bluuebunny/crossref_metadata_2025 huggingface dataset:
Electron videography of a lipid–protein tango
Authors: Smith John W. , Carnevale Lauren N. , Das Aditi , Chen Qian
Published: April 2024

Biological phenomena, from enzymatic catalysis to synaptic transmission, originate in the structural transformations of biomolecules and biomolecular assemblies in liquid water. However, directly imaging these nanoscopic dynamics without probes or labels has been a fundamental methodological challenge. Here, we developed an approach for “electron videography”—combining liquid phase electron microscopy with molecular modeling—with which we filmed the nanoscale structural fluctuations of individual, suspended, and unlabeled membrane protein nanodiscs in liquid. Systematic comparisons with biochemical data and simulation indicate the graphene encapsulation involved can afford sufficiently reduced effects of the illuminating electron beam for these observations to yield quantitative fingerprints of nanoscale lipid–protein interactions. Our results suggest that lipid–protein interactions delineate dynamically modified membrane domains across unexpectedly long ranges. Moreover, they contribute to the molecular mechanics of the nanodisc as a whole in a manner specific to the protein within. Overall, this work illustrates an experimental approach to film, quantify, and understand biomolecular dynamics at the nanometer scale.
Last Glacial Maximum pattern effects reduce climate sensitivity estimates
Authors: Cooper Vincent T. , Armour Kyle C. , Hakim Gregory J. , Tierney Jessica E. , Osman Matthew B. , Proistosescu Cristian , Dong Yue , Burls Natalie J. , Andrews Timothy , Amrhein Daniel E. , Zhu Jiang , Dong Wenhao , Ming Yi , Chmielowiec Philip
Published: April 2024

Here, we show that the Last Glacial Maximum (LGM) provides a stronger constraint on equilibrium climate sensitivity (ECS), the global warming from increasing greenhouse gases, after accounting for temperature patterns. Feedbacks governing ECS depend on spatial patterns of surface temperature (“pattern effects”); hence, using the LGM to constrain future warming requires quantifying how temperature patterns produce different feedbacks during LGM cooling versus modern-day warming. Combining data assimilation reconstructions with atmospheric models, we show that the climate is more sensitive to LGM forcing because ice sheets amplify extratropical cooling where feedbacks are destabilizing. Accounting for LGM pattern effects yields a median modern-day ECS of 2.4°C, 66% range 1.7° to 3.5°C (1.4° to 5.0°C, 5 to 95%), from LGM evidence alone. Combining the LGM with other lines of evidence, the best estimate becomes 2.9°C, 66% range 2.4° to 3.5°C (2.1° to 4.1°C, 5 to 95%), substantially narrowing uncertainty compared to recent assessments.
Antarctic Slope Undercurrent and onshore heat transport driven by ice shelf melting
Authors: Si Yidongfang , Stewart Andrew L. , Silvano Alessandro , Naveira Garabato Alberto C.
Published: April 2024

Elevated ice shelf melt rates in West Antarctica have been attributed to transport of warm Circumpolar Deep Water (CDW) onto the continental shelf via bathymetric troughs. These inflows are supplied by an eastward, subsurface slope current (referred to as the Antarctic Slope Undercurrent) that opposes the westward momentum input from local winds and tides. Despite its importance to basal melt, the mechanism via which the undercurrent forms, and thus what controls the shoreward heat transport, remains unclear. In this study, the dynamics of the undercurrent are investigated using high-resolution process-oriented simulations with coupled ocean, sea ice, and ice shelf components. It is shown that the bathymetric steering of the undercurrent toward the ice shelf is driven by upwelling of meltwater within the ice shelf cavity. Increased basal melt therefore strengthens the undercurrent and enhances onshore CDW transport, which indicates a positive feedback that may accelerate future melt of ice shelves, potentially further destabilizing the West Antarctic Ice Sheet.
Mitochondrial energy state controls AMPK-mediated foraging behavior in
C. elegans
Authors: Vodičková Anežka , Müller-Eigner Annika , Okoye Chidozie N. , Bischer Andrew P. , Horn Jacob , Koren Shon A. , Selim Nada Ahmed , Wojtovich Andrew P.
Published: April 2024

Organisms surveil and respond to their environment using behaviors entrained by metabolic cues that reflect food availability. Mitochondria act as metabolic hubs and at the center of mitochondrial energy production is the protonmotive force (PMF), an electrochemical gradient generated by metabolite consumption. The PMF serves as a central integrator of mitochondrial status, but its role in governing metabolic signaling is poorly understood. We used optogenetics to dissipate the PMF in
Caenorhabditis elegans
tissues to test its role in food-related behaviors. Our data demonstrate that PMF reduction in the intestine is sufficient to initiate locomotor responses to acute food deprivation. This behavioral adaptation requires the cellular energy regulator AMP-activated protein kinase (AMPK) in neurons, not in the intestine, and relies on mitochondrial dynamics and axonal trafficking. Our results highlight a role for intestinal PMF as an internal metabolic cue, and we identify a bottom-up signaling axis through which changes in the PMF trigger AMPK activity in neurons to promote foraging behavior.
Associations of excessive internet use, sleep duration and physical activity with school absences: a cross-sectional, population-based study of adolescents in years 8 and 9
Authors: Kosola Silja , Kullberg Marianne , Melander Katja , Engblom Janne , Ranta Klaus , Alanko Katarina
Published: April 2024

Background

Internet use has increased and sleep and physical activity (PA) have decreased in recent years among adolescents. Besides sleep and PA, another determinant of future health for adolescents is education. Our aim was to evaluate the associations of excessive internet use (EIU), short sleep duration and low PA with both unexcused absences and medical absences during lower secondary school.

