable cloud-computing environment and publicly release this new phased joint callset for use as a haplotype resource in phasing and imputation pipelines. This jointly called reference panel will serve as a key resource to support research of diverse ancestry populations., (© 2024 Koenig et al.; Published by Cold Spring Harbor Laboratory Press.)

Introduction: Cardiovascular diseases are a major public health issue and the leading cause of mortality globally. The global economic burden of out-of-pocket expenditure (OOPE) for cardiovascular surgeries and procedures is substantial, with average costs being significantly higher than other treatments. This imposes a heavy economic burden. Government insurance schemes like Ayushman Bharat Pradhan Mantri Jan Arogya Yojana (AB-PMJAY) aim to enhance affordability and access to cardiac care., Methodology: This retrospective study analyzed OOPE incurred for top cardiac surgeries under AB-PMJAY, private insurance, and uninsured patients at a tertiary care teaching hospital in Karnataka. Data of 1021 patients undergoing common cardiac procedures from January to July 2023 were analyzed using descriptive statistics (mean, median) and the Shapiro-Wilk test for normality. The study aims to evaluate financial risk protection offered by AB-PMJAY compared to private plans and inform effective policy-making in reducing the OOPE burden for surgeries in India., Results: The study analyzed OOPE across 1021 patients undergoing any of four surgeries at a tertiary care teaching hospital in Karnataka. AB-PMJAY patients incurred zero OOPE across all surgeries. Uninsured patients faced the highest median OOPE, ranging from ₹1,15,292 (1390.57 USD) to ₹1,72,490 (2080.45 USD) depending on surgery type. Despite the presence of private insurance, the median out-of-pocket expenditure ranged from ₹1,689 (20.38 USD) to ₹68,788 (829.67 USD). Significant variations in OOPE were observed within different payment groups. Private insurance in comparison with AB-PMJAY had limitations like co-payments, deductibles, and limited coverage resulting in higher OOPE for patients., Discussion: The results illustrate the efficacy of AB-PMJAY in reducing the financial burden and improving the affordability of cardiac procedures compared to private insurance. This emphasizes the significance of programmmes funded by the government in reducing the OOPE burden and ensuring equitable healthcare access. The comprehensive and particular estimates of OOPE for different surgical procedures, categorized by payment methods provide valuable information to guide the development of policies that aim to reduce OOPE and progress toward universal health coverage in India., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Kasturba Medical College and Kasturba Hospital Institutional Ethics Committee – 2 issued approval IEC2:564/2023, dated November 20, 2023. The Institutional Review Board of Prasanna School of Public Health (PSPH) is the Kasturba Medical College (KMC) and Kasturba Hospital Institutional Ethics Committee – 2. Both PSPH and KMC are constituent units of the Manipal Academy of Higher Education (MAHE), Karnataka, India. In line with regulatory norms, MAHE has mandated all hospital-based studies in MAHE to apply to the KMC and Kasturba Hospital Institutional Ethics Committee. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kamath et al.)

Objective: Our aim was to assess the level and socio-demographic correlates of the ability to maintain health among children in Albania, a post-communist country in the Western Balkans., Methods: A cross-sectional study was conducted in Albania in September 2022. The study population consisted of a nationwide representative sample of 7,831 schoolchildren (≈54% girls) aged 12-15 years. A structured self-administered and anonymous questionnaire inquired about the children's attitudes toward health promotion (ability to maintain and improve health) and a range of key dimensions on knowledge and practices regarding healthcare services. Socio-demographic data were also collected. Binary logistic regression was used to assess the socio-demographic correlates of children's ability to maintain health., Results: Overall, about 71% of schoolchildren exhibited the best attitudes toward health promotion (ability to maintain and improve health). In the multivariable adjusted logistic regression models, poorer attitudes toward health promotion (ability to maintain and improve health) were significantly related to older age (OR=1.2, 95% CI=1.0-1.3), middle/low maternal education (OR=1.2, 95%CI=1.1-1.3), poor/very poor economic situation (OR=1.5, 95%CI=1.2-1.8), lack of appropriate knowledge about rights to healthcare (OR=1.3, 95% CI=1.1-1.5), lack of knowledge about obtaining healthcare services (OR=1.7, 95%CI=1.4-2.2), and lack of consultations/visits with health professionals excluding vaccinations (OR=1.2, 95%CI=1.1-1.4)., Conclusions: Almost 1/3 rd of Albanian schoolchildren included in this study did not exhibit the best attitudes toward health promotion (ability to maintain and improve health). The best attitudes were related to a higher socioeconomic level and adequate knowledge and practices regarding healthcare services. There is thus a need to increase health literacy levels among children in order to ultimately induce sustainable healthy behavioural/lifestyle practices., (© 2024 Herion Muja et al., published by Sciendo.)

