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Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.
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BACKGROUND: Evolving epidemiological data and increasing antibiotic resistance mandate an update of the European and North American Societies of Pediatric Gastroenterology, Hepatology and Nutrition guidelines. METHODS: Certainty of evidence and strength of recommendations were rated by experts according to the Grading of Recommendation Assessment, Development, and Evaluation approach. PICO (patient population, intervention, comparator, and outcome) questions were developed and voted on by the group. Recommendations were formulated using the Evidence to Decision framework. RESULTS: The current literature supports many of the previous recommendations and several new recommendations. Invasive testing with strain antimicrobial susceptibility analysis is recommended for the diagnosis and selection of eradication therapy for H. pylori infection. Molecular methods are acceptable for detection of infection and of antibiotic resistance in gastric biopsy specimens. Reliable, noninvasive tests can be used as a screening method for children with history of gastric cancer in a first-degree relative. When investigating causes of chronic immune thrombocytopenic purpura, testing for H. pylori is no longer recommended. When investigating other diseases such as inflammatory bowel disease, celiac disease, or eosinophilic esophagitis, specific diagnostic biopsies for H. pylori infection are not indicated. However, if H. pylori is an incidental finding, treatment may be considered after discussing the risks and benefits. Treatment should be based on antibiotic antimicrobial susceptibility testing and, if unavailable, regimens containing clarithromycin should be avoided. CONCLUSIONS: Due to decreasing prevalence of infection, increasing challenges with antibiotic resistance, and emerging evidence regarding complications of infection, clinicians must be aware of these recommended changes to appropriately manage H. pylori infection and its clinical sequelae in children.
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PURPOSE: To explore the patterning, practices, and drivers of female genital mutilation (FGM) in Ethiopia's Afar region. METHODS: This article draws on mixed-methods research conducted in 2022 in 18 rural communities in three districts of Ethiopia's Afar region. Survey data were collected from 1,022 adolescents and their caregivers. Qualitative interviews were conducted with approximately 270 adults and adolescents. RESULTS: The survey found that FGM remains practically universal (97% of sampled adolescent girls), and infibulation remains the norm (87% of girls). Most adolescent girls and caregivers reported that FGM is required by religion and should continue. When queried about the main reason for FGM, however, most cited culture rather than religion. Female caregivers and adolescent girls were more likely to report that FGM has benefits than risks; the reverse was true for male caregivers. Qualitative evidence suggests that even girls who are not reported as infibulated generally, and that the social benefits of FGM--especially regarding controlling girls' sexuality and facilitating their marriageability--are perceived to outweigh health risks. Where there are shifts in type of FGM, it is largely due to efforts of religious leaders who preach against infibulation and for "milder" types--and the growing scope of fathers to input into mothers' FGM decision-making and advocate for less invasive types. DISCUSSION: Eliminating FGM requires focusing on contexts where the practice is most invasive and progress is not yet visible. Given complex intrahousehold and intragenerational dynamics, this will necessitate engaging whole communities with sustained multipronged approaches to shift social norms.
