Title: Hepatitis (Viral Hepatitis A, B, C, D, E, G)
Category: Diseases and Conditions
Created: 12/31/1997 12:00:00 AM
Last Editorial Review: 8/8/2022 12:00:00 AM

Title: Hepatitis C Infection Can Kill, But Less Than a Third of Patients Get Treatment
Category: Health News
Created: 8/10/2022 12:00:00 AM
Last Editorial Review: 8/10/2022 12:00:00 AM

Title: What Is the Main Cause of Leaky Gut, and How Do You Fix It?
Category: Diseases and Conditions
Created: 8/23/2022 12:00:00 AM
Last Editorial Review: 8/23/2022 12:00:00 AM

Title: Cold, Flu, Allergy Treatments
Category: Diseases and Conditions
Created: 9/24/1999 12:00:00 AM
Last Editorial Review: 7/15/2022 12:00:00 AM

Title: Sore Throat
Category: Diseases and Conditions
Created: 12/31/1997 12:00:00 AM
Last Editorial Review: 7/21/2022 12:00:00 AM

Title: Smoking Rates Drop for Americans Battling Depression, Substance Abuse
Category: Health News
Created: 4/27/2022 12:00:00 AM
Last Editorial Review: 4/27/2022 12:00:00 AM

Title: Postpartum Depression Can Hit Both Mom & Dad, Sometimes at Same Time
Category: Health News
Created: 6/27/2022 12:00:00 AM
Last Editorial Review: 6/28/2022 12:00:00 AM

Title: What Are 4 Symptoms of Seasonal Affective Disorder?
Category: Diseases and Conditions
Created: 12/10/2021 12:00:00 AM
Last Editorial Review: 7/6/2022 12:00:00 AM

Title: Most Post-Stroke Depression Still Goes Untreated
Category: Health News
Created: 7/25/2022 12:00:00 AM
Last Editorial Review: 7/25/2022 12:00:00 AM

Extract

We read with great interest the correspondence by T. Bitter and co-workers in the European Respiratory Review, about our recently published review entitled "Central sleep apnoea: not just one phenotype" [1]. We first want to express our gratefulness to the authors for their support and appreciation of our work, particularly regarding the urgent need for an increasingly differentiated view of central sleep apnoea (CSA) in the context of precision medicine.

Extract

Living with a respiratory illness requires patients to manage a wide range of symptoms, many of which will worsen as a disease progresses. Breathlessness is a hallmark feature of respiratory conditions, occurring in almost all individuals with COPD and interstitial lung disease (ILD) [1, 2]. Cough is present in 78% of people with ILD and is frequently distressing, with physical, social and emotional impacts [1, 3].

Extract

We read with great interest the review article by Randerath et al. [1] recently published in the European Respiratory Review. We would like to congratulate the authors on this clearly structured review, which emphasises the urgent need for an increasingly differentiated view of central sleep apnoea (CSA) in the context of precision medicine.

Background

Immature lung development and respiratory morbidity place preterm-born children at high risk of long-term pulmonary sequelae. This systematic review and meta-analysis aims to quantify lung function in preterm-born children and identify risk factors for a compromised lung function.

Respiratory syncytial virus (RSV) is a major global pathogen, causing lower respiratory tract disease in at-risk populations including young children. Antibodies form a crucial layer of protection from RSV disease, particularly in immunologically naïve infants. Such antibodies are derived from the mother via transplacental transfer and breast milk, but may be particularly low in high-risk infants such as those born preterm. Maternally derived antibodies can now be supplemented by the administration of anti-RSV monoclonal antibodies, while a rising wave of maternal and paediatric vaccine strategies are approaching. The implementation of these prophylactics may profoundly decrease the healthcare burden of RSV. In this article, we review the role of antibody-mediated immunity in protecting children from RSV. We focus on maternally derived antibodies as the main source of protection against RSV and study factors that influence the scale of this transfer. The role of passive and active prophylactic approaches in protecting infants against RSV are discussed and knowledge gaps in our understanding of antibody-mediated protection against RSV are identified.

