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Risk factors of metabolic dysfunction-associated steatotic liver disease in a cohort of patients with chronic hepatitis B.
BACKGROUND AND AIMS: Chronic hepatitis B (CHB) and metabolic dysfunction-associated steatotic liver disease (MASLD) commonly co-exist, with conflicting data in prevalence and disease severity. We aimed to investigate these discrepancies. METHODS: This multicentre study included consecutive CHB patients from 19 European centres. A survey on standard of care for MASLD screening in CHB was circulated. RESULTS: 1709 CHB patients were included; median age: 53 (42-64), males 60.7%, BMI 25.6 (14-63), 57.3% White. MASLD prevalence (1510 consecutive patients) was 42.3%. BMI (OR=1.27, 95% CI:1.19-1.36), ferritin (OR=1.00, 95% CI:1.00-1.00) and type-2-diabetes (T2DM) (OR=2.60, 95% CI:1.12-6.02) were independently associated with MASLD. The prevalence of advanced fibrosis was 18% (255/1420) in the whole cohort, 25.4% (162/639) among CHB with MASLD, and 13.7% in those without MASLD. Independent predictors of advanced fibrosis were MASLD (OR:2.76, 95%CI:1.50-5.05), BMI (OR:1.08, 95%CI:1.02-1.15), ALT (OR:1.01, 95%CI:1.00-1.03), lower PLTs (OR:0.99, 95%CI:0.98-0.99), insulin-treatment (OR:13.88, 95%CI:2.95-65.28) and long-term antivirals (OR:4.86, 95%CI:2.40-9.85). During follow-up (48 months), only patients without MASLD showed significant LSM improvement over time (p<0.001). Among patients with MASLD, FIB-4 and LSM performed moderately at predicting advanced fibrosis (AUROC 0.71 vs 0.70, p=0.38), against histology. As standard of care, 68.4% centres screened all CHB patients for MASLD. 52.6% followed the same treatment indication in those with CHB and MASLD vs CHB only. CONCLUSION: In this large European cohort, MASLD and fibrosis were highly prevalent among CHB, while MASLD aggravated liver fibrosis. Though screening strategies remain inconsistent, ferritin levels, increased BMI and T2DM may inform on the presence of MASLD. Biomarkers showed modest performance in predicting fibrosis.
Understanding the interaction of upper respiratory tract infection with respiratory syncytial virus and Streptococcus pneumoniae using a human challenge model: a multicenter, randomized controlled study protocol.
BACKGROUND: Streptococcus pneumoniae (pneumococcus) and respiratory syncytial virus (RSV) are major causes of respiratory infections globally. Viral and bacterial co-infections are commonly observed in respiratory infections and there is evidence that these pathogens interact synergistically to evade host responses and lead to more severe disease. Notably, RSV seasonal outbreaks are associated with increased hospitalization and a subsequent peak in invasive pneumococcal disease cases, particularly in pediatric populations. Here, we summarize a protocol for a controlled human infection model aiming to evaluate pathogen interaction dynamics and immune responses in a combined pneumococcus and RSV model. The primary objective is to determine whether primary RSV challenge increases the risk of secondary pneumococcal colonization. METHODS: This is an open-label, multi-center, randomized controlled human co-infection study, inclusive of a pilot phase. Individuals will be randomized to primary inoculation with either pneumococcus (serotype 6B) or RSV (subtype RSV-A) intra-nasally on day 0 followed by a reciprocal challenge on day 7. During pilot phase A up to 10 participants will be monitored in an in-patient facility for 7-10 days following RSV-A challenge. If there are no safety concerns, we will then progress to an outpatient phase where participants will self-isolate at home. Clinical samples to be taken from participants include nasal swabs and washes for pathogen detection; and nasal cells, nasal lining fluid, and blood samples to examine mucosal and systemic immune responses. DISCUSSION: This work will lead to important scientific knowledge on the interaction and dynamics between pneumococcus and RSV. This knowledge could help inform pneumococcal and RSV vaccination strategies, particularly for groups at risk of developing severe pneumococcal and RSV disease. TRIAL REGISTRATION: The study is registered on ISRCTN (The UKs Clinical Study Registry). DOI https://doi.org/10.1186/ISRCTN12036902.