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Circuncisión Femenina , Toma de Decisiones , Humanos , Circuncisión Femenina/psicología , Circuncisión Femenina/estadística & datos numéricos , Etiopía , Femenino , Adolescente , Adulto , Masculino , Adulto Joven , Población Rural , Investigación Cualitativa , Cuidadores/psicología , Cuidadores/estadística & datos numéricos , Encuestas y Cuestionarios , Niño , Conocimientos, Actitudes y Práctica en Salud , Persona de Mediana EdadRESUMEN
PURPOSE: Despite the impact of physician-scientists on scientific discovery and translational medicine, several reports have signalled their declining workforce, reduced funding, and insufficient protected research time. Given the paucity of outcome data on Canadian MD/PhD programs, this study presents a national portrait of the sociodemographic characteristics, training trajectories, productivity, and satisfaction in trainees and alumni from Canadian MD/PhD and MD/MSc programs. METHODS: Quantitative data were collected in a national survey launched in 2021. Respondents included 74 MD/PhD alumni and 121 trainees across 12 Canadian MD/PhD and MD/MSc programs. RESULTS: Among MD/PhD alumni, 51% were independent practitioners/researchers while others underwent residency training. Most trainees (88%) were in MD/PhD programs. Significantly more alumni identified as men than did trainees. Significantly more alumni conducted clinical and health services research, while more trainees conducted basic science research. Average time to MD/PhD completion was 8 years, with no correlation to subsequent research outcomes. Self-reported research productivity was highest during MD/PhD training. Concerning training trajectories, most alumni completed residency, pursued additional training, and practised in Canada. Finally, regression models showed that trainees and alumni were satisfied with programs, with significant moderators in trainee models. CONCLUSION: Survey findings showed Canadian MD/PhD and MD/MSc programs recruit more diverse cohorts of trainees than before, provide productive research years, and graduate alumni who pursue training and academic employment in Canada. Both alumni and trainees are largely satisfied with these training programs. The need to collect in-depth longitudinal data on Canadian MD/PhD graduates to monitor diversity and success metrics is discussed.
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Satisfacción Personal , Canadá , Humanos , Masculino , Encuestas y Cuestionarios , Femenino , Adulto , Investigación Biomédica/estadística & datos numéricosRESUMEN
Discriminatory gender norms can intersect and interact with other dimensions of discrimination-such as age, race, ethnicity, disability, education status, and sexual orientation-to shape individuals' experiences and impact their health and wellbeing. This interaction is referred to as intersectionality. Although the theory has been in circulation since the late 1980s, only recently has it gained traction in low-income and middle-income settings, and it has yet to fully penetrate global research on adolescence. The social and structural intersectional drivers of adolescent health and wellbeing, particularly during early adolescence (age 10-14 years), are poorly understood. The evidence base for designing effective interventions for this formative period of life is therefore relatively small. In this Review, we examine how gender intersects with other forms of disadvantage in the early stages of adolescence. Analysing data from hybrid observation-intervention longitudinal studies with young adolescents in 16 countries, our aim is to inform the health and wellbeing of girls and boys from a range of social contexts, including in conflict settings. Adolescents' perceptions about gender norms vary by context, depend on individual opinion, and are shaped by socioecological drivers of gender inequalities in health. Shifting those perceptions is therefore challenging. We argue for the importance of applying an intersectionality lens to improve health and wellbeing outcomes for young adolescents and conclude with five practical recommendations for programme design and research.
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Salud del Adolescente , Humanos , Adolescente , Masculino , Femenino , Estudios Longitudinales , Niño , Normas Sociales , Identidad de GéneroRESUMEN
Background: Trypanosoma brucei is a protozoan parasite that evades the mammalian host's adaptive immune response by antigenic variation of the highly immunogenic variant surface glycoprotein (VSG). VSGs form a dense surface coat that is constantly recycled through the endosomal system. Bound antibodies are separated in the endosome from the VSG and destroyed in the lysosome. For VSGs it has been hypothesized that pH-dependent structural changes of the VSG could occur in the more acidic environment of the endosome and hence, facilitate the separation of the antibody from the VSG. Methods: We used size exclusion chromatography, where molecules are separated according to their hydrodynamic radius to see if the VSG is present as a homodimer at both pH values. To gain information about the structural integrity of the protein we used circular dichroism spectroscopy by exposing the VSG in solution to a mixture of right- and left-circularly polarized light and analysing the absorbed UV spectra. Evaluation of protein stability and molecular dynamics simulations at different pH values was performed using different computational methods. Results: We show, for an A2-type VSG, that the dimer size is only slightly larger at pH 5.2 than at pH 7.4. Moreover, the dimer was marginally more stable at lower pH due to the higher affinity (ΔG = 353.37 kcal/mol) between the monomers. Due to the larger size, the predicted epitopes were more exposed to the solvent at low pH. Moderate conformational changes (ΔRMSD = 0.35 nm) in VSG were detected between the dimers at pH 5.2 and pH 7.4 in molecular dynamics simulations, and no significant differences in the protein secondary structure were observed by circular dichroism spectroscopy. Conclusions: Thus, the dissociation of anti-VSG-antibodies in endosomes cannot be explained by changes in pH.