Methods

The School Health Promotion study is a national survey of adolescents conducted biennially in Finland. We used data collected in 2019, when EIU was assessed for the first time. Cumulative odds ratio analysis was conducted with unexcused absences and medical absences as outcome variables. Besides EIU, sleep duration and PA, the associations of maternal education and parental relations were assessed.

Results

The mean age of the 86 270 participants was 15.3 years. Girls scored higher than boys on EIU. In all, 34.7% of participants slept less than 8 hours per night during the school week, and 34.3% reported low PA (ie, less than 3 days per week with minimum 1 hour of PA per day). EIU, short sleep and low PA were associated with both unexcused absences and medical absences from school. Longer sleep during weekends showed no association with absences, but good parental relations had the strongest protective association with both unexcused and medical absences.

Conclusions

EIU, short sleep duration and low PA were associated with both unexcused and medical absences from school. This has important implications for both the promotion of general health and the support offered to students with alarming school absences.
Heyde’s syndrome: a challenging case of severe aortic stenosis and gastrointestinal bleeding
Authors: Abouzid Mohamed , Abdelhakeem Ahmed , Elshafie Shorouk , Ghorab Ahmad
Published: April 2024

We present the case of an elderly man with a history of diastolic congestive heart failure, severe aortic stenosis and atrial fibrillation, who presented with fatigue, weakness, coffee ground emesis and black tarry stool. Haemoglobin was 68 g/L. Lactate dehydrogenase was elevated at 1038. Evaluation by cardiology and gastroenterology specialists revealed reflux oesophagitis and a mild hiatal hernia on oesophagogastroduodenoscopy, normal colonoscopy and small bowel series without obstruction. Capsule endoscopy identified angiodysplasia in the small intestine.

The patient was diagnosed with Heyde’s syndrome based on the triad of severe aortic stenosis, gastrointestinal bleeding from angiodysplasia and acquired von Willebrand syndrome. The patient underwent transcatheter aortic valve replacement, resulting in the resolution of symptoms.

Heyde’s syndrome represents a challenging clinical entity requiring a multidisciplinary approach for accurate diagnosis and management. Early recognition, prompt intervention and interdisciplinary collaboration are crucial in optimising patient outcomes.
Quality of reporting inflammatory bowel disease randomised controlled trials: a systematic review
Authors: Gordon Morris , Khudr Jamal , Sinopoulou Vassiliki , Lakunina Svetlana , Rane Aditi , Akobeng Anthony
Published: April 2024

Objective

Our objective was to perform a systemic evaluation of the risk of bias in randomised controlled trial (RCT) reports published on inflammatory bowel disease (IBD).

Design

We assessed the risk of bias using the Cochrane tool, as indicators of poor methodology or subsequently poor reporting. We systematically selected, with dual independent judgements, all studies published on IBD with no time limits and assessed the methodological quality of included studies again using independent dual ratings.

Results

563 full texts were included after selection and review. No abstract publications were free of any source of bias. Full-text publications still fared badly, as only 103 full-text papers exhibited a low risk of bias in all reporting domains when excluding blinding. RCTs published in journals with higher impact factor (IF) were associated with an overall reduced rate of being at high risk. However, only 6% of full RCT publications in journals with an IF greater than 10, published in the past 5 years, were free of bias.

The trend over time is towards improved reporting in all areas. Trials published by larger author teams, in full-text form and by industry and public sponsorship were positively correlated with a lower risk of bias. Only allocation concealment showed a statistically significant improvement with time (p=0.037).

Conclusion

These findings are consistent with those of other specialties in the literature. While this unclear risk of bias may represent poor reporting of methods instead of poor methodological quality, it leaves readers and future secondary researchers with significant questions regarding such key issues.
A biosocial analysis of perinatal and late neonatal mortality among Indigenous Maya Kaqchikel communities in Tecpán, Guatemala: a mixed-methods study
Authors: Venzor Strader Anahí , Sotz Magda , Gilbert Hannah N , Miller Ann C , Lee Anne CC , Rohloff Peter
Published: April 2024

Introduction

Neonatal mortality is a global public health challenge. Guatemala has the fifth highest neonatal mortality rate in Latin America, and Indigenous communities are particularly impacted. This study aims to understand factors driving neonatal mortality rates among Maya Kaqchikel communities.