Small for Gestational Age sub-groups have differential morbidity, growth and neurodevelopment at age 2: the INTERBIO-21st Newborn Study.
BACKGROUND: Small for Gestational Age (SGA) is a complex perinatal syndrome associated with increased neonatal morbidity, mortality, and impaired childhood growth and neurodevelopment. Current classifications rely primarily on birth weight, which does not capture the heterogeneity of the condition nor predict long-term health outcomes. Here we aim to identify and characterise distinct SGA sub-groups and assess their neonatal and early childhood health trajectories. OBJECTIVES: To refine the classification of SGA by identifying sub-groups based on maternal, fetal, and environmental factors and evaluating their associations with neonatal morbidity, growth, and neurodevelopment at age 2. STUDY DESIGN: Prospective Cohort Study. In six countries worldwide, between 2012 and 2018, the INTERBIO-21st Study enrolled SGA and non-SGA newborns defined by the <10th centile of international standards with moderate (≥3rd to <10th centile) and severe (<3rd centile) SGA sub-groups; we assessed their growth, health, nutrition, motor development, and neurodevelopment up to age 2. We used 2-step cluster analysis to identify SGA sub-groups, and a probabilistic approach to choose the optimal sub-group model based on a statistical measure of fit. We performed logistic regression analysis (OR; 95% CI) to assess health and development outcomes among sub-groups using the non-SGA as reference group, adjusting for key confounders. RESULTS: We enrolled 5153 non-SGA and 1549 SGA newborns: moderate (≥3rd to <10th centile) SGA=947 and severe (<3rd centile) SGA=602). We identified nine SGA sub-groups: 'no main condition detected' (29.0%); 'previous low birth weight (LBW)/preterm birth (PTB)' (14.6%); 'severe maternal disease' (12.0%); 'maternal short stature (11.6%); 'hypertensive disorders' (9.6%); 'extrauterine infection' (6.8%); 'previous miscarriage(s)' (6.5%); 'smoking' (5.2%), and 'maternal under-nutrition' (4.7%). Severe SGA newborns in the 'severe maternal disease' (OR: 3.2; 95% CI, 1.8-6.0), 'previous LBW/PTB' (OR: 2.8; 95% CI, 1.6-4.8), and 'smoking' (OR: 5.4; 95% CI, 1.3-21.8) sub-groups had increased risk of neonatal and long-term morbidity, and low anthropometric measures at age 2 as compared to the non-SGA group. Moderate SGA newborns in the "hypertensive disorders" sub-group had increased risk of neonatal morbidity (OR: 2.6; 95% CI, 1.5-4.6), and higher odds of scoring <10th centile of normative values in language (OR: 3.5; 95%CI, 1.0-12.0) and positive behavior (OR: 2.2; 95%CI, 1.1-4.5). The 'severe maternal disease' sub-group had also higher risk of deficit (<10th centile of normative values) in language (OR: 5.7; 95%CI, 1.3-24.8), positive behavior (OR: 3.4; 95%CI, 1.5-7.6). CONCLUSIONS: SGA comprises heterogeneous sub-groups with distinct patterns of neonatal morbidity, postnatal growth, and neurodevelopmental outcomes up to age 2.
Selective remodelling of the adipose niche in obesity and weight loss.
Weight loss significantly improves metabolic and cardiovascular health in people with obesity1-3. The remodelling of adipose tissue (AT) is central to these varied and important clinical effects4. However, surprisingly little is known about the underlying mechanisms, presenting a barrier to treatment advances. Here we report a spatially resolved single-nucleus atlas (comprising 171,247 cells from 70 people) investigating the cell types, molecular events and regulatory factors that reshape human AT, and thus metabolic health, in obesity and therapeutic weight loss. We discover selective vulnerability to senescence in metabolic, precursor and vascular cells and reveal that senescence is potently reversed by weight loss. We define gene regulatory mechanisms and tissue signals that may drive a degenerative cycle of senescence, tissue injury and metabolic dysfunction. We find that weight loss reduces adipocyte hypertrophy and biomechanical constraint pathways, activating global metabolic flux and bioenergetic substrate cycles that may mediate systemic improvements in metabolic health. In the immune compartment, we demonstrate that weight loss represses obesity-induced macrophage infiltration but does not completely reverse activation, leaving these cells primed to trigger potential weight regain and worsen metabolic dysfunction. Throughout, we map cells to tissue niches to understand the collective determinants of tissue injury and recovery. Overall, our complementary single-nucleus and spatial datasets offer unprecedented insights into the basis of obese AT dysfunction and its reversal by weight loss and are a key resource for mechanistic and therapeutic exploration.
