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Hepatitis C virus cascade of care among adults in Sindh province, Pakistan: Findings from 2019-2020 household sero-survey.
Pakistan has the largest national burden of hepatitis C virus (HCV) infections (9.8 million). High levels of testing and treatment are needed to achieve HCV elimination, but little data exists on this in Pakistan. A household sero-survey from Sindh province (2019-2020) collected self-reported data from adults on previous HCV testing and treatment, and undertook HCV-antibody (HCV-Ab) testing of participants (2988 children (<18) and 3684 adults) and HCV-RNA testing of HCV-Ab positive individuals. We determined the self-reported HCV cascade-of-care among adults ever eligible for HCV treatment, defined as either having a past infection (HCV-Ab positive and HCV-RNA negative) with self-reported treatment history or current infection (HCV-RNA positive). We assessed factors associated with self-reporting ever being HCV-tested using multi-variable logistic regression. Overall, 10.8% (397/3684) of adults tested HCV Ab-positive in the sero-survey, of which 80.9% (321/397) had a HCV-RNA test result. Of adults defined as ever treatment eligible (n = 232), 40.9% (95/232) reported a previous HCV test and 91.2% (87/95) reported testing positive. Of these, HCV treatment was reported by 69.0% (60/87) and 46.7% (28/60) of treated individuals tested HCV-RNA-negative. Overall, 25.9% (60/232) of treatment-eligible adults reported being treated. The regression analysis suggested that males, older adults (>25 years), and adults with a secondary or higher education level were more likely to have ever been tested for HCV, as were individuals with a family history of hepatitis, received HBV vaccination or that had various risk factors linked to HCV transmission (e.g., blood transfusion, having tattoo/acupuncture, hospitalisation or therapeutic injection (s) history). The cascade-of-care for HCV needs improving to eliminate HCV in Pakistan, especially among younger adults, women and people with low education levels.
Prediction and characterisation of the human B cell response to a heterologous two-dose Ebola vaccine.
Ebola virus disease (EVD) outbreaks are increasing, posing significant threats to affected communities. Effective outbreak management depends on protecting frontline health workers, a key focus of EVD vaccination strategies. IgG specific to the viral glycoprotein serves as the correlate of protection for recent vaccine licensures. Using advanced cellular and transcriptomic analyses, we examined B cell responses to the Ad26.ZEBOV, MVA-BN-Filo EVD vaccine. Our findings reveal robust plasma cell and lasting B cell memory responses post-vaccination. Machine-learning models trained on blood gene expression predicted antibody response magnitude. Notably, we identified a unique B cell receptor CDRH3 sequence post-vaccination resembling known Orthoebolavirus zairense (EBOV) glycoprotein-binding antibodies. Single-cell analyses further detailed changes in plasma cell frequency, subclass usage, and CDRH3 properties. These results highlight the predictive power of early immune responses, captured through systems immunology, in shaping vaccine-induced B cell immunity.
Cohort profile: characterisation, determinants, mechanisms and consequences of the long-term effects of COVID-19 - providing the evidence base for health care services (CONVALESCENCE) in the UK.
PurposeThe pathogenesis of the long-lasting symptoms which can follow an infection with the SARS-CoV-2 virus ('long covid') is not fully understood. The 'COroNaVirus post-Acute Long-term EffectS: Constructing an evidENCE base' (CONVALESCENCE) study was established as part of the Longitudinal Health and Wellbeing COVID-19 UK National Core Study. We performed a deep phenotyping case-control study nested within two cohorts (the Avon Longitudinal Study of Parents and Children and TwinsUK) as part of CONVALESCENCE.ParticipantsFrom September 2021 to May 2023, 349 participants attended the CONVALESCENCE deep phenotyping clinic at University College London. Four categories of participants were recruited: cases of long covid (long covid(+)/SARS-CoV-2(+)), alongside three control groups: those with neither long covid symptoms nor evidence of prior COVID-19 (long covid(-)/SARS-CoV-2(-); control group 1), those who self-reported COVID-19 and had evidence of SARS-CoV-2 infection, but did not report long covid (long covid(-)/SARS-CoV-2(+); control group 2) and those who self-reported persistent symptoms attributable to COVID-19 but no evidence of SARS-CoV-2 infection (long covid(+)/SARS-CoV-2(-); control group 3). Remote wearable measurements were performed up until February 2024.Findings to dateThis cohort profile describes the baseline characteristics of the CONVALESCENCE cohort. Of the 349 participants, 141 (53±15 years old; 21 (15%) men) were cases, 89 (55±16 years old; 11 (12%) men) were in control group 1, 75 (49±15 years old; 25 (33%) men) were in control group 2 and 44 (55±16 years old; 9 (21%) men) were in control group 3.Future plansThe study aims to use a multiorgan score calculated as the cumulative total for each of nine domains (ie, lung, vascular, heart, kidney, brain, autonomic function, muscle strength, exercise capacity and physical performance). The availability of data preceding acute COVID-19 infection in cohorts may help identify the consequences of infection independent of pre-existing subclinical disease and also provide evidence of determinants that influence the development of long covid.
Aficamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: 48-Week Results From FOREST-HCM.
BackgroundLong-term safety and efficacy data for aficamten in symptomatic obstructive hypertrophic cardiomyopathy are needed.ObjectivesThis study aims to evaluate 48-week experience from the ongoing FOREST-HCM (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy) study.MethodsObstructive hypertrophic cardiomyopathy participants in an aficamten study (REDWOOD-HCM [Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM; NCT04219826]; SEQUOIA-HCM [Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT05186818]) could enroll in this phase 2/3, open-label, extension study. Participants received aficamten 5 mg once daily titrated ≤20 mg based on site-read echocardiographic assessments of Valsalva left ventricular outflow tract gradient and left ventricular ejection fraction.ResultsFrom May 2021 to October 2023, 213 participants enrolled; 46 participants with 48 weeks of follow-up were evaluated (mean age: 59.7 years; female: n = 26 [56.5%]). There were rapid, substantial, and sustained reductions in mean resting (-40 ± 34 mm Hg) and Valsalva peak left ventricular outflow tract gradient (-53 ± 39 mm Hg) from baseline to week 48. A total of 82% experienced ≥1 NYHA functional class improvement; 31% experienced a 20-point improvement in Kansas City Cardiomyopathy Questionnaire-Clinical Summary score. There were substantial reductions (mean change) in maximum left ventricular wall thickness (-1.2 ± 1.6 mm; P < 0.0001), left atrial volume index (-3.5 ± 6.6 mL/m2; P = 0.0008), lateral E/e' (-2.2 ± 6.1; P = 0.02), and cardiac biomarkers (P ≤ 0.0031). Aficamten was well tolerated with 2 (4.3%) asymptomatic and transient instances of left ventricular ejection fraction <50% (range: 47%-49%), neither resulting in drug discontinuation, and no new-onset atrial fibrillation.ConclusionsAficamten treatment over 48 weeks was well tolerated and associated with substantial and durable relief of obstruction and symptom burden, lower cardiac biomarker levels, and cardiac phenotypic changes, which may indicate favorable cardiac remodeling. (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506).
Pericardial and mediastinal fat-associated lymphoid clusters are rapidly activated in an alkane-induced model of systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disease predominated by auto-antibodies that recognise cellular components. Pleural involvement is the most common SLE-related lung disease. Natural antibodies are rapidly secreted by innate-like B cells following perturbation of homeostasis and are important in the early stages of immune activation. The serous cavities are home to large numbers of innate-like B cells present both within serous fluid and resident within fat-associated lymphoid clusters (FALCs). FALCs are important hubs for B-cell activation and local antibody secretion within the body cavities. Patients with SLE can develop anti-phospholipid antibodies and in rare situations develop alveolar haemorrhage. Utilising delivery of the hydrocarbon oil pristane in C57BL/6 mice as a model of SLE we identify a rapid expansion of pleural cavity B cells as early as day 3 after intra-peritoneal pristane delivery. Following pristane delivery, pericardial B1 B cells are proliferative, express the plasma-cell surface marker CD138, and secrete both innate and class-switched antibodies highlighting that this cavity niche may play an unrecognised role in the initiation of lupus pleuritis.
Distinct neutralization sensitivity between adult and infant transmitted/founder HIV-1 subtype C viruses to broadly neutralizing monoclonal antibodies.
