Genetics of environmental sensitivity to psychiatric and neurodevelopmental phenotypes: evidence from GWAS of monozygotic twins.

Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes. However, environmental sensitivity genetic variants have proven challenging to detect. GWAS of monozygotic twin differences is a family-based variance analysis method, which is more robust to systemic biases that impact population-based methods. We combined data from up to 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct the largest GWAS meta-analysis of monozygotic phenotypic differences in children and adolescents/adults for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder (ADHD) symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism, and wellbeing. The SNP-heritability of variance in these phenotypes were estimated (h2: 0% to 18%), but were imprecise. We identified a total of 13 genome-wide significant associations (SNP, gene, and gene-set), including genes related to stress-reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. Monozygotic twins are an important new source of evidence about the genetics of environmental sensitivity.

Development and validation of a biomechanically fidelic surgical training knee model.

Knee arthroplasty technique is constantly evolving and the opportunity for surgeons to practice new techniques is currently highly dependent on the availability of cadaveric specimens requiring certified facilities. The high cost, limited supply, and heterogeneity of cadaveric specimens has increased the demand for synthetic training models, which are currently limited by a lack of biomechanical fidelity. Here, we aimed to design, manufacture, and experimentally validate a synthetic knee surgical training model which reproduces the flexion dependent varus-valgus (VV) and anterior-posterior (AP) mechanics of cadaveric knees, while maintaining anatomic accuracy. A probabilistic finite element modeling approach was employed to design physical models to exhibit passive cadaveric VV and AP mechanics. Seven synthetic models were manufactured and tested in a six-degree-of-freedom hexapod robot. Overall, the synthetic models exhibited cadaver-like VV and AP mechanics across a wide range of flexion angles with little variation between models. In the extended position, two models showed increased valgus rotation (<0.5°), and three models showed increased posterior tibial translation (<1.7 mm) when compared to the 95% confidence interval (CI) of cadaveric measurements. At full flexion, all models showed VV and AP mechanics within the 95% CI of cadaveric measurements. Given the repeatable mechanics exhibited, the knee models developed in this study can be used to reduce the current reliance on cadaveric specimens in surgical training.

On the mechanism of carboxylate elimination from carbohydrate monoester-derived radicals.

A computational study of the mechanism of hydrogen atom transfer-induced carboxylate elimination from monoacylated 1,2-diol groups in pyranosides is presented. A comprehensive analysis of the 1,2-migration, elimination and fragmentation pathways reveals that concerted elimination via a 7-membered, hydrogen-bonded transition state is favored. Relative rates of elimination inferred from an intramolecular competition experiment are consistent with the trends obtained from the calculations.

Co-existing mental and somatic conditions in Swedish children with the avoidant restrictive food intake disorder phenotype.

Background: Avoidant restrictive food intake disorder (ARFID) is a feeding and eating disorder, characterized by limited variety and/or quantity of food intake impacting physical health and psychosocial functioning. Children with ARFID often present with a range of psychiatric and somatic symptoms, and therefore consult various pediatric subspecialties; large-scale studies mapping comorbidities are however lacking. To characterize health care needs of people with ARFID, we systematically investigated ARFID-related mental and somatic conditions in 616 children with ARFID and >30,000 children without ARFID. Methods: In a Swedish twin cohort, we identified the ARFID phenotype in 6-12-year-old children based on parent-reports and register data. From >1,000 diagnostic ICD-codes, we specified mental and somatic conditions within/across ICD-chapters, number of distinct per-person diagnoses, and inpatient treatment days between birth and 18th birthday (90 outcomes). Hazard ratios (HR) and incidence rate ratios (IRR) were calculated. Findings: Relative risks of neurodevelopmental, gastrointestinal, endocrine/metabolic, respiratory, neurological, and allergic disorders were substantially increased in ARFID (e.g., autism HR[CI95%]=9.7[7.5-12.5], intellectual disability 10.3[7.6-13.9], gastroesophageal reflux disease 6.7[4.6-9.9], pituitary conditions 5.6[2.7-11.3], chronic lower respiratory diseases 4.9[2.4-10.1], epilepsy 5.8[4.1-8.2]). ARFID was not associated with elevated risks of autoimmune illnesses and obsessive-compulsive disorder. Children with ARFID had a significantly higher number of distinct mental diagnoses (IRR[CI95%]=4.7[4.0-5.4]) and longer duration of hospitalizations (IRR[CI95%]=5.5[1.7-17.6]) compared with children without ARFID. Children with ARFID were diagnosed earlier with a mental condition than children without ARFID. No sex-specific differences emerged. Interpretation: This study yields the broadest and most detailed evidence of co-existing mental and somatic conditions in the largest sample of children with ARFID to date. Findings suggest a complex pattern of health needs in youth with ARFID, underscoring the critical importance of attention to the illness across all pediatric specialties. Funding: Fredrik and Ingrid Thurings Foundation, Mental Health Foundation.

