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Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

BACKGROUND & AIMS: Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed. METHODS: Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events. RESULTS: In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1-157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7-174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977-0.995; p = 0.002). CONCLUSIONS: Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors. IMPACT AND IMPLICATIONS: Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.

The PI3K enzymes modify phospholipids to regulate cell growth and differentiation. Somatic variants in PI3K are recurrent in cancer and drive a proliferative phenotype. Somatic mosaicism of PIK3R1 and PIK3CA are associated with vascular anomalies and overgrowth syndromes. Germline PIK3R1 variants are associated with varying phenotypes, including immunodeficiency or facial dysmorphism with growth delay, lipoatrophy, and insulin resistance associated with SHORT syndrome. There has been limited study of the molecular mechanism to unify our understanding of how variants in PIK3R1 drive both undergrowth and overgrowth phenotypes. Thus, we compiled genomic variants from cancer and rare vascular anomalies and sought to interpret their effects using an unbiased physics-based simulation approach for the protein complex. We applied molecular dynamics simulations to mechanistically understand how genetic variants affect PIK3R1 and its interactions with PIK3CA. Notably, iSH2 genetic variants associated with undergrowth destabilize molecular interactions with the PIK3CA receptor binding domain in simulations, which is expected to decrease activity. On the other hand, overgrowth and cancer variants lead to loss of inhibitory interactions in simulations, which is expected to increase activity. We find that all disease variants display dysfunctions on either structural characteristics or intermolecular interaction energy. Thus, this comprehensive characterization of novel mosaic somatic variants associated with two opposing phenotypes has mechanistic importance and biomedical relevance and may aid in future therapeutic developments.

The US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institute of Health (NIH), convened a virtual workshop on August 8-9th, 2023 to explore potential synergies between HIV vaccine approaches that are designed to induce cellular or humoral immune responses. The goal of this workshop was to review data on leading vaccine candidates and to discuss the best strategies for combining these approaches to optimize immunity against HIV. Here, we summarize the findings reviewed at the workshop and discuss the knowledge gaps and priorities for future studies that will help accelerate the development of a preventive HIV vaccine.

An estimated 38 million people live with human immunodeficiency virus (HIV) worldwide and are at excess risk for multiple cancer types. Elevated cancer risks in people living with HIV (PLWH) are driven primarily by increased exposure to carcinogens, most notably oncogenic viruses acquired through shared transmission routes, plus acceleration of viral carcinogenesis by HIV-related immunosuppression. In the era of widespread antiretroviral therapy (ART), life expectancy of PLWH has increased, with cancer now a leading cause of co-morbidity and death. Furthermore, the types of cancers occurring among PLWH are shifting over time and vary in their relative burden in different parts of the world. In this context, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) convened a meeting in September 2022 of multinational and multidisciplinary experts to focus on cancer in PLWH. This report summarizes the proceedings, including a review of the state of the science of cancer descriptive epidemiology, etiology, molecular tumor characterization, primary and secondary prevention, treatment disparities and survival in PLWH around the world. A consensus of key research priorities and recommendations in these domains is also presented.

