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Developing the next-generation of adenoviral vector vaccines.
The COVID-19 pandemic saw the first extensive use of adenoviral vector vaccines, with over 3 billion doses produced during the first year of the pandemic alone and an estimated 6 million lives saved. These vaccines were safe and effective, and could be produced at low cost in several continents allowing widespread use in low- and middle-income countries (LMICs). Despite their successful deployment against SARS-CoV-2, their impact has been overshadowed by relatively lower immunogenicity in contrast to mRNA vaccine technologies and very rare but serious adverse events such as vaccine-induced thrombotic thrombocytopaenia (VITT). The next-generation of adenoviral vector vaccines must address these challenges: here, we explore strategies to improve immunogenicity and safety by novel serotype selection, vector engineering, capsid modification and new delivery technologies, and discuss opportunities for next-generation adenoviral vectors against infectious disease and cancer.
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.
Characteristics, outcomes, and maternity care experiences of women with children’s social care involvement who subsequently died: national cohort study and confidential enquiry
Objectives To investigate maternal mortality in the context of children's social care (CSC) involvement, and to explore the quality of maternity care that women with CSC involvement received. Design National cohort study and confidential enquiry. Setting MBRRACE-UK (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK) national surveillance dataset for deaths that occurred during pregnancy or up to a year after pregnancy, UK, 2014-22. Participants 1451 women who died during or in the year after pregnancy in the UK; 420 women (28.9%) had CSC involvement. 47 women's healthcare records were included in the confidential enquiry to describe the care of a random sample of women who died during the perinatal period who had CSC involvement. Main outcome measures Rates and causes of maternal deaths by CSC involvement and quality of care. Results A third (420/1451, 28.9%) of the women who died during or in the year after pregnancy had CSC involvement for their (unborn) baby. Women with CSC involvement were more likely to be aged ≤20 years (rate ratio 1.85, 95% confidence interval 1.27 to 2.63, compared with those aged 21-29 years), living in the most deprived areas (rate ratio 2.19, 1.42 to 3.50, compared with those least deprived), and less likely to be from black (rate ratio 0.56, 0.35 to 0.84) or Asian ethnic backgrounds (rate ratio 0.26, 0.14 to 0.44, compared with white women) than women who died with no known CSC involvement. Deaths occurred predominantly between six weeks and the year after pregnancy (75%), and higher proportions of deaths were caused by suicide, other psychiatric causes, including substance overdose, and homicide. A confidential enquiry identified that risk assessment and recognition, medication management, coordination of care, and staff competencies were essential components in providing personalised, holistic, and trauma-informed care when dealing with medical and social complexity. Multiple individual and systemic barriers hindered access and engagement with healthcare. Conclusions Women with CSC involvement who died during or in the year after pregnancy encountered multiple inequalities and were at an increased risk of maternal mortality from psychiatric causes and homicide. A critical review of current care pathways and policy changes is urgently needed to tailor care to the needs of this group of women and to look at the inequalities that disproportionately affect them.
Ex vivo model of functioning human lymph node reveals role for innate lymphocytes and stroma in response to vaccine adjuvant.
Immunological processes that underpin human immune responses to therapeutics and vaccine components, such as vaccine adjuvants, remain poorly defined due to a paucity of models that faithfully recapitulate immune activation in lymphoid tissues. We describe precision-cut human lymph node (LN) slices as a functioning, architecturally preserved, full-organ cross-sectional model system. Using single-cell transcriptomics and multiplexed imaging, we explore early inflammatory response to a potent, clinically relevant liposomal vaccine adjuvant containing a TLR4-agonist and QS-21 saponin. Both TLR4 and NLRP3 inflammasome activation are involved in the direct initiation of the inflammatory response to adjuvant by monocytes and macrophages (Mon./Mac.) with secretion of interleukin (IL)-1β, but not IL-18, dependent on TLR4 signaling. Innate lymphoid cells, including natural killer cells, are indirectly activated by Mon./Mac.-produced cytokines, signaling downstream to B cells via interferon-γ secretion. Resident LN stromal populations, primed both directly and indirectly by vaccine adjuvant, are instrumental in mediating inflammatory cell recruitment, particularly neutrophils.
