bluuebunny/crossref_metadata_2025 huggingface dataset:
Experiences of medical students and doctors with dyslexia: A systematic review
Authors: Tarafdar Suhail Amin , Seoudi Noha , Luo Ruoyin , Winston Kalman
Published: February 2025

Introduction

Dyslexia can be defined as a neurodevelopmental learning difficulty characterised by issues with phonological awareness, affecting performance and progression within medical education. There is a need to identify how to provide effective support for medical students and postgraduate doctors with dyslexia. The aim of this systematic review was to explore the experiences of, and identify strategies for, undergraduate medical students and postgraduate medical doctors with dyslexia within existing literature.

Methods

A search strategy was undertaken on databases relevant to medical education. Included studies concerned either medical students or postgraduate medical doctors with dyslexia. A quality appraisal was undertaken and narrative synthesis employed to produce a final report.

Results

Thirty‐one articles were included in the final synthesis, with seven deemed high‐risk of bias. Four overarching themes were identified. There are largely negative experiences, such as stigma, reported. Furthermore, dyslexia can impact assessment performance, with reasonable adjustments effective for written examinations. Moreover, strategies employed to reduce difficulties include peer support, organisational inclusivity and interactive educational methodologies. Additionally, dyslexia impacts the career trajectory of doctors.

Discussion

Training programmes should promote an inclusive environment through raised awareness and provision of reasonable adjustments. A range of potential strategies have been identified to improve the educational experiences of students with dyslexia, but these should be flexible according to individual needs. Further research is warranted within postgraduate medical training and experiences in the United States.
Myth Busting in a Post‐Assad Syria
Authors: Pinfold Rob Geist
Published: February 2025

This article challenges common misconceptions about the fall of Syrian President Bashar al‐Assad. It debunks the notion of a simplistic rebel/regime dichotomy and instead delineates the diversity of actors and interests in a post‐Assad Syria. It also critiques the perception that Hayat Tahrir al‐Sham won a decisive battlefield victory and illustrates that this was as much a political triumph as it was a military one. It then assesses how genuine the group's transformation from jihadist to pragmatist really is. Further, it shows any claims that Russia and Iran will leave Syria are unrealistic, while Israel's role in the country is often misunderstood. It concludes by critiquing the assertion that the international community has no good options in Syria and should therefore stay away. Instead, it advocates cautious engagement with the new regime. Overall, the analysis highlights Syria's complex power dynamics and warns against oversimp‐lifications in devising policies for Syria's post‐conflict reconstruction and rehabilitation.
Public Administration, Local and Regional Governance, and Domestic Terrorism
Authors: Hunter Lance Y. , Meares Wesley L. , Ginn Martha H. , Hatcher William
Published: February 2025

This study examines how the nature of public administration and local and regional governance affects domestic terrorism in 73 mixed and democratic countries from multiple regions and levels of development. In conducting a cross‐national statistical analysis from 1991 to 2019 with standard political, economic, and social controls, and controlling for endogeneity, we find that domestic terrorism increases when public administration is more partial, biased, corrupt, and unreliable, and as local and regional governments are controlled to a greater extent by unelected bodies. In addition, we find that the nature of public administration and local and regional governance influences the types of institutions that are most likely to be targeted in domestic terror attacks. These findings have important implications in considering how public administration and local and regional governance affect political violence in mixed and democratic regimes.
Intracellular signalling in arterial chemoreceptors during acute hypoxia and glucose deprivation: role of ATP
Authors: Torres‐López María , González‐Rodríguez Patricia , Colinas Olalla , Rho Hee‐Sool , Torres‐Torrelo Hortensia , Castellano Antonio , Gao Lin , Ortega‐Sáenz Patricia , López‐Barneo José
Published: February 2025

The carotid body (CB) is the main oxygen (O2) sensing organ that mediates reflex hyperventilation and increased cardiac output in response to hypoxaemia. Acute O2 sensing is an intrinsic property of CB glomus cells, which contain special mitochondria to generate signalling molecules (NADH and H2O2) that modulate membrane K+ channels in response to lowered O2 tension (hypoxia). In parallel with these membrane‐associated events, glomus cells are highly sensitive to mitochondrial electron transport chain (ETC) inhibitors. It was suggested that a decrease in oxidative production of ATP is a critical event mediating hypoxia‐induced cell depolarization. Here, we show that rotenone [an inhibitor of mitochondrial complex (MC) I] activates rat and mouse glomus cells but abolishes their responsiveness to hypoxia. Rotenone does not prevent further activation of the cells by cyanide (a blocker of MCIV) or glucose deprivation. Responsiveness to glucose deprivation is enhanced in O2‐insenstive glomus cells with genetic disruption of MCI. These findings suggest that acute O2 sensing requires a functional MCI but that a decrease in intracellular ATP, presumably produced by the simultaneous inhibition of MCI and MCIV, is not involved in hypoxia signalling. In support of this concept, ATP levels in single glomus cells were unaltered by hypoxia, but rapidly declined following exposure of the cells to low glucose or to inhibitors of oxidative phosphorylation. These observations indicate that a reduction in intracellular ATP does not participate in physiological acute O2 sensing. However, local decreases in ATP of glycolytic origin may contribute to low glucose signalling in glomus cells.

image

Key points

The carotid body contains oxygen‐sensitive glomus cells with specialized mitochondria that generate signalling molecules (NADH and H2O2) to inhibit membrane K+ channels in response to hypoxia.

