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Syndromic Forms of Inherited Retinal Dystrophies: A Comprehensive Molecular Diagnosis of Consanguineous Pakistani Families Using Capture Panel Sequencing
No full textBackground: Inherited retinal dystrophies (IRDs) represent a clinically and genetically heterogeneous group of genetic disorders that involve photoreceptors and/or retinal pigment epithelium degeneration. IRDs may occur as an isolated condition or may represent an ocular manifestation of a multisystemic disorder referred as syndromic IRD. To increase the understanding of the molecular determinants of syndromic IRD-related genes in the Pakistani population, we revealed the genetic profile of 13 consanguineous Pakistani families using capture panel sequencing.
Methods: We performed comprehensive molecular testing on 72 IRD segregating Pakistani families using targeted capture panel sequencing of 344 known genes. The pathogenicity of candidate variants was assessed using American College of Medical Genetics and Genomics guidelines, followed by Sanger sequencing for segregation analysis.
Results: Causative variants in previously reported syndromic IRDs genes were detected in 13/72 (18%) IRD families, including 5/72 (6.94%), 4/72 (5.55%), 2/72 (2.8%), 1/72(1.38%) and 1/72 (1.38%) in Usher syndrome, Bardet-Biedl syndrome, Batten disease, retinitis pigmentosa with situs inversus and Stickler syndrome segregated families, respectively. Disease-causing variants included nine previously reported and six novel homozygous variants, i.e., c.1143G\u3eC in USH2A, c.470G\u3eA in MYO7A, c.877-2A\u3eG in PCDH15, c.347C\u3eT in ARL6, c.581C\u3eT in CLN5 and c.100+1G\u3eT in ARL2BP gene segregation with disease phenotype in eight families. Two heterozygous variants of the USH2A gene, i.e., c.12093C\u3eA and c.9815C\u3eT, were segregated in a compound heterozygous form in family RP243. Furthermore, RP151 showed segregation of a heterozygous variant c.247G\u3eA in a Stickler syndrome gene, i.e., COL2A1, in an autosomal dominant manner.
Conclusions: This study reaffirms the clinical and genetic heterogeneity of syndromic IRD-associated genes and confirms the usefulness of molecular methods in advancing our understanding of these conditions in consanguineous populations. The most commonly mutated Bardet-Biedl syndrome gene was ARL6 (75%) and the most commonly mutated Usher syndrome genes were USH2A (40%) and MYO7A (40%). Our data could serve as a reference for future studies and the development of treatment modalities for affected families of Pakistani origin
Social Determinants of Health Patterns in Children with Severe Disease Due to SARS-CoV-2 Infection-An Exploratory Approach
No full textBackground/Objectives: Research on the association of adverse social determinants of health (SDOH) with severe pediatric coronavirus disease (COVID-19) is limited. We examined associations between SDOH patterns and COVID-19 severity in children.
Methods: We conducted a prospective, observational study of children (\u3c 18 years) with symptomatic SARS-CoV-2 infection evaluated in an urban pediatric emergency department (March 2021-April 2022) in Detroit, Michigan. Caregivers completed a 34-item survey based on the Healthy People 2030 framework. Severe disease was defined as the occurrence of respiratory/cardiac failure or death within four weeks of diagnosis. Continuous and categorical variables were described using medians and percentages, respectively. Associations between disease severity and risk factors were determined using chi-square tests. Association rule mining was used for feature selection, followed by multivariate logistic regression.
Results: We analyzed data from 354 children [6-12 years: 31.1%, Female: 51.1%, Black: 59%, not Hispanic: 84.7%, public insurance: 77.1%, chronic condition: 27.4%]. Of the total, 113 children had severe disease. Most caregivers were 30-44 years old (53.1%), had less than a college degree (70.4%), and income \u3c USD 50,000 (75.2%). Adverse SDOH reported included food/housing insecurity (24.6%), no support (64.7%), unmet childcare needs (35.9%), and lack of transportation (12.7%). After controlling for age, sex, medical history, income, and obesity, severe disease was associated with caregiver use of drugs/alcohol (OR:5.92, p \u3c 0.001) and social discrimination/lack of support (OR: 1.74, p = 0.030).