Background: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined., Methods: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center., Results: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments., Conclusions: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Objective: Unfair medicines prices have been discussed widely as an obstacle for patient access. This article aims to structure the discussion about fair pricing of medicines, analyses the elements for a fair price, and assesses its practical implications., Methods: A systematic literature research has been undertaken and complemented by gray literature. Definitions and elements of a fair price have been extracted from the sample, categorized via a thematic and a quantitative analysis, and mirrored against the traditional framework of 'iustum pretium' (fair price)., Results: The most often attributes of a fair price mentioned were affordability (n = 30), followed by value and research and development (R&D) investment (n = 20). Other frequently mentioned attributes are profitability (n = 19), transparency of R&D costs (n = 18), cost-effectiveness (n = 17), and manufacturing (n = 14). Nearly all definitions present fair price as a balance between different objectives., Conclusions: Most publications stipulate that medicines are a common good and should be affordable. At the same time, most publications also propose a pricing approach based on covering costs for R&D and/or on value. Consequently, most of the attempts to clarify fair price result in a value-affordability dilemma, which does not necessarily warrant patient access. Many social health systems implement pricing regardless of the debate. This systematic review offers a set of attributes for fair price and helps refining the existing pricing and reimbursement regulations. Once complemented by empirical datapoints, it provides the basis for developing a framework for fair pricing., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Salivary stones are hardened, stony calcifications that primarily develop in the drainage duct of a salivary gland. They can lead to obstruction of the saliva flow, resulting in swelling and pain. Since the aetiology of salivary stones remains largely unclear, this was further investigated in this PhD study. A case-control review of patient records showed that systemic diseases and lifestyle factors most likely do not play a role in their occurrence. The biochemical composition of salivary stones removed by oral-maxillofacial surgeons was examined, revealing that large salivary stones have a different inorganic composition than small salivary stones. Several salivary proteins were detected in submandibular salivary stones, including lysozyme, s-IgA, and -amylase. Clumping together of these proteins may play a role in the initial formation of salivary stones.