Glomus cells are highly sensitive to electron transport chain (ETC) blockers. It was suggested that a decrease in intracellular ATP is the main signal inducing K+ channel inhibition and depolarization in response to hypoxia or ETC blockade.

Rotenone, an inhibitor of mitochondrial complex (MC) I, activates glomus cells but abolishes their responsiveness to hypoxia. However, rotenone does not prevent further activation of glomus cells by cyanide (an MCIV blocker) or glucose deprivation.

Single‐cell ATP levels were unaltered by hypoxia, but decreased rapidly following exposure of glomus cells to 0 mM glucose or inhibitors of oxidative phosphorylation.

A reduction in intracellular ATP does not participate in signalling acute hypoxia. However, it may contribute to hypoglycaemia signalling in glomus cells.
Differential Volterra filter: A two-stage decoupling method for audible sounds generated by parametric array loudspeakers based on Westervelt equation
Authors: Ma Wenyao , Zhu Yunxi , Ji Peifeng , Kuang Zheng , Wu Ming , Yang Jun
Published: February 2025

Parametric array loudspeakers (PALs) produce highly directional sounds due to the parametric process in air. Its application in creating personal audio zones requires simple modeling of the audible sound field near the PAL, which is crucial for subsequent designs to reduce inherent nonlinear distortion. However, current accurate methods for describing the sound field, reliant on numerical solutions to wave equations, are computationally intensive. To achieve both effectiveness and simplicity, this paper proposes a time-domain model for audible sounds generated in the Westervelt far field, called the differential Volterra filter (Diff-VF). It is obtained through two stages: first, a narrow-band (NB) approximation is introduced to decouple the virtual source energy density from interactions of ultrasonic beams when solving the Westervelt equation. This results in a NB Westervelt solution for time-domain inputs. Second, to further develop a generic response independent of inputs, a temporal-spatial discretization is used to simplify the NB Westervelt solution into the Diff-VF model with a one-dimensional kernel. Numerical simulations confirmed the effectiveness of the NB Westervelt solution when compared with an exact solution, whether on- and off-axis. Experimental results validated that the Diff-VF model achieved superior prediction performance over existing VF-based models, with insensitivity to inputs and lower complexity.
When Is “Tough Love” Too Much? An Exploratory Study of Tough Love Coaching in Sport
Authors: Sadler Sarah M. , Gould Daniel , Driska Andy
Published: February 2025

Tough love is often discussed in sport but is not clearly understood. The purpose of this study was to explore athletes’ perceptions of tough love coaching, and whether, and when, tough love coaching can become inappropriate, or abusive. Semistructured interviews were conducted to explore 12 athletes’ experiences with and conceptualizations of tough love in sport, and reflexive content analysis was used to identify relevant themes in the data. Analysis of participant responses revealed a multifaceted conceptualization of tough love coaching as being dual and temporal in nature. Tough love was perceived to be harmful or abusive if the tough love criticized the person instead of the behavior, the coach emphasized performance outcomes above athlete well-being, or the tough love negatively impacted athlete well-being long-term. Practical implications are provided for coaches, coach educators, and researchers in the field of coach education.
Physical Activity and Ischemic Heart Disease Risk: A Prospective Cohort Study Among Chinese Adults
Authors: Li Yuhui , Chen Yunhui , Huang Kejia , Sun Dianjianyi , Pei Pei , Yu Canqing , Lv Jun , Duan Haiping , Gao Ruqin , Pang Zengchang , Tian Xiaocao
Published: February 2025

Background: Type-specific physical activity (PA) may be associated with different risks of ischemic heart disease (IHD), but few large studies have examined this. This study aimed to assess the incidence and dose–response relationships between total PA and 4 different types of PA and IHD risk in Chinese adults. Methods: The prospective China Kadoorie Biobank enrolled 35,508 adults from Qingdao from 2004 to 2008, including 33,342 IHD-free participants in this analysis. PA was collected through a self-report questionnaire, calculating metabolic equivalents of task-hours per day based on duration and frequency. Cox regression analysis was used to assess the association between PA and IHD risk. Results: During a median 9.2 years of follow-up, 2712 incident IHD cases were recorded. Total, occupational, commuting, and leisure-time PAs were inversely associated with IHD risk. Compared with the participants in the bottom quintiles of PA, the participants in the top quintiles of total PA, occupational PA, commuting PA, and leisure-time PA had 43% (hazard ratio [HR] = 0.57; 95% CI, 0.49–0.66), 38% (HR = 0.62; 95% CI, 0.50–0.75), 38% (HR = 0.62; 95% CI, 0.44–0.87), and 21% (HR = 0.79; 95% CI, 0.67–0.95) lower IHD risk, respectively. A negative association between household PA and IHD risk was found only in males (HR = 0.83; 95% CI, 0.70–0.98). The restricted cubic spline  regression analysis revealed a linear relationship between total PA and IHD risk (P for nonlinear = .5687). Conclusion: Among Chinese adults, higher total, occupational, commuting, and leisure-time PA was associated with significantly lower risks of IHD, and increased household PA could reduce IHD risk in males.
Received and Perceived Peer Acceptance in Relation to Enjoyment, Social Competence, and Physical Activity in Primary School Physical Education and the Role of Peer-Relatedness Need Satisfaction
Authors: de Bruijn Anne G.M. , Grimminger-Seidensticker Elke
Published: February 2025

