bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of an antibiotic from an HTS targeting EF-Tu:tRNA interaction: a prospective topical treatment for MRSA skin infections
Authors: Mandecki Wlodek , Chudaev Maxim , Ye Wenjuan , Wang Amy Q. , Wilson Kenneth J. , Xu Xin , Kim Jisun , Parker Dane , Alland David , Kumar Pradeep , Li Barry , Yang Jason H. , Kreiswirth Barry , Mediavilla Jose R. , Marugan Juan J. , Henderson Mark J. , Goldman Emanuel
Published: December 2024

Because of the urgent need for new antibiotics to treat drug-resistant bacterial pathogens, we employed an assay that rapidly screens large quantities of compounds for their ability to interfere with bacterial protein synthesis, in particular, the delivery of amino acids to the ribosome via tRNA and elongation factor Tu (EF-Tu). We have identified a drug lead, named MGC-10, which kills Gram-positive bacteria, including methicillin-resistant
Staphylococcus aureus
(MRSA), with a MIC of 6 µM, while being harmless to mammalian cells
in vitro
in that concentration range. The antibacterial activity of MGC-10 was broad against over 50 strains of antibiotic-resistant samples obtained from hospital infections, where MGC-10 inhibited all tested strains of MRSA. Extensive selection and screening with MGC-10 did not yield any resistant strains, indicating it may have universal antibacterial activity against
S. aureus
. Pharmacokinetics performed in mice suggested that MGC-10 was too toxic for systemic use; however, it appears to have potential as a topical treatment for difficult-to-treat wounds or skin infections by Gram-positive pathogens such as MRSA. In a mouse skin-infection model with MRSA, MGC-10 performed as well or better than the present topical drug of choice, mupirocin. MGC-10 showed little, if any, accumulation in the livers of topically treated mice. These results bode well for the future use of MGC-10 in clinical application as it could be used to treat a broad range of
S. aureus
skin infections that are resistant to known antibiotics.

IMPORTANCE

There is a critical need for new antibiotics to treat bacterial infections caused by pathogens resistant to many if not all currently available antibiotics. We describe here the identification of a prospective new antibiotic from high-throughput screening of a chemical library. The screening was designed to detect the inhibition of formation of a complex required for bacterial protein synthesis in all bacteria, the “ternary complex,” comprised of elongation factor Tu (EF-Tu), aminoacyl-tRNA, and GTP. The inhibitory compound, renamed MGC-10, was effective against all Gram-positive bacteria, including a wide variety of methicillin-resistant
Staphylococcus aureus
(MRSA) strains. Although apparently too toxic for systemic use, the compound was safe and effective for topical use for treating skin infections in a mouse model. No resistance to the compound has been detected thus far, suggesting the potential to develop this compound for topical use to treat infections, especially those caused by pathogens resistant to existing antibiotics.
Evolutionary and functional divergence of Sfx, a plasmid-encoded H-NS homolog, underlies the regulation of IncX plasmid conjugation
Authors: Wang Avril , Cordova Martha , Navarre William Wiley
Published: December 2024

Conjugative plasmids are widespread among prokaryotes, highlighting their evolutionary success. Conjugation systems on most natural plasmids are repressed by default. The negative regulation of F-plasmid conjugation is partially mediated by the chromosomal nucleoid-structuring protein (H-NS). Recent bioinformatic analyses have revealed that plasmid-encoded H-NS homologs are widespread and exhibit high sequence diversity. However, the functional roles of most of these homologs and the selective forces driving their phylogenetic diversification remain unclear. In this study, we characterized the functionality and evolution of Sfx, a H-NS homolog encoded by the model IncX2 plasmid R6K. We demonstrate that Sfx, but not chromosomal H-NS, can repress R6K conjugation. Notably, we find evidence of positive selection acting on the ancestral Sfx lineage. Positively selected sites are located in the dimerization, oligomerization, and DNA-binding interfaces, many of which contribute to R6K repression activity—indicating that adaptive evolution drove the functional divergence of Sfx. We additionally show that Sfx can physically interact with various chromosomally encoded proteins, including H-NS, StpA, and Hha. Hha enhances the ability of Sfx to regulate R6K conjugation, suggesting that Sfx retained functionally important interactions with chromosomal silencing proteins. Surprisingly, the loss of Sfx does not negatively affect the stability or dissemination of R6K in laboratory conditions, reflecting the complexity of selective pressures favoring conjugation repression. Overall, our study sheds light on the functional and evolutionary divergence of a plasmid-borne H-NS-like protein, highlighting how these loosely specific DNA-binding proteins evolved to specifically regulate different plasmid functions.