Methods

We used sequential explanatory mixed methods. The quantitative phase was a secondary analysis of 2014–2016 data from the Global Maternal and Newborn Health Registry from Chimaltenango, Guatemala. Multivariate logistic regression models identified factors associated with perinatal and late neonatal mortality. A number of 33 in-depth interviews were conducted with mothers, traditional Maya midwives and local healthcare professionals to explain quantitative findings.

Results

Of 33 759 observations, 351 were lost to follow-up. There were 32 559 live births, 670 stillbirths (20/1000 births), 1265 (38/1000 births) perinatal deaths and 409 (12/1000 live births) late neonatal deaths. Factors identified to have statistically significant associations with a higher risk of perinatal or late neonatal mortality include lack of maternal education, maternal height <140 cm, maternal age under 20 or above 35, attending less than four antenatal visits, delivering without a skilled attendant, delivering at a health facility, preterm birth, congenital anomalies and presence of other obstetrical complications. Qualitative participants linked severe mental and emotional distress and inadequate maternal nutrition to heightened neonatal vulnerability. They also highlighted that mistrust in the healthcare system—fueled by language barriers and healthcare workers’ use of coercive authority—delayed hospital presentations. They provided examples of cooperative relationships between traditional midwives and healthcare staff that resulted in positive outcomes.

Conclusion

Structural social forces influence neonatal vulnerability in rural Guatemala. When coupled with healthcare system shortcomings, these forces increase mistrust and mortality. Collaborative relationships among healthcare staff, traditional midwives and families may disrupt this cycle.
Estimated health benefits, costs and cost-effectiveness of eliminating industrial trans-fatty acids in Nigeria: cost-effectiveness analysis
Authors: Marklund Matti , Aminde Leopold N , Wanjau Mary Njeri , Ale Boni M , Ojo Adedayo E , Okoro Clementina E , Adegboye Abimbola , Huang Liping , Veerman J Lennert , Wu Jason HY , Huffman Mark D , Ojji Dike B
Published: April 2024

Introduction

Nigeria is committed to reducing industrialtrans-fatty acids (iTFA) from the food supply, but the potential health gains, costs and cost-effectiveness are unknown.

Methods

The effect on ischaemic heart disease (IHD) burden, costs and cost-effectiveness of a mandatory iTFA limit (≤2% of all fats) for foods in Nigeria were estimated using Markov cohort models. Data on demographics, IHD epidemiology andtrans-fatty acid intake were derived from the 2019 Global Burden of Disease Study. Avoided IHD events and deaths; health-adjusted life years (HALYs) gained; and healthcare, policy implementation and net costs were estimated over 10 years and the population’s lifetime. Incremental cost-effectiveness ratios using net costs and HALYs gained (both discounted at 3%) were used to assess cost-effectiveness.

Results

Over the first 10 years, a mandatory iTFA limit (assumed to eliminate iTFA intake) was estimated to prevent 9996 (95% uncertainty interval: 8870 to 11 118) IHD deaths and 66 569 (58 862 to 74 083) IHD events, and to save US$90 million (78 to 102) in healthcare costs. The corresponding lifetime estimates were 259 934 (228 736 to 290 191), 479 308 (95% UI 420 472 to 538 177) and 518 (450 to 587). Policy implementation costs were estimated at US$17 million (11 to 23) over the first 10 years, and US$26 million USD (19 to 33) over the population’s lifetime. The intervention was estimated to be cost-saving, and findings were robust across several deterministic sensitivity analyses.

Conclusion

Our findings support mandating a limit of iTFAs as a cost-saving strategy to reduce the IHD burden in Nigeria.
Colchicine for the treatment of patients with COVID-19: an updated systematic review and meta-analysis of randomised controlled trials
Authors: Cheema Huzaifa Ahmad , Jafar Uzair , Shahid Abia , Masood Waniyah , Usman Muhammad , Hermis Alaa Hamza , Naseem Muhammad Arsal , Sahra Syeda , Sah Ranjit , Lee Ka Yiu
Published: April 2024

Objectives

We conducted an updated systematic review and meta-analysis to investigate the effect of colchicine treatment on clinical outcomes in patients with COVID-19.

Design

Systematic review and meta-analysis.

Data sources

We searched PubMed, Embase, the Cochrane Library, medRxiv and ClinicalTrials.gov from inception to January 2023.

Eligibility criteria

All randomised controlled trials (RCTs) that investigated the efficacy of colchicine treatment in patients with COVID-19 as compared with placebo or standard of care were included. There were no language restrictions. Studies that used colchicine prophylactically were excluded.

Data extraction and synthesis

We extracted all information relating to the study characteristics, such as author names, location, study population, details of intervention and comparator groups, and our outcomes of interest. We conducted our meta-analysis by using RevMan V.5.4 with risk ratio (RR) and mean difference as the effect measures.

