bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Prebiotic Supplementation on Markers of Exercise-Induced Gastrointestinal Syndrome in Response to Exertional Heat Stress
Authors: Rauch Christopher E. , Henningsen Kayla , Martinez Isabel , Young Pascale , Mika Alice , Huschtscha Zoya , McCubbin Alan , Henry Rebecca , Anderson Doville , Costa Ricardo J.S.
Published: February 2025

Exercise perturbs various aspects of gastrointestinal integrity and function, which may lead to performance impeding gastrointestinal symptoms (GIS) and/or precipitate clinical issues warranting medical management. This study aimed to determine the impact of prebiotic supplementation on gastrointestinal integrity and functional status in response to exertional heat stress (EHS). Sixteen endurance athletes completed two trials of 3-hr running at 60% in 30 °C at baseline (T1) and following an 8-week supplementation period (T2), with 16 g/day prebiotic (PREBIOTIC) or matched placebo (PLACEBO). Blood samples were collected pre-EHS and post-EHS and in recovery for determination of stress response (cortisol), intestinal epithelial injury (intestinal fatty acid binding protein), bacterial endotoxemia (sCD14), and systemic inflammation (C-reactive protein). GIS and feeding tolerance variables were assessed throughout the EHS. Orocecal transit time was determined via a lactulose challenge given at 2.5 hr into EHS. Plasma cortisol (combined mean: +252 ng/ml), intestinal fatty acid binding protein (+800 pg/ml), and sCD14 (+487 ng/ml) concentrations increased in response to EHS in T1 (p ≤ .05), but not for C-reactive protein (+0.8 μg/ml; p > .05), in both PREBIOTIC and PLACEBO. PREBIOTIC supplementation resulted in a blunted intestinal fatty acid binding protein response on T2 (+316 pg/ml) compared with an increase (+1,001 ng/ml) in PLACEBO (p = .005). Lower sCD14 was observed at T2 (2,799 ng/ml) versus T1 (3,246 ng/ml) in PREBIOTIC only (p = .039). No intervention effects were observed for C-reactive protein. No difference within or between PREBIOTIC and PLACEBO at T1 and T2 was observed for orocecal transit time, GIS, and feeding tolerance. In conclusion, 8 weeks of prebiotic supplementation modestly attenuates EHS associated perturbations to intestinal integrity, but does not further impair gastrointestinal transit and/or exacerbate EHS associated GIS or feeding tolerance.
Fluctuating Running Speed During 10-km Running Elevates Physiological Strain
Authors: Sumi Daichi , Takii Yasuho , Abe Satoru , Sakaguchi Masanori
Published: February 2025

Purpose: Although it is anecdotally believed that fluctuating running speed during competition has a negative impact on running performance, its influence on physiological strain remains unclear. Therefore, the purpose of the present study was to determine the effect of fluctuating running speed during 10-km running on physiological strain compared with constant running speed. Methods: Ten male endurance runners completed 2 trials on different days, consisting of either fluctuating (FLU) or constant (CON) running speed during 10-km running on a treadmill. In the CON trial, running speed was constant at 80% of maximal oxygen uptake (), while running speed fluctuated between 75% and 85% of in the FLU trial. Blood lactate levels were evaluated before and after running. Moreover, oxygen uptake () and expired minute ventilation () were measured with running. Results: The time to complete 10-km running was the same between the 2 trials (FLU 38.6 [5.1] min, CON 38.6 [5.1] min). The FLU trial showed greater exercise-induced blood lactate elevation compared with the CON trial (FLU 4.5 [1.5] mmol/L, CON 2.9 [1.4] mmol/L). The mean values of (FLU 48.6 [3.5] mL·kg−1·min−1, CON 47.1 [3.6] mL·kg−1·min−1) and (FLU 95 [14] L/min, CON 87 [11] L/min) during running were significantly higher in the FLU trial than in the CON trial. Conclusion: Fluctuating running speed elevated physiological strain compared with constant running speed during 10-km running, even if the time to complete 10-km running was the same.
Modulation of blood-tumor barrier transcriptional programs improves intratumoral drug delivery and potentiates chemotherapy in GBM
Authors: Jimenez-Macias Jorge L. , Vaughn-Beaucaire Philippa , Bharati Ayush , Xu Zheyun , Forrest Megan , Hong Jason , Sun Michael , Schmidt Andrea , Clark Jasmine , Hawkins William , Mercado Noe , Real Jacqueline , Huntington Kelsey , Zdioruk Mykola , Nowicki Michal O. , Cho Choi-Fong , Wu Bin , Li Weiyi , Logan Theresa , Manz Katherine E. , Pennell Kurt D. , Fedeles Bogdan I. , Bertone Paul , Punsoni Michael , Brodsky Alexander S. , Lawler Sean E.
Published: February 2025