Broadly neutralizing antibodies (bnAbs), passively administered or elicited through vaccination, are a promising strategy for novel HIV prevention, treatment or inducing ART-free remission. However, HIV diversity and evolution are a barrier to the efficacy of bnAbs and there is therefore an urgent need for continuous virus surveillance to identify bnAbs with optimal neutralization breadth and potency against transmitted/founder (TF) viruses, especially in high-burden regions. We determined the neutralization sensitivity of TF viruses isolated within seven days after first detection of heterosexually acquired infection from young women 18-23 years old (n = 39) and within 1 month after birth from in-utero infected infants (n = 21) from FRESH and Baby Cure cohorts respectively, in KwaZulu-Natal, South Africa, where HIV-1 subtype C predominates. Neutralization sensitivities of 47 viruses from FRESH and 21 viruses from Baby Cure were assessed against nine bnAbs targeting different regions on the HIV-1 Env trimer. HIV-1 env sequences within and between bnAb epitopes were compared with database. The bnAbs VRC07-523LS, CAP256-VRC26.25, PGDM1400, 10E8 and PGT151 displayed higher neutralization breadth and potency than other bnAbs against FRESH TF viruses (>70% coverage, starting concentration of 10 μg/ml). Furthermore, VRC07-523LS showed higher neutralization breadth and potency than other bnAbs against Baby Cure TF viruses (p = 0.02). Interestingly, CAP256-VRC26.25 and PGT151 had lower neutralization coverage against infant TF viruses (<60% coverage). Moreover, 40% of infants TF had escape mutations within the V2 loop compared to 28% observed in FRESH and these mutations may explain the observed differences in neutralization sensitivities. However, few mutations were observed in gp120-gp41 interface in both adults and infants. Our findings suggest that intervention studies may have to consider different antibody combinations in adult versus paediatric settings. Moreover, high transmission of escape variants in both vertical and heterosexual transmissions is of concern. This information may be important in the selection of bnAbs that will undergo clinical testing in subtype C settings.
The role of untranslated region variants in Mendelian disease: a review
Abstract Untranslated regions (UTRs) flank the protein-coding sequence of a gene. 5′UTR and 3′ UTR sequences mediate post-transcriptional regulation via linear and structural elements, controlling RNA stability, cellular localisation and the rate of protein translation. Variants within both 5′ and 3′ UTRs have been shown to cause disease through a variety of diverse mechanisms. However, for these variants to be routinely annotated and interpreted in clinical genetic testing, we need a better understanding of these regions and the spectrum of disease-causing variants within them. In this review, we systematically assess previously identified Mendelian disease-causing variants within UTRs and catalogue their underlying mechanisms. With genome sequencing becoming readily available and increasingly incorporated in diagnostic settings, this review will provide a valuable resource for the consideration and interpretation of UTR variants.
Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation
AbstractUnderstanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson’s disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chambered microfluidic platform and established a cortico-striato-nigral microcircuit partially recapitulating the striatal presynaptic landscape in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, cortical glutamatergic projections facilitated MSN synaptic activity, and dopaminergic transmission enhanced maturation of MSNs in vitro. Replacement of wild-type iPSC-derived dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-related GBA-N370S mutation led to a depolarisation of resting membrane potential and an increase in rheobase in iPSC-MSNs, as well as a reduction in both voltage-gated sodium and potassium currents. Such deficits were resolved in late microcircuit cultures, and could be reversed in younger cultures with antagonism of protein kinase A activity in iPSC-MSNs. Taken together, our results highlight the unique utility of modelling striatal neurons in a modular physiological circuit to reveal mechanistic insights into GBA1 mutations in PD.
αSynuclein and Mitochondrial Dysfunction: A Pathogenic Partnership in Parkinson’s Disease?
Parkinson’s Disease (PD) is a complex, chronic, progressive, and debilitating neurodegenerative disorder. Neither a cure nor effective long-term therapy exist and the lack of knowledge of the molecular mechanisms responsible for PD development is a major impediment to therapeutic advances. The protein αSynuclein is a central component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD patients and this review explores the strong possibility that αSynuclein and mitochondrial dysfunction have an inter-relationship responsible for underlying the disease pathology. Amplifying cycles of mitochondrial dysfunction and αSynuclein toxicity can be envisaged, with either being the disease-initiating factor yet acting together during disease progression. Multiple potential mechanisms exist in which mitochondrial dysfunction and αSynuclein could interact to exacerbate their neurodegenerative properties. Candidates discussed within this review include autophagy, mitophagy, mitochondrial dynamics/fusion/fission, oxidative stress and reactive oxygen species, endoplasmic reticulum stress, calcium, nitrosative stress and αSynuclein Oligomerization.