Determination of preoperative risk factors for iliopsoas tendonitis after total hip arthroplasty: A simulation study.

This study aims to identify preoperative risk factors for iliopsoas tendonitis after total hip arthroplasty, a complication typically attributed to acetabular cup position and orientation, using a validated iliopsoas impingement detection simulation. Analyzing CT scans and X-rays of 448 patients using a validated preoperative planning protocol, patients were simulated for iliopsoas impingement and categorized into at-risk and not at-risk groups based on a prior validation study, with a 23% at-risk incidence. Implementing a propensity score matching algorithm to reduce covariate imbalance, we identified factors that may exacerbate risk of iliopsoas tendonitis. Parameters that were investigated included standing pelvic tilt, functional femoral rotation, and the difference between the planned acetabular cup diameter and native femoral head diameter (ΔC-NFH). Comparing pelvic tilt, we found a significant difference between the groups (at-risk: -6.0°, not at-risk: -0.7°; p << 0.01). A similar trend was noted for ΔC-NFH (at-risk: +5.7 mm, not at-risk: +5.1 mm; p = 0.01). Additional simulations of at-risk patients indicated increased anteversion of the acetabular cup reduces impingement risk more effectively than medialisation. These findings suggest that spinopelvic parameters may exacerbate iliopsoas irritation risk, underscoring their importance in preoperative planning and patient expectation management. Similar findings of a greater than 6 mm difference between cup size and native femoral head diameter being a significant risk for iliopsoas tendonitis have been observed before, underscoring its potential veracity. These results may provide surgeons with a simple threshold that can be used in determining a cup size to reduce the risk of iliopsoas tendonitis.

Supervised machine learning for the prediction of post-operative clinical outcomes of hip and knee replacements: a review.

Prediction models are being increasingly used in the medical field to identify risk factors and possible outcomes. Some of these are presently being used to develop guidelines for improving clinical practice. The application of machine learning (ML), comprising a powerful set of computational tools for analysing data, has been clearly expanding in the role of predictive modelling. This paper reviews the latest developments of supervised ML techniques that have been used to analyse data related to post-operative total hip and knee replacements. The aim was to review the most recent findings of relevant published studies by outlining the methodologies employed (most-widely used supervised ML techniques), data sources, domains, limitations of predictive analytics and the quality of predictions.

What Is the Most Appropriate Comparator to Use in Assessing the Comparative Performance of Primary Total Knee Prostheses? A Registry-Based Study.

Background: The Australian Orthopedic Association National Joint Replacement Registry has developed a standardized multi-stage approach to identify prostheses with a higher-than-anticipated rate of revision when comparing a prosthesis of interest to all other prostheses within the same broad class. However, the approach does not adequately differentiate between the conventional and complex design prostheses, and the comparator classes need to be re-evaluated. This study aimed to identify a more relevant comparator to better reflect conventional and complex surgical practices according to the stability design and also explore how the rate of revision estimated in the comparator groups affects the identification of "prosthesis outliers." Methods: The cumulative percent revision (CPR) was calculated for 640,045 primary total knee replacements (TKRs) undertaken for Osteoarthritis from 1 January 2003 to 31 December 2019. At first, survivorship analyses were undertaken to calculate the rate of revision for primary TKR by stability design. A modified TKR comparator group was developed by excluding the "complex" group of prostheses with fully stabilized and hinged designs. The effectiveness of the modified comparator groups, including cruciate retaining and posterior stabilized designs, was evaluated based on the ability to detect additional prostheses by performing the Australian Orthopedic Association National Joint Replacement Registry standardized method for identifying prosthesis outliers. Results: The modified comparator to include only conventional designs had a 10-year CPR of 5.2% (5.1, 5.3). When the fully stabilized and hinged design groups were combined as a comparator group of complex devices to reflect devices used only for specific purposes in primary TKR, the CPR at 10 year was 10.3% (8.6, 12.0). Conclusions: The use of modified comparator groups led to identifying additional conventional prostheses but fewer complex designs as being at risk and has the potential to improve the early assessment of TKR prostheses.