The Risk-Benefit Balance of Oral Corticosteroid Treatment for Asthma Attacks: A Discrete Choice Experiment of Patients and Healthcare Professionals in the UK and New Zealand.
BACKGROUND AND OBJECTIVE: Oral corticosteroids (OCS) are the guideline recommended treatment for all asthma attacks, but benefits must be considered alongside the potential for cumulative side-effects. There is interest in trialling biomarker-directed management of attacks to rationalise OCS treatment in those with least benefit. Understanding stakeholder perspectives on the risks and benefits associated with OCS treatment can inform trial design and shared decision-making discussions in clinical practice. The aim was to examine patients' and healthcare professionals' preferences for the risks and benefits associated with OCS treatment for asthma attacks. METHODS: Discrete choice experiment (DCE) by patients with asthma and HCPs in the UK and New Zealand. Preferences were analysed using logit models. RESULTS: Eight hundred and twenty-four patients and 171 HCPs completed the DCE. Avoiding the risks of permanent side effects had the greatest impact on treatment preference by patients and HCPs. Avoidance of side effects was weighted higher by patients than HCPs. Patients with uncontrolled asthma were more prepared to trade risk for benefit. Symptom recovery was the most valued clinical benefit to patients and HCPs. Patients preferred 'improving lung function' over 'avoiding additional GP treatment or hospitalisation', whereas HCPs preferred avoidance of further healthcare utilisation. Based on their responses we estimated the minimum clinically important difference for the treatment failure outcome at 20%. CONCLUSION: Patients and HCPs will trade-off treatment benefits to avoid the side-effects associated with OCS. The risk-benefit balance of OCS should feature in shared decision-making discussions with patients experiencing outpatient asthma attacks. The findings support developing trials to personalise acute asthma treatment.
Analysis of airway inflammation demonstrates a mechanism for T2-biologic failure in asthma.
BACKGROUND: Targeted T2 biologics have transformed asthma care, but the clinical response to biologic therapy varies between patients. OBJECTIVE: Assess airways inflammation in T2-high asthma patients treated with anti-IL5 biologics to investigate if differential mechanisms of airway inflammation explains varied response to biologics. METHODS: Proteomic analysis (Olink®, 1463 protein panel) & high sensitivity cytokine analysis (ELISAs) were performed on induced sputum from T2-high, severe asthma patients in the UK multicentre Mepolizumab EXacerbation (MEX) study. Samples included were pre-mepolizumab (n=28), stable on mepolizumab (n= 43) & at first exacerbation (n=26). RESULTS: Clustering of sputum proteins while stable on mepolizumab identified two clusters. Cluster 1 had increased differentially expressed sputum proteins pre-mepolizumab, stable on mepolizumab & at exacerbation. Cluster 1 were younger at diagnosis, had a longer duration of asthma, lower FEV1% & higher ACQ5 on mepolizumab. Cluster 1 had increased expression of pro-inflammatory cytokines (IL1β, IL6, sIL6R), epithelial alarmins (TSLP, IL 33) and neutrophil activation (MPO, NE & Neutrophil extracellular trap (NET). All patients were T2-high with no difference in FeNO, eosinophil number or activity (EDN) across the two clusters. CONCLUSION: In a cohort of T2-high severe asthma patients, a subgroup of patients with long duration of disease had worse clinical parameters, increased sputum proteins with increased markers of neutrophil activity, proinflammatory cytokines and epithelial alarmins even when stable on mepolizumab. This suggests the presence of biology not treated by targeted T2-biologics which may contribute to poorer outcomes on biologics and could be a treatable airways trait in severe asthma.
