Long read sequencing enhances pathogenic and novel variation discovery in patients with rare diseases.

With ongoing improvements in the detection of complex genomic and epigenomic variations, long-read sequencing (LRS) technologies could serve as a unified platform for clinical genetic testing, particularly in rare disease settings, where nearly half of patients remain undiagnosed using existing technologies. Here, we report a simplified funnel-down filtration strategy aimed at enhancing the identification of small and large deleterious variants as well as abnormal episignature disease profiles from whole-genome LRS data. This approach detected all pathogenic single nucleotide, structural, and methylation variants in a positive control set (N = 76) including an independent sample set with known methylation profiles (N = 57).

Differentiating Therapeutic Responses That Reduce Restrictive Practice Use and Situational Aggression in an Acute Mental Health Unit.

Aim: An analysis of mental health nursing de-escalation logs for 249 days from a regional adult inpatient unit in New South Wales, Australia, was completed to identify groups of cooccurring nursing therapeutic responses to aggression and examine their associations with reductions in restrictive practices and situational aggression.

Design: A single-centre retrospective study was undertaken.

Method: Hierarchical clustering of nursing interventions established groups of cooccurring nursing responses.

Practical resistance to spinosad in an onion maggot (Diptera: Anthomyiidae) population in New York.

Onion maggot, Delia antiqua (Meigen), is a significant constraint on onion production across the temperate regions of North America. Early season infestations can reduce plant stands up to 75% if untreated. Effective management of D.

Uptake, utility and resource requirements of a genetic counselling telephone helpline within the BRCA-DIRECT digital pathway for mainstreamed BRCA testing in patients with breast cancer.

Background: We trialled the first digital pathway (BRCA-DIRECT) aiming to improve capacity for mainstreamed BRCA testing within UK breast oncology services. Patients received standardised digital pretest information, with saliva sampling and consent to testing completed at home. For individualised support, we offered access to a clinical genetics professional via a telephone helpline (TH).

High Systemic Disease Risk and Therapeutic Delays in Plaque Psoriasis: A Retrospective Analysis of Apremilast Use in the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR).

Introduction: We describe comorbidities and cardiovascular diseases (CVD) risk in patients with psoriasis prescribed apremilast in UK clinical practice. Such real-world data are currently sparse.

Methods: This observational, retrospective analysis of British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) included adults with plaque psoriasis first prescribed apremilast between October 2015 and March 2021.

'Constipation': One word, many meanings amongst persons with cancer: An observational study.

Background: Constipation is common in people with advanced cancer and is associated with significant morbidity and health economic burden, but it is often sub-optimally managed. Despite international consensus diagnostic criteria for functional and opioid-induced constipation (Rome IV diagnostic criteria), the term 'constipation' means different things to different people, impacting assessment, diagnosis and management.

Aim: To investigate the association between persons with advanced cancer self-reporting of constipation, response to the Rome IV diagnostic criteria statements for opioid-induced constipation and differences according to personal demographics.

Barriers and Facilitators to Cross-Institutional Referrals: System Configuration Analysis of VA Staff Experiences.

Background: In 2014 and 2018, respectively, Congress passed the Veterans Access, Choice, and Accountability Act (Choice Act) and the Maintaining Internal Systems and Strengthening Integrated Outside Networks Act (MISSION Act), which expanded eligibility for and use of cross-institutional referrals among U.S. Veterans enrolled in the Veterans Health Administration.

A comparison of calcification mechanisms in haploid and diploid cells of the coccolithophore Calcidiscus leptoporus (Murray & Blackman 1898).

Coccolithophores are prominent marine pelagic calcifiers due to their production of calcite coccoliths. Diploid coccolithophores produce heterococcoliths intracellularly, with an organic cellulose baseplate scale acting as a nucleating substrate. However, coccolith production in the haploid life phase has not been extensively studied.

Compositional variation in eye-infiltrating immune cells distinguishes human uveitis subtypes.