Purpose: This study explored associations between actually received and perceived peer acceptance; their role for peer-relatedness need satisfaction; and enjoyment, social competence, and physical activity level during physical education (PE). Method: Two hundred and twenty-seven children (48% boys, mean age: 11.4 years, ± 0.98) from 13 classes of three Dutch primary schools filled in questionnaires to measure their received and perceived peer acceptance, peer-relatedness need satisfaction, enjoyment, and self-perceived social competence in PE. Accelerometers assessed moderate to vigorous physical activity levels during PE. Results: Structural equation models in Mplus showed a medium correlation between received and perceived peer acceptance. Only perceived peer acceptance predicted satisfaction of the peer-relatedness need. Received peer acceptance predicted social competence and moderate to vigorous physical activity, perceived peer acceptance linked to PE enjoyment, and indirectly, via satisfaction of peer relatedness, to social competence. Conclusion: A PE environment where children are, and, feel, socially accepted seems vital for bringing about positive PE experiences.
Intercellular NETwork-facilitated sarcoplasmic reticulum targeting for myocardial ischemia-reperfusion injury treatment
Authors: Jiang Peihang , Huang Fangyang , Chen Liqiang , Zhou Hao , Deng Yudi , Li Lian , Chen Mao , Huang Yuan
Published: February 2025

Myocardial ischemia-reperfusion injury (MIRI) often leads to irreversible myocardium dysfunction, while existing therapies are palliatives that transiently alleviate the disease symptoms. Repairing sarcoplasmic reticulum Ca
2+
-ATPase (SERCA) could reverse MIRI, which, however, requires precise drug delivery to the sarcoplasmic reticulum (SR). To this end, we leverage cell-cell “NETwork” of neutrophils to deliver SERCA activator-loaded SR-localized nanoparticles (L-P-NPs) to the damaged myocardial cells, following a hierarchical targeting process: (i) chemotactic neutrophils deliver L-P-NPs to ischemia-reperfused heart, achieving tissue level targeting; (ii) neutrophils produce neutrophil extracellular traps (NETs) to transport L-P-NPs to injured myocardial cell, achieving cellular level targeting; (iii) L-P-NPs escort therapeutic payloads to the SR, achieving subcellular targeting. We showed that this platform profoundly restored SERCA activity, augmented cardiac function, and ameliorated adverse heart remodeling. Our study provides insight into the direct restoration of SR for the effective treatment of MIRI and other muscle diseases.
Nonstop mutations cause loss of renal tumor suppressor proteins
VHL
and
BAP1
and affect multiple stages of protein translation
Authors: Pal Jagriti , Riester Marisa , Ganner Athina , Ghosh Avantika , Dhamija Sonam , Mookherjee Debdatto , Voss Christian , Frew Ian J. , Kotsis Fruzsina , Neumann-Haefelin Elke , Spang Anne , Diederichs Sven
Published: February 2025

Nonstop extension or stop-loss mutations lead to the extension of a protein at its carboxyl terminus. Recently, nonstop mutations in the tumor suppressor
SMAD Family Member 4
(
SMAD4
) have been discovered to lead to proteasomal SMAD4 degradation. However, this mutation type has not been studied in other cancer genes. Here, we explore somatic nonstop mutations in the tumor suppressor genes
BRCA1 Associated Protein 1
(
BAP1
) and
Von Hippel-Lindau
(
VHL
) enriched in renal cell carcinoma. For
BAP1
, nonstop mutations generate an extremely long extension. Instead of proteasomal degradation, the extension decreases translation and depletes
BAP1
messenger RNA from heavy polysomes. For
VHL
, the short extension leads to proteasomal degradation. Unexpectedly, the mutation alters the selection of the translational start site shifting VHL isoforms. We identify germline
VHL
nonstop mutations in patients leading to the early onset of severe disease manifestations. In summary, nonstop extension mutations inhibit the expression of renal tumor suppressor genes with pleiotropic effects on translation and protein stability.
Double-opponent spiking neuron array with orientation selectivity for encoding and spatial-chromatic processing
Authors: Li Dingwei , Liu Guolei , Li Fanfan , Ren Huihui , Tang Yingjie , Chen Yitong , Wang Yan , Wang Rui , Wang Saisai , Xing Lixiang , Huang Qi , Zhu Bowen
Published: February 2025

Color spiking encoding and opponent preprocessing are critical for energy-efficient object perception in the human visual system. Emulating the retina and brain’s integration of spatial and chromatic spiking signals holds promise for enhancing the efficiency of vision sensors. Here, we introduce an artificial visual neuron array that generates excitatory or inhibitory spiking responses to specific wavelengths with orientation selectivity. The neuron array can function as double-opponent receptive fields for spatial-chromatic opponent preprocessing to color signals, emulating the neural pathway from the retina to the cortex. With the color spiking preprocessing function of the neuron array, the recognition accuracy is improved almost twofold compared to direct perception of underexposure objects, and the noise robustness is also strengthened. This architecture leverages biological mechanisms for simultaneous spike encoding and antagonistic preprocessing of color information, offering the potential for highly efficient neuromorphic vision systems.
In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene
Authors: De Giorgi Marco , Park So Hyun , Castoreno Adam , Cao Mingming , Hurley Ayrea , Saxena Lavanya , Chuecos Marcel A. , Walkey Christopher J. , Doerfler Alexandria M. , Furgurson Mia N. , Ljungberg M. Cecilia , Patel Kalyani R. , Hyde Sarah , Chickering Tyler , Lefebvre Stephanie , Wassarman Kelly , Miller Patrick , Qin June , Schlegel Mark K. , Zlatev Ivan , Han Jun , Beeton Christine , Li Rich Gang , Kim Jong , Martin James F. , Bissig Karl-Dimiter , Jadhav Vasant , Bao Gang , Lagor William R.
Published: February 2025