Introduction: Tobacco usage is an epidemic as statistics point towards smoking as the second leading cause of death. Populations experiencing humanitarian emergencies may experience a higher propensity for tobacco, alcohol, and other substance abuse disorders. This review aimed to map tobacco prevention and control interventions in humanitarian settings., Methods: The search for this scoping review was conducted in six databases and supplemented with a gray literature search. Articles were screened at title-abstract and full-text by two pairs of authors, and data was abstracted by three individuals independently. An adapted diffusion of governance framework is used to discuss the findings., Results: A total of 26 articles were included from the searches conducted in the databases and grey literature. The interventions targeted all age groups. The documents retrieved from the grey literature search were classified as population-based interventions, as they were not restricted to a particular group of individuals. Interventions were delivered at various locations, using different methods and engaging multiple stakeholders. Interventions assessed were grouped into packaging, labeling, and other policy interventions (pricing and taxes)., Conclusion: There are few tobacco prevention and control interventions in the humanitarian context. The diffusion of governance perspective in implementing these interventions in humanitarian settings provides a cue for inter-sectoral cooperation among different stakeholders and disciplines beyond the health sector. Our review recommends exploring complementarity between the demand and supply side interventions for tobacco control., Implications: The scoping review has highlighted various tobacco prevention and control efforts in humanitarian settings. The interventions were delivered using various modes, and yet the burden of smoking is higher among the humanitarian population. Further research may use impact evaluation techniques to assess the impact of these interventions to facilitate the re-design of the implementation approach and policy priorities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Objective : To determine which salivary proteins adhere onto sport mouthguards, and to evaluate the effectiveness of different cleaning strategies in removing deposited protein. Methods : Fifteen healthy volunteers used a mouthguard for 1 h. The deposited salivary proteins were analyzed using gel electrophoresis and Western blotting techniques and compared with the protein composition of unstimulated saliva. In addition, the effectiveness of two different cleaning strategies to remove proteins from the mouthguards were compared: rinsing the mouthguards after use with cold tap water and cleaning the mouthguard with a soluble effervescent tablet. Results : Gel electrophoresis showed deposition of proteins of 50-60 kDa and 14 kDa on the mouthguards used in the mouth for 1 h. Western blotting identified these bands as amylase and lysozyme, respectively. Rinsing the mouthguard with cold tap water after use removed 91% of the total amount of deposited proteins, while cleaning with an effervescent tablet removed 99%. Conclusions : During the use of mouthguards, salivary proteins are deposited on their surface. Because salivary proteins can potentially affect bacterial adhesion to mouthguards, proper cleaning after use is recommended. Cleaning the mouthguard with cold tap water or using an effervescent tablet both seem to be effective strategies to remove proteins deposited on sport mouthguards.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs., Competing Interests: Declaration of interests H.L.R. and M.E.T. have received support from Illumina and Microsoft to support rare disease gene discovery and diagnosis. A.O’D.-L. is on the scientific advisory board for Congenica Inc. D.G.M. is a paid advisor to GlaxoSmithKline, Insitro, Variant Bio, and Overtone Therapeutics and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Google, Merck, Microsoft, Pfizer, and Sanofi-Genzyme. C.A.W. is a paid advisor to Maze Therapeutics. M.E.T. has also received reagents and/or research support from Levo Therapeutics, Pacific Biosciences, Oxford Nanopore, and Ionis Pharmaceuticals., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

Purpose: Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively., Methods: ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID., Results: The ES diagnostic yield was 42 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8 of 9 single-nucleotide variations/copy-number variations undetected in older ES, confirming a GS-unique diagnostic rate of 1 in 32 (3%). Episignatures contributed diagnostic information in 9% with GS corroboration in 1 of 32 (3%) and diagnostic clues in 2 of 32 (6%). A genetic etiology for ID was detected in 51 of 74 (69%) families. Twelve candidate disease genes were identified. Contemporary ES followed by GS cost US$4976 (95% CI: $3704; $6969) per diagnosis and first-line GS at a cost of $7062 (95% CI: $6210; $8475) per diagnosis., Conclusion: Performing GS only in ID trios would be cost equivalent to ES if GS were available at $2435, about a 60% reduction from current prices. This study demonstrates that first-line GS achieves higher diagnostic rate than contemporary ES but at a higher cost., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic has highlighted the importance of local evidence ecosystems in which academia and practice in the Public Health Service (PHS) are interconnected. However, appropriate organizational structures and well-trained staff are lacking and evidence use in local public health decision-making has to be integrated into training programs in Germany. To address this issue, we developed a framework incorporating a toolbox to conceptualize training programs designed to qualify public health professionals for working at the interface between academia and practice. We conducted a scoping review of training programs, key-informant interviews with public health experts, and a multi-professional stakeholder workshop and triangulated their output. The resulting toolbox consists of four core elements, encompassing 15 parameters: (1) content-related aspects, (2) context-related aspects, (3) aspects relevant for determining the training format, and (4) aspects relevant for consolidation and further development. Guiding questions with examples supports the application of the toolbox. Additionally, we introduced a how-to-use guidance to streamline the creation of new training programs, fostering knowledge transfer at the academia-practice interface, equipping public health researchers and practitioners with relevant skills for needs-based PHS research. By promoting collaborative training development across institutions, our approach encourages cross-institutional cooperation, enhances evidence utilization, and enables efficient resource allocation. This collaborative effort in developing training programs within local evidence ecosystems not only strengthens the scientific and practical impact but also lays a foundation for implementing complex public health measures effectively at the local level., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Arnold 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.)