Uveitis is a heterogeneous group of ocular inflammatory diseases that respond inadequately to empiric therapy, underscoring the need to define pathophysiologic subtypes. Toward this goal, we applied single-cell transcriptional and immune receptor profiling to ocular fluid biopsies from 23 patients with diverse clinical features. We found that a subset of ocular T cells undergoes local clonal expansion, indicating that antigens trigger uveitis in some patients.

Sequencing by Expansion (SBX) - a novel, high-throughput single-molecule sequencing technology.

Remarkable advances in high-throughput sequencing have enabled major biological discoveries and clinical applications, but achieving wider distribution and use depends critically on further improvements in scale and cost reduction. Nanopore sequencing has long held the promise for such progress, but has had limited market penetration. This is because efficient and accurate nanopore sequencing of nucleic acids has been challenged by fundamental signal-to-noise limitations resulting from the poor spatial resolution and molecular distinction of nucleobases.

Evaluation of Aldosterone Suppression by Cinnarizine, a Putative Cav1.3 Inhibitor.

Context: Primary aldosteronism (PA) is commonly caused by somatic mutations of CACNA1D encoding Cav1.3, one of the four L-type calcium channels. The over-the-counter drug, cinnarizine, fits the Cav1.

A mixed methods protocol for an impact and implementation evaluation of the Pharmacy First Services for management of common conditions in England.

Objectives: In response to high levels of demand for primary medical services in England, characterized by longer appointment waiting times and delayed referrals, the Government developed its National Health Service (NHS) Primary Care Recovery Plan. A key component of the plan is Pharmacy First (PF), which involves participating community pharmacies supplying prescription-only medicine after consultation with a pharmacist for seven common conditions: earache, uncomplicated urinary tract infections in women, sore throat, sinusitis, impetigo, shingles, and infected insect bites. The study aims to evaluate the implementation of the PF service and its impact on the volume of prescribing, case mix of General Practitioner consultations, accident and emergency department and other hospital use, equity of access, and cost for different groups of patients in different contexts, as well as its acceptability and fidelity.

GeneFEAST: the pivotal, gene-centric step in functional enrichment analysis interpretation.

Summary: GeneFEAST, implemented in Python, is a gene-centric functional enrichment analysis summarisation and visualisation tool that can be applied to large functional enrichment analysis (FEA) results arising from upstream FEA pipelines. It produces a systematic, navigable HTML report, making it easy to identify sets of genes putatively driving multiple enrichments and to explore gene-level quantitative data first used to identify input genes. Further, GeneFEAST can juxtapose FEA results from multiple studies, making it possible to highlight patterns of gene expression amongst genes that are differentially expressed in at least one of multiple conditions, and which give rise to shared enrichments under those conditions.

Understanding degenerative cervical myelopathy in musculoskeletal practice.

Background: Degenerative cervical myelopathy (DCM) is a clinical syndrome characterized by a progressive compression of the spinal cord. DCM often looks like common symptoms of aging or bilateral carpal tunnel syndrome in its early stages, requiring careful differential diagnosis. Identifying DCM is a real challenge as no validated screening tools are available for making the DCM diagnosis.

A multifunctional organelle coordinates phagocytosis and chlorophagy in a marine eukaryote phytoplankton Scyphosphaera apsteinii.

Mixotrophy via phagocytosis can have profound consequences for the survival of marine phytoplankton and the efficiency of carbon transfer in marine systems. Little is known about the cellular mechanisms that underly nutrient acquisition via prey uptake and processing in mixotrophic phytoplankton. We used confocal microscopy, flow cytometry, and electron microscopy to assess phagocytosis and intracellular prey processing in the diploid calcifying coccolithophore Scyphosphaera apsteinii.

Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes.

Background: Activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. We hypothesized that differences in mitochondrial dynamics, structure and bioenergetics in humans would explain the onset and progression of type 2 diabetes (T2D).

Methods: Fifty-eight sedentary adults (37 ± 12 years) were enrolled into one of three groups: (1) healthy weight (HW), (2) overweight and obesity (Ow/Ob), or (3) T2D.

A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations.

Background Gene-environment interactions may enhance our understanding of hypertension. Our previous study highlighted the importance of considering psychosocial factors in gene discovery for blood pressure (BP) but was limited in statistical power and population diversity. To address these challenges, we conducted a multi-population genome-wide association study (GWAS) of BP accounting for gene-depressive symptomatology (DEPR) interactions in a larger and more diverse sample.

