Distinct patterns of vital sign and inflammatory marker responses in adults with suspected bloodstream infection.

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.

Continuous endosomes form functional subdomains and orchestrate rapid membrane trafficking in trypanosomes.

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.

Polymeric nanoparticle-based mRNA vaccine is protective against influenza virus infection in ferrets.

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.

A multicentre observational study to investigate feasibility of a direct oral penicillin challenge in de-labelling 'low risk' patients with penicillin allergy by non-allergy healthcare professionals (SPACE study): Implications for healthcare systems.

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.

"People will talk about her if she is not circumcised": Exploring the patterning, drivers and gender norms around female genital mutilation in Ethiopia's Somali region.

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.

Vector-borne Trypanosoma brucei parasites develop in artificial human skin and persist as skin tissue forms.

Transmission of Trypanosoma brucei by tsetse flies involves the deposition of the cell cycle-arrested metacyclic life cycle stage into mammalian skin at the site of the fly's bite. We introduce an advanced human skin equivalent and use tsetse flies to naturally infect the skin with trypanosomes. We detail the chronological order of the parasites' development in the skin by single-cell RNA sequencing and find a rapid activation of metacyclic trypanosomes and differentiation to proliferative parasites. Here we show that after the establishment of a proliferative population, the parasites enter a reversible quiescent state characterized by slow replication and a strongly reduced metabolism. We term these quiescent trypanosomes skin tissue forms, a parasite population that may play an important role in maintaining the infection over long time periods and in asymptomatic infected individuals.

Reconciling chemical flame retardant exposure and fire risk in domestic furniture.

INTRODUCTION: Evidence suggests that standards for resistance of furniture to ignition may lead to an increase in use of chemical flame retardants (CFRs). This is motivating the development of new approaches that maintain high levels of fire safety while facilitating a reduction in use of CFRs. However, reconciling potential fire risk with use of CFRs in relation to specific policy objectives is challenging. OBJECTIVES: To inform the development of a new policy in the UK for the fire safety of furniture, we developed for domestic furniture quantitative models of fire risk and potential for CFR exposure. We then combined the models to determine if any lower fire risk, higher CFR exposure categories of furniture were identifiable. METHODS: We applied a novel mixed-methods approach to modelling furniture fire risk and CFR exposure in a data-poor environment, using literature-based concept mapping, qualitative research, and data visualisation methods to generate fire risk and CFR exposure models and derive furniture product rankings. RESULTS: Our analysis suggests there exists a cluster of furniture types including baby and infant products and pillows that have comparable overall properties in terms of lower fire risk and higher potential for CFR exposure. DISCUSSION: There are multiple obstacles to reconciling fire risk and CFR use in furniture. In particular, these include a lack of empirical data that would allow absolute fire risk and exposure levels to be quantified. Nonetheless, it seems that our modelling method can potentially yield meaningful product clusters, providing a basis for further research.

Validity of the UCEEM in use: How Does it Triangulate with Qualitative Data in Measuring the Effect of an Educational Intervention?

Objectives: Improving medical student placements relies on being able to reliably evaluate how students experience clinical learning environments. The Undergraduate Clinical Education Environment Measure (UCEEM) is an increasingly used validated tool designed to allow such evaluations. This study aims to further characterize how the UCEEM relates to qualitative evaluation. methods: Students on placement at one hospital were invited to complete the UCEEM before and after the implementation of an innovative new placement structure. Additionally, focus groups were employed to collect qualitative data on their experiences. a novel protocol to triangulate the output of the UCEEM with the qualitative data was developed. Results: The UCEEM showed good internal consistency (Cronbach's Alpha 0.79-0.91) and internal correlation. Implementation of the intervention created significant improvements in the overall UCEEM scores (P = .008) and in the "Learning in and through work and quality of supervision" (P = .048), "Preparedness for student entry" (P = .033) and "Workplace interaction patterns and student inclusion" (P = .039) domains. The triangulation of qualitative data with UCEEM output showed that the UCEEM allowed evaluation of some perceptions not reached through open questioning. However, mixed interpretations of UCEEM items by students led to the conflation of themes and challenges in deriving the meaning behind the score. This appeared to be the case for 14 of the 24 UCEEM items. Conclusion: This investigation adds to the literature supporting the UCEEM as a validated tool. It also elucidates the limitations and relationships to qualitative data that investigators need to be aware of in its use.