To analyze the portrayal of dentists in films, 259 films from the period 1907 - 2018 featuring one or more dentists, were systematically analyzed. A total of 333 dentists were identified, mostly of Caucasian origin (85%) and male (86%). 228 dentists depicted dental procedures, sometimes using gloves (41%), (splash) glasses (35%), and mouth masks (24%). The depicted dental procedures mainly consist of the use of pocket probes and mirrors (46%), drilling/filling (31%), and extractions (25%). Furthermore, dentists in films are relatively often involved in negative activities such as physical violence (29%) and sexual offences (18%). In 16 films (6%), dentists murdered people. Although there is no single stereotypical portrayal of dentists in films, the overall picture seems to need improvement as it is not contributing to the reputation of the dental profession.

Advances in sequencing and imaging technologies enable enhanced assessment in the prenatal space, with a goal to diagnose and predict the natural history of disease, to direct targeted therapies, and to implement clinical management, including transfer of care, election of supportive care, and selection of surgical interventions. The current lack of standardization and aggregation stymies variant interpretation and gene discovery, which hinders the provision of prenatal precision medicine, leaving clinicians and patients without an accurate diagnosis. With large amounts of data generated, it is imperative to establish standards for data collection, processing, and aggregation. Aggregated and homogeneously processed genetic and phenotypic data permits dissection of the genomic architecture of prenatal presentations of disease and provides a dataset on which data analysis algorithms can be tuned to the prenatal space. Here we discuss the importance of generating aggregate data sets and how the prenatal space is driving the development of interoperable standards and phenotype-driven tools., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

In recent years, the five-year survival rate for childhood cancer has increased to about 80%. However, childhood cancer therapy can have serious long-term adverse effects on general health later in life. Of survivors, 75% experience 1 or more late effects. This PhD research aimed to gain more insight into the long-term effects on oral health of childhood cancer therapy, 15 years or more after diagnosis. This study, which is part of the Dutch Childhood Cancer Survivor Study Late Effects 2 (DCCSS LATER 2 Study), showed that oral complications such as dental developmental disorders and hyposalivation occur frequently. Most important risk factors were head and neck radiotherapy of the salivary glands, (alkylating) cytostatic agents, and age at the time of the cancer diagnosis. Dentists should be aware of childhood cancer in the medical history of their patient and of the type of therapy received. Regular dental visits are an essential part of long-term follow-up care of childhood cancer survivors.

Background: Health security as a domain has gained tremendous importance in the recent past. Emerging and re-emerging diseases globally, coupled with the derailment of the determinants of health mainly the socio-political environment, has made health security a cross-cutting entity in diverse fields including International Relations (IR). With the ongoing global polycrisis, the health-related issues which were previously sidelined as a concept of less strategic importance in the IR field, are now contributing to the shift of the world order. This has instilled an increased participation of IR scholars in the discussions and debates on health security concerns. The field of IR contains numerous theoretical lenses through which scholars analyze such situations, policies, and systems of the world., Methods: In this paper, we use a scoping review method to inspect how IR theories have been applied in analyzing health security concerns., Results: We observed that various diverging IR theories have been used to deliberate on states' actions in tackling the recent pandemic and have also been prescriptive about the changing notions of multilateralism and international governing organizations. Realism, liberalism, and securitization were among the most frequently applied IR theories in the context of health security discussions., Conclusions: This work provides an impetus to enhance the interaction among interdisciplinary teams leading to evolving solutions that can address issues of global importance in the contemporary world., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Pattanshetty S et al.)