Definition and diagnostic criteria of retained products of conception following first-trimester pregnancy loss: a systematic review.
Retained products of conception (RPOC) is a common complication following first-trimester pregnancy loss. However, there are no formal recommendations regarding the diagnosis of RPOC. This systematic review aimed to synthesise and critically appraise the existing evidence on the definition and diagnostic criteria for RPOC. We registered this systematic review prospectively with PROSPERO (CRD42023444456). A comprehensive literature search was conducted in October 2024 using the following databases: Embase (OVID), Medline (OVID), Global Health, CINAHL on EBSCOhost, Cochrane Central and Web of Science. Databases were searched using free-text keywords and subject headings for the key concepts of 'early', 'miscarriage' and 'retained'. Data were extracted and 2 by 2 tables populated. Risk of bias and quality assessments were performed using the QUADAS-2 tool. The literature search yielded 2,014 articles that were screened for eligibility, resulting in the inclusion of 17 studies in the final analysis. Ultrasound scan was the primary diagnostic tool, used in 16 of the 17 included studies. Ultrasound diagnostic markers included: endometrial thickness (ET), the presence of hyperechoic or echogenic material, and colour flow Doppler. One study used persistent bleeding for more than 14 days as the primary diagnostic marker. There was significant variation in the diagnostic thresholds used and no single ultrasound marker demonstrated consistent reliability in diagnosing RPOC. The findings of this review highlight the limitations of ultrasound as a standalone diagnostic tool for RPOC. Given the lack of clear diagnostic criteria, clinicians should integrate ultrasound findings with clinical symptoms to improve diagnostic accuracy. RPOC appears to be a distinct pathology within the spectrum of early pregnancy loss, characterised by the persistence of pregnancy tissue within the uterine cavity despite initial management which distinguishes it from incomplete miscarriage. This review provides a foundation for future research and calls for a Delphi consensus to refine the diagnosis and management of RPOC.
Respiratory viral detection in children hospitalized with pneumonia during periods of major population disruptions in Nepal, 2014-2018.
BACKGROUND: Respiratory viruses commonly cause pneumonia in children. We aimed to identify respiratory viral nucleic acids in the nasopharynx of children admitted with pneumonia from 2014 to 2018, a period including a major earthquake (April 2015), PCV10 introduction (August 2015), and a fuel shortage (October 2015 to March 2016). METHODS: Children 2 months to 14 years admitted to Patan Hospital between March 2014 and February 2018 with a clinical diagnosis of pneumonia had nasopharyngeal swabs collected and tested with a multiplex panel for the presence of genetic material from 23 respiratory pathogens. RESULTS: Of 1343 children with pneumonia, 974 (72.5%) had the nucleic acids of at least one respiratory virus in the nasopharynx. The median age of children with any viral genetic material detected was lower than those without (1.18, IQR: 0.59-2.39 years; versus 2.01 years, IQR: 0.81-4.34 years; p<0.001). Commonly detected viral nucleic acids included those of RSV (21.0%), rhino/enterovirus (30.8%), and parainfluenza (7.4%). The odds of detecting any respiratory viral genetic material in children with pneumonia increased by 1.88 (95% confidence interval: 1.15, 3.06) in the year after the earthquake, when there were several aftershocks and a fuel crisis, relative to other periods and accounting for other potential confounding factors. CONCLUSIONS: These findings highlight the importance of viral diagnostics in pediatric pneumonia and suggest that public health measures addressing environmental conditions during disasters might help reduce respiratory infections.
Bowel urgency in ulcerative colitis: effect of baseline urgency and change in urgency in response to mirikizumab.