Background

Severe asthma significantly impacts a minority of children with asthma, leading to frequent symptoms, hospitalisations and potential long-term health consequences. However, accurate global data on severe asthma epidemiology is lacking. This study aims to address this gap, providing data on severe asthma epidemiology, regional differences and associated comorbidities.

Pulmonary hypertension (PH) is highly prevalent in patients with interstitial lung disease (ILD) and is associated with increased morbidity and mortality. Widely available noninvasive screening tools are warranted to identify patients at risk for PH, especially severe PH, that could be managed at expert centres. This review summarises current evidence on noninvasive diagnostic modalities and prediction models for the timely detection of PH in patients with ILD. It critically evaluates these approaches and discusses future perspectives in the field. A comprehensive literature search was carried out in PubMed and Scopus, identifying 39 articles that fulfilled inclusion criteria. There is currently no single noninvasive test capable of accurately detecting and diagnosing PH in ILD patients. Estimated right ventricular pressure (RVSP) on Doppler echocardiography remains the single most predictive factor of PH, with other indirect echocardiographic markers increasing its diagnostic accuracy. However, RVSP can be difficult to estimate in patients due to suboptimal views from extensive lung disease. The majority of existing composite scores, including variables obtained from chest computed tomography, pulmonary function tests and cardiopulmonary exercise tests, were derived from retrospective studies, whilst lacking validation in external cohorts. Only two available scores, one based on a stepwise echocardiographic approach and the other on functional parameters, predicted the presence of PH with sufficient accuracy and used a validation cohort. Although several methodological limitations prohibit their generalisability, their use may help physicians to detect PH earlier. Further research on the potential of artificial intelligence may guide a more tailored approach, for timely PH diagnosis.

Bronchiectasis is a chronic lung condition which is characterised by recurrent chest infections, chronic sputum production and cough, and limited exercise tolerance. While bronchiectasis may be caused by various aetiologies, these features are shared by most patients with bronchiectasis regardless of the cause. This review consolidates the existing evidence on patient-managed interventions for adults with bronchiectasis, while also outlining areas for future research. Airway clearance techniques and hyperosmolar agents are key components of the bronchiectasis management and consistently recommended for clinical implementation. Questions around their prescription, such as optimal sequence of delivery, are still to be answered. Pulmonary rehabilitation and exercise are also recommended for patients with bronchiectasis. Relatively strong evidence underpins this recommendation during a clinically stable stage of the disease, although the role of pulmonary rehabilitation following an exacerbation is still unclear. Additionally, self-management programmes feature prominently in bronchiectasis treatment, yet the lack of consensus regarding their definition and outcomes presents hurdles to establishing a cohesive evidence base. Moreover, cough, a cardinal symptom of bronchiectasis, warrants closer examination. Although managing cough in bronchiectasis may initially appear risky, further research is necessary to ascertain whether strategies employed in other respiratory conditions can be safely and effectively adapted to bronchiectasis, particularly through identifying patient responder populations and criteria where cough may not enhance airway clearance efficacy and its control is needed. Overall, there is a growing recognition of the importance of patient-managed interventions in the bronchiectasis management. Efforts to improve research methodologies and increase research funding are needed to further advance our understanding of these interventions, and their role in optimising patient care and outcomes.

The prognosis of people with cystic fibrosis (pwCF) has improved dramatically with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm). The ageing of the cystic fibrosis (CF) population is changing the disease landscape with the emergence of different needs and increasing comorbidities related to both age and long-term exposure to multiple treatments including CFTRm. Although the number of pwCF eligible for this treatment is expected to increase, major disparities in care and outcomes still exist in this population. Moreover, the long-term impact of the use of CFTRm is still partly unknown due to the current short follow-up and experience with their use, thus generating some uncertainties. The future spread and initiation of these drugs at an earlier stage of the disease is expected to reduce the systemic burden of systemic inflammation and its consequences on health. However, the prolonged life expectancy is accompanied by an increasing burden of age-related comorbidities, especially in the context of chronic disease. The clinical manifestations of the comorbidities directly or indirectly associated with CFTR dysfunction are changing, along with the disease dynamics and outcomes. Current protocols used to monitor slow disease progression will need continuous updates, including the composition of the multidisciplinary team for CF care, with a greater focus on the needs of the adult population.

