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Facilitators and barriers to the implementation of maternal and perinatal death surveillance and response in Ethiopia: a systematic review.
Ethiopia was one of the pioneer countries to implement the World Health Organization's Maternal and Perinatal Death Surveillance and Response (MPDSR) system to accelerate the reduction in maternal and perinatal mortality. However, there has been no systematic evaluation of its implementation in Ethiopia and that's why we conducted this systematic review. A systematic review was conducted to synthesize the evidence on coverage, facilitators or barriers to MPDSR implementation in Ethiopia. We searched PubMed, Embase, Web of Science, PubMed Central, and Google Scholar using relevant key terms. In addition, Ethiopian Public Health Institute websites searched for additional data. Articles published before 2013 excluded from this review. The methodological quality of the studies assessed using the Joanna Briggs Institute's quality appraisal tool. For quantitative studies, descriptive analysis conducted; thematic synthesis used for qualitative studies. From twenty studies included, 12 only reported maternal death reviews while eight included maternal and perinatal death reviews. During the reporting period, the coverage of maternal and perinatal deaths remained less than 22.1% and 12.1% of the expected deaths respectively. Reported facilitators were community involvement, sufficient capacity building, and supportive supervision. Reported barriers were lack of conducive learning environment, fear of blame and litigation, lack of financial resources, high staff turnover, and defensive attitudes and practices. Despite all efforts, the uptake of MPDSR has been low. Addressing identified barriers and utilizing identified facilitators essential for optimising MPDSR implementation in Ethiopia. PROSPERO Registration Number: CRD42022315199.
Prognostic factors for wound complications after childbirth-related perineal trauma: A systematic review and meta-analysis
Introduction: Although childbirth-related perineal trauma affects the majority of women after vaginal birth, very few healthcare resources are allocated to reducing morbidity from perineal trauma. Wound complications are frequent after perineal trauma has been sustained; however, we know little about which factors are predictive of developing a wound issue. To target possible interventions effectively, it is crucial that those at higher risk are identified. Here, we perform a systematic review and meta-analysis of prognostic factors for sustaining wound complications after childbirth-related perineal trauma. Material and Methods: Medline, Embase, Web of Science, and CINAHL were searched from inception to December 2024 using relevant search terms. There were no restrictions on language or year of publication. Observational studies that investigated two or more potential prognostic factors for wound complications after childbirth related-perineal trauma, where adjusted risks were calculated, were eligible for inclusion. We included all types of tears, sustained through spontaneous or assisted vaginal birth. Meta-analysis was performed where five or more studies investigated a particular prognostic factor for perineal wound complications. Odds ratios (ORs) were pooled using a random effects model. The review was prospectively registered in PROSPERO (CRD42023458738). Results: Fifteen studies were eligible for inclusion, involving 71409 women. Studies included were published between 2006 and 2024 across six different countries. Assisted vaginal birth (10 studies, 65 375 women: OR 2.77, 95% confidence interval [CI] 1.89–4.06) was a significant risk factor for wound complication. Raised body mass index (six studies, 64 770 women: OR 1.33, 95% CI 0.56–3.18) was not a significant risk factor. Prolonged second stage of labor, smoking, and episiotomy were each investigated in three primary studies; therefore, data was insufficient for meta-analysis; however, individual studies indicated that there might be an association with perineal wound complication. Conclusions: Assisted vaginal birth is a significant risk factor for perineal wound complication after childbirth-related perineal trauma. Overall, there are limited studies investigating prognostic factors for perineal wound complication after childbirth related-perineal trauma. Whilst we highlight potential prognostic factors, we recommend that a robust, well-powered primary research study with clearly defined wound complication outcomes and prognostic factors is needed.
Structural basis for HIV-1 capsid adaption to a deficiency in IP6 packaging.
Inositol hexakisphosphate (IP6) promotes HIV-1 assembly by stabilizing the immature Gag lattice and becomes enriched within virions, where it is required for mature capsid assembly. Previously, we identified Gag mutants that package little IP6 yet assemble particles, though they are non-infectious due to defective capsid formation. Here, we report a compensatory mutation, G225R, in the C-terminus of capsid protein (CA) that restores capsid assembly and infectivity in these IP6-deficient mutants. G225R also enhances in vitro assembly of CA into capsid-like particles at far lower IP6 concentrations than required for wild-type CA. CryoEM structures of G225R CA hexamers and lattices at 2.7 Å resolution reveal that the otherwise disordered C-terminus becomes structured, stabilizing hexamer-hexamer interfaces. Molecular dynamics simulations support this mechanism. These findings uncover how HIV-1 can adapt to IP6 deficiency and highlight a previously unrecognized structural role of the CA C-terminus, while offering tools for capsid-related studies.