Efficient drug delivery to glioblastoma (GBM) is a major obstacle as the blood-brain barrier (BBB) and the blood-tumor barrier (BTB) prevent passage of the majority of chemotherapies into the brain. Here, we identified a transcriptional 12-gene signature associated with the BTB in GBM. We identified CDH5 as a core molecule in this set and confirmed its expression in GBM vasculature using transcriptomics and immunostaining of patient specimens. The indirubin-derivative, 6-bromoindirubin acetoxime (BIA), down-regulates CDH5 and other BTB signature genes, causing endothelial barrier disruption in vitro and in murine GBM xenograft models. Treatment with BIA increased intratumoral cisplatin accumulation and potentiated DNA damage by targeting DNA repair pathways. Last, using an injectable BIA nanoparticle formulation, PPRX-1701, we significantly improved cisplatin efficacy in murine GBM. Our work reveals potential targets of the BTB and the bifunctional properties of BIA as a BTB modulator and a potentiator of chemotherapy, supporting its further development.
A photovoltaic-electrolysis system with high solar-to-hydrogen efficiency under practical current densities
Authors: Zhang Qingran , Shan Yihao , Pan Jian , Kumar Priyank , Keevers Mark J. , Lasich John , Kour Gurpreet , Daiyan Rahman , Perez-Wurf Ivan , Thomsen Lars , Cheong Soshan , Jiang Junjie , Wu Kuang-Hsu , Chiang Chao-Lung , Grayson Kristian , Green Martin A. , Amal Rose , Lu Xunyu
Published: February 2025

The photovoltaic-alkaline water (PV-AW) electrolysis system offers an appealing approach for large-scale green hydrogen generation. However, current PV-AW systems suffer from low solar-to-hydrogen (STH) conversion efficiencies (e.g., <20%) at practical current densities (e.g., >100 mA cm
−2
), rendering the produced H
2
not economical. Here, we designed and developed a highly efficient PV-AW system that mainly consists of a customized, state-of-the-art AW electrolyzer and concentrator photovoltaic (CPV) receiver. The highly efficient anodic oxygen evolving catalyst, consisting of an iron oxide/nickel (oxy)hydroxide (Fe
2
O
3
-NiO

x

H

y

) composite, enables the customized AW electrolyzer with unprecedented catalytic performance (e.g., 1 A cm
−2
at 1.8 V and 0.37 kgH
2
/m
−2
hour
−1
at 48 kWh/kgH
2
). Benefiting from the superior water electrolysis performance, the integrated CPV-AW electrolyzer system reaches a very high STH efficiency of up to 29.1% (refer to 30.3% if the lead resistance losses are excluded) at large current densities, surpassing all previously reported PV-electrolysis systems.
Anthropogenic intensification of Arctic anticyclonic circulation
Authors: Liu Zhongfang , Risi Camille , Codron Francis , Gastineau Guillaume , Huan Xiaohe , Lan Haimao , Xu Wanling , Bowen Gabriel J.
Published: February 2025