BACKGROUND: Mirikizumab has demonstrated efficacy in moderately to severely active ulcerative colitis. A 1-2-point change in Urgency Numeric Rating Scale (NRS) score can be meaningful for patients. In these post-hoc analyses, we evaluated the efficacy of mirikizumab compared to placebo by baseline Urgency NRS score groups (0-3, 4-6, and 7-10) and its effect on bowel urgency severity over time. METHODOLOGY: Urgency NRS was measured as a secondary outcome at baseline, week 12, and week 52. Bowel urgency improvement was assessed for patients who achieved and did not achieve multiple efficacy endpoints. Data were analyzed using Fisher's exact test with nonresponder imputation. RESULTS: At weeks 12 and 52, a significantly higher percentage of mirikizumab-treated patients achieved clinical response as well as clinical, endoscopic, and symptomatic remission compared to placebo-treated patients, regardless of baseline Urgency NRS score category (higher proportions versus placebo, delta 9%-45%). Improvement in Urgency NRS score category at weeks 12 and 52 for mirikizumab-treated patients was observed when other efficacy outcomes were achieved (13%-90%) and not achieved (12%-75%). CONCLUSIONS: A greater proportion of mirikizumab-treated patients with ulcerative colitis achieved symptomatic, clinical, and endoscopic remission endpoints compared to placebo-treated patients, regardless of baseline bowel urgency severity. After one year, bowel urgency was improved to a greater extent with mirikizumab than with placebo, even for patients who did not achieve other clinical outcomes. Small improvements in bowel urgency are associated with significant health-related quality-of-life improvements. Monitoring shifts in urgency severity over time using the Urgency NRS can aid in understanding patients' treatment outcomes. TRIAL REGISTRATION: LUCENT-1 (NCT03518086) Registered 04 May 2018 https://clinicaltrials.gov/study/NCT03518086 . LUCENT-2 (NCT03524092) Registered 10 May 2018 https://clinicaltrials.gov/study/NCT03524092 .
Development and validation of peripheral blood DNA methylation signatures to predict response to biological therapy in adults with Crohn's disease (EPIC-CD): an epigenome-wide association study.
BACKGROUND: Biological therapeutics are widely used in Crohn's disease, with evidence of efficacy from randomised trials and real-world experience. Primary non-response is a common, poorly understood problem. We aimed to assess blood methylation as a predictor of response to adalimumab, vedolizumab, or ustekinumab in patients with Crohn's disease. METHODS: This epigenome-wide association study used data from two ongoing biobanks (one from the Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands [discovery cohort] and the other from the John Radcliffe Hospital, Oxford, UK [validation cohort]) that recruited patients between Oct 1, 2009, and June 17, 2022. Adult participants (age ≥18 years) with active symptomatic and endoscopic Crohn's disease who were scheduled to start adalimumab, vedolizumab, or ustekinumab treatment were included. Patients with ongoing malignancy or serious concomitant inflammatory diseases were excluded. Treatment response was assessed after a median of 28 weeks of treatment (IQR 18-36). Response was defined as a combination of endoscopic criteria (50% or more reduction in the Simple Endoscopic Score for Crohn's Disease) with either clinical or biochemical criteria (corticosteroid-free clinical response: ≥3 point decrease in Harvey-Bradshaw Index [HBI] score or remission [HBI ≤4] and no systemic steroids at follow up; biochemical response: C-reactive protein reduction ≥50% or ≤5 mg/L and faecal calprotectin reduction ≥50% or ≤250 μg/g) compared with baseline. Epigenome-wide DNA methylation and transcriptome-wide gene expression analyses were done on whole peripheral blood leukocyte samples that were collected before the start of treatment. To identify baseline DNA methylation markers associated with response or non-response to treatment, we performed supervised machine learning through stability selected gradient boosting. In a post-hoc analysis, we compared our DNA methylation-based prediction model with clinical decision support tools (CDSTs). FINDINGS: We profiled the peripheral blood DNA methylome of 273 adults with Crohn's disease scheduled to start adalimumab, vedolizumab, or ustekinumab in the discovery (Amsterdam, n=183; 108 [59·0%] female and 75 [41·0%] male) and the validation cohort (Oxford, n=90; 46 [51·1%] female and 44 [48·9%] male). In the discovery cohort, we defined a panel of DNA methylation biomarkers