BACKGROUND: In contrast to fine particles, less is known of the inflammatory and coagulation impacts of coarse particulate matter (PM10-2.5, particulate matter with aerodynamic diameter ≤10μm and>2.5μm). Toxicological research suggests that these pathways might be important processes by which PM10-2.5 impacts health, but there are relatively few epidemiological studies due to a lack of a national PM10-2.5 monitoring network. OBJECTIVES: We used new spatiotemporal exposure models to examine associations of both 1-y and 1-month average PM10-2.5 concentrations with markers of inflammation and coagulation. METHODS: We leveraged data from 7,071 Multi-Ethnic Study of Atherosclerosis and ancillary study participants 45-84 y of age who had repeated plasma measures of inflammatory and coagulation biomarkers. We estimated PM10-2.5 at participant addresses 1 y and 1 month before each of up to four exams (2000-2012) using spatiotemporal models that incorporated satellite, regulatory monitoring, and local geographic data and accounted for spatial correlation. We used random effects models to estimate associations with interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen, and D-dimer, controlling for potential confounders. RESULTS: Increases in PM10-2.5 were not associated with greater levels of inflammation or coagulation. A 10-μg/m3 increase in annual average PM10-2.5 was associated with a 2.5% decrease in CRP [95% confidence interval (CI): -5.5, 0.6]. We saw no association between annual average PM10-2.5 and the other markers (IL-6: -0.7%, 95% CI: -2.6, 1.2; fibrinogen: -0.3%, 95% CI: -0.9, 0.3; D-dimer: -0.2%, 95% CI: -2.6, 2.4). Associations consistently showed that a 10-μg/m3 increase in 1-month average PM10-2.5 was associated with reduced inflammation and coagulation, though none were distinguishable from no association (IL-6: -1.2%, 95% CI: -3.0 , 0.5; CRP: -2.5%, 95% CI: -5.3, 0.4; fibrinogen: -0.4%, 95% CI: -1.0, 0.1; D-dimer: -2.0%, 95% CI: -4.3, 0.3). DISCUSSION: We found no evidence that PM10-2.5 is associated with higher inflammation or coagulation levels. More research is needed to determine whether the inflammation and coagulation pathways are as important in explaining observed PM10-2.5 health impacts in humans as they have been shown to be in toxicology studies or whether PM10-2.5 might impact human health through alternative biological mechanisms. https://doi.org/10.1289/EHP12972.

PURPOSE: Injectable biologics have not only been described and developed to treat dermal wounds, cardiovascular disease, and cancer, but have also been reported to treat chronic pain conditions. Despite emerging evidence supporting regenerative medicine therapy for pain, many aspects remain controversial. METHODS: The American Society of Pain and Neuroscience (ASPN) identified the educational need for an evidence-based guideline on regenerative medicine therapy for chronic pain. The executive board nominated experts spanning multiple specialties including anesthesiology, physical medicine and rehabilitation, and sports medicine based on expertise, publications, research, and clinical practice. A steering committee selected preliminary questions, which were reviewed and refined. Evidence was appraised using the United States Preventive Services Task Force (USPSTF) criteria for evidence level and degree of recommendation. Using a modified Delphi approach, consensus points were distributed to all collaborators and each collaborator voted on each point. If collaborators provided a decision of disagree or abstain, they were invited to provide a rationale in a non-blinded fashion to the committee chair, who incorporated the respective comments and distributed revised versions to the committee until consensus was achieved. RESULTS: Sixteen questions were selected for guideline development. Questions that were addressed included type of injectable biologics and mechanism, evidence in treating chronic pain indications (eg, tendinopathy, muscular pathology, osteoarthritis, intervertebral disc disease, neuropathic pain), role in surgical augmentation, dosing, comparative efficacy between injectable biologics, peri-procedural practices to optimize therapeutic response and quality of injectate, federal regulations, and complications with mitigating strategies. CONCLUSION: In well-selected individuals with certain chronic pain indications, use of injectable biologics may provide superior analgesia, functionality, and/or quality of life compared to conventional medical management or placebo. Future high-quality randomized clinical trials are warranted with implementation of minimum reporting standards, standardization of preparation protocols, investigation of dose-response associations, and comparative analysis between different injectable biologics.

INTRODUCTION: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN. OBJECTIVE: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN. METHODS: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process. RESULTS: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria. CONCLUSION: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.

Introduction Noncommunicable diseases are a leading cause of death worldwide, claiming 41 million lives annually. Notably, type 2 diabetes not only presents well-known complications but also increases the risk of cardiovascular disease silently. Furthermore, concerningly high rates of undiagnosed diabetes and hypertension emphasize the need for improved diagnostic capabilities and enhanced awareness. The growing prevalence of prediabetes, a precursor to diabetes, further underscores the urgency for proactive action. Therefore, addressing the silent killers through early detection and comprehensive management strategies is crucial to combat this global health crisis. Objective The objective of the study was to assess the prevalence of prediabetes and prehypertension and the factors associated with them among the rural population of Puducherry district. Methodology A community-based cross-sectional study was conducted among 203 adults more than 30 years of age residing in rural field practice areas of a private medical college in the Puducherry district over 8 months (January 2023 to August 2023). Multistage sampling was employed. After obtaining written informed consent, data collection included a pretested questionnaire, and anthropometric measurements (weight, height, waist circumference, hip circumference) and blood pressure measurements were recorded; on subsequent days, fasting capillary blood sugar levels were checked. The data were analyzed using SPSS v21. Results On categorization based on the Indian Diabetes Risk Score, the results showed that 14.4% of participants were high-risk for diabetes, with 74% and 11.5% falling into medium- and low-risk categories, respectively. Also, the prevalence of hypertension was 31.3%, with an additional 13% prehypertensive and 55.8% normotensive. Notably, 64.6% of hypertensive individuals had Stage I and 35.4% had Stage II. Family history, self-reported diet, physical activity, and body mass index were significantly associated with prediabetes/diabetes (P value < 0.05). In addition to this, there has been a significant association between the risk of developing diabetes and systolic blood pressure (P value = 0.011). Conclusion Family history emerged as a significant risk factor for both diabetes and hypertension, highlighting the importance of genetic predisposition and the potential benefit of targeted family-based interventions. These findings raise concerns regarding the high prevalence of diabetes and hypertension risk factors within this population.