Dental caries is a major public health problem and untreated caries has serious consequences for children. Psychosocial factors have multiple consequences, among others on the composition of saliva. Therefore, this study investigated whether stress and various salivary protein levels are associated with dental caries experience in children. The activity of the Matrix Metalloproteinases MMP-8 and MMP-9 and the total proteolytic activity in saliva turned out to be indicators for the caries experience. Salivary Alpha-Amylase seems to be a protector and was a strong indicator for caries experience. In cases where children were exposed to two different dental treatments, the level of salivary cortisol- and alpha-amylase increased, in which a distinction could be made between non-invasive and invasive treatment. The results of the study emphasise the need for further research into the way stress and salivary protein concentrations can affect the caries experience and how different dental treatments can influence the behaviour and stress levels in children.

Malaria is a major public health problem in developing countries. The burden of malaria in fragile and conflict-affected states (FCAS) is increasing year by year. Moreover, the population living in FCAS is often the most vulnerable and at high risk of malaria due to factors, such as deteriorating healthcare system, mass relocations, and reduced resilience to shocks. Therefore, this scoping review aims to map the interventions that are conducted at the FCAS on malaria prevention among the general population. In addition, this review can help policy-makers and international health bodies, providing a comprehensive overview that can lead to more targeted, effective, and context-specific interventions. Databases, such as PubMed, EBSCO-CINAHL, Web of Science, ProQuest, and Cochrane Central Register of Controlled Trials, were searched using specified search terms. A total of 3601 studies were retrieved from the search. After screening, 62 studies were included in the synthesis that met the eligibility criteria. Narrative analysis of the findings was done. The results revealed that in fragile countries, interventions for children below 5 years of age included IPTi, TDA, and ACT. In conflicted countries, interventions for children below 5 years of age included TDA, LLINs, SMC, drug trials, and vaccination. Similar interventions were reported for other age groups and populations. Despite ongoing conflicts, malaria interventions have been maintained in these countries, but a persistent high burden of malaria remains. To achieve the goals of malaria elimination, the results of the review highlight the need for continued research and evaluation of malaria control interventions to assess their effectiveness and impact. Strengthening health systems, building partnerships, utilizing digital health technologies, and conducting context-specific research are recommended to improve healthcare access and reduce the burden of malaria in FCAS., (© 2024. The Author(s).)

The aim of this study was to compare the diagnostic accuracy of nasal sampling using a novel anterior nasal swab (ANS) (Rhinoswab) versus combined oro-nasopharyngeal (OP/NP) sampling in COVID-19 suspected patients. This prospective observational study was performed from 11 November to 2 December 2021 (part 1), and from 16 January to 22 February 2022 (part 2). Adult patients who attended the emergency room with suspected COVID-19 were asked to participate. One ANS and one OP/NP sample were consecutively collected, and both were analyzed via reverse transcription polymerase chain reaction (RT-PCR). The result of the OP/NP sample was considered to be the reference standard. A total of 412 patients were included, of whom 171 (41.5%) had a positive RT-PCR of the OP/NP swab, whereas 139 (33.7%) were positive on the ANS sample. The overall diagnostic accuracy for ANS sampling in terms of sensitivity, specificity, positive predictive value, and negative predictive value was 80.7% (95% CI 73.8-86.2), 99.6% (95% CI 97.3-100), 99.3% (95% CI 95.5-100), and 87.9% (95% CI 83.3-91.4), respectively. In conclusion, ANS sampling with the Rhinoswab identified 80.7% of all presented COVID-19 patients in an emergency department. Future studies should investigate if nasal Rhinoswab self-sampling is suitable for reliable diagnosis of COVID-19 in an outpatient setting.