Results

We included 23 RCTs (28 249 participants) in this systematic review. Colchicine did not decrease the risk of mortality (RR 0.99; 95% CI 0.93 to 1.05; I2=0%; 20 RCTs, 25 824 participants), with the results being consistent among both hospitalised and non-hospitalised patients. There were no significant differences between the colchicine and control groups in other relevant clinical outcomes, including the incidence of mechanical ventilation (RR 0.75; 95% CI 0.48 to 1.18; p=0.22; I2=40%; 8 RCTs, 13 262 participants), intensive care unit admission (RR 0.77; 95% CI 0.49 to 1.22; p=0.27; I2=0%; 6 RCTs, 961 participants) and hospital admission (RR 0.74; 95% CI 0.48 to 1.16; p=0.19; I2=70%; 3 RCTs, 8572 participants).

Conclusions

The results of this meta-analysis do not support the use of colchicine as a treatment for reducing the risk of mortality or improving other relevant clinical outcomes in patients with COVID-19. However, RCTs investigating early treatment with colchicine (within 5 days of symptom onset or in patients with early-stage disease) are needed to fully elucidate the potential benefits of colchicine in this patient population.

PROSPERO registration number

CRD42022369850.
Randomised controlled, patient-blinded, multicentre, superiority trial to evaluate the efficacy of the line-attached sheath-type traction device for endoscopic submucosal dissection in patients with superficial gastric neoplasms
Authors: Abe Hirofumi , Sako Tomoya , Yamamoto Yoshinobu , Ikeda Atsushi , Kawara Fumiaki , Ose Takayuki , Takao Toshitatsu , Kitamura Yasuaki , Ariyoshi Ryusuke , Morita Yoshinori , Ishida Tsukasa , Ikegawa Takuya , Ishida Ryosuke , Yoshizaki Tetsuya , Sakaguchi Hiroya , Toyonaga Takashi , Kodama Yuzo
Published: April 2024

Introduction

EndoTrac is a line-attached sheath-type traction device that enables us to control the direction and the force of traction during endoscopic submucosal dissection (ESD). The efficacy of EndoTrac for gastric ESD has not been fully verified.

Methods and analysis

The G-Trac study is a multicentre (nine general hospitals and two university hospitals in Japan) collaborative trial assessing the efficacy of EndoTrac for gastric ESDs. Patients with superficial gastric neoplasms will be enrolled and randomly assigned to undergo either conventional ESD or EndoTrac ESD. Allocation will be stratified according to tumour location, operator experience and tumour diameter at an allocation rate of 1:1. The type of endoknife used will be confirmed before randomisation. The primary outcome, procedure time, will be compared between the groups in both intention-to-treat and per-protocol analyses using the Wilcoxon rank sum test. The efficacy-related, safety-related and device-related outcomes will be assessed in the secondary analysis. The planned sample size of the 142 patients in the two groups will enable us to detect a difference with a power of 80% by using the Wilcoxon rank sum test, assuming an effect size of 0.54, asymptotic relative efficiency of 0.864 and a two-sided type 1 error rate of 5%.

Ethics and dissemination

This trial was approved by the certified review board of Kobe University (22 December 2022). The results from this trial will be disseminated through peer-review journals, presentations at national and international conferences, and data sharing with other researchers.

Trial registration number

jRCT1052220166.
Evaluation of a manualised neurofeedback training in psychosomatic-psychotherapeutic outpatient treatment (Neuro-pp-out): study protocol for a clinical mixed-methods pilot study
Authors: Schmidt Kira Leandra , Kowalski Axel , Schweda Adam , Dörrie Nora , Skoda Eva Maria , Bäuerle Alexander , Teufel Martin
Published: April 2024

Introduction

Electroencephalographic neurofeedback (NFB), as a non-invasive form of brainwave training, has been shown to be effective in the treatment of various mental health disorders. However, only few results regarding manualised and standardised NFB trainings exist. This makes comparison as well as replication of studies difficult. Therefore, we developed a standard manual for NFB training in patients with mental health disorders attending a psychosomatic outpatient clinic. The current study aims at investigating the conduction of a standardised manual for NFB training in patients with mental health disorders. If successful, the study provides new opportunities to investigate NFB in a more controlled and comparable manner in clinical practice.

Methods and analysis

30 patients diagnosed with a mental health disorder will be included. After the educational interview, patients will undergo baseline diagnostics (T0). The subsequent intervention consists of 10 sessions of NFB training aiming at increasing sensorimotor rhythm and alpha-frequency amplitudes and decreasing theta-frequency and high beta-frequency amplitudes to induce relaxation and decrease subjective stress. All patients will undergo a post-treatment diagnostic assessment (T1) and a follow-up assessment 8 weeks following the closing session (T2). Changes in amplitude bands (primary outcome) will be recorded with electroencephalography during pre-assessments, post-assessments and follow-up assessments and during NFB sessions. Physiological (respiratory rate, blood volume pulse, muscle tension) and psychometric parameters (distress, perceived stress, relaxation ability, depressive and anxiety symptoms, insomnia, self-efficacy and quality of life) will be assessed at T0, T1 and T2. Moreover, satisfaction, acceptance and usability will be assessed at T1 after NFB training. Further, qualitative interviews about the experiences with the intervention will be conducted with NFB practitioners 6 months after the study starts. Quantitative data will be analysed using repeated measures analysis of variance as well as mediation analyses on mixed linear models. Qualitative data will be analysed using Mayring’s content analysis.