Background

People living with serious respiratory illness experience a high burden of symptoms. This review aimed to determine whether multicomponent services reduce symptoms in people with serious illness related to respiratory disease.

Background

In adults with serious respiratory illness, fatigue is prevalent and under-recognised, with few treatment options. The aim of this review was to assess the impact of graded exercise therapy (GET) on fatigue in adults with serious respiratory illness.

Background

In adults with serious respiratory illness, breathlessness is prevalent and associated with reduced health-related quality of life. The aim of this review was to assess the impact of breathing techniques on breathlessness in adults with serious respiratory illness.

Background

People living with serious respiratory illness experience a high burden of distressing symptoms. Although opioids are prescribed for symptom management, they generate adverse events, and their benefits are unclear.

Retrotransposable elements (RTEs) are common mobile genetic elements comprising ~42% of the human genome. RTEs play critical roles in gene regulation and function, but how they are specifically involved in complex diseases is largely unknown. Here, we investigate the cellular heterogeneity of RTEs using 12 single-cell transcriptome profiles covering three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. We identify cell type marker RTEs in neurons, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells that are related to these diseases. The differential expression analysis reveals the landscape of dysregulated RTE expression, especially L1s, in excitatory neurons of multiple neurodegenerative diseases. Machine learning algorithms for predicting cell disease stage using a combination of RTE and gene expression features suggests dynamic regulation of RTEs in AD. Furthermore, we construct a single-cell atlas of retrotransposable elements in neurodegenerative disease (scARE) using these data sets and features. scARE has six feature analysis modules to explore RTE dynamics in a user-defined condition. To our knowledge, scARE represents the first systematic investigation of RTE dynamics at the single-cell level within the context of neurodegenerative diseases.

PWAS (proteome-wide association study) is an innovative genetic association approach that complements widely used methods like GWAS (genome-wide association study). The PWAS approach involves consecutive phases. Initially, machine learning modeling and probabilistic considerations quantify the impact of genetic variants on protein-coding genes’ biochemical functions. Secondly, for each individual, aggregating the variants per gene determines a gene-damaging score. Finally, standard statistical tests are activated in the case-control setting to yield statistically significant genes per phenotype. The PWAS Hub offers a user-friendly interface for an in-depth exploration of gene–disease associations from the UK Biobank (UKB). Results from PWAS cover 99 common diseases and conditions, each with over 10,000 diagnosed individuals per phenotype. Users can explore genes associated with these diseases, with separate analyses conducted for males and females. For each phenotype, the analyses account for sex-based genetic effects, inheritance modes (dominant and recessive), and the pleiotropic nature of associated genes. The PWAS Hub showcases its usefulness for asthma by navigating through proteomic-genetic analyses. Inspecting PWAS asthma-listed genes (a total of 27) provide insights into the underlying cellular and molecular mechanisms. Comparison of PWAS-statistically significant genes for common diseases to the Open Targets benchmark shows partial but significant overlap in gene associations for most phenotypes. Graphical tools facilitate comparing genetic effects between PWAS and coding GWAS results, aiding in understanding the sex-specific genetic impact on common diseases. This adaptable platform is attractive to clinicians, researchers, and individuals interested in delving into gene–disease associations and sex-specific genetic effects.

Sequence variation observed in populations of pathogens can be used for important public health and evolutionary genomic analyses, especially outbreak analysis and transmission reconstruction. Identifying this variation is typically achieved by aligning sequence reads to a reference genome, but this approach is susceptible to reference biases and requires careful filtering of called genotypes. There is a need for tools that can process this growing volume of bacterial genome data, providing rapid results, but that remain simple so they can be used without highly trained bioinformaticians, expensive data analysis, and long-term storage and processing of large files. Here we describe split k-mer analysis (SKA2), a method that supports both reference-free and reference-based mapping to quickly and accurately genotype populations of bacteria using sequencing reads or genome assemblies. SKA2 is highly accurate for closely related samples, and in outbreak simulations, we show superior variant recall compared with reference-based methods, with no false positives. SKA2 can also accurately map variants to a reference and be used with recombination detection methods to rapidly reconstruct vertical evolutionary history. SKA2 is many times faster than comparable methods and can be used to add new genomes to an existing call set, allowing sequential use without the need to reanalyze entire collections. With an inherent absence of reference bias, high accuracy, and a robust implementation, SKA2 has the potential to become the tool of choice for genotyping bacteria. SKA2 is implemented in Rust and is freely available as open-source software.