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OBJECTIVE: To understand the relationship between the COVID-19 pandemic and menstrual hygiene management (MHM) among adolescent girls in Ethiopia and to explore which girls were most affected by pandemic disruptions. DESIGN: Two rounds of data from surveys and interviews were collected with adolescent girls immediately prior to and during the COVID-19 pandemic. The primary analysis is cross-sectional, controlling for pre-COVID-19 covariates. SETTING: The setting was three zones in two regions of Ethiopia: East Hararghe and East Shewa Zones in Oromia and South Gondar Zone in Amhara. Data were collected in December 2019-March 2020 and September 2020-February 2021. PARTICIPANTS: 742 adolescent girls, ages 11-25 years. OUTCOME MEASURES: Four primary outcomes were explored (1) the number of challenges girls experienced; (2) adolescent-identified challenges managing menstrual hygiene; (3) adolescent-identified difficulties accessing MHM products and (4) adolescent-identified difficulties accessing soap or water. RESULTS: Girls who were more vulnerable to COVID-19 were more likely to have worse MHM outcomes. An SD increase in household vulnerability to COVID-19 was associated with an 8.7 percentage point increase in the likelihood that the respondent had difficulty getting MHM products (p<0.001), a 6 percentage point increase in the likelihood that she reported facing a challenge managing her menstruation (p=0.003) and a 5.2 percentage point increase in the likelihood she lacked soap or water (p=0.001). Qualitative themes, used to triangulate the quantitative findings, suggest that mobility restrictions, shutdowns of the local market, disruptions in supply chains, poverty, stigma and fear about contracting COVID-19 affected girls' access to MHM supplies. CONCLUSIONS: The results of this study suggest that MHM was left behind in the COVID-19 response. New programming and policy interventions need to address financial hardship and disruptions to supplies to manage menstruation as well as tackle the inequitable gender norms that stigmatise menstruation during emergencies.
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COVID-19 , Higiene , Menstruación , SARS-CoV-2 , Humanos , Femenino , COVID-19/epidemiología , COVID-19/prevención & control , Adolescente , Etiopía/epidemiología , Adulto Joven , Estudios Longitudinales , Estudios Transversales , Niño , Productos para la Higiene Menstrual/provisión & distribución , Adulto , Pandemias , Conocimientos, Actitudes y Práctica en SaludRESUMEN
OBJECTIVES: This study aims to explore characteristics and clinical outcomes of patients with congenital heart disease (CHD) in the European Registry for Patients with Mechanical Circulatory Support (EUROMACS). METHODS: This is a retrospective study of EUROMACS participants receiving MCS as bridge-to-transplant, possible bridge-to-transplant, or rescue therapy/bridge-to-recovery from 2011 to 2023 (n = 5340). Adult and paediatric cohorts were analysed separately. The primary outcome was mortality on MCS; secondary outcomes included recovery, transplant and complications including bleeding, cerebrovascular events, and sepsis. RESULTS: Among adult patients, mortality at 1-year was 33.3% among the CHD cohort vs 22.1% in the non-CHD cohort. Adult CHD patients had higher hazards of mortality within the first year after MCS implantation [hazard ratios 1.98, 95% confidence interval (CI) 1.35-2.91, P < 0.001] and bleeding events (subdistribution hazard ratios 2.10, 95% CI 1.40-3.16, P < 0.001) compared with non-CHD patients. Both associations remained significant after accounting for multiple mediators. Among paediatric patients, mortality at 1 year was 22.1% in the CHD cohort vs 17.3% in the non-CHD cohort (hazard ratios 1.39, 95% CI 0.83-2.32, P = 0.213). CONCLUSIONS: Adult and paediatric patients with CHD on MCS have higher adverse event risk compared with non-CHD MCS patients, though children did not have greater risk of mortality. As the number of CHD patients requiring advanced heart failure management continues to grow, these findings can enhance informed decision-making. CLINICAL TRIAL REGISTRATION NUMBER: Registry name: EUROMACS.