Ethics and dissemination

The study was approved by the ethics committee of the Medical Faculty of the University of Duisburg-Essen (23–11140-BO) and patient enrolment began in April 2023. Before participation, written informed consent by each participant will be required. Results will be published in peer-reviewed journals and conference presentations.

Trial registration number

Prospectively registered on 28 March 2023 in the German clinical trials register, DRKS00031497.
Short-duration aerobic high-intensity intervals versus moderate exercise training intensity in patients with peripheral artery disease: study protocol for a randomised controlled trial (the Angiof-HIIT Study)
Authors: Lanzi Stefano , Pousaz Anina , Fresa Marco , Besson Cyril , Desgraz Benoit , Gremeaux-Bader Vincent , Mazzolai Lucia
Published: April 2024

Introduction

Supervised exercise training is among the first-line therapies for patients with peripheral artery disease (PAD). Current recommendations for exercise include guidance focusing on claudication pain, programme and session duration, and frequency. However, no guidance is offered regarding exercise training intensity. This study aims to compare the effects of 12-week-long supervised walking exercise training (high-intensity interval training (HIIT) vs moderate-intensity exercise (MOD)) in patients with chronic symptomatic PAD.

Methods and analysis

This study is a monocentric, interventional, non-blinded randomised controlled trial. 60 patients (30 in each group) will be randomly allocated (by using the random permuted blocks) to 12 weeks (three times a week) of HIIT or MOD. For HIIT, exercise sessions will consist of alternating brief high-intensity (≥85% of the peak heart rate (HRpeak)) periods (≤60 s) of work with periods of passive rest. Patients will be asked to complete 1 and then 2 sets of 5–7 (progressing to 10–15×60 s) walking intervals. For the MOD group, exercise training sessions will consist of an alternation of periods of work performed at moderate intensity (≤76% HRpeak) and periods of passive rest. Interventions will be matched by training load. The primary outcome will be the maximal walking distance. Secondary outcomes will include functional performance, functional capacity, heath-related quality of life, self-perceived walking abilities, physical activity and haemodynamic parameters.

Ethics and dissemination

The Angiof-HIIT Study was approved by the Human Research Ethics Committee of the Canton de Vaud (study number: 2022-01752). Written consent is mandatory prior to enrolment and randomisation. The results will be disseminated via national and international scientific meetings, scientific peer-reviewed journals and social media.

Trial registration number

NCT05612945.
COVID-19 vaccine acceptance in the general population and under-resourced communities from high-income countries: realist review
Authors: Gonzalez-Jaramillo Nathalia , Abbühl Dominik , Roa-Díaz Zayne Milena , Kobler-Betancourt Cristopher , Frahsa Annika
Published: April 2024

Objective

To compare vaccination willingness before rollout and 1 year post-rollout uptake among the general population and under-resourced communities in high-income countries.

Design

A realist review.

Data sources

Embase, PubMed, Dimensions ai and Google Scholar.

Setting

High-income countries.

Definitions

We definedvaccination willingnessas the proportion of participants willing or intending to receive vaccines prior to availability. We defined vaccine uptake as the real proportion of the population with complete vaccination as reported by each country until November 2021.

Results

We included data from 62 studies and 18 high-income countries. For studies conducted among general populations, the proportion of vaccination willingness was 67% (95% CI 62% to 72%). In real-world settings, the overall proportion of vaccine uptake among those countries was 73% (95% CI 69% to 76%). 17 studies reported pre-rollout willingness for under-resourced communities. The summary proportion of vaccination willingness from studies reporting results among people from under-resourced communities was 52% (95% CI 0.46% to 0.57%). Real-world evidence about vaccine uptake after rollout among under-resourced communities was limited.

Conclusion

Our review emphasises the importance of realist reviews for assessing vaccine acceptance. Limited real-world evidence about vaccine uptake among under-resourced communities in high-income countries is a call to context-specific actions and reporting.
Using active learning strategies during a quality improvement collaborative: exploring educational games to enhance learning among healthcare professionals
Authors: da Silva Marianilza Lopes , Franco Flavia Fernanda , Vieira Jessica Alves , da Silva Juliana Fernandes , Santos Guilherme Cesar Silva Dias , da Cunha Beatriz Marques , Pereira Fernando Enrique Arriel , Nardoni Natalia , Gomes Francielle Bendersky , Cocentino Brunno Cesar Batista , Marques Roberta Gonçalves , de Melo Natalia Souza , Petenate Ademir Jose , Hamada Andreza Pivato Susin , Cristalda Cristiane Maria Reis , Ue Luciana Yumi , de Barros Claudia Garcia , Vernal Sebastian
Published: April 2024

Background

The Breakthrough Series model uses learning sessions (LS) to promote education, professional development and quality improvement (QI) in healthcare. Staff divergences regarding prior knowledge, previous experience, preferences and motivations make selecting which pedagogic strategies to use in LS a challenge.