Homology-directed repair (HDR)–based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested Repair Drive, a platform technology for selectively expanding HDR-corrected hepatocytes in adult mice in vivo. Repair Drive involves transient conditioning of the liver by knocking down an essential gene,
fumarylacetoacetate hydrolase
(
Fah
), and delivering an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive increased the percentage of correctly targeted hepatocytes in healthy wild-type mice up to 25%, which resulted in a fivefold increased expression of a therapeutic transgene,
human factor IX
(
FIX
). Repair Drive was well tolerated and did not induce toxicity or tumorigenesis during a 1-year follow-up. This approach may broaden the range of liver diseases that can be treated with somatic genome editing.
Tracing the evolution: the rise of
Salmonella
Thompson co-resistant to clinically important antibiotics in China, 1997–2020
Authors: Zhai Weishuai , Lu Mi , Zhao Lanxin , Du Pengcheng , Cui Shenghui , Liu Yang , Tan Dongmei , Zeng Xianying , Yang Baowei , Li Ruichao , Fanning Séamus , Liu Dejun , Li Lanqi , Zhang Xiaoman , Wang Yang , Bai Li
Published: February 2025

As clinical
Salmonella enterica
serovar Thompson (
S
. Thompson) emerged among the top ten prevalent serovars in China, understanding the distribution and origin of its multidrug-resistant (MDR) strains becomes imperative. This study employed antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatics analysis to investigate the prevalence and genomic profiles of clinically important
S
. Thompson ST26 across China from 1997 to 2020. Upon analyzing 141 isolates from various sources, we identified 29 isolates, derived from 25 diarrhea patients and four animal-derived foods, displayed co-resistance to ciprofloxacin, cefotaxime, and azithromycin (CIP
R
CTX
R
AZI
R
), all of which are considered the front-line and critically-important antimicrobial agents for treating
Salmonella
infections in humans. The IncC plasmid was the predominant mobile vector identified among the CIP
R
CTX
R
AZI
R
isolates, harboring four crucial resistance genes
qnrS1
,
qepA4
,
bla
CMY-2
, and
mph
(A) that confer resistance to three critically important antimicrobials. However, the closely related and clustered IncC-harboring CIP
R
CTX
R
AZI
R
isolates (0–23 single nucleotide polymorphisms [SNPs]) indicated the clonal spreading of these clinically important isolates in different provinces of China. Notably, the CIP
R
CTX
R
AZI
R
isolates appeared in aquatic products of animal-derived food, highlighting the possibility of aquaculture practices in the emergence and transmission of important antimicrobial resistance. Our findings emphasize the critical public health implications of IncC-carrying clinically important
S
. Thompson ST26. The study calls for enhanced surveillance of the clinically important
S
. Thompson ST26 clone in clinical and aquaculture and implementation of targeted interventions to mitigate its spread, thereby protecting food safety and public health.

IMPORTANCE

We highlighted the critical veterinary public health issue of clinically important
Salmonella enterica
serovar Thompson (
S
. Thompson) prevalence in animal-derived foods, particularly aquatic products, calling for urgent action. The ability of
S
. Thompson to resist critically important antimicrobials across diverse environments highlights the transmission and survival of resistant strains within the livestock and poultry industry, aquaculture, and food production chains. This study underscores the importance of continuous surveillance of clinically important
S
. Thompson, especially in aquaculture settings, and considers the global trade of aquatic products as a potential vector for international dissemination. Further investigation on the factors contributing to the clone spread of clinically important
Salmonella
strain and the development of intervention strategies to mitigate its public health impact.
Realistic fundus photograph generation for improving automated disease classification
Authors: Pandey Prashant U , Micieli Jonathan A , Ong Tone Stephan , Eng Kenneth T , Kertes Peter J , Wong Jovi C Y
Published: February 2025

Aims

This study aims to investigate whether denoising diffusion probabilistic models (DDPMs) could generate realistic retinal images, and if they could be used to improve the performance of a deep convolutional neural network (CNN) ensemble for multiple retinal disease classification, which was previously shown to outperform human experts.

Methods

We trained DDPMs to generate retinal fundus images representing diabetic retinopathy, age-related macular degeneration, glaucoma or normal eyes. Eight board-certified ophthalmologists evaluated 96 test images to assess the realism of generated images and classified them based on disease labels. Subsequently, between 100 and 1000 generated images were employed to augment training of deep convolutional ensembles for classifying retinal disease. We measured the accuracy of ophthalmologists in correctly identifying real and generated images. We also measured the classification accuracy, F-score and area under the receiver operating curve of a trained CNN in classifying retinal diseases from a test set of 100 fundus images.

Results

Ophthalmologists exhibited a mean accuracy of 61.1% (range: 51.0%–68.8%) in differentiating real and generated images. Augmenting the training set with 238 generated images in the smallest class statistically significantly improved the F-score and accuracy by 5.3% and 5.8%, respectively (p<0.01) in a retinal disease classification task, compared with a baseline model trained only with real images.