The COVID-19 pandemic has highlighted the critical role of genomic surveillance for guiding policy and control. Timeliness is key, but sequence alignment and phylogeny slow most surveillance techniques. Millions of SARS-CoV-2 genomes have been assembled. Phylogenetic methods are ill equipped to handle this sheer scale. We introduce a pangenomic measure that examines the information diversity of a k-mer library drawn from a country's complete set of clinical, pooled, or wastewater sequence. Quantifying diversity is central to ecology. Hill numbers, or the effective number of species in a sample, provide a simple metric for comparing species diversity across environments. The more diverse the sample, the higher the Hill number. We adopt this ecological approach and consider each k-mer an individual and each genome a transect in the pangenome of the species. Structured in this way, Hill numbers summarize the temporal trajectory of pandemic variants, collapsing each day's assemblies into genome equivalents. For pooled or wastewater sequence, we instead compare days using survey sequence divorced from individual infections. Across data from the UK, USA, and South Africa, we trace the ascendance of new variants of concern as they emerge in local populations well before these variants are named and added to phylogenetic databases. Using data from San Diego wastewater, we monitor these same population changes from raw, unassembled sequence. This history of emerging variants senses all available data as it is sequenced, intimating variant sweeps to dominance or declines to extinction at the leading edge of the COVID-19 pandemic.

High-throughput sequencing (HTS) technologies have been instrumental in investigating biological questions at the bulk and single-cell levels. Comparative analysis of two HTS data sets often relies on testing the statistical significance for the difference of two negative binomial distributions (DOTNB). Although negative binomial distributions are well studied, the theoretical results for DOTNB remain largely unexplored. Here, we derive basic analytical results for DOTNB and examine its asymptotic properties. As a state-of-the-art application of DOTNB, we introduce DEGage, a computational method for detecting differentially expressed genes (DEGs) in scRNA-seq data. DEGage calculates the mean of the sample-wise differences of gene expression levels as the test statistic and determines significant differential expression by computing the P-value with DOTNB. Extensive validation using simulated and real scRNA-seq data sets demonstrates that DEGage outperforms five popular DEG analysis tools: DEGseq2, DEsingle, edgeR, Monocle3, and scDD. DEGage is robust against high dropout levels and exhibits superior sensitivity when applied to balanced and imbalanced data sets, even with small sample sizes. We utilize DEGage to analyze prostate cancer scRNA-seq data sets and identify marker genes for 17 cell types. Furthermore, we apply DEGage to scRNA-seq data sets of mouse neurons with and without fear memory and reveal eight potential memory-related genes overlooked in previous analyses. The theoretical results and supporting software for DOTNB can be widely applied to comparative analyses of dispersed count data in HTS and broad research questions.

Most studies of genome organization have focused on intrachromosomal (cis) contacts because they harbor key features such as DNA loops and topologically associating domains. Interchromosomal (trans) contacts have received much less attention, and tools for interrogating potential biologically relevant trans structures are lacking. Here, we develop a computational framework that uses Hi-C data to identify sets of loci that jointly interact in trans. This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets of trans-contacting loci. We validate trans-C in three increasingly complex models of established trans contacts: the Plasmodium falciparum var genes, the mouse olfactory receptor "Greek islands," and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes coregulated by the same trans-acting element (i.e., a transcription or splicing factor) colocalize in three dimensions to form "RNA factories" that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same DNA-binding proteins interact with one another in trans, especially those bound by factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA-binding proteins correlates with trans interaction of the encoding loci. We observe that these trans-interacting loci are close to nuclear speckles. These findings support the existence of trans-interacting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types of trans interactions, empowering studies of a poorly understood aspect of genome architecture.