Aim

We aimed to assess new active-learning strategies: two educational games, a card game and an escape room-type game, for training in healthcare-associated infection prevention.

Methods

This descriptive case study evaluated the performance of educational strategies during a Collaborative to reduce healthcare-associated infections in Brazilian intensive care units (ICUs). A post-intervention survey was voluntarily offered to all participants in LS activities.

Results

Seven regional 2-day LS were held between October and December 2022 (six for adult ICUs and one for paediatric/neonatal ICUs). Of 194 institutions participating in a nationwide QI initiative, 193 (99.4%) participated in these activities, totalling 850 healthcare professionals. From these, 641 participants responded to the survey (75.4%). The post-intervention survey showed that the participants responded positively to the educational activities.

Conclusion

The participants perceived the various pedagogical strategies positively, which shows the value of a broad and diverse educational approach, customised to local settings and including game-based activities, to enhance learning among healthcare professionals.
Locum doctor working and quality and safety: a qualitative study in English primary and secondary care
Authors: Ferguson Jane , Stringer Gemma , Walshe Kieran , Allen Thomas , Grigoroglou Christos , Ashcroft Darren M , Kontopantelis Evangelos
Published: April 2024

Background

The use of temporary doctors, known as locums, has been common practice for managing staffing shortages and maintaining service delivery internationally. However, there has been little empirical research on the implications of locum working for quality and safety. This study aimed to investigate the implications of locum working for quality and safety.

Methods

Qualitative semi-structured interviews and focus groups were conducted with 130 participants, including locums, patients, permanently employed doctors, nurses and other healthcare professionals with governance and recruitment responsibilities for locums across primary and secondary healthcare organisations in the English NHS. Data were collected between March 2021 and April 2022. Data were analysed using reflexive thematic analysis and abductive analysis.

Results

Participants described the implications of locum working for quality and safety across five themes: (1) ‘familiarity’ with an organisation and its patients and staff was essential to delivering safe care; (2) ‘balance and stability’ of services reliant on locums were seen as at risk of destabilisation and lacking leadership for quality improvement; (3) ‘discrimination and exclusion’ experienced by locums had negative implications for morale, retention and patient outcomes; (4) ‘defensive practice’ by locums as a result of perceptions of increased vulnerability and decreased support; (5) clinical governance arrangements, which often did not adequately cover locum doctors.

Conclusion

Locum working and how locums were integrated into organisations posed some significant challenges and opportunities for patient safety and quality of care. Organisations should take stock of how they work with the locum workforce to improve not only quality and safety but also locum experience and retention.
Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides
Authors: Garcia-Marquez Maria Alejandra , Thelen Martin , Bauer Eugen , Maas Lukas , Wennhold Kerstin , Lehmann Jonas , Keller Diandra , Nikolić Miloš , George Julie , Zander Thomas , Schröder Wolfgang , Müller Philipp , Yazbeck Ali M , Bruns Christiane , Thomas Roman , Gathof Birgit , Quaas Alexander , Peifer Martin , Hillmer Axel M , von Bergwelt-Baildon Michael , Schlößer Hans Anton
Published: April 2024

Background

The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunogenic peptides.

Methods

HLA genotypes and sequences of either (1) 10 relevant tumor-associated antigens (TAAs) or (2) patient-specific mutation-associated neoantigens (MANAs) were used to predict good-affinity binders using an in silico approach for MHC-binding (www.iedb.org). Imbalanced or lost expression of HLA-I-A/B/C alleles was analyzed by transcriptome sequencing. FluoroSpot assays and TCR sequencing were used to determine peptide-specific T-cell responses.

Results

We show that germline homozygosity of HLA-I genes is significantly enriched in EGA patients (n=80) compared with an HLA-matched reference cohort (n=7605). Whereas the overall mutational burden is similar, the repertoire of potentially immunogenic peptides derived from TAAs and MANAs was lower in homozygous patients. Promiscuity of peptides binding to different HLA-I molecules was low for most TAAs and MANAs and in silico modeling of the homozygous to a heterozygous HLA genotype revealed normalized peptide repertoires. Transcriptome sequencing showed imbalanced expression of HLA-I alleles in 75% of heterozygous patients. Out of these, 33% showed complete loss of heterozygosity, whereas 66% had altered expression of only one or two HLA-I molecules. In a FluoroSpot assay, we determined that peptide-specific T-cell responses against NY-ESO-1 are derived from multiple peptides, which often exclusively bind only one HLA-I allele.