The national distribution of lymphatic filariasis cases in Malawi using patient mapping and geostatistical modelling.

BACKGROUND: In 2020 the World Health Organization (WHO) declared that Malawi had successfully eliminated lymphatic filariasis (LF) as a public health problem. Understanding clinical case distributions at a national and sub-national level is important, so essential care packages can be provided to individuals living with LF symptoms. This study aimed to develop a national database and map of LF clinical cases across Malawi using geostatistical modelling approaches, programme-identified clinical cases, antigenaemia prevalence and climate information. METHODOLOGY: LF clinical cases identified through programme house-to-house surveys across 90 sub-district administrative boundaries (Traditional Authority (TA)) and antigenaemia prevalence from 57 sampled villages in Malawi were used in a two-step geostatistical modelling process to predict LF clinical cases across all TAs of the country. First, we modelled antigenaemia prevalence in relation to climate covariates to predict nationwide antigenaemia prevalence. Second, we modelled clinical cases for unmapped TAs based on our antigenaemia prevalence spatial estimates. PRINCIPLE FINDINGS: The models estimated 20,938 (95% CrI 18,091 to 24,071) clinical cases in unmapped TAs (70.3%) in addition to the 8,856 (29.7%), programme-identified cases in mapped TAs. In total, the overall national number of LF clinical cases was estimated to be 29,794 (95% CrI 26,957 to 32,927). The antigenaemia prevalence and clinical case mapping and modelling found the highest burden of disease in Chikwawa and Nsanje districts in the Southern Region and Karonga district in the Northern Region of the country. CONCLUSIONS: The models presented in this study have facilitated the development of the first national LF clinical case database and map in Malawi, the first endemic country in sub-Saharan Africa. It highlights the value of using existing LF antigenaemia prevalence and clinical case data together with modelling approaches to produce estimates that may be used for the WHO dossier requirements, to help target limited resources and implement long-term health strategies.

Combinations of the azaquinazoline anti-Wolbachia agent, AWZ1066S, with benzimidazole anthelmintics synergise to mediate sub-seven-day sterilising and curative efficacies in experimental models of filariasis.

Lymphatic filariasis and onchocerciasis are two major neglected tropical diseases that are responsible for causing severe disability in 50 million people worldwide, whilst veterinary filariasis (heartworm) is a potentially lethal parasitic infection of companion animals. There is an urgent need for safe, short-course curative (macrofilaricidal) drugs to eliminate these debilitating parasite infections. We investigated combination treatments of the novel anti-Wolbachia azaquinazoline small molecule, AWZ1066S, with benzimidazole drugs (albendazole or oxfendazole) in up to four different rodent filariasis infection models: Brugia malayi-CB.17 SCID mice, B. malayi-Mongolian gerbils, B. pahangi-Mongolian gerbils, and Litomosoides sigmodontis-Mongolian gerbils. Combination treatments synergised to elicit threshold (>90%) Wolbachia depletion from female worms in 5 days of treatment, using 2-fold lower dose-exposures of AWZ1066S than monotherapy. Short-course lowered dose AWZ1066S-albendazole combination treatments also delivered partial adulticidal activities and/or long-lasting inhibition of embryogenesis, resulting in complete transmission blockade in B. pahangi and L. sigmodontis gerbil models. We determined that short-course AWZ1066S-albendazole co-treatment significantly augmented the depletion of Wolbachia populations within both germline and hypodermal tissues of B. malayi female worms and in hypodermal tissues in male worms, indicating that anti-Wolbachia synergy is not limited to targeting female embryonic tissues. Our data provides pre-clinical proof-of-concept that sub-seven-day combinations of rapid-acting novel anti-Wolbachia agents with benzimidazole anthelmintics are a promising curative and transmission-blocking drug treatment strategy for filarial diseases of medical and veterinary importance.