Incidence of discordant pleural fluid exudates and diagnostic patterns - a retrospective cohort study.
BackgroundLight's criteria utilises pleural fluid protein and lactate dehydrogenase (LDH) to differentiate pleural effusions as exudative or transudative. In a subset of exudative pleural effusions, discordance occurs between LDH and protein (protein high, LDH low or vice versa). Research QuestionWhat is the incidence and diagnostic profile associated with discordant pleural fluid biochemistry?Study design and methodsWe conducted a retrospective analysis of 995 pleural fluid samples between 2015-2017 from a UK tertiary centre. Exudates were subdivided into concordant or discordant, with low protein defined as <30g/L and low LDH <170IU/L. Demographics and diagnostic patterns were assessed in both groups. Demographics and diagnostic patterns were assessed in both groups. Chi-squared tests and odds ratios (+/- 95% confidence interval) were calculated for each diagnosis between discordant and concordant pleural effusions, and adjusted ORs calculated using multivariable logistic regression.ResultsIn 715 exudative pleural fluid samples, 229 (32%) were discordant. 85 (37%) of these displayed low protein, with high LDH, and 144 (63%) low LDH with high protein. The median age was higher in the discordant group than the concordant group (75 versus 70 years, p=0.01). The proportion of patients with the following diagnoses were significantly higher in the discordant group compared to concordant: fluid overload (24/229, 10% discordant vs 10/486, 2% concordant, p<0.0001), benign asbestos related pleural effusion (33/229, 14% vs 44/486, 9%, p=0.031) and ICU associated effusion (20/229, 9% vs 15/486, 3%, p=0.001). The following were less frequent in the discordant group: pleural infection (14/229, 6% vs 79/486, 16%, p<0.0001), and malignant pleural effusion (77/229 34% vs 206/486, 42%, p=0.025). These patterns were maintained when adjusting for age and sex.InterpretationDiscordant pleural effusions are common, and represent a biologically distinct entity with different diagnostic patterns compared to concordant effusions. Clinicians should assess for discordance early and tailor investigations accordingly.
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.
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.
Incidence and prevalence of asthma, chronic obstructive pulmonary disease and interstitial lung disease between 2004 and 2023: harmonised analyses of longitudinal cohorts across England, Wales, South-East Scotland and Northern Ireland.
BackgroundWe describe the epidemiology of asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) from 2004 to 2023 in England, Wales, Scotland and Northern Ireland (NI) using a harmonised approach.MethodsData from the National Health Service England (NHSE), Clinical Practice Research Datalink Aurum in England, Secure Anonymised Information Linkage Databank in Wales, DataLoch in South-East Scotland and the Honest Broker Service in NI were used. A harmonised approach to COPD, asthma and ILD case definitions, study designs and study populations across the four nations was performed. Age-sex-standardised incidence rates and point prevalence were calculated between 2004 and 2023 depending on data availability. Logistic and negative binomial regression compared incidence and prevalence rates between the start and end of each study period. Linear extrapolation projected incidence rates between 2020 and 2023 to illustrate how observed and projected rates differed.ResultsIncidence rates were lower in 2019 versus 2005 for asthma (England: incidence rate ratio 0.89, 95% CI 0.88 to 0.90; Wales: 0.66, 0.65 to 0.68; Scotland: 0.67, 0.64 to 0.71; NI: 0.84, 0.81 to 0.86), COPD (England: 0.83, 0.82 to 0.85; Wales: 0.67, 0.65 to 0.69) and higher for ILD (England: 3.27, 3.05 to 3.50; Wales: 1.39, 1.27 to 1.53; Scotland: 1.63, 1.36 to 1.95; NI: 3.03, 2.47 to 3.72). In NHSE, the incidence of asthma was similar in June 2023 versus November 2019, but lower for COPD and higher for ILD. Prevalence of asthma in 2019 in England, Wales, Scotland and NI was 9.7%, 15.9%, 13.2% and 7.0%, respectively, for COPD 4.5%, 5.1%, 4.4% and 3.0%, and for ILD 0.4%, 0.5%, 0.6% and 0.3%. Projected incidence rates were 2.8, 3.4 and 1.8 times lower for asthma, COPD and ILD compared with observed rates at the height of the pandemic.InterpretationAsthma, COPD and ILD affect over 10 million people across the four nations, and a substantial number of diagnoses were missed during the pandemic.