The past four decades have witnessed a strengthening of the winter anticyclonic circulation over the Barents-Kara Sea (BKS), a change that has contributed substantially to amplified local warming and sea ice loss, as well as to Eurasian cooling. However, the cause of this trend in the BKS atmospheric circulation remains unknown. Here we show that anthropogenic greenhouse gases are the primary driver of the strengthening of the BKS anticyclonic circulation, with anthropogenic aerosols playing a secondary role, both together accounting for about 86% of the observed circulation trend. Both forcings induce an amplified BKS low-tropospheric warming through coupling with strong sea ice loss. This amplified warming raises geopotential height aloft through thermal expansion, causing an anomalous anticyclonic anomaly, which in turn enhances warming and sea ice loss, forming a positive feedback loop. Our work provides a theoretical framework for understanding Arctic atmospheric circulation responses to anthropogenic warming and may have implications for climate and environment in the Arctic and beyond.
Transformation of flg22 perception into electrical signals decoded in vasculature leads to sieve tube blockage and pathogen resistance
Authors: Furch Alexandra C. U. , Zimmermann Matthias R. , Noll Gundula A. , Wrobel Lisa S. , Scholz Sandra S. , Buxa-Kleeberg Stefanie V. , Hafke Jens B. , Fliegmann Judith , Mithöfer Axel , Ehlers Katrin , Haufschild Tom , Nötzold Jonas , Koch Aline M. , Grabe Veit , Teutemacher Florian , Maaß Jan-Peter , Prüfer Dirk , Oelmüller Ralf , Peiter Edgar , Kogel Karl-Heinz , van Bel Aart J. E.
Published: February 2025

This study focuses on the question how and where information acquired by FLS2 perception of flg22 is transformed into electrical signals crucial for generation of local and systemic defense responses. In
Arabidopsis thaliana
and
Vicia faba
leaves, FLS2 density was high in the epidermis and vascular parenchyma, low in mesophyll, and absent in sieve elements (SEs). Aequorin-based examinations disclosed dual cytosolic Ca
2+
peaks shortly after flg22 application, which corresponded with two voltage shifts from the epidermis to SEs. These signals were converted into rapid long-range action potentials (APs) or slower short-range variation potentials (VPs). Modified phytohormone-levels demonstrated systemic AP effects. Jasmonic acid up-regulation was significantly higher in wild-type than
Atseor1/2
mutants. Abundant Ca
2+
influx associated with VPs was responsible for transient sieve element occlusion (SEO) near the flg22 perception site, whereas SEO was absent in
Atseor1/2
and
Atfls2
mutants. Biological relevance of SEO was demonstrated by higher susceptibility of
Atseor1/2
mutants to
Pseudomonas syringae
than wild-type plants.
Manipulating the coordination dice: Alkali metals directed synthesis of Co-N-C catalysts with CoN
4
sites
Authors: Huang Mengxue , Zhu Xuya , Shi Wenwen , Qin Qianqian , Yang Jie , Liu Shanshan , Chen Lifang , Ding Ruimin , Gan Lin , Yin Xi
Published: February 2025

Nitrogen-coordinated metal sites (MN

x

) in metal- and nitrogen-codoped carbon (M-N-C) catalysts offer promising electrocatalytic activity, but selective synthetic design of MN

x

sites with specific coordination environments remains challenging. Here, we manipulate the formation statistics of MN

x

sites by using sacrifice alkali metals (AM = Li, Na, and K) to form metal vacancy-N

x

carbon (AM-MVN

x

-C) templates, which are used to direct the solution-phase formation of CoN
4
sites in Co-N-C catalysts. We build a probability weight function based on the embedding energy of M in MN

x

sites as the descriptor for MN

x

formation statistics, and we predict that the alkali metals are prone to induce the formation of MVN
4
sites. By coordinating Co
2+
ions with AM-MVN

x

-C templates, we synthesize Co-N-C with CoN
4
sites, demonstrating remarkable oxygen reduction activity in anion exchange membrane fuel cells. These results highlight the statistical thermodynamics of MN

x

formation and open up the possibility for the rational design of complex M-N-C electrocatalysts with well-defined MN

x

sites.
Bone marrow transplant protects mice from sickle cell–mediated large artery remodeling
Authors: Hatoum Liana , Song Hannah , Alexander David , Omojola Victor O. , Moore Hannah , Frank Julia N. , Botchwey Edward A. , Platt Manu O.
Published: February 2025