Elimination of lymphatic filariasis as a public health problem in Malawi.

BACKGROUND: Lymphatic filariasis (LF) is a parasitic disease transmitted by mosquitoes, causing severe pain, disfiguring, and disabling clinical conditions such as lymphoedema and hydrocoele. LF is a global public health problem affecting 72 countries, primarily in Africa and Asia. Since 2000, the World Health Organization (WHO) has led the Global Programme to Eliminate Lymphatic Filariasis (GPELF) to support all endemic regions. This paper focuses on the achievements of the Malawi LF Elimination Programme between 2000 and 2020 to eliminate LF as a public health problem, making it the second sub-Saharan country to receive validation from the WHO. METHODOLOGY/PRINCIPAL FINDINGS: The Malawi LF Programme addressed the widespread prevalence of LF infection and disease across the country, using the recommended WHO GPELF strategies and operational research initiatives in collaboration with key national and international partners. First, to stop the spread of infection (i.e., interrupt transmission) and reduce the circulating filarial antigen prevalence from as high as 74.4% to below the critical threshold of 1-2% prevalence, mass drug administration (MDA) using a two-drug regime was implemented at high coverage rates (>65%) of the total population, with supplementary interventions from other programmes (e.g., malaria vector control). The decline in prevalence was monitored and confirmed over time using several impact assessment and post-treatment surveillance tools including the standard sentinel site, spot check, and transmission assessment surveys and alternative integrated, hotspot, and easy-access group surveys. Second, to alleviate suffering of the affected populations (i.e., control morbidity) the morbidity management and disability prevention (MMDP) package of care was implemented. Specifically, clinical case estimates were obtained via house-to-house patient searching activities; health personnel and patients were trained in self-care protocols for lymphoedema and/or referrals to hospitals for hydrocoele surgery; and the readiness and quality of treatment and services were assessed with new survey tools. CONCLUSIONS: Malawi's elimination of LF will ensure that future generations are not infected and suffer from the disfiguring and disabling disease. However, it will be critical that the Malawi LF Elimination programme remains vigilant, focussing on post-elimination surveillance and MMDP implementation and integration into routine health systems to support long-term sustainability and ongoing success. SUMMARY: Lymphatic filariasis, also known as elephantiasis, is a disabling, disfiguring, and painful disease caused by a parasite that infected mosquitoes transmit to millions of people worldwide. Since 2000, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) has supported endemic countries such as Malawi in south-eastern Africa, to eliminate the disease as a public health problem. The Malawi National LF Elimination Programme has worked tirelessly over the past two decades to implement the GPELF recommended strategies to interrupt the transmission with a two-drug regime, and to alleviate suffering in patients with lymphoedema and/or hydrocoele through morbidity management and disability prevention. Additionally, the LF Programme has collaborated with national and international stakeholders to implement a range of supplementary operational research projects to address outstanding knowledge gaps and programmatic barriers. In 2020, the World Health Organisation validated that Malawi had successfully eliminated LF as a public health problem, making it the second country in sub-Saharan Africa to achieve this, which is remarkable given that Malawi previously had very high infection rates. The LF Programme now remains vigilant, putting its efforts towards post-elimination surveillance and the continued implementation of care for patients with chronic conditions. Malawi's elimination of LF will ensure that future generations are not affected by this devastating disease.

Sustained looking at faces at 5 months of age is associated with socio-communicative skills in the second year of life.