IMPORTANCE

Conjugative plasmids play a crucial role in spreading antimicrobial resistance and virulence genes. Most natural conjugative plasmids conjugate only under specific conditions. Therefore, studying the molecular mechanisms underlying conjugation regulation is essential for understanding antimicrobial resistance and pathogen evolution. In this study, we characterized the conjugation regulation of the model IncX plasmid R6K. We discovered that Sfx, a H-NS homolog carried by the plasmid, represses conjugation. Molecular evolutionary analyses combined with gain-of-function experiments indicate that positive selection underlies the conjugation repression activity of Sfx. Additionally, we demonstrate that the loss of Sfx does not adversely affect R6K maintenance under laboratory conditions, suggesting additional selective forces favoring Sfx carriage. Overall, this work underscores the impact of protein diversification on plasmid biology, enhancing our understanding of how molecular evolution affects broader plasmid ecology.
First-year dynamics of the anaerobic microbiome and archaeome in infants’ oral and gastrointestinal systems
Authors: Neumann Charlotte J. , Mohammadzadeh Rokhsareh , Woh Pei Yee , Kobal Tanja , Pausan Manuela-Raluca , Shinde Tejus , Haid Victoria , Mertelj Polona , Weiss Eva-Christine , Kolovetsiou-Kreiner Vassiliki , Mahnert Alexander , Kumpitsch Christina , Jantscher-Krenn Evelyn , Moissl-Eichinger Christine
Published: December 2024

Recent research provides new insights into the early establishment of the infant gut microbiome, emphasizing the influence of breastfeeding on the development of gastrointestinal microbiomes. In our study, we longitudinally examined the taxonomic and functional dynamics of the oral and gastrointestinal tract (GIT) microbiomes of healthy infants (
n
= 30) in their first year, focusing on the often-over-looked aspects, the development of archaeal and anaerobic microbiomes. Breastfed (BF) infants exhibit a more defined transitional phase in their oral microbiome compared to non-breastfed (NBF) infants, marked by a decrease in
Streptococcus
and the emergence of anaerobic genera such as
Granulicatella
. This phase, characterized by increased alpha-diversity and significant changes in beta-diversity, occurs earlier in NBF infants (months 1–3) than in BF infants (months 4–6), suggesting that breastfeeding supports later, more defined microbiome maturation. We demonstrated the presence of archaea in the infant oral cavity and GIT microbiome from early infancy, with
Methanobrevibacter
being the predominant genus. Still, transient patterns show that no stable archaeome is formed. The GIT microbiome exhibited gradual development, with BF infants showing increased diversity and complexity between the third and eighth months, marked by anaerobic microbial networks. NBF infants showed complex microbial co-occurrence patterns from the start. These strong differences between BF and NBF infants’ GIT microbiomes are less pronounced on functional levels than on taxonomic levels. Overall, the infant microbiome differentiates and stabilizes over the first year, with breastfeeding playing a crucial role in shaping anaerobic microbial networks and overall microbiome maturation.

IMPORTANCE

The first year of life is a crucial period for establishing a healthy human microbiome. Our study analyses the role of archaea and obligate anaerobes in the development of the human oral and gut microbiome, with a specific focus on the impact of breastfeeding in this process. Our findings demonstrated that the oral and gut microbiomes of breastfed infants undergo distinct phases of increased dynamics within the first year of life. In contrast, the microbiomes of non-breastfed infants are more mature from the first month, leading to a steadier development without distinct transitional phases in the first year. Additionally, we found that archaeal signatures are present in infants under 1 year of age, but they do not form a stable archaeome. In contrast to this, we could track specific bacterial strains transitioning from oral to gut or persisting in the gut over time.
Exploiting gasdermin-mediated pyroptosis for enhanced antimicrobial activity of phage endolysin against
Pseudomonas aeruginosa
Authors: Kuc-Ciepluch Dorota , Ciepluch Karol , Augustyniak Daria , Guła Grzegorz , Maciejewska Barbara , Kowalik Artur , Jop Ewelina , Drulis-Kawa Zuzanna , Arabski Michał
Published: December 2024

Pyroptosis is an inflammatory immune response of eukaryotic cells to bacterial lipopolysaccharide (LPS) and other pathological stimuli, leading to the activation of the gasdermin D (GSDMD) and secretion of pore-forming domain GSDMD
Nterm
, facilitating the release of cytokines. Additionally, GSDMD
Nterm
exhibits antibacterial properties through interactions with bacterial outer membranes (OM). We explored alternative antimicrobial strategy to determine whether inducing natural pyroptosis via GSDMD activation by
P. aeruginosa
LPS could enhance the effectiveness of recombinant phage endopeptidase KP27 (peptidoglycan-degrading enzyme) against
P. aeruginosa
, enabling penetration through OM and bacterial killing synergistically. Our findings demonstrated that recombinant GSDMD alone exhibited antibacterial effects against wild-type
P. aeruginosa
with smooth LPS, while recombinant GSDMD
Nterm
efficiently permeabilized both smooth LPS-bearing and O-chain-deficient
P. aeruginosa
potentially synergizing with endolysin KP27. Transcriptomic analyses revealed the activation of the immune system pathways in response to LPS, mainly in monocytic cells, in contrast to epithelial A549 or HeLa cell lines. LPS-induced pyroptosis in monocytes led to GSDMD cleavage and the release of interleukins, regardless of the nature/origin of the LPS used. However, the pyroptosis stimulation by LPS in the antibacterial assay was not effective enough for bacterial OM permeabilization and enhancement of endolysin activity. We assume that leveraging pyroptosis induction in monocytic cells to augment the bactericidal activity of endolysins may be limited.