Sickle cell disease (SCD) is a hereditary blood disorder that causes sickling of red blood cells under deoxygenation, which stiffens and damages the cells. Individuals homozygous for the mutant β-globin S allele (SS) endure complications including progressive arterial damage and heightened risk of stroke. The effectiveness of bone marrow transplantation (BMT), now the only curative treatment for SCD, in halting or reversing SCD-mediated arteriopathy remains unclear. This study used two distinct conditioning regimens, x-ray irradiation and chemotherapy, in a Townes humanized murine model of SCD. Mice homozygous for the SS allele underwent BMT at 2 or 4 months of age, time points that we deemed early or late, respectively. Label-free magnetic resonance angiography (MRA) was performed to longitudinally monitor common carotid artery luminal areas in living mice pre- and repeatedly post-BMT, followed by histological analysis of the arteries at euthanasia. Myeloablative chemotherapy demonstrated higher survivability in SS mice compared with x-ray irradiation. SS mice exhibited arterial outward expansion by 3 months and thinning of the medial layer at 5 months, which are characteristics of a weakened arterial wall. BMT at 2 months effectively halted this expansion, maintaining smaller luminal areas in SS mice. However, BMT at 4 months did not reverse arteriopathy, indicating the importance of early intervention. This work emphasizes how MRA can be used as a noninvasive method for assessing arteriopathy progression and demonstrates that the timing of BMT is crucial in mitigating sickle cell–induced large artery remodeling.
Identification and characterization of an invasive, hyper-aerotolerant
Campylobacter jejuni
strain causing bacteremia in a pediatric leukemia patient
Authors: Zeng Ximin , Lloyd Kevin M. , Hamdy Rana F. , Shapiro Craig A. , Fisher Mark A. , Lin Jun , Liu Benjamin M.
Published: February 2025

Background

Campylobacter jejuni
is a leading pathogen causing gastroenteritis in humans. Invasive
C. jejuni
strains crossing the gut-blood barrier can cause bacteremia. Despite its microaerophilicity (preferring <5% O
2
atmosphere), hyper-aerotolerant (HAT)
C. jejuni
has recently been isolated from intestines in poultry and humans. Elevated aerotolerance may enhance
C. jejuni
survival in the ecosystem, thereby promoting its transmission. However, invasive HAT isolates of
C. jejuni
have not been reported in bacteremia in humans.

Case Summary

A
C. jejuni
strain (CNH-HAT-1) was isolated from a 7% CO
2
(~16% O
2
) atmosphere subculture of an aerobic blood culture from a 5-year-old boy with B-cell acute lymphoblastic leukemia presenting with bloody stool, fever, and neutropenia. The organism identification was determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S-rRNA sequencing. HAT phenotype of this isolate was confirmed by aerotolerance testing. Belonging to the ST-21 clonal complex, CNH-HAT-1 is phylogenetically close to recently reported invasive
C. jejuni
sheep abortion strains and some bacteremia-associated strains. CNH-HAT-1 possesses a CJIE-1 prophage element, a functional enterobactin receptor CfrB, and G250A mutation in the major outer-membrane protein PorA, which likely contributes to
C. jejuni
invasiveness. CNH-HAT-1 is resistant to penicillins/cephalosporins but susceptible to aminoglycosides, fluoroquinolones, and macrolides. The patient improved with intravenous gentamicin, followed by enteral therapy with azithromycin.