Asgard archaea are of great interest as the progenitors of Eukaryotes, but little is known about the mobile genetic elements (MGEs) that may shape their ongoing evolution. Here, we describe MGEs that replicate in Atabeyarchaeia, a wetland Asgard archaea lineage represented by two complete genomes. We used soil depth–resolved population metagenomic data sets to track 18 MGEs for which genome structures were defined and precise chromosome integration sites could be identified for confident host linkage. Additionally, we identified a complete 20.67 kbp circular plasmid and two family-level groups of viruses linked to Atabeyarchaeia, via CRISPR spacer targeting. Closely related 40 kbp viruses possess a hypervariable genomic region encoding combinations of specific genes for small cysteine-rich proteins structurally similar to restriction-homing endonucleases. One 10.9 kbp integrative conjugative element (ICE) integrates genomically into the Atabeyarchaeum deiterrae-1 chromosome and has a 2.5 kbp circularizable element integrated within it. The 10.9 kbp ICE encodes an expressed Type IIG restriction-modification system with a sequence specificity matching an active methylation motif identified by Pacific Biosciences (PacBio) high-accuracy long-read (HiFi) metagenomic sequencing. Restriction-modification of Atabeyarchaeia differs from that of another coexisting Asgard archaea, Freyarchaeia, which has few identified MGEs but possesses diverse defense mechanisms, including DISARM and Hachiman, not found in Atabeyarchaeia. Overall, defense systems and methylation mechanisms of Asgard archaea likely modulate their interactions with MGEs, and integration/excision and copy number variation of MGEs in turn enable host genetic versatility.

Somatic mutations arise and accumulate during tissue culture and vegetative propagation, potentially affecting various traits in horticultural crops, but their characteristics are still unclear. Here, somatic mutations in regenerated woodland strawberry derived from tissue culture of shoot tips under different conditions and 12 cultivated strawberry individuals are analyzed by whole genome sequencing. The mutation frequency of single nucleotide variants is significantly increased with increased hormone levels or prolonged culture time in the range of 3.3 x 10^–8–3.0 x 10^–6 mutations per site. CG methylation shows a stable reduction (0.71%–8.03%) in regenerated plants, and hypoCG-DMRs are more heritable after sexual reproduction. A high-quality haplotype-resolved genome is assembled for the strawberry cultivar "Beni hoppe." The 12 "Beni hoppe" individuals randomly selected from different locations show 4731–6005 mutations relative to the reference genome, and the mutation frequency varies among the subgenomes. Our study has systematically characterized the genetic and epigenetic variants in regenerated woodland strawberry plants and different individuals of the same strawberry cultivar, providing an accurate assessment of somatic mutations at the genomic scale and nucleotide resolution in plants.

The poly(A) signal, together with auxiliary elements, directs cleavage of a pre-mRNA and thus determines the 3' end of the mature transcript. In many species, including humans, the poly(A) signal is an AAUAAA hexamer, but we recently found that the deeply branching eukaryote Giardia lamblia uses a distinct hexamer (AGURAA) and lacks any known auxiliary elements. Our discovery prompted us to explore the evolutionary dynamics of poly(A) signals and auxiliary elements in the eukaryotic kingdom. We use direct RNA sequencing to determine poly(A) signals for four protists within the Metamonada clade (which also contains G. lamblia) and two outgroup protists. These experiments reveal that the AAUAAA hexamer serves as the poly(A) signal in at least four different eukaryotic clades, indicating that it is likely the ancestral signal, whereas the unusual Giardia version is derived. We find that the use and relative strengths of auxiliary elements are also plastic; in fact, within Metamonada, species like G. lamblia make use of a previously unrecognized auxiliary element where nucleotides flanking the poly(A) signal itself specify genuine cleavage sites. Thus, despite the fundamental nature of pre-mRNA cleavage for the expression of all protein-coding genes, the motifs controlling this process are dynamic on evolutionary timescales, providing motivation for future biochemical and structural studies as well as new therapeutic angles to target eukaryotic pathogens.