Conclusion

The high frequency of germline homozygosity in EGA patients suggests reduced cancer immunosurveillance leading to an increased cancer risk. Therapeutic targeting of allelic imbalance of HLA-I molecules should be considered in EGA.
Preclinical evaluation of two phylogenetically distant arenavirus vectors for the development of novel immunotherapeutic combination strategies for cancer treatment
Authors: Raguz Josipa , Pinto Catarina , Pölzlbauer Theresa , Habbeddine Mohamed , Rosskopf Sandra , Strauß Judith , Just Valentin , Schmidt Sarah , Bidet Huang Katell , Stemeseder Felix , Schippers Timo , Stewart Ethan , Jez Jakub , Berraondo Pedro , Orlinger Klaus K. , Lauterbach Henning
Published: April 2024

Background

Engineered arenavirus vectors have recently been developed to leverage the body’s immune system in the fight against chronic viral infections and cancer. Vectors based on Pichinde virus (artPICV) and lymphocytic choriomeningitis virus (artLCMV) encoding a non-oncogenic fusion protein of human papillomavirus (HPV)16 E6 and E7 are currently being tested in patients with HPV16+ cancer, showing a favorable safety and tolerability profile and unprecedented expansion of tumor-specific CD8+T cells. Although the strong antigen-specific immune response elicited by artLCMV vectors has been demonstrated in several preclinical models, PICV-based vectors are much less characterized.

Methods

To advance our understanding of the immunobiology of these two vectors, we analyzed and compared their individual properties in preclinical in vivo and in vitro systems. Immunogenicity and antitumor effect of intratumoral or intravenous administration of both vectors, as well as combination with NKG2A blockade, were evaluated in naïve or TC-1 mouse tumor models. Flow cytometry, Nanostring, and histology analysis were performed to characterize the tumor microenvironment (TME) and T-cell infiltrate following treatment.

Results

Despite being phylogenetically distant, both vectors shared many properties, including preferential infection and activation of professional antigen-presenting cells, and induction of potent tumor-specific CD8+T-cell responses. Systemic as well as localized treatment induced a proinflammatory shift in the TME, promoting the infiltration of inducible T cell costimulator (ICOS)+CD8+T cells capable of mediating tumor regression and prolonging survival in a TC-1 mouse tumor model. Still, there was evidence of immunosuppression built-up over time, and increased expression of H2-T23 (ligand for NKG2A T cell inhibitory receptor) following treatment was identified as a potential contributing factor. NKG2A blockade improved the antitumor efficacy of artARENA vectors, suggesting a promising new combination approach. This demonstrates how detailed characterization of arenavirus vector-induced immune responses and TME modulation can inform novel combination therapies.

Conclusions

The artARENA platform represents a strong therapeutic vaccine approach for the treatment of cancer. The induced antitumor immune response builds the backbone for novel combination therapies, which warrant further investigation.
Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C
Authors: Gomar Celia , Di Trani Claudia Augusta , Bella Angela , Arrizabalaga Leire , Gonzalez-Gomariz Jose , Fernandez-Sendin Myriam , Alvarez Maite , Russo-Cabrera Joan Salvador , Ardaiz Nuria , Aranda Fernando , Schippers Timo , Quintero Marisol , Melero Ignacio , Orlinger Klaus K , Lauterbach Henning , Berraondo Pedro
Published: April 2024

Background

Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored.

Methods

We assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination’s efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials.

Results

Intratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8+T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8+T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included.

Conclusion

Intratumoral injection of poly(I:C) sensitizes MHClowtumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.
Spatial comparison of molecular features associated with resistance to pembrolizumab in BCG unresponsive bladder cancer
Authors: Meghani Khyati , Frydenlund Noah , Yu Yanni , Choy Bonnie , Meeks Joshua J
Published: April 2024

Intravenous immune checkpoint inhibition achieves a 40% 3-month response in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ. Yet, only half of the early responders will continue to be disease-free by 12 months, and resistance mechanisms are poorly defined. We performed spatial profiling of BCG-unresponsive tumors from patients responsive or resistant to intravenous pembrolizumab treatment, analyzing samples both before initiating and 3 months post-intravenous pembrolizumab treatment. We analyzed 119 regions of interest, which included 59 pairs of epithelial and adjacent stromal segments across five patients: two responders and three non-responders. We demonstrate that BCG unresponsive tumors with an inflamed PanCK+ tumor area and an infiltrated stromal segment respond better to intravenous pembrolizumab. Furthermore, using segment-specific gene signatures generated from a cohort of BCG unresponsive NMIBC treated with intravesical BCG+pembrolizumab, we find that non-inflamed, immune-cold tumors that do not respond to intravenous pembrolizumab exhibit a favorable outcome to the combined application of BCG and pembrolizumab. For the first time, we have identified molecular features of tumors associated with response and resistance to intravenous pembrolizumab in BCG unresponsive NMIBCs. Further research with more patients and alternative checkpoint inhibitors is essential to validate our findings. We anticipate that using a transcriptomics signature like the one described here can help identify tumors with a higher possibility of responding to intravenous pembrolizumab.
Tumor-targeted therapy with BRAF-inhibitor recruits activated dendritic cells to promote tumor immunity in melanoma
Authors: Hornsteiner Florian , Vierthaler Janine , Strandt Helen , Resag Antonia , Fu Zhe , Ausserhofer Markus , Tripp Christoph H , Dieckmann Sophie , Kanduth Markus , Farrand Kathryn , Bregar Sarah , Nemati Niloofar , Hermann-Kleiter Natascha , Seretis Athanasios , Morla Sudhir , Mullins David , Finotello Francesca , Trajanoski Zlatko , Wollmann Guido , Ronchese Franca , Schmitz Marc , Hermans Ian F , Stoitzner Patrizia
Published: April 2024

Background

Tumor-targeted therapy causes impressive tumor regression, but the emergence of resistance limits long-term survival benefits in patients. Little information is available on the role of the myeloid cell network, especially dendritic cells (DC) during tumor-targeted therapy.