Introduction: The HPV vaccine is characterized by its significant effectiveness in preventing the occurrence of cervical cancer. However, the South Asian countries face multiple challenges in implementing the human papillomavirus vaccine (HPV) at scale. Implementation of human papillomavirus vaccination for eliminating cervical cancer necessitates investigating the factors that impact the health system of these nations. Hence, this review will map the evidence on factors influencing the scaling up of human papillomavirus vaccination in South Asia., Methods: The proposed scoping review will follow the steps given by Arksey and O'Malley and Levac et al. The search approach will follow McGowan et al. (14) evidence-based manual for Peer Analysis of Electronic Search Strategies (PRESS 2015) for systematic searches. Using a comprehensive search, the literature from 2006 onward will be identified from PubMed, CINAHL, EMBASE, Web of Science, and Scopus. The search strategy will include terms relating to the HPV vaccine and implementation. A predefined criterion for the inclusion and exclusion of studies will be adopted by three review authors independently to determine the eligible studies. The results will be narratively synthesized and examined in addition to being quantitatively presented to provide an outline. The review will be presented per the "Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping review (PRISMA-ScR)" guidelines., Conclusions/discussion: The evaluation is anticipated to map the barriers and enablers influencing the rollout of the human papillomavirus vaccine. Lessons learned from the South Asian countries, where the vaccine has been implemented, may contribute to aiding the implementation of the vaccine in countries with similar health systems in an effective manner., Systematic Review Registration: The protocol was prospectively registered on the "open science framework". The registration DOI is https://doi.org/10.17605/OSF.IO/T5SW9 ., (© 2023. The Author(s).)

Matrix metalloproteinases (MMPs) are enzymes involved in the remodelling and degradation of the extracellular matrix, which is essential for maintaining healthy oral tissues. It is therefore important for dental students to know the role of MMPs in biological processes and diseases. Using a questionnaire, a cross-sectional study was conducted among master's dental students from 3 universities in the Netherlands and Belgium. The general level of knowledge about MMPs of the 80 respondents was predominantly low (91.3%). Significant differences were observed among students from the various dental schools, with students from the University of Groningen and Ghent University scoring significantly higher than those from the Academic Centre for Dentistry in Amsterdam (ACTA). Gender was associated with a few questions on the relationship between MMPs and dentistry, with female students achieving higher scores. Improving dental curricula regarding MMPs and their role in dental processes seems warranted.

The implementation of Human Papillomavirus (HPV) vaccination is crucial for eliminating cervical cancer in India. The infodemic, characterised by misleading information, could hinder the successful implementation of the initiative. Misinformation related to the HPV vaccine, such as rumours, has been reported and circulated, contributing to an alarming pattern of vaccine hesitancy observed on social media. This study aimed to identify the public sentiment towards HPV vaccination based on the 'Behavioral and Social Drivers (BeSD)' framework through geospatial, content and sentiment analysis. A total of 1,487 tweets were extracted. After preprocessing, 1010 tweets were identified for sentiment and content analysis. The sentiments expressed towards the HPV vaccine are mixed, with a generally positive outlook on the vaccines. Within the population, there is a pervasive proliferation of misinformation, primarily focusing on vaccine safety and efficacy, contentious subjects, ethical considerations, and a prevalent sense of uncertainty in selecting the appropriate vaccine. These observations are crucial for developing targeted strategies to address public concerns and enhance vaccination rates. The insights gained from these results will guide policymakers, healthcare practitioners, and public health organisations to implement evidence-based interventions, thereby countering vaccine hesitancy and improving public health outcomes.

After a fall from his wheelchair, a 23-year-old wheelchair-dependent patient with spinal muscular atrophy type 1 was initially seen by an emergency dentist, who repositioned and splinted the luxated teeth number 31 and 32. For stabilization, the patient was subsequently referred to a centre for special dental care. In the past, few treatments had been carried out on the patient. A jaw defect and very limited mouth opening compromised dental treatment. In addition, due to the muscle disease, the patient had respiratory and breathing problems, for which he used respiratory equipment. This case describes the importance of a multidisciplinary team in the treatment of patients with spinal muscular atrophy, and the options for performing minimally invasive dental treatment, where the priority is a painless dentition.