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Cardiopatías Congénitas , Corazón Auxiliar , Sistema de Registros , Humanos , Cardiopatías Congénitas/cirugía , Cardiopatías Congénitas/mortalidad , Masculino , Femenino , Estudios Retrospectivos , Adulto , Europa (Continente)/epidemiología , Niño , Corazón Auxiliar/estadística & datos numéricos , Corazón Auxiliar/efectos adversos , Adolescente , Preescolar , Lactante , Trasplante de Corazón/estadística & datos numéricos , Adulto Joven , Persona de Mediana EdadRESUMEN
Endocytosis is a common process observed in most eukaryotic cells, although its complexity varies among different organisms. In Trypanosoma brucei, the endocytic machinery is under special selective pressure because rapid membrane recycling is essential for immune evasion. This unicellular parasite effectively removes host antibodies from its cell surface through hydrodynamic drag and fast endocytic internalization. The entire process of membrane recycling occurs exclusively through the flagellar pocket, an extracellular organelle situated at the posterior pole of the spindle-shaped cell. The high-speed dynamics of membrane flux in trypanosomes do not seem compatible with the conventional concept of distinct compartments for early endosomes (EE), late endosomes (LE), and recycling endosomes (RE). To investigate the underlying structural basis for the remarkably fast membrane traffic in trypanosomes, we employed advanced techniques in light and electron microscopy to examine the three-dimensional architecture of the endosomal system. Our findings reveal that the endosomal system in trypanosomes exhibits a remarkably intricate structure. Instead of being compartmentalized, it constitutes a continuous membrane system, with specific functions of the endosome segregated into membrane subdomains enriched with classical markers for EE, LE, and RE. These membrane subdomains can partly overlap or are interspersed with areas that are negative for endosomal markers. This continuous endosome allows fast membrane flux by facilitated diffusion that is not slowed by multiple fission and fusion events.
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Endosomas , Trypanosoma , Membranas , Membrana Celular , Vesículas TransportadorasRESUMEN
OBJECTIVES: To identify patterns in inflammatory marker and vital sign responses in adult with suspected bloodstream infection (BSI) and define expected trends in normal recovery. METHODS: We included patients ≥16 y from Oxford University Hospitals with a blood culture taken between 1-January-2016 and 28-June-2021. We used linear and latent class mixed models to estimate trajectories in C-reactive protein (CRP), white blood count, heart rate, respiratory rate and temperature and identify CRP response subgroups. Centile charts for expected CRP responses were constructed via the lambda-mu-sigma method. RESULTS: In 88,348 suspected BSI episodes; 6908 (7.8%) were culture-positive with a probable pathogen, 4309 (4.9%) contained potential contaminants, and 77,131(87.3%) were culture-negative. CRP levels generally peaked 1-2 days after blood culture collection, with varying responses for different pathogens and infection sources (p < 0.0001). We identified five CRP trajectory subgroups: peak on day 1 (36,091; 46.3%) or 2 (4529; 5.8%), slow recovery (10,666; 13.7%), peak on day 6 (743; 1.0%), and low response (25,928; 33.3%). Centile reference charts tracking normal responses were constructed from those peaking on day 1/2. CONCLUSIONS: CRP and other infection response markers rise and recover differently depending on clinical syndrome and pathogen involved. However, centile reference charts, that account for these differences, can be used to track if patients are recovering line as expected and to help personalise infection.