Methods

Here, we investigated therapy-mediated immunological alterations in the tumor microenvironment (TME) and tumor-draining lymph nodes (LN) in the D4M.3A preclinical melanoma mouse model (harboring the V-Raf murine sarcoma viral oncogene homolog B (BRAF)V600Emutation) by using high-dimensional multicolor flow cytometry in combination with multiplex immunohistochemistry. This was complemented with RNA sequencing and cytokine quantification to characterize the immune status of the tumors. The importance of T cells during tumor-targeted therapy was investigated by depleting CD4+or CD8+T cells in tumor-bearing mice. Tumor antigen-specific T-cell responses were characterized by performing in vivo T-cell proliferation assays and the contribution of conventional type 1 DC (cDC1) to T-cell immunity during tumor-targeted therapy was assessed using Batf3−/−mice lacking cDC1.

Results

Our findings reveal that BRAF-inhibitor therapy increased tumor immunogenicity, reflected by an upregulation of genes associated with immune activation. The T cell-inflamed TME contained higher numbers of activated cDC1 and cDC2 but also inflammatory CCR2-expressing monocytes. At the same time, tumor-targeted therapy enhanced the frequency of migratory, activated DC subsets in tumor-draining LN. Even more, we identified a cDC2 population expressing the Fc gamma receptor I (FcγRI)/CD64 in tumors and LN that displayed high levels of CD40 and CCR7 indicating involvement in T cell-mediated tumor immunity. The importance of cDC2 is underlined by just a partial loss of therapy response in a cDC1-deficient mouse model. Both CD4+and CD8+T cells were essential for therapy response as their respective depletion impaired therapy success. On resistance development, the tumors reverted to an immunologically inert state with a loss of DC and inflammatory monocytes together with the accumulation of regulatory T cells. Moreover, tumor antigen-specific CD8+T cells were compromised in proliferation and interferon-γ-production.

Conclusion

Our results give novel insights into the remodeling of the myeloid landscape by tumor-targeted therapy. We demonstrate that the transient immunogenic tumor milieu contains more activated DC. This knowledge has important implications for the development of future combinatorial therapies.
Use of risk chart algorithms for the identification of psoriatic arthritis patients at high risk for cardiovascular disease: findings derived from the project CARMA cohort after a 7.5-year follow-up period
Authors: Polo y La Borda Jessica , Castañeda Santos , Heras-Recuero Elena , Sánchez-Alonso Fernando , Plaza Zulema , García Gómez Carmen , Ferraz-Amaro Ivan , Sanchez-Costa Jesús Tomás , Sánchez-González Olga Carmen , Turrión-Nieves Ana Isabel , Perez-Alcalá Ana , Pérez-García Carolina , González-Juanatey Carlos , Llorca Javier , Gonzalez-Gay Miguel Angel
Published: April 2024

Objective

To assess the predictive value of four cardiovascular (CV) risk algorithms for identifying high-risk psoriatic arthritis (PsA) patients.

Methods

Evaluation of patients with PsA enrolled in the Spanish prospective project CARdiovascular in RheuMAtology. Baseline data of 669 PsA patients with no history of CV events at the baseline visit, who were followed in rheumatology outpatient clinics at tertiary centres for 7.5 years, were retrospectively analysed to test the performance of the Systematic Coronary Risk Assessment (SCORE), the modified version (mSCORE) European Alliance of Rheumatology Associations (EULAR) 2015/2016, the SCORE2 algorithm (the updated and improved version of SCORE) and the QRESEARCH risk estimator version 3 (QRISK3).

Results

Over 4790 years of follow-up, there were 34 CV events, resulting in a linearised rate of 7.10 per 1000 person-years (95% CI 4.92 to 9.92). The four CV risk scales showed strong correlations and all showed significant associations with CV events (p<0.001). SCORE, mSCORE EULAR 2015/2016 and QRISK3 effectively differentiated between low and high CV risk patients, although the cumulative rate of CV events observed over 7.5 years was lower than expected based on the frequency predicted by these risk scales. Additionally, model improvement was observed when combining QRISK3 with any other scale, particularly the combination of QRISK3 and SCORE2, which yielded the lowest Akaike information criterion (411.15) and Bayesian information criterion (420.10), making it the best predictive model.

Conclusions

Risk chart algorithms are very useful for discriminating PsA at low and high CV risk. An integrated model featuring QRISK3 and SCORE2 yielded the optimal synergy of QRISK3’s discrimination ability and SCORE2’s calibration accuracy.