Efficiently processing information from faces in infancy is foundational for nonverbal communication. We studied individual differences in 5-month-old infants' (N = 517) sustained attention to faces and preference for emotional faces. We assessed the contribution of genetic and environmental influences to individual differences in these gaze behaviors, and the association between these traits and other concurrent and later phenotypes. We found an association between the mean duration of looking at a face (before looking away from it) at 5 months and socio-communicative abilities at 14 months (ß = 0.17, 95% CI: 0.08; 0.26, p < 0.001). Sustained attention to faces predicted socio-communicative abilities over and above variance captured by mean fixation duration. We also found a statistically significant but weak tendency to prefer looking at smiling faces (relative to neutral faces), but no indication that variability in this behavior was explained by genetic effects. Moderate heritability was found for sustained attention to faces (A = 0.23, CI: 0.06; 0.38), while shared environmental influences were non-significant for both phenotypes. These findings suggest that sustained looking at individual faces before looking away is a developmentally significant 'social attention' phenotype in infancy, characterized by moderate heritability and a specific relation to later socio-communicative abilities.

'Evaluation of testamentary capacity: A systematic review'.

OBJECTIVE: To systematically review the literature on methods for the standardized and objective assessment of Testamentary Capacity (TC), to identify the best evidence-based and clinically pragmatic method to assess TC. Doubts concerning TC can have far-reaching legal and financial implications. METHOD: A systematic search of the literature was conducted, using PRISMA guidelines, to identify studies which describe methods or tools for the assessment of TC. RESULTS: The Testamentary Definition Scale (TDS); the Testamentary Capacity Assessment Tool (TCAT); and the Testamentary Capacity Instrument (TCI) all have good psychometric properties, but TDS only partially assesses TC, and the TCI is designed for research rather than day-to-day clinical practice. CONCLUSION: The TCAT could usefully supplement the clinical assessment of TC, coupled with a standardized examination of cognition. There is room to develop an all-encompassing TC assessment tool. Currently, the clinical judgement of a medical professional, taking account of the medical, legal, ethical issues informing a capacity or competency decision, remains the gold standard for assessing TC.

Axonal excitability as an early biomarker of nerve involvement in hereditary transthyretin amyloidosis.

OBJECTIVES: The treatment of hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) has been revolutionised by genetic therapies, with dramatic improvements in patient outcomes. Whilst the optimal timing of treatment initiation remains unknown, early treatment is desirable. Consequently, the aim of the study was to develop biomarkers of early nerve dysfunction in ATTRv-PN. METHODS: Ulnar motor and sensory axonal excitability studies were prospectively undertaken on 22 patients with pathogenic hereditary transthyretin amyloid (ATTRv) gene variants, 12 with large fibre neuropathy (LF+) and 10 without (LF-), with results compared to age- and sex-matched healthy controls. RESULTS: In motor axons we identified a continuum of change from healthy controls, to LF- and LF+ ATTRv with progressive reduction in hyperpolarising threshold electrotonus (TEh40(10-20 ms): p = 0.04, TEh40(20-40 ms): p = 0.01 and TEh40(90-10 ms): p = 0.01), suggestive of membrane depolarisation. In sensory axons lower levels of subexcitability were observed on single (SubEx) and double pulse (SubEx2) recovery cycle testing in LF+ (SubEx: p = 0.015, SubEx2: p = 0.015, RC(2-1): p = 0.04) suggesting reduced nodal slow potassium conductance, which promotes sensory hyperexcitability, paraesthesia and pain. There were no differences in sensory or motor excitability parameters when comparing different ATTRv variants. CONCLUSIONS: These progressive changes seen across the disease spectrum in ATTRv-PN suggest that axonal excitability has utility to identify early and progressive nerve dysfunction in ATTRv, regardless of genotype. SIGNIFICANCE: Axonal excitability is a promising early biomarker of nerve dysfunction in ATTRv-PN.

Comparison of iliopsoas tendonitis after hip resurfacing arthroplasty and total hip arthroplasty: A case-controlled investigation using a validated simulation.