IMPORTANCE

Recombinant GSDMD
Nterm
protein was able to efficiently permeabilize
P. aeruginosa
outer membranes and increase endolysin activity against bacteria, producing either long LPS O-chains or lack them entirely. The obtained results suggest the limited possibility of using the natural process of pyroptosis occurring in monocytic cells to enhance the bactericidal effect of recombinant phage endolysins against Gram-negative bacteria infection.
Another way? An investigation into an institution’s use of the Wayson stain in re-evaluating “no organisms seen” on Gram stain smears from positive blood cultures
Authors: Attaway Christopher C. , Smith Jessica , Rhoads Daniel D.
Published: December 2024

Automated continuous monitoring blood culture instruments identify metabolism byproducts and flag blood culture bottles as “positive.” A Gram stain is used to visualize and characterize the microbial growth in the broth and initiate additional testing. When no organisms are seen (NOS) on Gram stain, in our laboratory, bottles are reevaluated with a Wayson stain, a rapid one-step stain that provides contrast between organisms and the background, especially in Gram-negative organisms. In this study, we assess the performance of the Wayson stain on reevaluation of Gram stain NOS blood culture bottles. The study period, August 2022 to July 2023, includes blood cultures that were flagged as positive by the automated blood culture instrument (BACTEC) with accompanying Gram and Wayson stain interpretations and organism identification. 133,463 blood cultures were performed during the study period, and 20,129 cultures were flagged as positive by BACTEC. 601 NOS Gram stain cultures were identified of which 76 had a positive Wayson. The Wayson stain procedure increased the sensitivity of direct organism visualization from 99.32% to 99.71% by identifying 55% (76 of 137) of NOS Gram stain blood culture bottles. Of blood cultures that were positive by BACTEC with NOS Gram and Wayson stains (475), 414 were finalized as no growth and 61 had an isolate (false negatives) of which 49% (30) were yeasts. The Wayson stain aided in detecting gram-negative genera such as
Capnocytophaga
,
Campylobacter
, and
Fusobacterium
species and other rarely identified species.

IMPORTANCE

The Wayson stain, a rapid one-step stain that provides contrast between microorganisms and the background, was historically used for the presumptive diagnosis of
Yersinia pestis
from bubo specimen. In our laboratory, the Wayson stain has long been used to reevaluate blood culture Gram-stained smears from bottles that were flagged as positive by the automated continuous monitoring instrument but where no organisms are seen. In this study, we show that the Wayson stain provides an easily implemented and interpreted technique, other than a repeat Gram stain or acridine orange, to increase the sensitivity of direct organism visualization from blood culture bottles, particularly for Gram-negative organisms.
Cohort profile: the potentially preventable burden of community-acquired pneumonia in South African adults in the era of widespread PCV13 immunisation and antiretroviral therapy roll-out, before and during the COVID-19 pandemic – the multicentre, multimethod PotPrev Study
Authors: Nabeemeeah Firdaus , Sabet Nadia , Otwombe Kennedy , Hlongwane Khuthadzo , Mlambo Lebohang M , Moloantoa Tumelo , Wong Michelle , Mangena Phetho , Abraham Pattamukkil , Swanepoel Floris , Moosa Fahima , von Gottberg Anne , Cohen Cheryl , Southern Jo , Fletcher Mark , Dunne Eileen , Ndungane-Tlakula Bha , Begier Elizabeth , Gray Sharon , Gessner Bradford D , Naidoo Jerusha , Milovanovic Minja , Variava Ebrahim , Martinson Neil
Published: December 2024

Purpose

In the setting of an established childhood pneumococcal vaccination programme with immediate initiation and treatment of antiretroviral therapy (ART) for people living with HIV (PLWH), the risk of adult pneumococcal community-acquired pneumonia (CAP) is not recently described. We aimed to investigate CAP incidence, recurrence, mortality, risk factors and microbiology before and during the COVID-19 pandemic.

Participants

Adults aged ≥18 years were enrolled in three South African provinces from March 2019 to October 2021, with a brief halt during the initial COVID-19 lockdown. The first group, PdCAP, a surveillance cohort, had their data abstracted to estimate the population incidence of physician-diagnosed CAP by counting incident CAP patients presenting to emergency rooms (ER) and mapping them to catchment areas linked to census data. From those admitted to wards from ERs, a prospective cohort (HospCAP) was enrolled and followed up to 1 year after discharge. Microbiology testing was performed and data were abstracted and collected for economic assessments. A third group (StART) of PLWH without respiratory illness at enrolment, attending primary healthcare clinics to initiate or reinitiate ART, was prospectively enrolled and followed. HospCAP and StART participants (totalling 2950 participants) were followed for at least 1 year and assessed for CAP episodes, hospitalisations and mortality.

Findings to date

Surveillance identified 6546 patients attending ERs with physician-diagnosed CAP; 61/6546 (0.9%) died in the ER. We prospectively enrolled 2000 hospitalised patients with CAP of whom 1079/2000 (54.0%) were PLWH. Overall, 271/2000 (13.6%) hospitalised CAP patients died during their first admission and 298/2000 (14.9%) died during follow-up. Among StART cohort, 18/950 (1.9%) died during follow-up.