Conclusion

We identified a novel invasive bloodstream
C. jejuni
strain proven
in vitro
to be HAT, shedding light on key genomic features linking with its pathogenesis. Given its enhanced survival of HAT
C. jejuni
in ecosystem, a clinical microbiology lab should be vigilant with detecting them from blood cultures.
Use of gastrointestinal syndromic multiplex molecular assays and detection of
Escherichia coli
pathotypes in pediatric wards
Authors: Bizot Etienne , Bonacorsi Stéphane , Labé Pauline , Pinhas Yael , Cointe Aurélie , Ferroni Agnès , Cohen Jérémie F. , Lécuyer Hervé , Toubiana Julie
Published: February 2025

Escherichia coli
pathotypes are enteric pathogens detected in gastrointestinal multiplex polymerase chain reaction (mPCR), with controversial clinical relevance. Our study aimed to describe clinical features and therapeutic decisions associated with
E. coli
detections in gastrointestinal mPCR. Children with positive mPCR for enteroaggregative (EAEC)
,
enteropathogenic (EPEC)
,
enterotoxigenic (ETEC), Shiga toxin-producing
E. coli
(STEC), and enteroinvasive
E. coli
(EIEC)/
Shigella
identified in two pediatric hospitals over 18 months (2020–2021) were included. We described the frequency of
E. coli
detection and subsequent modifications in antibiotic strategies. Among the 2,471 mPCRs performed, 338 (14%) tested positive for at least one
E. coli
pathotype. The patient's mean age was 4.2 years, with 95% experiencing gastrointestinal symptoms. Clinical presentation was generally comparable between
E. coli
pathotypes. A recent travel abroad was reported in 68/338 (20%) cases and was mainly observed in EIEC/
Shigella
infections. An
E. coli
was detected alone in 177/338 (52%) cases and with another virus, bacteria, or parasite in 161 (48%) cases. Multiple enteric pathogens were mainly detected with ETEC (
n
= 24/26, 92%) and EAEC (
n
= 82/121, 68%) detections. Antibiotic therapy was prescribed in 136/338 (40%) cases, with initiation based on mPCR results in 69/338 (20%). No antibiotic therapy was discontinued following positive mPCR results. Among the 69 initiations, 31 were deemed inappropriate after retrospective chart review.
E. coli
detection with mPCR tests may lead to inappropriate antibiotic initiation. Caution is advised when interpreting results from gastrointestinal mPCRs in children, as clinicians may be unaware of their often unclear or irrelevant clinical significance.

IMPORTANCE

Escherichia coli
pathotypes are increasingly detected through the widely used syndromic gastrointestinal multiplex PCR panels. However, their clinical significance and impact on antibiotic therapy in children remain uncertain. This study describes the clinical and microbiological characteristics associated with
E. coli
detections, as well as the subsequent modifications in antibiotic strategies. It highlights the frequent detection of
E. coli
pathotypes, often in association with other enteric pathogens, and reveals that nearly half of the antibiotics prescribed following these results were deemed inappropriate. These results underscore the need to enhance clinicians' interpretation of
E. coli
-positive results and reassess treatment strategies to optimize patient care.
Cell differentiation controls iron assimilation in the choanoflagellate
Salpingoeca rosetta
Authors: Leon Fredrick , Espinoza-Esparza Jesus M. , Deng Vicki , Coyle Maxwell C. , Espinoza Sarah , Booth David S.
Published: February 2025

Marine microeukaryotes have evolved diverse cellular features that link their life histories to surrounding environments. How those dynamic life histories intersect with the ecological functions of microeukaryotes remains a frontier to understanding their roles in critical biogeochemical cycles. Choanoflagellates, phagotrophs that cycle nutrients through filter feeding, provide models to explore this intersection, for many choanoflagellate species transition between life history stages by differentiating into distinct cell types. Here, we report that cell differentiation in the marine choanoflagellate
Salpingoeca rosetta
endows one of its cell types with the ability to utilize insoluble ferric colloids. These colloids are a predominant form of iron in marine environments and are largely inaccessible to cell-walled microbes. Therefore, choanoflagellates and other phagotrophic eukaryotes may serve critical ecological roles by cycling this essential nutrient through iron utilization pathways. We found that
S. rosetta
can utilize these ferric colloids via the expression of a cytochrome b561 iron reductase (
cytb561a
). This gene and its mammalian ortholog, the duodenal cytochrome b561 (
DCYTB
) that reduces ferric cations for uptake in gut epithelia, belong to a subgroup of cytochrome b561 proteins with distinct biochemical features that contribute to iron reduction activity. Overall, our findings provide insight into the ecological roles choanoflagellates perform and inform reconstructions of early animal evolution where functionally distinct cell types became an integrated whole at the origin of animal multicellularity.