Conclusions

Latent diffusion models generated highly realistic retinal images, as validated by human experts. Adding generated images to the training set improved performance of a CNN ensemble without requiring additional real patient data.
Outcomes of oral vancomycin therapy in children with atypical ulcerative colitis with or without confirmed primary sclerosing cholangitis: a real-world observational study
Authors: Räisänen Laura , Balouch Fariha , McLaren-Kennedy Annette , Clark Julia Elizabeth , Lewindon Peter
Published: February 2025

Objectives

Atypical ulcerative colitis (UC) presenting reverse gradient colitis, backwash ileitis, or rectal sparing and/or positive atypical antineutrophil cytoplasmic antibody serology is often associated with primary sclerosing cholangitis (PSC) and can be resistant to conventional medical therapies (CMT) for inflammatory bowel diseases. We report short-term and long-term outcomes of oral vancomycin therapy (OVT) in children with atypical UC and confirmed PSC in imaging/biopsy (PSC-UC) or treatment-resistant atypical UC without detectable PSC (aUC-non-PSC).

Methods

In this retrospective real-world observational study from a tertiary paediatric centre in Brisbane, Australia, 44 children with aUC (29 PSC-UC, 15 aUC-non-PSC) received 79 OVT courses between 2014 and 2023. Pre–post-OVT characteristics were compared and relapses/repeated courses were recorded.

Results

Pre-OVT, all had active colitis by Paediatric Ulcerative Colitis Activity Index (PUCAI), Feacal Calprotectin (FC) and/or colonoscopy. Post-OVT, PUCAI reduced from 15 (IQR 5–33) to 0 (IQR 0–5); 85% of children with pre-OVT PUCAI ≥10 achieved clinical remission (100% PSC-UC vs 64% aUC-non-PSC, p=0.019). FC reduced from 995 (IQR 319–1825) to 44 (IQR 16–79) µg/g; 83% of children with pre-OVT FC ≥100 µg/g achieved biochemical remission (92% PSC-UC vs 64% aUC-non-PSC, p=0.063). Colonoscopy confirmed Mayo 0 healing in 62% (67% PSC-UC vs 54% aUC-non-PSC, p=0.443) and 46% achieved pan-colonic histological remission (54% PSC-UC vs 31% aUC-non-PSC, p=0.173). All pre–post-OVT changes in these four markers were significant in both groups. After ceasing first OVT, 25/44 relapsed within 8.2 (IQR 1.9–14.5) months. Recommencing OVT regained biomarker remission in 13/25. During 3.8 (IQR 2.0–5.3) years of follow-up, 79 OVT courses in conjunction with CMT maintained deep remission in 67%. Routine stool testing (n=138) detected no vancomycin-resistant Enterococcus (VRE).

Conclusions

OVT induced and reinduced remission in children with atypical UC. Relapse often followed ceasing vancomycin, half responded to reinduction. No VRE was developed.
The economic burden of ischaemic heart diseases on health systems: a systematic review
Authors: Rittiphairoj Thanitsara , Bulstra Caroline , Ruampatana Chochat , Stavridou Maria , Grewal Sagar , Reddy Che L , Atun Rifat
Published: February 2025

Introduction

There is a dearth of evidence regarding the global economic burden of ischaemic heart diseases (IHDs). This systematic review aims to synthesise national-level studies worldwide quantifying the economic burden of IHDs from a provider’s perspective.

Methods

We searched PubMed, Embase, Cochrane, DARE and EconLit databases from 1 January 2000 to 29 June 2022. We included observational, cost-of-illness and economic modelling studies reporting direct healthcare cost data for IHDs at the national level. At least two reviewers independently screened titles and abstracts and full texts, extracted data and assessed quality using a seven-question assessment tool. We synthesised findings by country, focusing on three key economic estimates: total annual costs of IHDs, costs of managing acute IHD episodes and chronic IHD care. We correlated these costs with country-specific macroeconomic measures and disease burden.

Results

We included 65 national-level studies conducted in 21 countries worldwide, with a majority in high-income countries. The median direct healthcare cost per episode of IHDs was 8062 Int$ 2019 (IQR: 5770–9580), and the median direct healthcare cost of IHDs per patient-year was 10 064 Int$ 2019 (IQR: 7619–14 818). These estimates positively correlated with country-specific macroeconomic and DALY measures.

Conclusion

IHDs impose a substantial economic burden on health systems globally. Economic costs in countries exceed per capita public health expenditure, primarily driven by acute episodes. National-level data were available for only 21 countries, and none from low-middle-income and low-income countries. Economic costs of IHDs need to be quantified to inform resource allocation decisions at national and global levels.

CRD42022337577.
Seasonal influenza surveillance and vaccination policies in the WHO South-East Asian Region
Authors: Haider Saleh , Hassan Md Zakiul
Published: February 2025

The WHO South-East Asia Region (SEAR), with its high population density, is recognised by epidemiologists as a critical reservoir for the emergence and global dissemination of novel influenza strains, making it a potential epicentre for future influenza pandemics. Despite this significant risk, most SEAR countries lack comprehensive seasonal influenza vaccination policies, resulting in low vaccine uptake across the region. This review analysed the latest WHO National Influenza Programme factsheets from the 11 SEAR member states and supplemented this with extensive manual literature searches using electronic databases and government websites. As of October 2022, only three countries—India, Bhutan and Thailand—had established seasonal influenza vaccination policies. Among them, Bhutan and Thailand have policies that cover all five WHO-recommended high-risk groups. While national influenza surveillance systems are in place across SEAR, only India and the Democratic People’s Republic of Korea claim full population coverage. Influenza vaccine production capacity is limited to Bangladesh, India and Indonesia. The region’s varied climatic conditions and insufficient local data have further obscured the true burden of influenza. Thailand offers a successful model for other countries in the region, beginning with the most vulnerable groups and gradually expanding coverage. To effectively develop and implement national influenza vaccination policies, SEAR countries must close the evidence gap by strengthening surveillance systems to provide accurate, timely data and prioritise context-specific research, leverage existing vaccine infrastructure, enhance public education and finally engage with local and international stakeholders to establish strong international cooperation to support these efforts and improve pandemic preparedness.
Immunoglobulin unresponsive Guillain-Barré syndrome: rinse or repeat? A systematic review
Authors: Roe Thomas , Gordon Alex , Gourd Nicholas , Thomas Charlotte , Ward James , Osman Chinar , Dushianthan Ahilanandan
Published: February 2025