Iliopsoas tendonitis, typically caused by impingement with the acetabular cup, occurs in up to 18% of patients after total hip arthroplasty (THA) and up to 30% of patients after hip resurfacing arthroplasty (HRA). We have developed a simulation for detecting iliopsoas impingement and validated it in a previous study of THA patients. However, due to the difference in incidence between HRA and THA, this study had two aims. First, to validate the simulation in a cohort of HRA patients and, second, to comparethe results of the HRA and THA patients to understand any differences in their etiology. We conducted a retrospective search in an experienced surgeon's database for HRA patients with iliopsoas tendonitisand control patients without iliopsoas tendonitis, resulting in two cohorts of 12 patients. Using CT scans, 3D models of the each patient's prosthetic and bony anatomy were generated, landmarked, and simulated. Regarding validation of the simulation for HRA patients, impingement significantly predicted the probability of iliopsoas tendonitis in logistic regression models and the simulation had a sensitivity of 83%, specificity of 100%, and an AUC ROC curve of 0.95. Unexpectedly, the HRA cohort exhibited less impingement than the THA cohort. Our novel simulation has now been demonstrated to detect iliopsoas impingement and differentiate between the symptomatic and asymptomatic cohorts in investigations of THA and HRA patients. This tool has the potential to be used preoperatively, to guide decisions about optimal cup placement, and postoperatively, to assist in the diagnosis of iliopsoas tendonitis.

Boronic Acid-Catalyzed Regio- and Stereoselective N-Glycosylations of Purines and Other Azole Heterocycles: Access to Nucleoside Analogues.

In the presence of an arylboronic acid catalyst, azole-type heterocycles, including purines, tetrazoles, triazoles, indazoles, and benzo-fused congeners, undergo regio- and stereoselective N-glycosylations with furanosyl and pyranosyl trichloroacetimidate donors. The protocol, which does not require stoichiometric activators, specialized leaving groups, or drying agents, provides access to nucleoside analogues and enables late-stage N-glycosylation of azole-containing pharmaceutical agents. A mechanism involving simultaneous activation of the glycosyl donor and acceptor by the organoboron catalyst has been proposed, supported by kinetic analysis and computational modeling.

A systematic literature review of the 'commercialisation effect' on public attitudes towards biobank and genomic data repositories.

Initiatives that collect and share genomic data to advance health research are widespread and accelerating. Commercial interests in these efforts, while vital, may erode public trust and willingness to provide personal genomic data, upon which these initiatives depend. Understanding public attitudes towards providing genomic data for health research in the context of commercial involvement is critical. A PRISMA-guided search of six online academic databases identified 113 quantitative and qualitative studies using primary data pertaining to public attitudes towards commercial actors in the management, collection, access, and use of biobank and genomic data. The presence of commercial interests yields interrelated public concerns around consent, privacy and data security, trust in science and scientists, benefit sharing, and the ownership and control of health data. Carefully considered regulatory and data governance and access policies are therefore required to maintain public trust and support for genomic health initiatives.

Implementation of Extracorporeal CPR Programs for Out-of-Hospital Cardiac Arrest: Another Tale of Two County Hospitals.

Extracorporeal cardiopulmonary resuscitation (ECPR) is a form of intensive life support that has seen increasing use globally to improve outcomes for patients who experience out-of-hospital cardiac arrest (OHCA). Hospitals with advanced critical care capabilities may be interested in launching an ECPR program to offer this support to the patients they serve; however, to do so, they must first consider the significant investment of resources necessary to start and sustain the program. The existing literature describes many single-center ECPR programs and often focuses on inpatient care and patient outcomes in hospitals with cardiac surgery capabilities. However, building a successful ECPR program and using this technology to support an individual patient experiencing refractory cardiac arrest secondary to a shockable rhythm depends on efficient out-of-hospital and emergency department (ED) management. This article describes the process of implementing 2 intensivist-led ECPR programs with limited cardiac surgery capability. We focus on emergency medical services and ED clinician roles in identifying patients, mobilizing resources, initiation and management of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in the ED, and ongoing efforts to improve ECPR program quality. Each center experienced a significant learning curve to reach goals of arrest-to-flow times of cannulation for ECPR. Building consensus from multidisciplinary stakeholders, including out-of-hospital stakeholders; establishing shared expectations of ECPR outcomes; and ensuring adequate resource support for ECPR activation were all key lessons in improving our ECPR programs.

Multimethod evaluation of health services integration for neglected tropical diseases requiring case management in Liberia.