IMPORTANCE

This study examines how cell differentiation in a choanoflagellate enables the uptake of iron, an essential nutrient. Choanoflagellates are widespread, aquatic microeukaryotes that are the closest living relatives of animals. Similar to their animal relatives, we found that the model choanoflagellate,
S. rosetta
, divides metabolic functions between distinct cell types. One cell type uses an iron reductase to acquire ferric colloids, a key source of iron in the ocean. We also observed that
S. rosetta
has three variants of this reductase, each with distinct biochemical properties that likely lead to differences in how they reduce iron. These reductases are variably distributed across ocean regions, suggesting a role for choanoflagellates in cycling iron in marine environments.
Detection of mpox and other orthopoxviruses using a lateral flow device as a point-of-care diagnostic
Authors: Laidlaw Stephen M. , Ulaeto David , Lonsdale Steve , Clark Graeme , Sumner Rebecca , Edwards Thomas , Adams Emily , Logist Anne-Sophie , Van Holm Bram , Maluquer de Motes Carlos , Horby Peter , Maes Piet , Carroll Miles W.
Published: February 2025

In 2022, the World Health Organization declared the worldwide outbreak of mpox to be a public health emergency of international concern. The causative monkeypox virus (MPXV) belonged to clade IIb and is transmitted through sexual contact with a low case fatality rate (0.1%), which, together with under-detection, all contributed to a rapid global spread particularly within the MSM (men who have sex with men) community. As MPXV clade II remains circulating worldwide, a new outbreak of the more fatal clade I disease has been declared in Central and East Africa, and remains uncontrolled in part due to the lack of point-of-care (POC) diagnostics for rapid decisions on treatment and self-isolation. To address the lack of POC solutions for mpox, we have designed and evaluated an orthopoxvirus-specific lateral flow device (LFD) that could be used for the diagnosis of mpox. Using an LFD comprising four monoclonal antibodies against the A27 protein, we demonstrate sensitivity to 3 × 10
5
pfu/mL. This sensitivity is expected to be sufficient for the detection of MPXV from lesion sites and may also be sufficient for other sample types such as saliva and urine. We found that the presence of guanidinium thiocyanate, a common ingredient in inactivating viral transport media, masked the LFD antigen, resulting in false negatives. POC diagnosis of mpox may be possible using an LFD to reduce delays arising from sample shipment to centralized laboratory testing facilities. In order to achieve this, our work demonstrates that an LFD-optimized buffer is required, as the sample collection buffer may have a detrimental impact on sensitivity for clinical material.

IMPORTANCE

Mpox cases have dramatically increased both in traditionally monkeypox virus endemic countries and also worldwide. This increase comes at a time when immunity derived from smallpox vaccination is no longer available. Diagnosis of mpox is complicated due to both disease presentation and the availability of local diagnostic laboratories. The availability of a point-of-care diagnostic tool such as an lateral flow device (LFD) would play an important role to both diagnose and prevent onward transmission. This manuscript provides developers and assessors with key data for defining true sensitivity and specificity of a successful LFD in addition to buffer conditions for sample collection.
Supplemental Material: Chert Lagerstätten as a new window to the biological revolution across the Ediacaran–Cambrian boundary
Authors: Luo Cui , Zhu Maoyan
Published: February 2025

Tables S1–S12 and raw data for Figures 1–4. 
Tolicizumab effectively controls giant cell arteritis and prevents recurrence of steroid-induced concomitant toxoplasmosis chorioretinitis
Authors: Cheng Anny M S , Gupta Shailesh K , Abdelaziz Wafa , Chalam Kakarla V
Published: February 2025