Direct visualization of HIV-1 core nuclear import and its interplay with the nuclear pore.
Direct visualization of HIV-1 nuclear import through the nuclear pore complex (NPC) presents a technical challenge due to the rarity of this process. To enable systematic investigation, we developed a robust in situ system that mimics HIV-1 nuclear import in a near-native context using isolated HIV-1 virus like particles (VLP) cores and permeabilized CD4 + T lymphocyte (CEM) cells. This approach supports docking and translocation of abundant viral cores through nuclear pores into the nucleus. For high-resolution visualization, we implemented an integrated correlative approach to guide cryo-focused ion beam (cryo-FIB) milling and cryo-electron tomography (cryo-ET) imaging, enabling precise targeting and structural characterization of individual nuclear import events. Using this workflow, we visualized 510 HIV-1 VLP cores at distinct stages of nuclear import, capturing key snapshots of the full progression of nuclear import. Subsequent statistical and structural analyses allow classification of core morphologies and identification of translocation-associated remodeling in nuclear pores. This work provides a methodological foundation for dissecting HIV-1 and potentially other viruses nuclear import processes and post-entry events in a controlled and quantitative manner.
Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 6-17 years: Final results of a phase 2, single-blind, randomised controlled trial (COV006).
Paediatric COVID-19 vaccination programmes were initiated in response to the coronavirus pandemic declared by the World Health Organisation (WHO) in 2020. Ten COVID-19 vaccines received WHO Emergency Use Listing, however, only five were approved for use in children. ChAdOx1 nCoV-19 (AZD1222) was approved in adults in a two-dose regimen. We previously reported interim findings of a phase 2 study of ChAdOx1 nCoV-19 in children with immunogenicity, comparable with adults. Final results after 12 month follow-up are reported. Single-blind, randomised controlled trial across four UK centres, recruiting 261 children and adolescents (aged 6-17 years). Participants received either two doses of ChAdOx1 nCoV-19 or Bexsero vaccine (controls). The primary outcome was safety (adverse events for 28 days following vaccination and serious adverse events throughout), and secondary outcome was immunogenicity (measured by SARS-CoV-2 anti-spike enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot (ELISpot)). Five serious adverse events and four adverse events of special interest were reported. None were related to study vaccinations, and there were no deaths. Geometric mean titres (GMTs) from an anti-spike (Wuhan) ELISA in participants aged 6-11 years were 1 EU/ml (95% CI 1-2) at baseline versus 796 EU (95% CI 161-3948, n =4) at D364. In participants aged 12-17 years, GMTs were 1 EU/ml (95% CI 1-2, n=3) at baseline versus 1432 EU/ml (95% CI 2337-6083; n=6) at D364 (2 dose regimen at 112-day interval), compared to 3 EU/ml (95% CI 0-62) at baseline versus 392 EU/ml (95% CI 24, 6493; n=3) at D364 (2 dose regimen at a 28-day interval). A two-dose regimen of ChAdOx1 nCoV-19 was immunogenic and safe in the trial population. No vaccine-related serious adverse events were reported. Immune responses persisted to 12 months in participants who did not experience breakthrough infection, This trial was registered with ISRCTN, trial number 15638344. The study was funded by the Department of Health and Social Care, through the National Institute for Health Research, and AstraZeneca.
MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines
Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes—mucosal-associated invariant T (MAIT) cells and Vδ2 + γδ T cells—which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)–mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell–derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ–licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.
TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord
Abstract Neuronal and glial cytoplasmic inclusions positive for TAR DNA-binding protein 43 (TDP-43) are the defining pathological hallmark of 97% of amyotrophic lateral sclerosis (ALS) and 50% of frontotemporal dementia (FTD). The ALS-FTD clinicopathological spectrum variably involves cortical and spinal anterior horn cell pathology. The broader protein composition of these inclusions is of major importance to understanding pathogenesis, clinical heterogeneity and biomarker development. This study examined the proteome associated with TDP-43 inclusions in ALS, using mass spectrometry-based proteomic analysis of spinal cord and cerebral cortex from donors with phosphoTDP-43 positive ALS (n = 16), alpha-synuclein positive Parkinson’s disease (PD, n = 8), phosphotau and beta-amyloid positive Alzheimer’s disease (AD, n = 8) and age matched non-neurological controls (n = 8), comparing ALS with non-ALS conditions, spinal cord with cerebral cortex samples, and detergent-soluble with -insoluble fractions. Increased abundance of TDP-43 in the detergent-insoluble fraction of ALS cortex and spinal cord tissue confirmed disease-specific protein enrichment by serial fractionation. The most striking alterations between ALS and other conditions were found in the detergent-insoluble fraction of spinal cord, with predominant enrichment of endosomal and extracellular vesicle pathways. In the cortex mitochondrial membrane/envelope and ion transmembrane transport pathways were enriched in the detergent-insoluble fraction. RNA/DNA metabolic processes (in spinal cord) versus mitochondrial and synaptic protein pathways (in cortex) were upregulated in the detergent-soluble fraction of ALS cases and downregulated in the insoluble protein fraction. Whilst motor cortex and spinal cord may not optimally reflect disease-specific pathways in AD, in PD a significant enrichment of alpha-synuclein in the detergent-insoluble fraction of spinal cord was found. Among proteins concordantly elevated in the detergent-insoluble fractions of spinal cord and cortex, there was greater representation of proteins encoded by ALS-associated genes, specifically Cu/Zn superoxide dismutase 1, valosin containing protein and TDP-43 (odds ratio 16.34, p = 0.002). No significant increase in TDP-43 interacting proteins was observed in either detergent-soluble or -insoluble fractions. Together, this study shows a divergence in the composition of proteins associated with TDP-43 positive detergent-insoluble inclusions between spinal cord and cerebral cortex. A common upregulation of proteins encoded by ALS-causing genes implicates their role in the pathogenesis of the ALS-FTD spectrum of diseases beyond TDP-43. Data are available via ProteomeXchange with identifier PXD067060.
Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: Results from COV-BOOST trial.
BackgroundHeterologous schedules of booster vaccines for COVID-19 following initial doses of mRNA or adenoviral vector vaccines have been shown to be safe and immunogenic. There are few data on booster doses following initial doses of protein nanoparticle vaccines.MethodsParticipants of the phase 3 clinical trial of the COVID-19 vaccine NVX-CoV2373 (EudraCT 2020-004123-16) enroled between September 28 and November 28, 2020, who received 2 doses of NVX-CoV2373 administered 21 days apart were invited to receive a third dose booster vaccine of BNT162b2 (wild type mRNA vaccine) as a sub-study of the COV-BOOST clinical trial, and were followed up for assessment of safety, reactogenicity and immunogenicity to day 242 post-booster.ResultsThe BNT162b2 booster following two doses of NVX-COV2373 was well-tolerated. Most adverse events were mild to moderate, with no serious vaccine-related adverse events reported. Immunogenicity analysis showed a significant increase in spike IgG titres and T-cell responses post-third dose booster. Specifically, IgG levels peaked at day 14 with a geometric mean concentration (GMC) of 216,255 ELISA laboratory units (ELU)/mL (95% CI 191,083-244,743). The geometric mean fold increase from baseline to day 28 post-boost was 168.6 (95% CI 117.5-241.8). Spike IgG titres were sustained above baseline levels at day 242 with a GMC of 58,686 ELU/mL (95% CI 48,954-74,652), with significant decay between days 28 and 84 (geometric mean ratio 0.58, 95% CI 0.53-0.63). T-cell responses also demonstrated enhancement post-booster, with a geometric mean fold increase of 5.1 (95% CI 2.9-9.0) at day 14 in fresh samples and 3.0 (95% CI 1.8-4.9) in frozen samples as measured by ELISpot. In an exploratory analysis, participants who received BNT162b2 after two doses of NVX-COV2373 exhibited higher anti-spike IgG at Day 28 than those who received homologous three doses of BNT162b2, with a GMR of 5.02 (95% CI: 3.17-7.94). This trend remained consistent across all time points, indicating a similar decay rate between the two schedules.ConclusionsA BNT162b2 third dose booster dose in individuals primed with two doses of NVX-COV2373 is safe and induces strong and durable immunogenic responses, higher than seen in other comparable studies. These findings support the use and investigation of heterologous booster strategies and early investigation of heterologous vaccine technology schedules should be a priority in the development of vaccines against new pathogens.
In-cell structure and variability of pyrenoid Rubisco.
Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is central to global CO2 fixation. In eukaryotic algae, its catalytic efficiency is enhanced through the pyrenoid - a protein-dense organelle within the chloroplast that concentrates CO2. Although Rubisco structure has been extensively studied in vitro, its native structure, dynamics and interactions within the pyrenoid remain elusive. Here, we present the native Rubisco structure inside the green alga Chlamydomonas reinhardtii determined by cryo-electron tomography and subtomogram averaging of cryo-focused ion beam milled cells. Multiple structural subsets of Rubisco are identified, stochastically distributed throughout the pyrenoid. While Rubisco adopts an active conformation in the best-resolved map, comparison among the subsets reveals significant local variations at the active site, at the large subunit dimer interfaces, and at binding protein contact regions. These findings offer a comprehensive understanding of the structure, dynamics, and functional organization of native Rubisco within the pyrenoid, providing valuable insights into its critical role in CO2 fixation.
TCF1 and LEF1 promote B-1a cell homeostasis and regulatory function.
B-1 cells are innate-like immune cells abundant in serosal cavities with antibodies enriched in bacterial recognition, yet their existence in humans has been controversial1-3. The CD5+ B-1a subset expresses anti-inflammatory molecules including IL-10, PDL1 and CTLA4 and can be immunoregulatory4-6. Unlike conventional B cells that are continuously replenished, B-1a cells are produced early in life and maintained through self-renewal7. Here we show that the transcription factors TCF1 and LEF1 are critical regulators of B-1a cells. LEF1 expression is highest in fetal and bone marrow B-1 progenitors, whereas the levels of TCF1 are higher in splenic and peritoneal B-1 cells than in B-1 progenitors. TCF1-LEF1 double deficient mice have reduced B-1a cells and defective B-1a cell maintenance. These transcription factors promote MYC-dependent metabolic pathways and induce a stem-like population upon activation, partly via IL-10 production. In the absence of TCF1 and LEF1, B-1 cells proliferate excessively and acquire an exhausted phenotype with reduced IL-10 and PDL1 expression. Furthermore, adoptive transfer of B-1 cells lacking TCF1 and LEF1 fails to suppress brain inflammation. These transcription factors are also expressed in human chronic lymphocytic leukaemia B cells and in a B-1-like population that is abundant in pleural fluid and circulation of some patients with pleural infection. Our findings define a TCF1-LEF1-driven transcriptional program that integrates stemness and regulatory function in B-1a cells.
Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.
BackgroundPlague is a high-consequence infectious disease with epidemic potential. Current treatment guidelines are based on weak evidence.MethodsWe enrolled persons (excluding pregnant persons) in Madagascar who had clinically suspected bubonic plague during 2020-2024. Using an open-label noninferiority design, we compared two treatments included in the national plague guidelines: oral ciprofloxacin for 10 days (ciprofloxacin monotherapy) or injectable aminoglycoside for 3 days followed by oral ciprofloxacin for 7 days (aminoglycoside-ciprofloxacin). The primary end point was treatment failure on day 11, with treatment failure defined as death, fever, secondary pneumonic plague, or alternative or prolonged plague treatment. To show noninferiority of ciprofloxacin monotherapy among patients with laboratory-confirmed or probable infections, the upper boundary of the 95% confidence interval around the risk difference had to be less than 15 percentage points.ResultsA total of 933 patients underwent screening; 450 patients with suspected bubonic plague were enrolled and underwent randomization. A total of 220 patients (110 per group) had confirmed infection, and 2 (1 per group) had probable infection. Of the patients who underwent randomization, 53.2% were male, and the median age was 14 years (range, 2 to 72). Ciprofloxacin monotherapy was noninferior to aminoglycoside-ciprofloxacin therapy: among the patients with confirmed or probable infection, treatment failure occurred in 9.0% (10 of 111 patients) in the ciprofloxacin monotherapy group and 8.1% (9 of 111 patients) in the aminoglycoside-ciprofloxacin group (difference, 0.9 percentage points; 95% confidence interval, -6.0 to 7.8). Noninferiority was consistent in other prespecified analysis populations. A total of 5 patients in the ciprofloxacin monotherapy group and 4 patients in the aminoglycoside-ciprofloxacin group died, and secondary pneumonic plague developed in 3 patients in each group. The incidence of adverse events among patients with confirmed or probable infections was similar in the two groups - 18.0% in the ciprofloxacin monotherapy group and 18.9% in the aminoglycoside-ciprofloxacin group had adverse events, and 7.2% and 5.4%, respectively, had serious adverse events.ConclusionsOral ciprofloxacin monotherapy for 10 days was noninferior to an aminoglycoside-ciprofloxacin sequential combination for the treatment of patients with bubonic plague. (Funded by the U.K. Foreign, Commonwealth, and Development Office and Wellcome; IMASOY ClinicalTrials.gov number, NCT04110340.).
Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors.