Impact of COVID-19 pandemic on rates of congenital heart disease procedures among children: prospective cohort analyses of 26 270 procedures in 17 860 children using CVD-COVID-UK consortium record linkage data.
BackgroundThe COVID-19 pandemic necessitated major reallocation of healthcare services. Our aim was to assess the impact on paediatric congenital heart disease (CHD) procedures during different pandemic periods compared with the prepandemic period, to inform appropriate responses to future major health services disruptions.Methods and resultsWe analysed 26 270 procedures from 17 860 children between 1 January 2018 and 31 March 2022 in England, linking them to primary/secondary care data. The study period included prepandemic and pandemic phases, with the latter including three restriction periods and corresponding relaxation periods. We compared procedure characteristics and outcomes between each pandemic period and the prepandemic period. There was a reduction in all procedures across all pandemic periods, with the largest reductions during the first, most severe restriction period (23 March 2020 to 23 June 2020), and the relaxation period following second restrictions (3 December 2020 to 4 January 2021) coinciding with winter pressures. During the first restrictions, median procedures per week dropped by 51 compared with the prepandemic period (80 vs 131 per week, p=4.98×10-08). Elective procedures drove these reductions, falling from 96 to 44 per week (p=1.89×10-06), while urgent (28 vs 27 per week, p=0.649) and life-saving/emergency procedures (7 vs 6 per week, p=0.198) remained unchanged. Cardiac surgery rates increased, and catheter-based procedure rates reduced during the pandemic. Procedures for children under 1 year were prioritised, especially during the first four pandemic periods. No evidence was found for differences in postprocedure complications (age-adjusted OR 1.1 (95% CI 0.9, 1.4)) or postprocedure mortality (age and case mix adjusted OR 0.9 (95% CI 0.6, 1.3)).ConclusionsPrioritisation of urgent, emergency and life-saving procedures during the pandemic, particularly in infants, did not impact paediatric CHD postprocedure complications or mortality. This information is valuable for future major health services disruptions, though longer-term follow-up of the effects of delaying elective surgery is needed.
Navigational Bronchoscopy or Transthoracic Needle Biopsy for Lung Nodules.
BackgroundEach year, millions of pulmonary nodules are identified incidentally or through lung cancer screening, and many involve biopsy to distinguish cancer from benign processes. Both navigational bronchoscopy and computed tomography-guided transthoracic needle biopsy are commonly used in patients undergoing biopsies of peripheral pulmonary nodules, but the relative diagnostic accuracy of these two approaches is unclear.MethodsIn this multicenter, randomized, parallel-group, noninferiority trial, we assigned patients with an intermediate-risk or high-risk peripheral pulmonary nodule measuring 10 to 30 mm in diameter to undergo navigational bronchoscopy or transthoracic needle biopsy at seven centers across the United States. The primary outcome was diagnostic accuracy, which was defined as the percentage of patients with biopsies that showed a specific diagnosis (cancer or a specific benign condition) that was confirmed to be accurate through 12 months of clinical follow-up (nonferiority margin, 10 percentage points). Secondary outcomes included procedural complications such as the occurrence of pneumothorax.ResultsAmong the 234 patients included in the primary-outcome analysis (5 of whom were lost to follow-up), biopsy resulted in a specific diagnosis that was confirmed to be accurate through month 12 in 94 of 119 patients (79.0%) in the navigational bronchoscopy group and in 81 of 110 patients (73.6%) in the transthoracic needle biopsy group (absolute difference, 5.4 percentage points; 95% confidence interval, -6.5 to 17.2; P = 0.003 for noninferiority; P = 0.17 for superiority). Pneumothorax occurred in 4 of 121 patients (3.3%) in the navigational bronchoscopy group and in 32 of 113 patients (28.3%) in the transthoracic needle biopsy group and led to the placement of a chest tube, hospital admission, or both in 1 patient (0.8%) and 13 patients (11.5%), respectively.ConclusionsThe diagnostic accuracy of navigational bronchoscopy was noninferior to that of transthoracic needle biopsy among patients with peripheral pulmonary nodules measuring 10 to 30 mm. (Funded by Medtronic and others; VERITAS ClinicalTrials.gov number, NCT04250194.).