Conclusions: Two SDOH patterns (caregiver use of drugs/alcohol and social discrimination/lack of support) were associated with severe COVID-19. Further studies are needed to confirm findings and develop interventions
Defining Three Principles for Credible Evidence Synthesis and Reviews in Health Professions Education
No full textAs reviews become increasingly central to informing educational practice and guiding research in health professions education, the need for methodological clarity and quality has grown. This Commentary highlights three foundational principles - alignment, rigor, and transparency - that underpin high-quality reviews, regardless of type. We illustrate how these principles apply across commonly used review types, including systematic, scoping, realist, and narrative reviews. By aligning the research question with the appropriate review methodology, employing rigorous processes for evidence collection and synthesis, and maintaining transparency in methodological reporting, review teams can produce credible, transferable, and dependable findings. Embracing these principles not only enhances the trustworthiness of reviews but also supports stakeholders in applying synthesized knowledge effectively, ultimately advancing evidence-informed decision-making in health professions education
Metabolic Signatures in Adipose Tissue Linking Lipophilic Persistent Organic Pollutant Mixtures to Blood Pressure Five Years After Bariatric Surgery Among Adolescents
No full textPersistent organic pollutants (POPs) are lipophilic environmental contaminants accumulated in the adipose tissue. Weight loss interventions, such as bariatric surgery, can mobilize POPs from adipose tissue into the bloodstream. We hypothesized that this mobilization could contribute to increases in blood pressure among 57 adolescents with severe obesity undergoing bariatric surgery. POPs and metabolic features were measured from visceral adipose tissue collected during surgery using gas and liquid chromatography, coupled with high-resolution mass spectrometry. Blood pressure was assessed at baseline, 6 months, and 5 years post-surgery. We used quantile g-computation to estimate associations of POP mixtures with blood pressure changes. With one quartile increase in POP mixtures, systolic blood pressure (SBP) increased by 6.4% five years after bariatric surgery compared to baseline SBP [95% confidence interval (CI): 0.4%, 12.4%]. The meet-in-the-middle approach identified overlapping metabolic features and pathways linking POP mixtures to SBP changes, highlighting the role of prostaglandin formation via arachidonic acid metabolism. POP mixtures were negatively associated with indole-3-acetate (−0.729, 95% CI: −1.234, −0.223), which was negatively associated with SBP changes at five years (−3.49%, 95% CI: −6.51%, −0.48%). Our findings suggested that lipophilic POP mixtures attenuated the beneficial effect of bariatric surgery on improved blood pressure among adolescents via alterations in lipid metabolism
Computer-Aided Reading of Chest Radiographs for Paediatric Tuberculosis: Current Status and Future Directions
No full textComputer-aided detection (CAD) systems for automated reading of chest x-rays (CXRs) have been developed and approved for tuberculosis triage in adults but not in children. However, CXR is frequently the only adjunctive tool for clinical assessment in the evaluation of paediatric tuberculosis in primary care settings, and children would benefit from CAD models that can detect their unique clinical and radiographic features. To advance CAD for childhood tuberculosis, large, diverse paediatric CXR datasets linked to standardised tuberculosis classifications are required. These datasets would be used to train and validate paediatric-specific models for tuberculosis screening, diagnosis, and severity stratification. Previous studies on CAD algorithms for reading paediatric CXRs have highlighted promising approaches, including the use of transfer learning with existing deep learning models. Including data from children in CAD models is essential to improve equity and reduce the global burden of tuberculosis disease
Case Studies in Heritable Vascular Disease: Proceedings of the UTHealth Houston Multidisciplinary Aortic Conference
Get PDFHeritable thoracic aortic disease is caused by dominantly inherited mutations in more than a dozen genes, including TGFB2 mutations that cause Loeys-Dietz syndrome. McGovern Medical School at UTHealth Houston convenes a regular conference that includes cardiothoracic and vascular surgeons, cardiologists, geneticists, radiologists, and pathologists to formulate multidisciplinary approaches for the management of complex heritable thoracic aortic disease cases. In this report, we highlight the unique management of individuals with distinct presentations of Loeys-Dietz syndrome owing to TGFB2 mutations
Definition and Classification of Dystonia.