Abstract Background Pulmonary amyloidosis often occurs as a part of systemic AL (amyloid light chain) amyloidosis. Localized tracheobronchial amyloidosis is a very rare entity. Most often, it is asymptomatic, or if symptomatic, it usually presents with vague symptoms such as cough, dyspnoea, hoarseness, wheezing, haemoptysis, and rarely respiratory failure. It is commonly misdiagnosed as asthma, tuberculosis, COPD, malignancy, or pneumonia. Case presentation We are presenting a case of an elderly male, aged 64 years, who presented with symptoms of productive cough, dyspnoea, wheezing, and significant weight loss over a period of 6 months. Investigations such as bronchoscopy, histopathology, and imaging studies showed an endobronchial mass and left-sided pleural effusion. Conclusions Endobronchial amyloidosis generally has a nodular appearance which can imitate an endobronchial tumour. The quality of life is decreased in these patients, and the life expectancy is approximately 8–10 years. Therefore, the early diagnosis of this disease is essential.

The purpose of this study is to investigate how schools integrate character education into their curriculum and culture to promote holistic student development and ethical values in the 21st century. Additionally, it aims to explore the impact of collaboration among stakeholders on the implementation of character education programs and students' character development. This study employed mixed methods for data collection and analysis. The principal instruments utilized included a student survey featuring both closed and open-ended questions and interviews conducted with principals, teachers, and parents of six schools in the Udupi district of Karnataka, India. These interviews were conducted through convenience sampling, gathering perspectives from principals, teachers, and students regarding their existing character education programs. The study's findings illuminate the intricate processes by which character education is interwoven into both the curriculum and the broader school culture with the aim of nurturing holistic student development, and delves into the crucial role of collaboration among stakeholders in influencing the successful implementation of character education initiatives. This study combines descriptive and analytical research elements, providing an in-depth examination of ethical school culture and character education practices in India.

Social media platforms such as Instagram are becoming increasingly popular sources for students to access anatomy educational resources. This review used content analysis to examine posts under the hashtag #anatomynotes and is the first to map the characteristics of anatomy education posts on Instagram and determine any temporal changes. Sample posts were gathered from April 2019 and April 2021 and categorized according to the technical format, purpose and author credentials. Engagement was recorded in the form of likes and comments. Overall, posts depicting illustrations remained the most popular format within both time periods. Three-dimensional models saw an increase in popularity with a 62.5% rise. Students remained the most common author type throughout and increased further in 2021 by 25%. Clinician authors and posts focusing on clinical education also increased in 2021 by 17.9% and 227%, respectively. Humor-based posts saw the greatest increase among the post purposes, with 1000% more recorded in 2021. Engagement overall saw a decline with notably significant reductions in average likes per post among all text-based posts (-72%, p < 0.0001), all illustrative posts (-51%, p = 0.0013), and a decline in the presence of comments among all text-based posts (-65.1%, p = 0.0158). These findings highlight that Instagram is a popular platform for facilitating near-peer teaching while increasingly providing a space where students and clinicians can interact. Additionally, it highlights the benefits of the platform for visually focused learners. However, future research should seek to determine whether Instagram can facilitate deeper learning and have an impact on academic and clinical performance.