Background: The stigma associated with monkeypox (mpox) may prevent people from following recommended guidelines. Using a "model of stigma communication," this study maps and determines the mpox stigma on Twitter among LGBTQ+ (Lesbian, gay, bisexual, transgender, queer and more) community., Methods: The tweets that contained the terms '#monkeypox', '#MPVS', '#stigma', and '#LGBTQ+' and were published between May 01, 2022 and Sept 07, 2022 were extracted. For sentiment analysis, the VADER, Text Blob, and Flair analysers were implemented. This study evaluated the dynamics of stigma communication based on the "model of stigma communication". A total of 70,832 tweets were extracted, from which 66,387 tweets were passed to the sentiment analyser and 3100 tweets were randomly selected for manual coding. Consolidated Criteria for Reporting Qualitative Research (COREQ) criteria was adopted to report this study ., Findings: This research provided insight on the cause, communication, and patterns of mpox stigma in the LGBTQ+ community. In the community, stigmatisation was influenced by the group's labelling as the source of monkeypox. Some users believed that mpox resembled previously observed diseases such as HIV/AIDS, and COVID-19. Despite officials and media outlets disseminating information about preventing mpox and stigmatisation, a number of individuals failed to comply. The LGBTQ+ community faced peril in the form of violence due to escalating stigma. Misinformation and misinterpretation spread further stigmatisation., Interpretation: This study indicates that authorities must address misinformation, stigmatization of the LGBTQ+ community, and the absence of a comprehensive risk-communication plan to improve the system. The effects of stigmatization on the vulnerable population must be handled in conjunction with a well-developed risk communication plan, without jeopardizing their wellbeing., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Hexane isomers play a vital role as feedstocks and fuel additives in the petrochemical industry. However, their similar physical and chemical properties lead to significant challenges in the separation process. Traditional thermal separation techniques are energy-intensive and lead to significant carbon footprint penalties. As such, there is a growing demand for the development of less energy-intensive nonthermal separation methods. Adsorption-based separation methods, such as using solid sorbents or membranes, have emerged as promising alternatives to distillation. Here, we report the successful synthesis of two novel metal-organic frameworks (MOFs), NU-2004 and NU-2005, by incorporating a carborane-based three-dimensional (3D) linker and using aluminum and vanadium nodes, respectively. These MOFs exhibit exceptional thermal stability and structural rigidity compared to other MIL-53 analogues, which is further corroborated using synchrotron studies. Furthermore, the inclusion of the quasi-spherical 3D linker in NU-2004 demonstrates significant advancements in the separation of hexane isomers compared to other MIL MOFs containing two-dimensional (2D) and aliphatic 3D linkers.