Introduction

Severe Guillain-Barré syndrome (GBS) patients may not show improvement after a single course of intravenous immunoglobulin (IVIg) therapy. Current treatment options include either a second course of IVIg or therapeutic plasma exchange (TPE). This systematic review aims to evaluate the current literature on the use of a second course of IVIg or TPE in patients who fail to show clinical improvement after the first IVIg course.

Methods

We searched PubMed, Embase and Medline databases up until 26 October 2023. Studies that evaluated adult patients with confirmed GBS who have failed one full course of IVIg and subsequently received either repeat IVIg or TPE were included. Risk of bias was performed using study-specific checklists. A narrative synthesis of results is presented.

Results

A total of 37 articles were identified (1 randomised controlled trial (RCT), 3 observational and 33 case reports/series), consisting of 422 patients in total. 12 studies evaluated repeat IVIg and 24 studies evaluated TPE after IVIg. There was no superiority of a repeat course of IVIg or TPE in all clinical outcome measures.

Conclusions

The evidence suggests with a low degree of certainty that there is no beneficial effect of further IVIg in unresponsive GBS. The quality of evidence regarding TPE after IVIg is insufficient to suggest any efficacy due to a lack of RCTs. We recommend standardised case reporting with consideration for a multinational case registry and RCTs to determine the efficacy of TPE after initial IVIg unresponsiveness.
Exploring the levels of variation, inequality and use of physical activity intervention referrals in England primary care from 2017–2020: a retrospective cohort study
Authors: Jani Anant , Liyanage Harshana , Okusi Cecilia , Sherlock Julian , Hoang Uy , McGagh Dylan , Williams John , Ferreira Filipa , Yonova Ivelina , de Lusignan Simon
Published: February 2025

Objectives

In this study, we explore the use of physical activity intervention referrals in primary care in England and compare their use with the rate of cardiovascular disease (CVD) risk factors in England from 2017 to 2020. We also explore variation and inequalities in referrals to these interventions in England across the study period.

Design

Retrospective cohort study.

Setting

England primary care via the Royal College of General Practitioners Research Surveillance Centre.

Participants

The Royal College of General Practitioners Research Surveillance Centre, a sentinel network across England covering a population of over 15 000 000 registered patients, was used for data analyses covering the 2017–2020 financial years and including patients with long-term conditions indicating CVD risk factors.

Outcome measures

An existing ontology of primary care codes was used to capture physical activity interventions and a new ontology was designed to cover long-term conditions indicating CVD risk factors. Single factor analysis of variance, paired samples t-test and two-tailed, one proportion z-tests were used to determine the significance of our findings.

Results

We observed statistically significant variation in physical activity intervention referrals for people with CVD risk factors from different ethnic groups and age groups across different regions of England as well as a marked decrease during the COVID-19 pandemic. Interestingly, a significant difference was not seen for different socioeconomic groups or sexes. Across all attributes and time periods (with the exception of the 18–39 group, 2017–2019), we observed a statistically significant underuse of physical activity intervention referrals.

Conclusions

Our findings identified statistically significant variation and underuse of physical activity referrals in primary care in England for individuals at risk of CVD for different population subgroups, especially different ethnicities and age groups, across different regions of England and across time, with the COVID-19 pandemic exerting a significant negative impact on referral rates.
Implementing Guidelines for hypothermia prevention with Local adaptation to keep periOperative patients Warm (GLOW): protocol of a stepped-wedge cluster randomised hybrid type II effectiveness-implementation study
Authors: Munday Judy , Duff Jed , Wood Fiona M , Sturgess David , Keogh Samantha , Ralph Nicholas , White Nicole M , Carter Hannah , Graham Ian D
Published: February 2025

Introduction

Perioperative hypothermia is a common and preventable complication of surgery. Systems level change that enables perioperative teams to integrate hypothermia prevention into practice in ways that are contextually appropriate is needed. The purpose of this trial is to evaluate the effectiveness and implementation of perioperative hypothermia prevention guidance with local adaptation on clinical, implementation and economic outcomes. Our objective is to decrease the risk of patients developing perioperative hypothermia.

Methods and analysis

A hybrid type II effectiveness-implementation study. An incomplete stepped-wedge cluster randomised controlled trial design will be used, with a 6-month transition period for implementation. Perioperative departments from five major public hospitals in South East Queensland, Australia, will participate over 27 months. The co-primary outcomes are (effectiveness) hypothermia on arrival to the post anaesthetic care unit (PACU) and (implementation) extent of temperature monitoring and active warming. Secondary clinical effectiveness outcomes include hypothermia at any perioperative time point, PACU and hospital length of stay, intraoperative or post-anaesthetic adverse events, blood transfusions and surgical site infection. Secondary implementation outcomes include pre-transition measures of adoptability and implementability, and post-transition measures of adoption, fidelity of implementation strategy and site team learning. Cost-effectiveness will evaluate implementation costs and quality-adjusted life years. Based on the number and unequal sizes of clusters, we used a constrained randomisation approach for sample size determination to minimise the imbalance between control and intervention period sample sizes. Generalised linear mixed models will be used to analyse primary and secondary outcomes.