Small-cell lung cancers (SCLCs) contain near-universal loss-of-function mutations in RB1 and TP53, compromising the G1-S checkpoint and leading to dysregulated E2F activity1. Other cancers similarly disrupt the G1-S checkpoint through loss of CDKN2A or amplification of cyclin D or cyclin E, also resulting in excessive E2F activity2,3. Although E2F activation is essential for cell cycle progression, hyperactivation promotes apoptosis4-9, presenting a therapeutic vulnerability. Cyclin proteins use a conserved hydrophobic patch to bind to substrates bearing short linear RxL motifs10-13. Cyclin A represses E2F through an RxL-dependent interaction10,14, which, when disrupted, hyperactivates E2F15. However, this substrate interface has remained difficult to target. Here we developed cell-permeable, orally bioavailable macrocyclic peptides that inhibit RxL-mediated interactions of cyclins with their substrates. Dual inhibitors of cyclin A and cyclin B RxL motifs (cyclin A/Bi) selectively kill SCLC cells and other cancer cells with high E2F activity. Genetic screens revealed that cyclin A/Bi induces apoptosis through cyclin B- and CDK2-dependent spindle assembly checkpoint activation. Mechanistically, cyclin A/Bi hyperactivates E2F and cyclin B by blocking cyclin A-E2F and cyclin B-MYT1 RxL interactions. Notably, cyclin A/Bi promoted the formation of neomorphic cyclin B-CDK2 complexes, which drive spindle assembly checkpoint activation and mitotic cell death. Finally, orally administered cyclin A/Bi showed robust anti-tumour activity in chemotherapy-resistant SCLC patient-derived xenografts. These findings reveal gain-of-function mechanisms through which cyclin A/Bi triggers apoptosis and support their development for E2F-driven cancers.
Temporo-spatial cellular atlas of the regenerating alveolar niche in idiopathic pulmonary fibrosis
Abstract Healthy alveolar repair relies on the ability of alveolar stem cells to differentiate into specialized epithelial cells for gas exchange. In chronic fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF), this regenerative process is abnormal but the underlying mechanisms remain unclear. Here, using human lung tissue that represents different stages of disease and a 33-plex single-cell imaging mass cytometry (IMC), we present a high-resolution, temporo-spatial cell atlas of the regenerating alveolar niche. With unbiased mathematical methods which quantify statistically enriched interactions, CD206himacrophage subtype and an alveolar basal intermediate epithelial cell emerge as the most statistically robust spatial association in the epithelial and immune cell interactome, found across all stages of disease. Spatially resolved receptor–ligand analysis further offers an in silico mechanism by which these macrophages may influence epithelial regeneration. These findings provide a foundational step toward understanding immune–epithelial dynamics in aberrant alveolar regeneration in IPF.
SLC45A4 is a pain gene encoding a neuronal polyamine transporter
Abstract Polyamines are regulatory metabolites with key roles in transcription, translation, cell signalling and autophagy1. They are implicated in multiple neurological disorders, including stroke, epilepsy and neurodegeneration, and can regulate neuronal excitability through interactions with ion channels2. Polyamines have been linked to pain, showing altered levels in human persistent pain states and modulation of pain behaviour in animal models3. However, the systems governing polyamine transport within the nervous system remain unclear. Here, undertaking a genome-wide association study (GWAS) of chronic pain intensity in the UK Biobank (UKB), we found a significant association between pain intensity and variants mapping to the SLC45A4 gene locus. In the mouse nervous system, Slc45a4 expression is enriched in all sensory neuron subtypes within the dorsal root ganglion, including nociceptors. Cell-based assays show that SLC45A4 is a selective plasma membrane polyamine transporter, and the cryo-electron microscopy (cryo-EM) structure reveals a regulatory domain and basis for polyamine recognition. Mice lacking SLC45A4 show normal mechanosensitivity but reduced sensitivity to noxious heat- and algogen-induced tonic pain that is associated with reduced excitability of C-polymodal nociceptors. Our findings therefore establish a role for neuronal polyamine transport in pain perception and identify a target for therapeutic intervention in pain treatment.
Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.
Platelets are anucleate blood cells vital for hemostasis and immunity. During cell death and aberrant mitosis, nucleated cells release DNA, resulting in "cell-free" DNA in plasma (cfDNA). An excess of cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA. We found that, despite lacking a nucleus, platelets contained a repertoire of DNA fragments mapping across the nuclear genome. We detected fetal DNA in maternal platelets and cancer-derived DNA in platelets from patients with premalignant and cancerous lesions. As current liquid biopsy approaches utilize platelet-depleted plasma, important genetic information contained within platelets is being missed. This study establishes a physiological role for platelets that has not previously been highlighted, with broad translational relevance.