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Biomarcadores , Proteína C-Reactiva , Signos Vitales , Humanos , Masculino , Femenino , Proteína C-Reactiva/análisis , Persona de Mediana Edad , Anciano , Biomarcadores/sangre , Adulto , Sepsis/sangre , Sepsis/diagnóstico , Adulto Joven , Recuento de Leucocitos , Frecuencia Cardíaca , Inflamación/sangre , Anciano de 80 o más Años , Frecuencia Respiratoria , Adolescente , Bacteriemia/diagnóstico , Bacteriemia/sangre , Bacteriemia/microbiología , Cultivo de Sangre , Temperatura CorporalRESUMEN
OBJECTIVES: Current guidelines recommend broad-spectrum antibiotics for high-severity community-acquired pneumonia (CAP), potentially contributing to antimicrobial resistance (AMR). We aim to compare outcomes in CAP patients treated with amoxicillin (narrow-spectrum) versus co-amoxiclav (broad-spectrum), to understand if narrow-spectrum antibiotics could be used more widely. METHODS: We analysed electronic health records from adults (≥16 y) admitted to hospital with a primary diagnosis of pneumonia between 01-January-2016 and 30-September-2023 in Oxfordshire, United Kingdom. Patients receiving baseline ([-12 h,+24 h] from admission) amoxicillin or co-amoxiclav were included. The association between 30-day all-cause mortality and baseline antibiotic was examined using propensity score (PS) matching and inverse probability treatment weighting (IPTW) to address confounding by baseline characteristics and disease severity. Subgroup analyses by disease severity and sensitivity analyses with missing covariates imputed were also conducted. RESULTS: Among 16,072 admissions with a primary diagnosis of pneumonia, 9685 received either baseline amoxicillin or co-amoxiclav. There was no evidence of a difference in 30-day mortality between patients receiving initial co-amoxiclav vs. amoxicillin (PS matching: marginal odds ratio 0.97 [0.76-1.27], p = 0.61; IPTW: 1.02 [0.78-1.33], p = 0.87). Results remained similar across stratified analyses of mild, moderate, and severe pneumonia. Results were also similar with missing data imputed. There was also no evidence of an association between 30-day mortality and use of additional macrolides or additional doxycycline. CONCLUSIONS: There was no evidence of co-amoxiclav being advantageous over amoxicillin for treatment of CAP in 30-day mortality at a population-level, regardless of disease severity. Wider use of narrow-spectrum empirical treatment of moderate/severe CAP should be considered to curb potential for AMR.
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Combinación Amoxicilina-Clavulanato de Potasio , Amoxicilina , Antibacterianos , Infecciones Comunitarias Adquiridas , Humanos , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/mortalidad , Amoxicilina/uso terapéutico , Masculino , Femenino , Antibacterianos/uso terapéutico , Anciano , Persona de Mediana Edad , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Reino Unido/epidemiología , Hospitalización/estadística & datos numéricos , Anciano de 80 o más Años , Adulto , Neumonía/mortalidad , Neumonía/tratamiento farmacológico , Resultado del Tratamiento , Estudios Retrospectivos , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/mortalidadRESUMEN
New therapies and vaccines based on nucleic acids combined with an efficient nanoparticle delivery vehicle have a broad applicability for different disease indications. An alternative delivery technology for the successfully applied lipid nanoparticles in mRNA SARS-CoV-2 vaccines are nanoparticles composed of biodegradable poly(amido)amine-based polymers with mRNA payload. To show that these polymeric nanoparticles can efficiently deliver influenza hemagglutinin mRNA to target tissues and elicit protective immune responses, a relevant ferret influenza challenge model was used. In this model, our nanoparticle-based vaccine elicited strong humoral and cellular immune responses in the absence of local and systemic reactogenicity. Upon virus challenge, vaccinated animals exhibited reduced clinical signs and virus load relative to unvaccinated control animals. Based on these findings, further investigation of the polymeric nanoparticles in the context of prophylactic vaccination is warranted. Future studies will focus on optimizing the payload, the nanoparticle stability, the efficacy in the context of pre-existing immunity, and the applicability of the technology to prevent other infectious diseases.