Ethics and dissemination

Ethical approval was obtained with a waiver of consent to access clinical records (reference: HREC/2023/MNHB/94571). Informed consent will be sought from patients completing surveys. Consent will be implied from clinicians participating in implementation evaluation. Findings will be disseminated through journal publications and conference presentations. Practice and policy recommendations will be collaboratively developed with partner organisations.

Trial registration number

Prospective registration of the trial was obtained on 28 July 2023 on the Australia and New Zealand Clinical Trials Registry Network: ACTRN12623000814673.
Association between the COVID-19 vaccination campaign and fertility trends: a population-level time series analysis for 22 countries
Authors: Jasilioniene Aiva , Jasilionis Domantas , Jdanov Dmitri , Myrskylä Mikko
Published: February 2025

Introduction

At the turn of 2021–2022, monthly birth rates declined in many higher-income countries. We explore how the rollout of COVID-19 vaccination was associated with this decline.

Methods

Using an interrupted time series design, we evaluate the impact of the onset of the COVID-19 pandemic and the start of COVID-19 vaccination on seasonally adjusted monthly total fertility rates in 22 high-income countries. We study the associations between COVID-19 vaccination and fertility by additionally controlling for youth unemployment, stringency index and vaccination coverage. Fertility data come from the Short-Term Fertility Fluctuations data series under the Human Fertility Database. Indicators used as control variables originate from Eurostat and OECD databases, Oxford COVID-19 Government Response Tracker and Our World in Data.

Results

The start of the pandemic had an immediate effect on fertility in most countries, although the size and direction of level changes considerably varied across them. The impact of COVID-19 vaccination was likewise extensive. While a relatively pronounced negative association between the COVID-19 vaccine rollout and fertility 9 months later was found only for 10 out of 22 countries, indications of a negative fertility response were detected in the vast majority of countries. For several countries, the decline was preceded by fertility increase that took place after the onset of the pandemic. Only 4 out of 22 countries had post-vaccination fertility declines that resulted in fertility being on lower level than what the pre-pandemic trend predicted. Additional control variables changed the associations only a little.

Conclusions

The COVID-19 vaccination campaign contributed to the variation in short-term fertility trends. Several countries experienced declines following the campaign, which often returned fertility closer to the pre-pandemic trend. Fertility appears to have responded in short run to vaccination, but only in few cases such that the long-term trajectory is below the pre-pandemic trend.
Understanding patient experiences during gynaecological procedures: a qualitative exploratory study
Authors: Gopisetty Deepti Divya , Rogers-Shepp India , Padron Elisa , Shankar Megha , Shaw Kate A
Published: February 2025

Background

Pain with gynaecological clinic-based procedures is common and undertreated. Prior research has focused on interventions for reducing pain and anxiety with analgesics, yet there remain gaps in understanding the myriad of facilitators and barriers to a person’s positive experience. We aimed to start to address these gaps by exploring factors that influence a person’s experience during gynaecological procedures beyond quantitative measures of pain.

Methods

A qualitative thematic analysis approach was used for this exploratory study. Through convenience sampling, we recruited 15 participants with gynaecological procedural experience with intrauterine device (IUD) insertions, surgical abortions, colposcopies and/or endometrial biopsies. We conducted in-depth, semi-structured 1:1 interviews that explored participants' experience of the procedure. We then used a mixed inductive and deductive approach for development of a codebook and thematic analysis based on the Person-Centered Care Framework for Reproductive Health Equity (PCFRHE).

Results

Four themes fundamental to understanding how patients process procedural experiences were identified: (1) Balancing preparation and anxiety, (2) Variable rapport with clinicians, (3) Self-advocacy and autonomy and (4) Clinician responsiveness to pain.

Conclusions

Person-centred care in an inclusive, trauma-responsive environment is essential for improving gynaecological procedural experience. Ensuring patient access to pre- and post-visit information and offering multiple options to increase comfort are tangible actions clinicians can take to improve patient experience. This study underscores the importance of person-centred care in gynaecological procedures, emphasising better preprocedural education and support.
Efficacy and safety of nivolumab plus ipilimumab in patients with metastatic variant histology (non-clear cell) renal cell carcinoma
Authors: Moussa Mohammad Jad , Khandelwal Jaanki , Wilson Nathaniel R , Malikayil Kiran L , Surasi Devaki Shilpa , Bathala Tharakeswara K , Lin Yiyun , Rao Priya , Tamboli Pheroze , Sircar Kanishka , Ajufo Helen , Elsayes Khaled M , Shah Amishi , Johns Andrew C , Goswami Sangeeta , Hasanov Elshad , Jonasch Eric , Msaouel Pavlos , Campbell Matthew T , Alhalabi Omar , Tannir Nizar M
Published: February 2025

Background

Nivolumab plus ipilimumab (nivo/ipi) is a standard of care first-line (1 L) therapy for patients with metastatic clear-cell renal cell carcinoma (ccRCC), but its role in patients with metastatic, non-ccRCC has not been fully defined. We report a single-institution experience with nivo/ipi in non-ccRCC.

