Search

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.

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.

GI cancer is not one cancer but is a term for the group of cancers that affect the digestive system including gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), esophageal cancer (EC), and pancreatic cancer (PC). Overall, the GI cancers are responsible for more cancers and more deaths from cancer than any other organ. 5 year survival of these cancers remains low compared to western world. Unlike the rest of the world where organ based specialities hepatobiliary, pancreatic, colorectal and esophagogastric exist , these cancers are managed in India by either a gastrointestinal surgeons, surgical oncologist, or a general surgeon with varying outcomes.The aim of this review was to collate data on GI cancers in indian continent. In colorectal cancers, data from tertiary care centres identifies the unique problem of mucinous and signet colorectal cancer. Results of rectal cancer resection in terms of technique (intersphincteric resection, extralevator aper, minimal invasive approach ) to be comparable with world literature. However long term outcome and data regarding colon cancers and nationally is needed. Gastric cancer at presentation are advanced and in surgically resected patients, there is need for a trial to compare chemoradiation vs chemotherapy alone to prevent loco regional recurrence. Data on minimal invasive gastric cancer surgery may be sparse for the same reason. Theree is a lot of data on surgical techniques and perioperatve outcomes in pancreatic cancer. There is a high volume of locally advanced gallbladder cancers with efforts on to decide whether neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy is better for down staging. Considering GI cancers, a heterogeneous disease with site specific treatment options and variable outcomes, the overall data and outcomes are extremely variable. Young patients with pathology unique to the Indian subcontinent (for example, signet ring rectal cancer, GBCs) need focussed attention. Solution for such pathology needs to come from the Indian continent itself. Joint efforts to improve outcomes for GI cancer can be integrated under the national cancer grid program.

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.

The longevity of an extraoral prosthesis depends on its physical and mechanical properties and user maintenance. Faced with multiple outcome measures, researchers find it difficult to determine the most appropriate extraoral prosthetic material. This comprehensive review evaluates the most used extraoral prosthesis materials and qualitatively assesses their longevity and function. The study aims to identify and interpret the results of current updates on the factors that affect longevity and functionality. This comprehensive review summarizes and evaluates differences in the properties of commonly used extraoral maxillofacial prosthetic materials. The review was planned to focus on all factors related to the longevity and function of the extraoral maxillofacial prosthetics. An electronic search covered English articles in PubMed, Scopus, Google Scholar, Web of Science, and grey literature. Manual searching was also performed. Six authors participated in the screening. Search engines extracted 1107 records, and 88 studies were included for qualitative and bias assessments. Silicones are the most frequently used extraoral maxillofacial prosthetic materials. Heat-cured silicones are more color-stable than those cured at room temperature. Additional ingredients and processing techniques affect prosthesis longevity.