Future plans

Planned analyses include incidence estimates of pneumococcal serotype-specific adult CAP and its recurrence, using Urinary Antigen Detection assay results to model the burden of pneumococcal CAP better and health economics analyses.
Efficacy of solution-focused brief therapy versus case management for psychological distress in adolescents and young adults in a community-based youth mental health service in Singapore: protocol for a randomised controlled trial
Authors: Foo Cheryl Yunn Shee , Hui Tianyi , Ngaiman Nur Khairunisa Binte , Dahjalarrajah Darshan s/o , Chua Yi Chian , Lee Yi Ping , Abdin Edimansyah , Vaingankar Janhavi Ajit , Tang Charmaine
Published: December 2024

Introduction

There are insufficient scalable, evidence-based treatments to meet increasing mental health needs of young people. Offering interim, brief interventions for young persons with psychological distress can improve access to care and mitigate adverse effects of long waiting times. This study tests the efficacy of solution-focused brief therapy (SFBT), a strength-based, goal-directed intervention, in adolescents and young adults at a community-based youth mental health service in Singapore.

Methods and analysis

This is a fully powered, randomised, single-centre, two-arm, parallel, superiority, controlled trial. From September 2023 to March 2025, the study will recruit 124 participants (aged 16–30) presenting at a national youth mental health service in Singapore (CHAT, Centre of Excellence for Youth Mental Health) with clinically assessed general psychological distress, subthreshold or prodromal symptoms, or a first episode of a mood disorder. Participants will be excluded if they have high risk of suicide, psychosis, cognitive impairments, or current psychological treatments. Participants will be randomised in a 1:1 ratio to receive six-session, case manager delivered SFBT or treatment as usual (TAU) case management, and be followed up for 3 months post-intervention. Participants receiving SFBT are hypothesised to have greater improvements in self-reported psychological distress, from baseline to 8 weeks, compared with the control group. Secondary outcomes are self-reported depression and anxiety symptoms, and functional impairment. The study will also explore whether SFBT is associated with increased self-efficacy and decreased hopelessness, decreased downstream referrals post-intervention, and sustained clinical gains 3 months post-intervention compared with TAU. Adverse events and clinical deterioration will be recorded and reported.

Ethics and dissemination

The Institute of Mental Health (IMH) Institutional Research Review Committee (reference 822–2022) and the Singapore National Health Group Domain Specific Review Board (DSRB) (reference 2023/00052) have approved the study protocol. Findings will be published in international, peer-reviewed scientific journals. Summaries will be disseminated to study funders, mental healthcare systems administrators, and clinicians.

Trial registration number

ISRCTN13671612https://doi.org/10.1186/ISRCTN13671612
Long-term sickness absence trajectories and associated occupational and lifestyle-related factors: a longitudinal study among young and early midlife Finnish employees with pain
Authors: Fagerlund Pi , Shiri Rahman , Walker-Bone Karen , Rahkonen Ossi , Lallukka Tea
Published: December 2024

Objectives

This study aimed to identify distinct trajectories of long-term sickness absence (LTSA, >10 consecutive working days) among young and early midlife Finnish employees who experienced pain at baseline. It also aimed to determine the pain characteristics and occupational and lifestyle factors associated with these LTSA patterns.

Design

Longitudinal occupational cohort study with register linkage.

Setting

The largest municipal employer in Finland.

Participants

The study population comprised 19–39-year-old Finnish municipal employees (n=1685) who reported pain in 2017.

Outcome measures

Prospective register data on all-cause LTSA through March 2020 were obtained from the Social Insurance Institution of Finland. Group-based trajectory modelling was used to identify distinct all-cause LTSA trajectories. Multinomial logistic regression was used to examine associations of pain characteristics and work- and lifestyle-related factors with trajectory group membership.

Results

Three distinct LTSA-trajectory groups were identified: no LTSA (74%), decreasing (18%) and increasing (8%). The decreasing trajectory group had a higher prevalence of chronic or multisite pain, smoking (average marginal effects (AME) 6% points, 95% CI 2 to 11), obesity (AME 8% points, 95% CI 2 to 13), manual or routine non-manual occupation (AME 9% points, 95% CI 4 to 13) and high physical workload, after adjusting for age and gender. No predictor was identified for the increasing trajectory.

Conclusion

A majority of young and early midlife employees with pain had no LTSA during follow-up; however, chronic and multisite pain, smoking, overweight or obesity, lower occupational class and higher physical workload were associated with the decreasing LTSA trajectory. Interventions at workplaces and in occupational healthcare to prevent LTSA should aim at supporting employees who work with pain and have these risk factors.
Physician’s perception and practices on antimicrobial resistance in a tertiary care hospital in Bangladesh: a cross-sectional study
Authors: Haque Mohibbul , Karim Mohammad Rezaul , Shohid Sabrin , Choudhury Shadman Sakib , Hossain Pilot , Sen Rotna Rani , Dey Chaity , Khan Sumaiya , Munni Meherun Nahar , Shopna Sonia Afroze , Shultana Razia , Al Fidah Md Fuad , Khan Md Abdullah Saeed , Farhana Nasreen
Published: December 2024

Background

Antimicrobial resistance (AMR) is a global health and development concern. Antimicrobial misuse and overuse are key contributors to the emergence of drug-resistant infections.

Objective

The current study aimed to determine the level of perception and practices of physicians regarding AMR in a tertiary-level hospital.

Design

Cross-sectional study.

Setting

A tertiary care hospital in Dhaka, Bangladesh.

Participants

The study included 360 physicians who worked for more than 6 months in different departments of the hospital.