Substance use disorder is a growing public health challenge in the United States. People who use drugs may be more vulnerable to ambient heat due to the effects of drugs on thermoregulation and their risk environment. There have been limited population-based studies of ambient temperature and drug-related morbidity. We examined short-term associations between daily ambient temperature and emergency department (ED) visits for use or overdose of amphetamine, cocaine and opioids in California during the period 2005 to 2019. Daily ZIP code-level maximum, mean, and minimum temperature exposures were derived from 1-km data Daymet products. A time-stratified case-crossover design was used to estimate cumulative non-linear associations of daily temperature for lag days 0 to 3. Stratified analyses by patient sex, race, and ethnicity were also conducted. The study included over 3.4 million drug-related ED visits. We found positive associations between daily temperature and ED visits for all outcomes examined. An increase in daily mean temperature from the 50th to the 95th percentile was associated with ED visits for amphetamine use (OR = 1.072, 95% CI: 1.058, 1.086), cocaine use (OR = 1.044, 95% CI: 1.021, 1.068 and opioid use (OR = 1.041, 95% CI: 1.025, 1.057). Stronger positive associations were also observed for overdose: amphetamine overdose (OR = 1.150, 95% CI: 1.085, 1.218), cocaine overdose (OR = 1.159, 95% CI: 1.053, 1.276), and opioid overdose (OR = 1.079, 95% CI: 1.054, 1.106). In summary, people who use stimulants and opioids may be a subpopulation sensitive to short-term higher ambient temperature. Mitigating heat exposure can be considered in harm reduction strategies in response to the substance use epidemic and global climate change.

Background: Diabetes is one of the top 10 contributors to death globally. It is affecting more and more younger populations due to lifestyle changes in India. Tools like the Indian Diabetic Risk Score (IDRS) help in screening high-risk individuals for diabetes. Early diagnosis and prompt treatment help in avoiding complications and disabilities due to diabetes. Hence, this study was conducted to calculate the risk of diabetes using IDRS and to determine the knowledge and risk perception of diabetes among the nondiabetics residing in the rural field practice area of a medical college. Methodology: A descriptive cross-sectional study was conducted in the rural field practice area of a medical college. A total of 885 people participated in our study. All nondiabetics above 18 years of age were involved. The data were collected using a questionnaire and the IDRS questionnaire was used to determine the risk of diabetes. Data were analyzed using IBM SPSS 20th version. Results: Majority of the participants were between the age of 18 and 50 years. About 65.8% of the study population had medium risk according to IDRS. There was a significant relationship between gender, body mass index, and IDRS. A majority had good knowledge about diabetes. Only 31.5% knew that diabetes can cause complications in other organs of the body. Conclusion: Compared to prior research on rural Indians, this study’s population knew more about diabetes. To encourage people to adhere to their medication and treatment, further health education sessions should concentrate on minimizing the risk factors and complications of diabetes.

Abstract 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.

Background The World Health Organization recommends that Isoniazid Preventive Therapy (IPT) should be administered to all People living with Human immunodeficiency virus (PLHIV) not currently suffering from tuberculosis (TB) to reduce the incidence of the same. The objectives of this study were to determine the incidence of PLHIV who contracted TB after receiving 6 months of IPT (followed up for ≥ 2 years), the incidence of PLHIV who developed tuberculosis when not on IPT, and the occurrence of adverse drug reactions due to IPT. Methods A Retrospective Cohort study was conducted in two ART centers in Mangalore, which included PLHIV who had completed 6 months of IPT from January 2017 to May 2018 and were followed up until May 2020; patients in the comparison group consisted of those attending ART centers during the same period who did not receive IPT. These data were retrieved from the case files of these patients from June to November 2020, entered into MS Excel, and analyzed using statistical package for social science (SPSS) version 25. Results The study included 1014 patients: 525 (51.8%) received IPT and 489 (48.2%) did not. Eight (1.5%) patients developed TB after IPT completion compared to 32 (6.5%) patients who developed TB from the non-IPT group. There was a 77% reduction in the incidence of developing TB in those patients who received IPT as compared to those who haven’t receive IPT (RR of 0.23, p value Conclusions This study indicated that the completion of IPT significantly reduced the TB burden, showing significant protection against TB for a minimum duration of 2 years. Thus, implementation of IPT should be strengthened, and strict compliance should be ensured to reduce TB infection among PLHIV.