that were associated with combined endoscopic and clinical or biochemical response to adalimumab (18 markers), vedolizumab (25 markers), or ustekinumab (68 markers), with an area under the curve (AUC) of 0·86 (95% CI 0·58-0·97) for adalimumab, 0·87 (0·67-0·98) for vedolizumab, and 0·89 (0·76-1·00) for ustekinumab. Validation in the Oxford cohort yielded an AUC of 0·25 (0·10-0·35) for adalimumab, 0·75 (0·65-0·85) for vedolizumab, and 0·75 (0·65-0·87) for ustekinumab. In comparison, implementing the CDSTs in the validation cohort yielded an AUC of 0·56 (0·44-0·68) for vedolizumab and 0·66 (0·54-0·77) for ustekinumab. Previous anti-TNF exposure was associated with a reduction in accuracy of the methylation models for vedolizumab (0·66 [0·55-0·73]) and ustekinumab (0·63 [0·52-0·70]) when analysed in the validation cohort. INTERPRETATION: Our findings provide evidence for the potential use of DNA methylation as a modality for personalised medicine for Crohn's disease by predicting response to vedolizumab and ustekinumab. The models were more accurate in biologically naive patients and outperform available vedolizumab and ustekinumab CDSTs. We were unable to predict response to adalimumab. The vedolizumab and ustekinumab prediction models are currently being tested in a multicentre randomised clinical trial. FUNDING: The Leona M and Harry B Helmsley Charitable Trust.
Fecal Calprotectin and C-Reactive Protein Association With Histologic and Endoscopic Endpoints in Mirikizumab-Treated Patients With Ulcerative Colitis
Background Fecal calprotectin (FC) and C-reactive protein (CRP) are noninvasive biomarkers used in ulcerative colitis (UC) clinical trials; however, thresholds defined as "normal"in trials may be higher than "normal"thresholds typically used in clinical practice. We assessed the relationship between FC and CRP improvement in the "normal"range across different cutoff thresholds for patients with moderately to severely active UC treated with mirikizumab. Methods Patients achieving clinical response to mirikizumab in LUCENT-1 (Weeks 0-12) proceeded to LUCENT-2 (Weeks 12-52 [52 weeks of continuous mirikizumab]). Associations between FC and CRP levels at multiple thresholds and histologic-endoscopic mucosal improvement (HEMI) and histologic-endoscopic mucosal remission (HEMR) at Weeks 12 and 52 were assessed by Fisher's exact test. Least squares means of FC and CRP changes from baseline at Weeks 12 and 52 were calculated using analysis of covariance with HEMI or HEMR status as factors and baseline FC or CRP values as covariates. Results At Weeks 12 and 52, greater proportions of patients with FC thresholds of ≤250, ≤150, ≤100, and ≤50 μg/g, and CRP thresholds of ≤6 and ≤5 mg/L, achieved HEMI and HEMR compared with those not achieving HEMI and HEMR. Changes from baseline in FC and CRP at Week 12 and FC at Week 52 were greater in patients who achieved HEMI and HEMR compared with those not achieving these endpoints. Conclusions These results show that FC and CRP analyses may contribute to a noninvasive monitoring strategy in clinical practice.
Which first? Surgery or biologic therapy for ileocolic Crohn’s disease in the real world
Background: A laparoscopic ileocolic resection could lead to a better outcome to infliximab for ileocolic Crohn’s disease. The aim of this study was to explore real world clinical outcomes in biologic-naïve patients with ileocolic Crohn’s disease. Research design and methods: All patients with ileocolic Crohn’s disease treated at our institution between January 2011 and December 2018 with biologics or surgical resection were included. Results: Overall, 222 patients were included, of which 149 (67%) underwent surgery before biologic therapy. Among these, 54 patients (36%) required post-operative biologic therapy. Seventy-three patients were treated with biologics first, of which 29 (40%) subsequently required a surgical resection (p = 0.60). There were 95 patients (43%) who were successfully treated with a surgery-first approach alone. Median follow-up was 73 months (0–406). Characteristics associated on multivariable analysis with change from surgery to biologics were: gender (female) (p = 0.010), presence of obstructive symptoms (p = 0.028), and smoking (p = 0.030). Characteristics associated with changing from biologics to surgery were: isolated terminal ileum disease (p = 0.001) and the presence of obstructive symptoms (p = 0.003). Conclusions: In our cohort, the risk of recurrent ileocolic Crohn’s disease was similar whether patients were treated with a ‘surgery first’ or ‘biologic first’ approach.