Primary and secondary outcome measures

Perceptions of AMR among physicians and secondary outcome measures were to find out the practices of physicians regarding AMR. The current study used 8 defined responses and 6 multiple-choice questions for scoring physicians’ perception of AMR and 12 items to score physicians’ self-reported practice regarding AMR. After converting these scores into percentages, the median split method was used to categorise them into poor and good categories.

Results

Among 360 physicians, 51% were male, the median (IQR) age was 30 (27.0–34.0) years and 46% had private practices. More than half (52%) had a poor perception of AMR but had good practice (57%) with no significant association between perception and practice. The perception of AMR was significantly associated with age (p=0.048), years in practice (p=0.011) and AMR training (p=0.030). Physicians with private practice had 1.71 times higher odds of having a good perception of AMR (95% CI 2.07 to 2.75, p=0.026) and 2.44 times higher odds of having good practice (95% CI 1.51 to 3.94, p<0.001). The odds of having a good perception of AMR increase 1.20 times with a 1-year increase in years of practice (95% CI 1.01 to 1.44, p=0.042).

Conclusion

The study revealed that most physicians had poor perception but good practice regarding AMR. Both poor perception and good practice were associated with private practice. To increase good practice and perception regarding AMR, efforts need to be made to establish an AMR education programme for practicing physicians as soon as possible. Moreover, medical audits and continuous quality improvement (such as programmes for antimicrobial stewardship) should be legislated, and monitoring prescribing behaviour and formulating policies accordingly are the way forward in combating AMR.
Healthcare ethics and artificial intelligence: a UK doctor survey
Authors: Warrington Daniel Joseph , Holm Søren
Published: December 2024

Objectives

To survey UK doctors on their uses of artificial intelligence (AI) and of their views on the ethics and regulation of AI in healthcare.

Design

Anonymous cross-sectional e-survey.

Setting

An online survey of UK General Medical Council (GMC) registered doctors.

Participants

272 individuals.

Main outcome measures

Likert-scale responses to questions covering personal use of AI, concerns about AI, requirements for introduction of AI and views on necessary AI regulation in healthcare.

Results

Most doctors rated themselves as slightly or moderately knowledgeable about AI, with men rating their knowledge levels higher than women. Doctors in training are more likely to have used AI than doctors after training. 37% of doctors who use AI reported using AI to help write the required reflective pieces for their portfolio. Doctors reported concerns about AI regarding patient safety and patients' right to confidentiality. They also expressed a strong desire for further regulation of AI in healthcare and, specifically, for their professional bodies to draft guidelines for the use of AI by doctors.

Conclusions

This study provides useful insights into UK doctors’ uses of AI in healthcare and their opinions on its introduction and regulation. It provides a case for guidance on the use of AI in the reflective practices of doctors and for further evaluation of doctors’ concerns about AI in healthcare. We call on doctors’ professional bodies (GMC, BMA and royal colleges) to draft professional guidance for doctors using AI.
Impact of alternative diagnostic labels for melanoma in situ on management choices and psychological outcomes: protocol for an online randomised study
Authors: Wu Zhuohan , Nickel Brooke , Boroumand Farzaneh , Elder David , Ferguson Peter M , Scolyer Richard A , O'Brien Blake , Barnhill Raymond , Adamson Adewole S , van Akkooi Alexander C J , Emery Jon , Parker Lisa , Low Donald , Low Cynthia , Davies Elspeth , Liu Sherrie , Lewis Stacey , Spongberg-Ross Bella , Bell Katy JL
Published: December 2024

Introduction

A diagnosis of melanoma in situ presents negligible risk to a person’s lifespan or physical well-being, but existing terminology makes it difficult for patients to distinguish these from higher risk invasive melanomas. This study aims to explore whether using an alternative label for melanoma in situ may influence patients’ management choices and anxiety levels.

Methods and analysis

This study is a between-subjects randomised online experiment, using hypothetical scenarios. Following consent, eligible participants will be randomised 1:1:1 to three labels: ‘melanoma in situ’ (control), ‘low-risk melanocytic neoplasm’ (intervention 1) and ‘low-risk melanocytic neoplasm, in situ’ (intervention 2). The required sample size is 1668 people. The co-primary outcomes are (1) choice between no further surgery or further surgery to ensure clear histological margins greater than 5 mm and (2) choice between patient-initiated clinical follow-up when needed (patient-led surveillance) and regular routinely scheduled clinical follow-up (clinician-led surveillance). Secondary outcomes include diagnosis anxiety, perceived risk of invasive melanoma and of dying from melanoma and management choice anxiety (after surgery choice and follow-up choice). We will make pairwise comparisons across the three diagnostic label groups using regression models (univariable and multivariable).

Ethics and dissemination

The study has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN12624000740594). Ethics approval has been received from The University of Sydney Human Research Ethics Committee (2024/HE000019). The results of the study will be published in a peer-reviewed medical journal, and a plain language summary of the findings will be shared on the Wiser Healthcare publication page (https://www.wiserhealthcare.org.au/category/publications/).

Trial registration number

Australian New Zealand Clinical Trials Registry (ID 386943).
Impact of the COVID-19 pandemic on primary care for hypertension in the UK: a population-based cohort study
Authors: Johnson Kyle , Beradid Sarah , Brophy James M. , Platt Robert W. , Renoux Christel
Published: December 2024

Objectives

To describe the impact of the COVID-19 pandemic on hypertension diagnosis and management in UK primary care.