Regulatory T cells attenuate chronic inflammation and cardiac fibrosis in hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart muscle disorder. Although the biophysical mechanisms by which gene variants in sarcomeric proteins disrupt cardiomyocyte function are largely understood, the cellular and molecular pathways leading to the complex, variable, and adverse remodeling of the non-myocyte compartment are unexplained. Here, we report that postmortem and explanted human HCM hearts exhibited chronic focal leukocyte infiltration and prominent activation of immune cells. Gene set enrichment analysis (GSEA) revealed that active immune responses were present in the mid- and late-stage HCM human hearts and in mouse hearts from several HCM mouse models. The alpha cardiac actin 1-E99K ( Actc1 E99K ) HCM mouse model was selected for the study because it closely recapitulates the features of progressive remodeling and fibrosis seen in advanced disease in patients. Genetic depletion of lymphocytes in recombination activating gene 1–knockout ( Rag-1 KO ) mice led to marked exacerbation of adverse cardiac remodeling in the Actc1 E99K mice. Detailed characterization of cardiac regulatory T cells (T reg cells) demonstrated a time-dependent increase in Actc1 E99K hearts with altered immunosuppressive profiles. Adoptive transfer of splenic T reg cells reduced cardiac fibrosis and improved systolic dysfunction in Actc1 E99K mice with or without lymphocytes. In addition, low-dose interleukin-2 (IL-2)/anti–IL-2 complex (IL-2/c), which specifically induced T reg cell expansion in vivo, ameliorated cardiac fibrosis and reduced macrophage infiltration and activation in Actc1 E99K mice. These data contribute to our understanding of HCM and support the use of T reg cells as a clinically testable therapeutic strategy for cardiac fibrosis in the HCM heart.
Synovial tissue atlas in juvenile idiopathic arthritis reveals pathogenic niches associated with disease severity
Precision application of targeted therapies is urgently needed to improve long-term clinical outcomes for children affected by inflammatory arthritis, known as juvenile idiopathic arthritis (JIA). Progress has been hampered by our limited understanding of the cellular basis of inflammation in the target tissue of the disease, the synovial membrane. Here, we analyzed biopsies from the inflamed joints of treatment-naïve children with JIA, early in the course of their disease, using single-cell RNA sequencing, multiplexed immunofluorescence, and spatial transcriptomics to establish a cellular atlas of the JIA synovium. We identified distinct spatial tissue niches, composed of specific stromal and immune cell populations. In addition, we localized genes linked to arthritis severity and disease risk to effector cell populations, including tissue resident SPP1 + macrophages and fibrin-associated myeloid cells. Combined analyses of synovial fluid and peripheral blood from matched individuals revealed differences in cellular composition, signaling pathways, and transcriptional programs across these distinct anatomical compartments. Furthermore, our analysis revealed several pathogenic cell populations that are shared with adult-onset inflammatory arthritis, as well as age-associated differences in tissue vascularity, prominence of innate immunity, and enrichment of TGF-β–responsive stromal subsets that up-regulate expression of disease risk–associated genes. Overall, our findings demonstrate the need for age-specific analyses of synovial tissue pathology to guide targeted treatment strategies in JIA.
HIV-1 nuclear import is selective and depends on both capsid elasticity and nuclear pore adaptability.
Lentiviruses, such as HIV-1, infect non-dividing cells by traversing the nuclear pore complex (NPC); however, the detailed molecular processes remain unclear. Here we reconstituted functional HIV-1 nuclear import using permeabilized T cells and isolated HIV-1 cores, which significantly increases import events, and developed an integrated three-dimensional cryo-correlative workflow to specifically target and image 1,489 native HIV-1 cores at 4 distinct nuclear import stages using cryo-electron tomography. We found HIV-1 nuclear import depends on both capsid elasticity and nuclear pore adaptability. The NPC acts as a selective filter, preferentially importing smaller cores, while expanding and deforming to accommodate their passage. Brittle mutant cores fail to enter the NPC, while CPSF6-binding-deficient cores enter but stall within the NPC, leading to impaired nuclear import. This study uncovers the interplay between the HIV-1 core and the NPC and provides a framework to dissect HIV-1 nuclear import and downstream events, such as uncoating and integration.