Unstable coronary artery plaque features in humans are associated with higher frequency of circulating CD56bright Natural Killer Cells.

Unstable human artery plaques can suddenly rupture, leading to MI or stroke. Identification of blood markers associated with unstable plaque features is clearly needed. Humans with symptomatic carotid atherosclerotic plaques have increased plaque infiltration of CD56bright Natural Killer (NK) cells, yet whether subjects with unstable coronary artery plaque features have increased frequencies of circulating CD56bright NK cells is unknown.

Statistical shape modelling of the left ventricle for patients with HeartMate2 and HeartMate3 ventricular assist devices.

Left ventricular assist devices (LVADs) have demonstrated promising outcomes in the management of end-stage heart failure. However, the altered intraventricular flow dynamics following LVAD implantation can lead to non-physiological shear rates and stagnant or recirculating zones, which increase the risk of thrombosis around the inflow cannula. There are conflicting recommendations regarding the optimal inflow cannula design and its association with thrombosis risk, possibly due to anatomical variations among patients.

Membrane Transport Modulates the pH-Regulated Feedback of an Enzyme Reaction Confined within Lipid Vesicles.

Understanding ion transport dynamics in reactive vesicles is pivotal for exploring biological and chemical processes and essential for designing synthetic cells. In this work, we investigate how proton transport and membrane potential regulate pH dynamics in an autocatalytic enzyme reaction within lipid vesicles. Combining experimental and numerical methods, we demonstrate that compartmentalization within lipid membranes accelerates internal reactions, attributed to protection from the external acidic environment.

Echocardiographic Characterization of Myocardial Stiffness in Healthy Volunteers, Cardiac Amyloidosis, and Hypertrophic Cardiomyopathy: A Case-Control Study Using Multimodality Imaging.

Background: Noninvasive tools to measure myocardial stiffness are limited. Intrinsic cardiac elastography in echocardiography relates to myocardial stiffness by measuring the propagation of the myocardial stretch generated by atrial contraction. The aims of the present study were (1) to evaluate myocardial stiffness using intrinsic cardiac elastography in healthy volunteers versus those with myocardial diseases (ie, cardiac amyloidosis [CA] and hypertrophic cardiomyopathy) and (2) to identify key factors that affect myocardial stiffness.

Trajectories of physical, mental health and health satisfaction before and after arthritis diagnosis: a UK population-based study.

Background: Few longitudinal studies have explored changes in physical and mental health in individuals prior to and after arthritis diagnosis. This is important for understanding timing of diagnosis in relation to symptoms and their broader health impacts.

Methods: Adults (≥ 16 years) reporting new diagnoses of arthritis between 2010 and 2023 in the UK Household Longitudinal Study (UKHLS) were included in the study (N = 5,258), along with a 1:1 matched sample of arthritis-free individuals.

Metabolomic and phenotypic effects of ocean acidification on cuttlefish differ across early life stages.

Ocean acidification (OA) affects the physiology and behaviour of some marine organisms, impacting their development and metabolism during vulnerable early-life stages. Among them, the embryo of the cuttlefish develops for about two months in encapsulated eggs with harsh perivitelline conditions of hypoxia and hypercapnia, potentially worsened by OA. In this study, common cuttlefish Sepia officinalis embryos and juveniles, were exposed to five pH conditions (pH 8.

Non-Coding RNA as Potential Therapeutics to Rescue Mitochondrial Dysfunction in Cardiovascular Diseases.

Non-coding RNAs (ncRNAs) are critical regulators of mitochondrial function in cardiovascular diseases. Several studies have explored the manipulation of ncRNAs in mitochondrial dysfunction in different cardiovascular disease contexts, however, there is a dearth of information on the exploration of these non-coding RNAs as actual therapeutics to ameliorate cardiovascular diseases. This systematic review examines the roles of various ncRNAs in modulating mitochondrial dysfunction across major cardiovascular diseases and how they can be targeted to the mitochondria.