Design

Population-based cohort study.

Setting

Over 2000 general practices across the UK contributing to the Clinical Practice Research Datalink.

Participants

A cohort of 23 076 390 patients over 18 years of age and registered with their general practice for at least 1 year between 2011 and 2022, who did not have a previous diagnosis of hypertension. From these patients, a subcohort of 712 461 patients diagnosed with hypertension between 2011 and 2022 was selected.

Primary and secondary outcome measures

Coprimary outcomes included rates of hypertension diagnosis and rates of antihypertensive treatment initiation, treatment change and blood pressure measurement in patients newly diagnosed with hypertension.

Results

In April 2020, the first month of lockdown, incident hypertension diagnosis rates fell by 65% (95% CI 64% to 67%) compared with historical trends and remained depressed until November 2021, leading to 51 000 fewer diagnoses than expected by March 2022. However, by March 2022, there were 2.6% fewer diagnoses than expected in Scotland, compared with 20%–30% fewer in other UK Nations. Rates of treatment initiation and change fell by 47% (95% CI 43% to 51%) and 36% (95% CI 33% to 38%), respectively, in April 2020. However, initiation rates rebounded above expectations and remained elevated until March 2022. Blood pressure measurements fell by 69% (95% CI 65% to 72%) in April 2020, recovering in February 2021.

Conclusions

Hypertension diagnosis and management in UK primary care were significantly disrupted during the COVID-19 pandemic. Future studies should investigate the potential clinical implications for the cardiovascular health of the UK population.
Feasibility and acceptability of multiple methods of recording injecting drug use episode data among people who inject drugs in Melbourne, Australia: a pilot evaluation study protocol
Authors: Djordjevic Filip , Stewart Ashleigh Cara , Vella-Horne Dylan , Gleeson Zoe , Pavlyshyn Damian , Gill Matthew , Petrovic Rebekka , Scott Nick , Higgs Peter , Roth Alexis , Cocchiaro Ben , Dietze Paul , O’Keefe Daniel
Published: December 2024

Introduction

Opioid overdose and blood-borne virus transmission are key health risks for people who inject drugs. Existing study methods that record data on injecting drug risks mostly rely on retrospective self-reporting that, while valid, are limited to being broad and subject to recall bias. The In-The-Moment-Expanded (ITM-Ex) study will evaluate the feasibility and acceptability of multiple novel data collection methods to capture in situ drug injecting data.

Methods and analysis

ITM-Ex will purposively recruit 50 participants from an existing longitudinal cohort (SuperMIX study) of people who inject drugs in Melbourne, Australia. Over a 4-week study period, participants will be asked to complete baseline/endline spirometry, continuously wear a heart rate monitoring device, complete short-form ecological momentary assessment (EMA) questionnaires for every injecting episode during the study period and return previously used needles/syringes for drug residue testing. These multiple data sources will be combined to conduct a comprehensive analysis of the physiological and risk characteristics of an estimated 800 individual injecting drug use episodes (if participants inject four times weekly). Finally, post-participation qualitative interviews will explore the acceptability of the data collection methods.

Ethics and dissemination

Ethics approval for ITM-Ex was obtained from Alfred Hospital Ethics Committee (project number 368/22). Results will be disseminated via national and international scientific and public health conferences and peer-reviewed journal publications.

Results from ITM-Ex may demonstrate vastly more complete and accurate methods of capturing data on injecting drug use risk and support future development and evaluation of devices to monitor and intervene during drug overdose. Further, ITM-Ex may demonstrate innovative methodologies to support myriad future public health research studies.
Descriptive analysis to establish the prevalence of lead-associated chronic conditions among adult public health registry participants in Flint, Michigan: identifying disparities to support focused recovery efforts
Authors: Yousef Mohannad , Haggerty Diana , Jones Nicole , LaChance Jenny , Tayler Brittany , Hanna Mona
Published: December 2024

Background

A population-level trauma, the Flint water crisis (FWC) exposed approximately 140 000 people to lead in water. In response, the Flint Registry (FR) was established by a local university in partnership with the community. Lead exposure has been linked to multiple adult-onset chronic diseases, and addressing the health needs of those exposed requires estimating the prevalence of these conditions. Our objective was to calculate the prevalence of chronic conditions among FR-enrolled adults and compare prevalence to state-wide surveillance estimates.

Methods

Data collection for the FR started 4.5 years after the onset of the FWC; this cross-sectional study included participants who completed their enrolment survey December 2018–July 2022. Participants reported if they had ever been diagnosed with 11 chronic conditions. We used crude and age-adjusted prevalence of the 11 chronic conditions and compared them to 2019–2021 Michigan Behavioral Risk Factor Surveillance System (MiBRFSS) estimates.

Results

We included 14 274 adult (≥18) participants in this study. Crude and age-adjusted prevalence was higher in FR participants than MiBRFSS estimates for 9 of the 11 chronic conditions, such as kidney disease. Age-adjusted results suggested that 8.1% of participants would have kidney disease if they had the same age distribution as the adult population of Michigan, whereas only 3.4% of the adult population in Michigan has a kidney disease diagnosis. Patterns for males, females, black and white participants were similar to the overall results, though differences between the black FR participants and MiBRFSS estimates were less extreme.