Understanding the evolution of chromatin conformation among species is fundamental to elucidate the architecture and plasticity of genomes. Nonrandom interactions of linearly distant loci regulate gene function in species-specific patterns, affecting genome function, evolution, and, ultimately, speciation. Yet, data from nonmodel organisms are scarce. To capture the macroevolutionary diversity of vertebrate chromatin conformation, here we generate de novo genome assemblies for two cryptodiran (hidden-neck) turtles via Illumina sequencing, chromosome conformation capture, and RNA-seq: Apalone spinifera (ZZ/ZW, 2n = 66) and Staurotypus triporcatus (XX/XY, 2n = 54). We detected differences in the three-dimensional (3D) chromatin structure in turtles compared to other amniotes beyond the fusion/fission events detected in the linear genomes. Namely, whole-genome comparisons revealed distinct trends of chromosome rearrangements in turtles: (1) a low rate of genome reshuffling in Apalone (Trionychidae) whose karyotype is highly conserved when compared to chicken (likely ancestral for turtles), and (2) a moderate rate of fusions/fissions in Staurotypus (Kinosternidae) and Trachemys scripta (Emydidae). Furthermore, we identified a chromosome folding pattern that enables "centromere–telomere interactions" previously undetected in turtles. The combined turtle pattern of "centromere–telomere interactions" (discovered here) plus "centromere clustering" (previously reported in sauropsids) is novel for amniotes and it counters previous hypotheses about amniote 3D chromatin structure. We hypothesize that the divergent pattern found in turtles originated from an amniote ancestral state defined by a nuclear configuration with extensive associations among microchromosomes that were preserved upon the reshuffling of the linear genome.

The transcription factor (TF) cone-rod homeobox (CRX) is essential for the differentiation and maintenance of photoreceptor cell identity. Several human CRX variants cause degenerative retinopathies, but most are variants of uncertain significance. We performed a deep mutational scan (DMS) of nearly all possible single amino acid substitutions in CRX using a cell-based transcriptional reporter assay, curating a high-confidence list of nearly 2000 variants with altered transcriptional activity. In the structured homeodomain, activity scores closely aligned to a predicted structure and demonstrated position-specific constraints on amino acid substitution. In contrast, the intrinsically disordered transcriptional effector domain displayed a qualitatively different pattern of substitution effects, following compositional constraints without specific residue position requirements in the peptide chain. These compositional constraints were consistent with the acidic exposure model of transcriptional activation. We evaluated the performance of the DMS assay as a clinical variant classification tool using gold-standard classified human variants from ClinVar, identifying pathogenic variants with high specificity and moderate sensitivity. That this performance could be achieved using a synthetic reporter assay in a foreign cell type, even for a highly cell type-specific TF like CRX, suggests that this approach shows promise for DMS of other TFs that function in cell types that are not easily accessible. Together, the results of the CRX DMS identify molecular features of the CRX effector domain and demonstrate utility for integration into the clinical variant classification pipeline.

Pleiotropy, measured as expression breadth across tissues, is one of the best predictors for protein sequence and expression conservation. In this study, we investigated its effect on the evolution of cis-regulatory elements (CREs). To this end, we carefully reanalyzed the Epigenomics Roadmap data for nine fetal tissues, assigning a measure of pleiotropic degree to nearly half a million CREs. To assess the functional conservation of CREs, we generated ATAC-seq and RNA-seq data from humans and macaques. We found that more pleiotropic CREs exhibit greater conservation in accessibility, and the mRNA expression levels of the associated genes are more conserved. This trend of higher conservation for higher degrees of pleiotropy persists when analyzing the transcription factor binding repertoire. In contrast, simple DNA sequence conservation of orthologous sites between species tends to be even lower for pleiotropic CREs than for species-specific CREs. Combining various lines of evidence, we propose that the lack of sequence conservation in functionally conserved pleiotropic CREs is owing to within-element compensatory evolution. In summary, our findings suggest that pleiotropy is also a good predictor for the functional conservation of CREs, even though this is not reflected in the sequence conservation of pleiotropic CREs.