INTRODUCTION: The WHO neglected tropical disease (NTD) roadmap stresses the importance of integrating NTDs requiring case management (CM) within the health system. The NTDs programme of Liberia is among the first to implement an integrated approach and evaluate its impact. METHODS: A retrospective study of three of five CM-NTD-endemic counties that implemented the integrated approach was compared with cluster-matched counties with non-integrated CM-NTD. We compared trends in CM-NTD integrated versus non-integrated county clusters. We conducted a pre-post comparison of WHO high-level outcomes using data collected during intervention years compared with baseline in control counties. Changes in health outcomes, effect sizes for different diseases and rate ratios with statistically significant differences were determined. Complementary qualitative research explored CM-NTD stakeholders' perceptions, analysed through the framework approach, which is a transparent, multistage approach for qualitative thematic interdisciplinary data analysis. RESULTS: The detection rates for all diseases combined improved significantly in the intervention compared with the control clusters. Besides leprosy, detection rates improved with large effects, over fourfold increase with statistically significant effects for individual diseases (p<0.000; 95% CI 3.5 to 5.4). Access to CM-NTD services increased in integrated counties by 71 facilities, compared with three facilities in non-integrated counties. Qualitative findings highlight training and supervision as inputs underpinning increases in case detection, but challenges with refresher training, medicine supply and incentives negatively impact quality, equity and access. CONCLUSIONS: Integrating CM-NTDs improves case detection, accessibility and availability of CM-NTD services, promoting universal health coverage. Early case detection and the quality of care need further strengthening.

Treatment and prevention of epilepsy in onchocerciasis-endemic areas is urgently needed.

BACKGROUND: There is increasing epidemiological evidence supporting the association between onchocerciasis and seizures, reinforcing the concept of onchocerciasis-associated epilepsy (OAE). The aim of this paper is to provide an update on the new knowledge about OAE and to propose recommendations to the World Health Organization how to address this public health problem. MAIN TEXT: During the 2nd International Workshop on OAE held on 19-21 September, 2023, in Antwerp, Belgium, participants recognised OAE as a substantial yet neglected public health problem, particularly in areas of sub-Saharan Africa where onchocerciasis remains hyperendemic. Evidence from prospective population-based studies suggest that strengthening onchocerciasis elimination efforts leads to a significant reduction of OAE incidence. There is a need to validate an OAE case definition to estimate the burden of disease and identify onchocerciasis-endemic areas requiring intensification of onchocerciasis elimination programmes and integration of epilepsy care. It is expected that raising awareness about OAE will boost the population uptake of ivermectin. The implementation of a community-based epilepsy treatment programme offering free anti-seizure medications (ASMs) has shown high effectiveness in reducing the frequency of seizures and improving the overall quality of life of people with epilepsy. CONCLUSIONS: To reduce OAE burden, enhanced collaboration between onchocerciasis and mental health programmes at community, national, and international levels is required. Urgent efforts are needed to ensure the uninterrupted provision of free ASMs in onchocerciasis-endemic areas. Furthermore, OAE should be included in the quantification of the onchocerciasis disease burden.

Age effects on autism heritability and etiological stability of autistic traits.

BACKGROUND: Autism and autistic traits onset in childhood but persist into adulthood. Little is known about how genetic and environmental factors influence autism and autistic traits into adulthood. We aimed to determine age effects on the heritability of clinically diagnosed autism and the etiological stability of autistic traits from childhood to adulthood using twin methods. METHODS: From 23,849 twin pairs in the Swedish Twin Register born between 1959 and 2010, we identified 485 individuals (1.01%, 31.5% female) with a clinical autism diagnosis. We estimated and compared the relative contribution of genetic, shared, and nonshared environmental influences to autism in childhood and adulthood. We further used multivariate twin analysis with four measurement points among 1,348 twin pairs in the longitudinal Twin Study of Child and Adolescent Development to assess the phenotypic and etiological stability of autistic traits - measured with three scales from the Child Behavior Checklist - from childhood to adulthood. RESULTS: Autism heritability was comparable from childhood, (96% [95% CI, 76-99%]) to adulthood (87% [67-96%]). Autistic traits were moderately stable (phenotypic correlation = 0.35-0.61) from childhood to adulthood, and their heritability varied between 52 and 71%. We observed stable as well as newly emerging genetic influences on autistic traits from ages 8-9 to 19-20, and unique nonshared environmental influences at each age. CONCLUSIONS: Genetic factors are important for autism and autistic traits in adulthood and separate genetic studies in adults are warranted.