Get PDFDystonia is a movement disorder with varied clinical features and diverse etiologies. Here we present a revision of the 2013 consensus definition and classification of dystonia in light of subsequent publications and experience with its application during the last decade. A panel of movement disorder specialists with expertise in dystonia reviewed the original document and proposed some revision. There was broad consensus to retain the definition of dystonia with only minor clarifications to the wording. Dystonia is defined as a movement disorder characterized by sustained or intermittent abnormal movements, postures, or both. Dystonic movements and postures are typically patterned and repetitive and may be tremulous or jerky. They are often initiated or worsened by voluntary action and frequently associated with overflow movements. The two-axis structure for classification of the many different presentations of dystonia was also retained, with some revision. Axis I summarizes key clinical characteristics of dystonia, including age at onset, family history, body distribution, temporal dimensions, phenomenology, and whether dystonia is isolated or combined with other neurological or medical problems. Axis II organizes information regarding its etiological basis, including genetic, acquired, and anatomical, and common disease mechanisms. This consensus provides an update to the original definition and classification of dystonia with the aim of facilitating its clinical recognition and management. The revision retains the essence of the original proposal and aims particularly to provide a structure facilitating a uniform implementation. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Molecular Logic for Cellular Specializations That Initiate the Auditory Parallel Processing Pathways
Get PDFThe cochlear nuclear complex (CN), the starting point for all central auditory processing, encompasses a suite of neuronal cell types highly specialized for neural coding of acoustic signals. However, the molecular logic governing these specializations remains unknown. By combining single-nucleus RNA sequencing and Patch-seq analysis, we reveal a set of transcriptionally distinct cell populations encompassing all previously observed types and discover multiple hitherto unknown subtypes with anatomical and physiological identity. The resulting comprehensive cell-type taxonomy reconciles anatomical position, morphological, physiological, and molecular criteria, enabling the determination of the molecular basis of the specialized cellular phenotypes in the CN. In particular, CN cell-type identity is encoded in a transcriptional architecture that orchestrates functionally congruent expression across a small set of gene families to customize projection patterns, input-output synaptic communication, and biophysical features required for encoding distinct aspects of acoustic signals. This high-resolution account of cellular heterogeneity from the molecular to the circuit level reveals the molecular logic driving cellular specializations, thus enabling the genetic dissection of auditory processing and hearing disorders with a high specificity
Gout Flare Burden in the United States: A Multiyear Cross-Sectional Survey Study
Get PDFOBJECTIVE: The objective of this study was to assess the burden of gout flares and examine associated patient characteristics and outcomes in a sample of US adults.
METHODS: Data were collected via an online survey of US adults ≥18 years using a random stratified sampling framework. Participants with gout completed questions about treatments, serum urate (SU) levels, severity, satisfaction with control, and gout flares. All participants completed the Veterans RAND 12-Item Health Survey, the Generalized Anxiety Disorder 7-Item Scale, and the Patient Health Questionnaire 9-Item Scale. Data were summarized using descriptive statistics. Multivariable-adjusted logistic regression analyses examined factors predictive of reporting gout flares to a physician.
RESULTS: A total of 933 participants met the study criteria for having gout. Those with gout tended to be older (58.3 [SD 13.3] years vs 45.4 [SD 16.1] years; P \u3c 0.001), male (76.3% vs 46.9%; P \u3c 0.001), White (80.5% vs 76.8%; P = 0.01), and married or living with their partner (58.9% vs 52.8%; P \u3c 0.001) compared with those without gout (n = 30,146). The total gout flare burden for those with gout was 6.6 gout flares per year. Nearly 72% of gout flares were either not reported to physicians or pretreated or prevented. Characteristics of those who were less likely to report gout flares included being younger, being less educated, having a lower Charlson Comorbidity Index score, not being diagnosed with gout by their doctor, and not taking a urate-lowering therapy.
CONCLUSION: This study confirmed that gout flares are common in US adults with gout and found that gout flares are underreported. Reliance on clinical documentation of physician-reported gout flares is insufficient to assess the true patient burden of gout
Early Tolerance and Late Persistence As Alternative Drug Responses in Cancer
No full textBacteria withstand antibiotic treatment through three alternative mechanisms: resistance, persistence or tolerance. While resistance and persistence have been described, whether drug-induced tolerance exists in cancer cells remains largely unknown. Here, we show that human cancer cells elicit a tolerant response when exposed to commonly used chemotherapy regimens, propelled by the pervasive activation of autophagy, leading to the comprehensive activation of DNA damage repair pathways. After prolonged drug exposure, such tolerant responses morph into persistence, whereby the increased DNA damage repair is entirely reversed. The central regulator of mitophagy PINK1 drives this reduction in DNA repair via the cytoplasmic relocalization of the cell identity master HNF4A, thus hampering HNF4A transcriptional activation of DNA repair genes. We conclude that exposing cancer cells to relevant standard-of-care antitumour therapies induces a pervasive drug-induced tolerant response that might be broadly exploited to increase the impact of first-line, adjuvant treatments and debulking in advanced cancers