As a major type of structural variants, tandem duplication plays a critical role in tumorigenesis by increasing oncogene dosage. Recent work has revealed that noncoding enhancers are also affected by duplications leading to the activation of oncogenes that are inside or outside of the duplicated regions. However, the prevalence of enhancer duplication and the identity of their target genes remains largely unknown in the cancer genome. Here, by analyzing whole-genome sequencing data in a non-gene-centric manner, we identify 881 duplication hotspots in 13 major cancer types, most of which do not contain protein-coding genes. We show that the hotspots are enriched with distal enhancer elements and are highly lineage-specific. We develop a HiChIP-based methodology that navigates enhancer–promoter contact maps to prioritize the target genes for the duplication hotspots harboring enhancer elements. The methodology identifies many novel enhancer duplication events activating oncogenes such as ESR1, FOXA1, GATA3, GATA6, TP63, and VEGFA, as well as potentially novel oncogenes such as GRHL2, IRF2BP2, and CREB3L1. In particular, we identify a duplication hotspot on Chromosome 10p15 harboring a cluster of enhancers, which skips over two genes, through a long-range chromatin interaction, to activate an oncogenic isoform of the NET1 gene to promote migration of gastric cancer cells. Focusing on tandem duplications, our study substantially extends the catalog of noncoding driver alterations in multiple cancer types, revealing attractive targets for functional characterization and therapeutic intervention.

The human major histocompatibility complex (MHC) is a ~4 Mb genomic segment on Chromosome 6 that plays a pivotal role in the immune response. Despite its importance in various traits and diseases, its complex nature makes it challenging to accurately characterize on a routine basis. We present a novel approach allowing targeted sequencing and de novo haplotypic assembly of the MHC region in heterozygous samples, using long-read sequencing technologies. Our approach is validated using two reference samples, two family trios, and an African-American sample. We achieved excellent coverage (96.6%–99.9% with at least 30x depth) and high accuracy (99.89%–99.99%) for the different haplotypes. This methodology offers a reliable and cost-effective method for sequencing and fully characterizing the MHC without the need for whole-genome sequencing, facilitating broader studies on this important genomic segment and having significant implications in immunology, genetics, and medicine.

The 10q11.22 chromosomal region is a duplication-rich interval of the human genome and one of the last to be fully assembled. It carries copy number–variable genes associated with intellectual disability, bipolar disorder, and obesity. In this study, we characterized the structural diversity at this locus by analyzing 64 haploid assemblies produced by the Human Pangenome Reference Consortium. We identified 11 alternative haplotypes that differ in the copy number and/or orientation of large genomic segments, ranging from hundreds of kilobase pairs (kbp) to over one megabase pair (Mbp). We uncovered a 2.4 Mbp size difference between the shortest and longest haplotypes. Breakpoint analysis revealed that genomic instability results from nonallelic homologous recombination between segmental duplication (SD) pairs with varying similarity (94.4%–99.6%). Nonetheless, these pairs generally recombine at positions where their identity is higher (>99.6%). Recurrent inversions occur with different breakpoints within the same inverted SD pair. Inversion polymorphisms shuffle the entire SD arrangement, creating new predispositions to copy-number variations. The SD architecture is associated with a catarrhine-specific subgroup of the AGAP gene family, which likely triggered the accumulation of SDs at this locus over the past 25 million years of human evolution. Our results reveal extensive structural diversity and genomic instability at the 10q11.22 locus, and expand the general understanding of the mutational mechanisms behind SD-mediated rearrangements.

The neuronal nucleus houses a meticulously organized genome. Within this structure, genetic material is not simply compacted but arranged into a precise and functional 3D chromatin landscape essential for cellular regulation. This mini-review highlights the importance of this chromatin landscape in healthy neurodevelopment, as well as the diseases that occur with aberrant chromatin architecture. We discuss insights into the fundamental mechanistic relationship between histone modifications, DNA methylation, and genome organization. We then discuss findings that reveal how these epigenetic features change throughout normal neurodevelopment. Finally, we highlight single-gene neurodevelopmental disorders that illustrate the interdependence of epigenetic features, showing how disruptions in DNA methylation or genome architecture can ripple across the entire epigenome. As such, we emphasize the importance of measuring multiple chromatin architectural aspects, as the disruption of one mechanism can likely impact others in the intricate epigenetic network. This mini-review underscores the vast gaps in our understanding of chromatin structure in neurodevelopmental diseases and the substantial research needed to understand the interplay between chromatin features and neurodevelopment.