Conclusion

The FR is a resource for the Flint community and an example for other communities experiencing mass environmental disruptions. We cannot assert the FWC caused any cases of the health conditions evaluated, however, establishing the prevalence of lead-associated conditions among people exposed to the FWC is needed to prioritise secondary prevention efforts and demonstrate the utility of a university-run registry in response to events like the FWC.
Core components of male-specific person-centred HIV care: a qualitative analysis from client and healthcare worker perspectives in Malawi
Authors: Hubbard Julie , Mphande Misheck , Robson Isabella , Balakasi Kelvin , Phiri Khumbo , Chikuse Elijah , Thorp Marguerite , Phiri Sam , Choko Augustine T , Cornell Morna , Coates Thomas , Dovel Kathryn
Published: December 2024

Introduction

Person-centred care (PCC) improves clinical outcomes for people living with HIV. Heterosexual men in sub-Saharan Africa are under-represented in HIV care, yet PCC interventions for men are lacking. We identified core components of a PCC intervention for men living with HIV (MLHIV) in Malawi from both client and healthcare worker (HCW) perspectives, as well as strategies for implementation in routine settings.

Methods

MLHIV≥15 years and not in care were enrolled in parent randomised trials to test the impact of male-tailored HIV services on 6-month treatment outcomes (n=1303). Clients received a PCC package including male-specific counselling+facility ART distribution or outside-facility ART distribution. 50 male clients were recruited for qualitative in-depth interviews using stratified random sampling to assess perceptions of the PCC packages. Focus group discussions were conducted with HCWs who delivered the intervention to understand implementation strategies and potential considerations for scale-up in routine settings. Interviews were audio recorded, translated into English, transcribed and coded in Atlas.ti V.9 and analysed using thematic analysis.

Results

36 MLHIV and 20 HCWs (10 lay cadre and 10 nurses) were interviewed between February and July 2022. Positive interactions with HCWs—characterised by kindness, reciprocity, privacy and focused conversations—and compelling, relevant counselling were considered the most important components of male PCC. While outside-facility ART dispensing was considered helpful, it was not as critical as these other components. HCWs outlined five steps to implementing male PCC: begin with kindness, apologise for past negative interactions, understand men’s holistic story, provide tailored counselling and support development of strategies for adherence. HCWs believed that male PCC enhanced their ability to support male clients but emphasised the need to be integrated into routine services.

Discussion

PCC strategies that foster positive HCW relationships and addresses men’s unique experiences are highly valued by MLHIV. HCWs identified several strategies for delivering PCC to MLHIV that may help close gaps in HIV care for men.

Trial registration numbers

NCT04858243;NCT05137210.
Incident chronic kidney disease among Canadian immigrants: a population-based cohort study
Authors: Olaye Ida-Ehosa , Sood Manish M , Yu Chengchun , Tuna Meltem , Akbari Ayub , Tanuseputro Peter , Mucsi Istvan , Knoll Greg A , Hundemer Gregory L
Published: December 2024

Introduction

A ‘healthy immigrant effect’ has been demonstrated for a number of chronic health conditions including cardiovascular disease, diabetes mellitus and dementia; however, the link between immigrant status and kidney health remains uncertain. We sought to compare the risk for incident chronic kidney disease (CKD) between Canadian immigrants and non-immigrants.

Methods

We conducted a population-level, observational cohort study of all adult (≥18 years of age) Ontario residents, including foreign-born immigrant Canadian citizens and non-immigrant Canadian citizens by birth, with normal baseline kidney function (outpatient estimated glomerular filtration rate (eGFR) ≥70 mL/min/1.73 m2) between 1 April 2007 and 30 September 2020 using provincial health administrative data. Multivariable Cox proportional hazard regression modelling was used to evaluate the relationship between immigrant status and the development of incident CKD (outpatient eGFR <60 mL/min/1.73m2).

Results

The study cohort included 10 440 210 Ontario residents, consisting of 22% immigrants (n=2 253 360) and 78% (n=8 186 850) non-immigrants. The mean (SD) age and eGFR were 45 (17) years and 102 (16) mL/min/1.73 m2, respectively, and 54% of individuals were female. A total of 117 028 immigrants (5%, 7 events per 1000 person-years) and 984 277 non-immigrants (12%, 16 events per 1000 person-years) developed incident CKD during follow-up. Immigrants experienced a 20% lower risk for incident CKD compared with non-immigrants (adjusted HR 0.80, 95% CI 0.80 to 0.81). Consistent findings were seen for refugee and non-refugee immigrants, immigrants with remote (1985–2004) and recent (2005–2020) landing dates, and immigrants from different world regions. Results were similar on re-defining incident CKD as two outpatient eGFR measurements <60 mL/min/1.73 m2at least 90 days apart, treating death as a competing risk, and adjusting for baseline albuminuria.