Methods

Between November 2017 and February 2024, 55 patients with metastatic non-ccRCC received nivo/ipi at MD Anderson Cancer Center. The tumor response was assessed by blinded radiologists using RECIST v1.1. The overall response rate (ORR), progression-free survival (PFS), PFS milestone, duration of response (DoR), and overall survival (OS) were determined. Next-generation sequencing (NGS) was performed on available tumor specimens.

Results

Twenty-five (45.5%) patients had papillary histology (pRCC), 12 (21.8%) patients had chromophobe (chRCC), and 18 (32.7%) patients had unclassified RCC (uRCC). Fifty-two (94.5%) patients received nivo/ipi in 1 L. Sarcomatoid features (SF) were found in 20 (36.4%) cases. ORR was 48% (12/25) in pRCC, 25% (3/12) in chRCC (all 3 cases had SF), 27.8% (5/18) in uRCC, and 55% (11/20) across histologies with SF.

The median PFS was 10.6 months (95% CI: 2.8 to 22.8) in pRCC, 3.6 months (95% CI: 0.9 – NE) in chRCC, and 3 months (95% CI: 2.1 to 7) in uRCC; 6-month milestone PFS was 56% (95% CI: 36.3 to 75.7), 41.7% (95% CI: 22 to 61.3), and 38.9% (95% CI: 21.7 to 56.1) in pRCC, chRCC, and uRCC, respectively. The median DoR for the entire cohort was 8.5 months (95% CI: 8 – NE). The median OS was 36.7 months (95% CI: 11.5 to 54.8) in pRCC, 25.7 months (95% CI: 0.9 – NE) in chRCC, and 11.1 months (95% CI: 6.5 – NE) in uRCC.

Ten (18.2%) patients discontinued treatment due to treatment-related adverse events (AEs). Grade 3/4 immune-mediated AEs were noted in 17 (30.9%) patients. We performed NGS on 26 cases:TP53(42%),PTEN(23%), andTERT(23%) alterations were most frequently found, withTERTandTP53mutations enriched in pRCC and chRCC, respectively.

Conclusion

Nivo/ipi produced favorable outcomes in patients with pRCC supporting its use as 1 L therapy. Responses in patients with chRCC were noted exclusively with SF. Despite achieving an ORR of 27.8% with nivo/ipi, patients with uRCC had short PFS and inferior OS.
Opioid use among injured workers: pain and the return-to-work experience
Authors: Nadalin Victoria , Carnide Nancy , Mustard Cameron , Severin Colette N , Furlan Andrea D , Smith Peter M
Published: February 2025

Objective

In this cross-sectional analysis, we explored how return-to-work (RTW) experiences and postinjury pain are associated with opioid use after a workplace injury/illness.

Methods

Workers with accepted lost-time claims, compensated by the workers’ compensation board in Ontario, Canada were interviewed by telephone 18 months following a work-related physical injury/illness. Participants were asked about their past-year opioid use, current pain, RTW timing and workplace accommodations. Separate logistic regression analyses were conducted to estimate the association between two independent variables and opioid use: one combining the presence of pain with workplace accommodation and a second combining the presence of pain with RTW timing, adjusted for sociodemographic, work, injury and health covariates.

Results

Of 1793 participants included in the analysis, 35.6% used opioids more than once in the past 12 months. Compared with those who did not return to work too soon and had no/mild pain, odds of opioid use were higher among those with severe pain, both those who returned too soon (OR 2.90, 95% CI 2.11 to 3.99) and those who did not return too soon (OR 3.01, 95% CI 2.16 to 4.19). Compared with those who had an offer of accommodation and no/mild pain, workers with severe pain and an accommodation offer (OR 2.78, 95% CI 2.16 to 3.57) or without an offer (OR 2.69, 95% CI 1.90 to 3.81) had increased odds of reporting use of opioids.

Conclusions

Findings suggest pain is the main factor associated with opioid use after a work-related injury, irrespective of RTW experiences. However, due to the limitations of this exploratory analysis, longitudinal research examining this issue is warranted.
Does selenium offset methylmercury toxicity across trophic levels in a primary producer, Auxenochlorella pyrenoidosa, and a detritovore, Aeolosoma variegatum?
Authors: Azmi Husnah , Melles Stephanie J. , Laursen Andrew E.
Published: February 2025

Methylmercury ([CH3Hg]+ or MeHg) is a potent neurotoxin that impairs functioning of the nervous system, and selenium (Se) is known to provide a protective effect against MeHg. Experiments were run to investigate the expected offsetting of MeHg toxicity by Se across trophic levels at the base of the aquatic food chain. An algal primary producer, Auxenochlorella pyrenoidosa, was exposed to MeHg (2 µg L−1) in the presence or absence of varying levels of Se (0 µg L−1, 2 µg L−1, and 5 µg L−1). Results showed that MeHg decreased the maximum density of Auxenochlorella, which Se did not offset. Equal amounts (8 mg) of the algal biomass produced under exposure conditions were subsequently fed to a detritovore, Aeolosoma variegatum (a small freshwater annelid worm). When consuming dietary Se in MeHg contaminated water, or when consuming dietary Se with dietary MeHg, Aeolosoma populations experienced a rescue effect against MeHg, i.e., they achieved greater final population density. Understanding safe levels of dietary Se that provide population level protection against MeHg is a critical step towards managing mercury in contaminated ecosystems.