Two decades into the era of Electronic Health Records (EHRs), the promise of streamlining clinical care, reducing burden, and improving patient outcomes has yet to be realized. A cross-sectional family physician census conducted by the American Board of Family Medicine in 2022 and 2023 included self-reported physician EHR satisfaction. Of the nearly 10,000 responding family physicians, only one-in-four (26.2%) report being very satisfied and one-in-three (33.8%) were not satisfied. These low levels of satisfaction point to the need for greater transparency in the marketplace and pressure to increase user-centric EHR design.

Background:

The COVID-19 pandemic social distancing requirements encouraged patients to avoid public spaces including in-office health care visits. Ambulatory-care-sensitive conditions (ACSCs) represent conditions that can be managed with quality primary care and when access is limited, these conditions can lead to avoidable emergency department (ED) visits.

The rising obesity epidemic is a phenomenon that has gained increasing attention from health providers and health policy makers. This led to recognition of nonalcoholic fatty liver disease (MASLD). The standard for its assessment has been histologic, which is neither practical nor acceptable by patients. Subsequently, a number of noninvasive assessment methods have been developed. However, despite ease of implementation, their confounding variables do hinder their accuracy. Nonetheless, the development of the liver stiffness measurement (LSM) and incorporation of other biological parameters has minimized but not eliminated the need for liver biopsy. Imaging methods are useful in evaluation, estimation, and following the progression of steatosis and fibrosis with particular attention to controlled attenuation parameter (CAP) and MRI–Proton Density Fat Fraction (MRI-PDFF). The choices for the family physician are broad and rely on tests’ availability, cost, and patient acceptance. Great efforts have been undertaken to produce more robust and novel noninvasive markers that indicate fibrinogenesis directly in an implementable and cost-effective way.

Family medicine physicians often see headache as the chief complaint when meeting patients within their practice. The goal is to try different treatment modalities without having to send the patient to a specialist. Headaches affect different individuals during their lifetime. Before any treatment begins, it is best that one rules out possible causes of the headache, for example, drug interactions or structural cerebrum conditions. Nonpharmacological treatment is recommended first before attempting a stepwise approach to cost-effective pharmacological treatment options. Pharmacological treatment options should include preventive and on-demand options. A family physician has all the resources to assist patients with different types of headaches.

Background:

Discharge communication between hospitalists and primary care clinicians is essential to improve care coordination, minimize adverse events, and decrease unplanned health services use. Health-related social needs are key drivers of health, and hospitalists and primary care clinicians value communicating social needs at discharge.

Background:

Nested within a growing body of evidence of a gender pay gap in medicine are more alarming recent findings from family medicine: a gender pay gap of 16% can be detected at a very early career stage. This article explores qualitative evidence of women’s experiences negotiating for their first job out of residency to ascertain women’s engagement with and approach to the negotiation process.

Purpose:

Providing medication abortion in the primary care setting is a promising way to increase access to abortion, a threatened service in many States. This study aimed to characterize primary care clinicians’ interest in prescribing medication abortion, what barriers they face in adding this service, and what support they need.

Background:

Continuous glucose monitoring (CGM) for patients with type 1 and type 2 diabetes is associated with improved clinical, behavioral, and psychosocial patient health outcomes and is part of the American Diabetes Association’s Standards of Medical Care. CGM prescription often takes place in endocrinology practices, yet 50% of adults with type 1 diabetes and 90% of all people with type 2 diabetes receive their diabetes care in primary care settings. This study examined primary care clinicians’ perceptions of barriers and resources needed to support CGM use in primary care.

Purpose:

Colorectal cancer (CRC) screening is recommended starting at age 45, but there has been little research on strategies to promote screening among patients younger than 50. This study assessed the effect of a multicomponent intervention on screening completion in this age group.

Background:

Screening rates for Human Immunodeficiency Virus (HIV) remain low despite guidelines by both the CDC and USPSTF recommending that all adolescents and adults be screened at least once. The aim of this quality improvement study was to increase HIV screening among eligible patients.

Background:

Certain health-related risk factors require legal interventions. Medical-legal partnerships (MLPs) are collaborations between clinics and lawyers that address these health-harming legal needs (HHLNs) and have been shown to improve health and reduce utilization.