Giant cell arteritis (GCA) affects various ocular structures and potentially leads to vision loss. Traditional therapy involves a tapering regimen of high-dose systemic corticosteroids which are associated with adverse effects, including the risk of opportunistic infections such as toxoplasmosis from immune suppression. Tocilizumab, a humanised monoclonal antibody directed against the interleukin-6 receptor, offers an effective treatment option for GCA. In this report, we detail the successful treatment of GCA-associated, steroid-induced recurrent toxoplasma chorioretinitis (RTRC) using intravenous tocilizumab. A female patient in her 70s presented with GCA treatment challenges with prednisone, and subsequent complications of RTRC are discussed. 12 months after the initial presentation, the patient was treated with intravenous tocilizumab, leading to rapid resolution of the active lesion. At the 1-year follow-up, the patient maintained 20/20 vision and showed no signs of inflammation or toxoplasmosis reactivation. This case suggests tocilizumab may be an effective alternative treatment for managing GCA, particularly in cases complicated by RTRC.
Comparative effectiveness and prescribing trends of modified release versus immediate release indapamide in patients with hypertension: cohort study
Authors: Yan Vincent Ka Chun , Ju Chengsheng , MacDonald Thomas MacLennan , Mackenzie Isla S , Flynn Robert , Williams Bryan , Chen Yang , Chan Esther W , George Jacob , Wei Li
Published: February 2025

Objective

To investigate the prescribing trends of indapamide, a thiazide-like diuretic, and the long term comparative effectiveness of modified release versus immediate release indapamide.

Design

Cohort study.

Setting

IQVIA Medical Research Data UK database, incorporating data from The Health Improvement Network database, 1 January 2005 to 31 December 2020.

Participants

Of 1 904 289 patients with hypertension, 86 388 started indapamide treatment during the study period. 30 021 patients received modified release and 56 367 immediate release indapamide.

Main outcome measures

Monthly prescribing trends of modified release and immediate release indapamide are described. A pragmatic trial was emulated to compare the five year risks of composite cardiovascular events (myocardial infarction and stroke) and death between modified release and immediate release indapamide. Intention-to-treat and per protocol effects of treatment were estimated with pooled logistic regression models. Confounding and selection bias were accounted for by multivariable adjustments and inverse probability weights.

Results

1 38 414 patients who used indapamide were identified among 1 904 289 patients with hypertension. A greater increase was seen in the proportion of users of immediate release indapamide (from 0.43% in 2005 to 2.31% in 2020) than in users of modified release indapamide (from 0.71% to 0.79%). 86 388 patients (30 021 and 56 367 who started modified release and immediate release indapamide, respectively) were eligible for the trial emulation. In the intention-to-treat analysis, no difference was found in the risk of cardiovascular events (hazard ratio 0.99, 95% confidence interval (CI) 0.90 to 1.08) or death (hazard ratio 0.97, 0.92 to 1.02) between modified release and immediate release indapamide. In the per protocol analysis, a lower risk of cardiovascular events was found with modified release indapamide than with immediate release indapamide (risk difference −0.39%, 95% CI −0.71% to −0.06%; hazard ratio 0.81, 95% CI 0.68 to 0.98), which was mainly driven by myocardial infarction (risk difference −0.36%, 95% CI −0.64% to −0.08%; hazard ratio 0.80, 95% CI 0.64 to 1.01). Similar risks of death (hazard ratio 1.03, 95% CI 0.90 to 1.17) were found for the two formulations.

Conclusions

In patients treated with indapamide for hypertension, starting treatment with modified release or immediate release indapamide had similar risks for cardiovascular events or all cause mortality. In an exploratory secondary analysis, sustained treatment with modified release preparations was associated with a lower the risk of cardiovascular events but not all cause mortality compared with immediate release preparations. These findings need to be confirmed in prospective studies.
Whole-body integral dose and post-radiotherapy lymphocytopaenia in solid tumours
Authors: Joseph Nuradh , Alagiyawanna Lanka , Ruwanpura Thilina , Gunasekera Sanjeeva , Ruvinda Lakitha , Madushan Sampath , Choudhury Ananya
Published: February 2025

Objective

Since modern radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) pivot on a strategy of dose redistribution, it may increase integral dose and consequently worsening of lymphocytopaenia. In this study, our objective was twofold: first to validate the correlation between integral body dose and post-treatment lymphocytopaenia in a cohort of patients treated with curative-intent radiotherapy and second to validate its prognostic impact.