In situ cryo-electron microscopy and tomography of cellular and organismal samples
As cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) continue to advance, the ability to visualize cellular and organismal structures with unprecedented clarity is redefining the landscape of structural biology. Breakthroughs in imaging technology, sample preparation and image processing now enable the detailed elucidation of cellular architecture, macromolecular organization, and dynamic biological processes at sub-nanometer resolution. Recent methodological advances have propelled the field to new frontiers, facilitating the investigation of complex biological questions across scales—from macromolecular complexes to organism-wide structural insights. This review explores rapidly emerging trends, highlights key innovations that are pushing the boundaries of in situ structural biology, and addresses persistent challenges in expanding the applicability of cryo-EM and cryo-ET across diverse biological systems.
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.
ABO-mismatched platelet and plasma transfusion practices and the potential for transfusion-related alpha-gal syndrome: The Biomedical Excellence for Safer Transfusion Collaborative Study.
BACKGROUND: Alpha-gal syndrome (AGS) is caused by IgE antibodies against the alpha-gal oligosaccharide, which is structurally similar to the Group B antigen. Recent case reports of severe allergic transfusion reactions (ATRs) in Group O patients receiving Group B plasma and platelets raise the possibility of a new adverse event, herein called transfusion-related AGS (TRAGS). The primary goal of this study was to assess the frequency of Groups B and AB plasma and platelet transfusions to Group O patients. STUDY DESIGN AND METHODS: In this multi-site retrospective study, participating sites submitted the numbers of platelet and plasma transfusions administered during a 2-year period categorized by patient and product ABO group. RESULTS: Fourteen sites from 10 countries participated. Group O patients received Group AB for an average of 9.9% (range 2.8%-29.2%) of plasma transfusions and Group B for 3.2% (0%-12.8%). AB plasma transfusion to Group O patients represented 4.5% (0.9%-14.6%) of the total plasma transfused; Group B 1.4% (0%-5.1%). Group O patients received Group AB for an average of 1.5% (range 0%-5.9%) of platelet transfusions and Group B for 4.1% (0%-14.2%). AB platelet transfusion to Group O patients represented 0.6% (0%-2.7%) of the total platelets transfused; Group B platelets were 1.8% (0%-6.7%). DISCUSSION: Evidence supporting the possibility of a new adverse event, TRAGS, is accumulating. This study quantifies how often Group O patients may be exposed to Group B antigen in Group B or AB plasma and/or platelet transfusions, providing an estimate of the scope of potential risk for TRAGS.
The spatiotemporal distribution of human pathogens in ancient Eurasia
Abstract Infectious diseases have had devastating effects on human populations throughout history, but important questions about their origins and past dynamics remain1. To create an archaeogenetic-based spatiotemporal map of human pathogens, we screened shotgun-sequencing data from 1,313 ancient humans covering 37,000 years of Eurasian history. We demonstrate the widespread presence of ancient bacterial, viral and parasite DNA, identifying 5,486 individual hits against 492 species from 136 genera. Among those hits, 3,384 involve known human pathogens2, many of which had not previously been identified in ancient human remains. Grouping the ancient microbial species according to their likely reservoir and type of transmission, we find that most groups are identified throughout the entire sampling period. Zoonotic pathogens are only detected from around 6,500 years ago, peaking roughly 5,000 years ago, coinciding with the widespread domestication of livestock3. Our findings provide direct evidence that this lifestyle change resulted in an increased infectious disease burden. They also indicate that the spread of these pathogens increased substantially during subsequent millennia, coinciding with the pastoralist migrations from the Eurasian Steppe4,5.
STAT3 phosphorylation in the rheumatoid arthritis immunological synapse.
Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naive CD4+ T cells. Our data demonstrates that LCK mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic LCK/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.