Conclusion

Immigrants experience a lower risk for incident CKD compared with non-immigrants. These findings provide evidence of a ‘healthy immigrant effect’ in relation to kidney health.
Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapy
Authors: Kang Seounghun , Mansurov Aslan , Kurtanich Trevin , Chun Hye Rin , Slezak Anna J , Volpatti Lisa R , Chang Kevin , Wang Thomas , Alpar Aaron T , Refvik Kirsten C , Hansen O Isabella , Borjas Gustavo J , Berg Brendan T K , Shim Ha-Na , Hultgren Kevin T , Gomes Suzana , Wang Yue , Solanki Ani , Ishihara Jun , Swartz Melody A , Hubbell Jeffrey A
Published: December 2024

Background

The use of immune checkpoint inhibitors (CPIs) has become a dominant regimen in modern cancer therapy, however immune resistance induced by tumor-associated macrophages (TAMs) with immune suppressive and evasion properties limits responses. Therefore, the rational design of immune modulators that can control the immune suppressive properties of TAMs and polarize them, as well as dendritic cells (DCs), toward a more proinflammatory phenotype is a principal objective in cancer immunotherapy.

Methods

Here, using a protein engineering approach to enhance cytokine residence in the tumor microenvironment, we examined combined stimulation of the myeloid compartment via tumor stroma-binding granulocyte–macrophage colony-stimulating factor (GM-CSF) to enhance responses in both DCs and T cells via stroma-binding interleukin-12 (IL-12). We evaluated tumor responses at the levels of outcome, cellular responses, and cytokine responses in both the tumors and the tumor-draining lymph nodes. We further investigated the potentiation of DC response to IL-12 by GM-CSF stimulation ex vivo.

Results

Engineered GM-CSF restored an antitumorigenic tumor myeloid microenvironment otherwise suppressed by TAMs, while engineered IL-12 provided effector signals to T cells, thereby boosting both tumor-resident antitumor macrophage and CD8+T cell populations. Furthermore, engineered GM-CSF potentiated DC response to IL-12, upregulating DC expression of IL-12 receptor and enhancing their expression of proinflammatory cytokines and chemokines on IL-12 exposure. This resulted in remarkable synergistic efficacy in multiple solid tumor models treated with the dual cytokine combination. The combination therapy also improved the efficacy of CPI in a CPI-resistant genetically-engineered melanoma model and exhibited synergistic antitumor efficacy in a pulmonary metastasis model.

Conclusion

Our strategy provides a rational design for combination immunotherapy targeting both myeloid and lymphoid compartments through complementary mechanisms.
The NHS England Jewish BRCA Testing Programme: overview after first year of implementation (2023–2024)
Authors: Torr Bethany , Bell Nicola , McCarthy Ruth , Hamill Monica , Nolan Joshua , Muralidharan Sudeekshna , Andrews Charlotte , Valganon-Petrizan Mikel , Clinch Yasmin , MacMahon Suzanne , Morilla Alison , George Angela , Ryves Paul , Dasani Pooja , Adegoroye Moses , Schlecht Helene , Burghel George J , Ornadel Wendy , Gordon Nicole , Steele Lisa , Lukic Susana , Watts Emily , Evans D Gareth , Manchanda Ranjit , Turnbull Clare
Published: December 2024

Background

The NHS Jewish BRCA Testing Programme is offering germlineBRCA1andBRCA2genetic testing to people with ≥1 Jewish grandparent. Who have an increased likelihood of having an Ashkenazi Jewish (AJ) founder germline pathogenic variant (gPV) compared with the general population.

Testing is offered via a self-referral, home-based saliva sampling pathway, supported by a genetic counsellor telephone helpline. A first-of-its-kind in the United Kingdom (UK) for population genetic testing, outside of research.

Methods

We reviewed data from germline testing of 5389 people who registered during the soft-launch phase (January 2023–January 2024) and their families to observe trends in uptake and outcomes of testing.

Results

Of the 5389 self-referrals, 4339 (80.5%) consented to testing. Of those with results returned, 2.3% (98/4,274) had a gPV (89.8% AJ founder and 10.2% non-AJ founder).

Notably, the detection rate was higher in men (42/790, 5.3%) compared with women (56/3484, 1.6%), with the proportion reporting known BRCA variants within the family prior to consent also significantly increased (13.1% compared with 9.2%, respectively).

Conclusion

Overall detection rates of gPVs are similar to those reported elsewhere from Jewish population testing. The pathway, particularly for males, may attract uptake of testing by those previously aware of familial gPVs.
Obesity, laypeople’s beliefs and implications for clinicians and leaders of healthcare organisations
Authors: Karnani Aneel , McFerran Brent , Mukhopadhyay Anirban
Published: December 2024

Background/Aim

Overweight and obesity (OAO) is a major and growing public health crisis in the world. There is convincing medical evidence that caloric overconsumption, rather than lack of exercise, is the primary driver of OAO.

Methods

In this translation piece, we summarise our programme of research on laypeople’s beliefs about the primary cause of OAO, the origins of these beliefs and implications for clinicians and leadership in healthcare organisations.

Results

In contrast to the medical consensus, our research conducted in several countries has found that approximately half of the population mistakenly believes that lack of exercise is the primary cause of obesity. These misbeliefs have consequences: people who mistakenly believe that exercise is the most important factor are more likely to be overweight or obese than people who correctly believe that diet is the primary cause of obesity. We argue that these misbeliefs are caused in part by systematic and multipronged communications efforts by the food and beverage industry—a phenomenon we term ‘leanwashing’.

Conclusions

Not only does leanwashing require public policy intervention by the government, healthcare professionals also need to respond appropriately. In this article, we focus on the implications of leanwashing for leaders of public health organisations, health delivery organisations and clinicians.