Incidence, outcomes and management of spontaneous haemoperitoneum in pregnancy: a UK population-based study.
BACKGROUND: Spontaneous haemoperitoneum in pregnancy (SHiP) is the occurrence during pregnancy of sudden intra-abdominal haemorrhage unrelated to extrauterine pregnancy, trauma or uterine rupture. SHiP is uncommon but is associated with preterm birth, high perinatal mortality and, more rarely, maternal mortality. We investigated the incidence of SHiP in the UK and its diagnosis, management and outcomes. METHODS: This two-year, prospective surveillance study used the UK Obstetric Surveillance System to collect anonymous data on all women who gave birth in a UK consultant-led maternity unit in 2016 and 2017 and who experienced SHiP. RESULTS: We confirmed 20 cases of SHiP, giving an estimated incidence of 1.3 cases per 100,000 maternities, or 1 per 75,614 maternities. The median gestational age at diagnosis was 35.7 weeks (IQR 29.9-38.4 weeks). A minority of affected women were receiving anticoagulant agents for prophylaxis (2/20) or treatment (4/20). The most common initial suspected diagnosis was placental abruption (7/20), followed by intra-abdominal bleeding, uterine rupture, or infection. SHiP was diagnosed using ultrasound in four women, using CT in five, and solely at surgery in 14. Aneurysms (4/20) and organ rupture or haematoma (5/20) were the most common bleeding source, and the condition was most commonly diagnosed and treated by laparotomy (11/20). Perinatal morbidity and mortality were high, with 16% of infants stillborn, an over 80% admission rate to the neonatal unit among the 16 live-born infants, major complications in a third of these infants, and one neonatal death. Maternal morbidity was also high, with 60% of women admitted to the intensive care unit, over half of whom experienced major morbidity, and one maternal death. CONCLUSIONS: SHiP is rare in the UK but when it occurs, it can be associated with major maternal morbidity and mortality, and perinatal outcomes are poor. International comparisons are complicated by differing definitions of SHiP.
Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation
Hypoxia-inducible factors (HIFs) mediate cellular responses to low oxygen, notably enhanced fermentation that acidifies poorly perfused tissues and may eventually become more damaging than adaptive. How pH feeds back on hypoxic signaling is unclear but critical to investigate because acidosis and hypoxia are mechanistically coupled in diffusion-limited settings, such as tumors. Here, we examined the pH sensitivity of hypoxic signaling in colorectal cancer cells that can survive acidosis. HIF-1α stabilization under acidotic hypoxia was transient, declining over 48 h. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (e.g., CA9, PDK1), but these did not reflect a proteome-wide downregulation. Enrichment analyses suggested a role for lysosomal degradation. Indeed, HIF-1α destabilization was blocked by inactivating lysosomes, but not proteasome inhibitors. Acidotic hypoxia stimulated lysosomal activity and autophagy via mammalian target of rapamycin complex I (mTORC1), resulting in HIF-1α degradation. This response protects cells from excessive acidification by unchecked fermentation. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling.
Immune–epithelial–stromal networks define the cellular ecosystem of the small intestine in celiac disease
Abstract The immune–epithelial–stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4+ T cells, intraepithelial lymphocytes, CD8+ and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune–epithelial ‘scar’. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell–B cell interactions. Receptor–ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.