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OBJECTIVE: The huge burden of inaccurate penicillin allergy labels (PALs) is an important driver of antimicrobial resistance. This is magnified by insufficient allergy specialists and lack of 'point-of-care' tests. We investigated the feasibility of non-allergy healthcare professionals (HCPs) delivering direct oral penicillin challenges (DPCs) for penicillin allergy de-labelling. METHODS: This prospective observational study was conducted in three hospitals in England across three settings (acute medical, pre-surgical and haematology-oncology). Patients with a PAL were screened and stratified as low risk/high risk. Low risk patients (non-immune mediated symptoms, benign rash, tolerated amoxicillin since and family history) underwent a DPC. RESULTS: N = 2257 PALs were screened, 1054 were eligible; 643 were approached, 373 declined, 270 consented and 259 risk stratified (low risk = 155; high risk = 104). One hundred and twenty-six low risk patients underwent DPC, 122 (96.8%) were de-labelled with no serious allergic reactions. Conversion rate from screening-to-consent was 12% [3.3% and 17.9% in acute and elective settings respectively; odds ratios for consent were 3.42 (p < 0.001) and 5.53 (p < 0.001) in haematology-oncology and pre-surgical setting respectively. Common reasons for failure to progress in the study included difficulty in reaching patients, clinical instability/medical reasons, lacking capacity to consent and psychological factors. INTERPRETATION: DPCs can be delivered by non-allergy HCPs. A high proportion of patients with PALs did not progress in the study pathway. Strategies to deliver DPC at optimal points of the care pathway are needed to enhance uptake. Elective settings offer greater opportunities than acute settings for DPC. The safety and simplicity of DPCs lends itself to adoption by healthcare systems beyond the UK, including in resource-limited settings.
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Hipersensibilidad a las Drogas , Hipersensibilidad , Humanos , Penicilinas/efectos adversos , Antibacterianos/efectos adversos , Estudios de Factibilidad , Pruebas Cutáneas , Hipersensibilidad a las Drogas/diagnóstico , Atención a la SaludRESUMEN
Over the past decade there has been a burgeoning literature on social norms and the need to understand their context-specific patterning and trends to promote change, including to address the harmful practice of female genital mutilation (FGM), which affects around 200 million girls and women globally. This article draws on mixed-methods data collected in 2022 and 2023 with 1,020 adolescents and their caregivers, as well as key informants, from Ethiopia's Somali region to explore the patterning, drivers, and decision-making around FGM. Findings indicate that almost all Somali girls can expect to undergo FGM before age 15, and that infibulation is near universal. Critically, however, we find that respondents' understanding of infibulation is rooted in traditional practice, and many girls are now "partially" infibulated-an invasive procedure that girls nonetheless see as an improvement over the past. These shifts reflect religious leaders' efforts to eliminate traditional infibulation--and the health risks it entails--by promoting "less invasive" types of FGM as a requirement of Islam. We also find evidence of emergent medicalization of the practice, as mothers-who are the primary decision-makers-seek to further reduce risks. Adult and adolescent respondents agree that FGM is a deeply embedded social norm, but distinguish between FGM as a perceived religious requirement, and infibulation as a cultural requirement. For girls and women, the importance of FGM is framed around social acceptance, whereas boys and men focus on FGM as a requirement for marriage as it allows families to control girls' sexuality. The article concludes by reflecting on the implications of our findings for programming in high-prevalence contexts. Key conclusions include that FGM interventions should not rely on empowering individuals as "champions of change" but rather prioritize engagement with whole communities, and should be open in the short term to incremental harm-reduction approaches.