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder., Competing Interests: Declaration of interests M.L. is currently an employee of, and holds equity in, Illumina Inc. J.R.L. has stock ownership in 23andMe and is a paid consultant for Genome International., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Purpose: Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls., Methods: We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria., Results: 9.04% of cases and 1.02% of controls had "likely pathogenic" variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were "variants of uncertain significance", occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance., Conclusion: These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs., Competing Interests: Conflict of Interest The authors declare no conflicts of interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hepatitis C is a disease with a strong social component, as its main transmission route is via blood, making it associated with lifestyle. Therefore, it is suitable to be worked on from the perspective of public health policy, which still has a lot of room to explore and improve, contrary to diagnoses and treatments, which are already very refined and effective., Objective: An interactive gamified policy tool, designated as Let's End HepC (LEHC), was created to understand the impact of policies related to hepatitis C on the disease's epidemiology on a yearly basis until 2030., Methods: To this end, an innovative epidemiological model was developed, integrating Markov chains to model the natural history of the disease and adaptive conjoint analysis to reflect the degree of application of each of the 24 public health policies included in the model. This double imputation model makes it possible to assess a set of indicators such as liver transplant, incidence, and deaths year by year until 2030 in different risk groups. Populations at a higher risk were integrated into the model to understand the specific epidemiological dynamics within the total population of each country and within segments that comprise people who have received blood products, prisoners, people who inject drugs, people infected through vertical transmission, and the remaining population., Results: The model has already been applied to a group of countries, and studies in 5 of these countries have already been concluded, showing results very close to those obtained through other forms of evaluation., Conclusions: The LEHC model allows the simulation of different degrees of implementation of each policy and thus the verification of its epidemiological impact on each studied population. The gamification feature allows assessing the adequate fulfillment of the World Health Organization goals for the elimination of hepatitis C by 2030. LEHC supports health decision makers and people who practice patient advocacy in making decisions based on science, and because LEHC is democratically shared, it ends up contributing to the increase of citizenship in health., International Registered Report Identifier (irrid): RR1-10.2196/38521., (©Ricardo Baptista-Leite, Henrique Lopes, Björn Vandewalle, Jorge Félix, Diogo Franco, Timo Clemens, Helmut Brand. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 25.09.2023.)

Genetic association studies have made significant contributions to our understanding of the etiology of neurodevelopmental disorders (NDDs). However, these studies rarely focused on the African continent. The NeuroDev Project aims to address this diversity gap through detailed phenotypic and genetic characterization of children with NDDs from Kenya and South Africa. We present results from NeuroDev's first year of data collection, including phenotype data from 206 cases and clinical genetic analyses of 99 parent-child trios. Most cases met criteria for global developmental delay/intellectual disability (GDD/ID, 80.3%). Approximately half of the children with GDD/ID also met criteria for autism. Analysis of exome-sequencing data identified a pathogenic or likely pathogenic variant in 13 (17%) of the 75 cases from South Africa and 9 (38%) of the 24 cases from Kenya. Data from the trio pilot are publicly available, and the NeuroDev Project will continue to develop resources for the global genetics community., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs., Competing Interests: Declaration of interests M.E.T. and H.R. receive research funding from Microsoft Inc and/or research reagents from Illumina Inc. M.E.T. also received research funding from Levo Therapeutics and research reagents from Ionis Therapeutics for unrelated research projects., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Dry mouth has a complex aetiology which makes proper diagnosis complicated. Until now, dry mouth diagnosis has mainly focused on the overall oral dryness, without taking into account regional differences within the mouth. This research showed, among other things, that there are unique patterns of oral dryness, each with its own cause. For example, patients suffering from Sjogren's syndrome mainly experienced dryness of the posterior of the palate. Patients with dry mouth due to the side effects of medication, in contrast, experienced the front part of the tongue as the driest. These findings suggest that mapping of intraoral dryness may be a useful diagnostic tool to differentiate between possible causes of dry mouth.

Copy number variants (CNVs) are major contributors to genetic diversity and disease. While standardized methods, such as the genome analysis toolkit (GATK), exist for detecting short variants, technical challenges have confounded uniform large-scale CNV analyses from whole-exome sequencing (WES) data. Given the profound impact of rare and de novo coding CNVs on genome organization and human disease, we developed GATK-gCNV, a flexible algorithm to discover rare CNVs from sequencing read-depth information, complete with open-source distribution via GATK. We benchmarked GATK-gCNV in 7,962 exomes from individuals in quartet families with matched genome sequencing and microarray data, finding up to 95% recall of rare coding CNVs at a resolution of more than two exons. We used GATK-gCNV to generate a reference catalog of rare coding CNVs in WES data from 197,306 individuals in the UK Biobank, and observed strong correlations between per-gene CNV rates and measures of mutational constraint, as well as rare CNV associations with multiple traits. In summary, GATK-gCNV is a tunable approach for sensitive and specific CNV discovery in WES data, with broad applications., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)