Methods and analysis

Patients treated with curative intent radiotherapy with complete blood counts were included in the study. Data on the following variables were collected: treatment site, prescribed dose, use of concurrent chemotherapy, mean body dose, mean body volume, treatment technique and disease-free survival.

Results

A total of 116 patients were included for analysis. There was a significant decline in lymphocyte counts after radiotherapy (2.2×109/L vs 0.8×109/L; p<0.001). Multivariate linear regression analysis of post-treatment lymphocytopaenia revealed a significant correlation with pretreatment lymphocyte counts, integral body dose, use of IMRT and use of concurrent radiosensitising chemotherapy. Univariate survival analysis was performed in 37 patients with squamous cell carcinoma of the head and neck. In the Cox proportional hazards model, post-treatment lymphocyte count was statistically significant as a continuous variable (Hazard Ratio=0.998, p=0.01) and as a dichotomous variable.

Conclusion

The negative correlation between integral body dose and post-treatment lymphocytopaenia was validated, and post-treatment lymphocytopaenia is an adverse prognostic factor in patients with head and neck cancer treated with curative-intent radiotherapy.
Evaluating the implementation of inclisiran in primary care: process evaluation interim findings from interviews with key stakeholders
Authors: Wilson Paul , Elvey Rebecca , Mathieson Amy , Bower Peter , Gibson Martin , Vell Tracey , Dixon Samantha
Published: February 2025

Objectives

VICTORION-Spirit was a hybrid study designed to assess the feasibility of implementing inclisiran, a novel cholesterol-lowering treatment and behavioural support within primary care centres in England. This process evaluation aimed to evaluate the implementation of inclisiran for patients with elevated low-density lipoprotein cholesterol and atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (n=900), from the perspectives of key stakeholders.

Design

VICTORION-Spirit was a phase IIIb, multicentre, randomised, controlled study. We followed a process evaluation strategy to collate the views of stakeholders via semistructured interviews and to gain insights on the ‘implementability’ of inclisiran in primary care. Data were generated via interviews with patients, healthcare providers and research nurses and analysed using a qualitative rapid analysis approach.

Setting

Primary care in Greater Manchester, UK.

Participants

84 participants were interviewed, including patients (n=56), professionals at participating practices in VICTORION-Spirit (n=13), health advisors (n=4) and research nurses (n=11).

Results

Interim findings suggest the process of receiving and providing inclisiran during the study was ‘straightforward’, and the behavioural support provided to some patients was generally viewed favourably. Beyond the trial, patients and healthcare providers thought the delivery of inclisiran could work well as a practice nurse-provided service. Barriers to implementing inclisiran were generally related to workforce and workload pressures in primary care, and an incentive structure to support delivery was recommended.

Conclusions

Patients and healthcare providers supported implementing inclisiran in primary care. It was convenient for patients to receive inclisiran in general practice, and most providers felt that the intervention was a useful addition to existing lipid-lowering treatments. Several barriers to implementation were highlighted, including concerns relating to general practice resources and costs.

Trial registration number

NCT04807400.
Predicting the risk of acute kidney injury in patients with acute pancreatitis complicated by sepsis using a stacked ensemble machine learning model: a retrospective study based on the MIMIC database
Authors: Li Fuyuan , Wang Zhanjin , Bian Ruiling , Xue Zhangtuo , Cai Junjie , Zhou Ying , Wang Zhan
Published: February 2025

Objective

This study developed and validated a stacked ensemble machine learning model to predict the risk of acute kidney injury in patients with acute pancreatitis complicated by sepsis.

Design

A retrospective study based on patient data from public databases.

Participants

This study analysed 1295 patients with acute pancreatitis complicated by septicaemia from the US Intensive Care Database.

Methods

From the MIMIC database, data of patients with acute pancreatitis and sepsis were obtained to construct machine learning models, which were internally and externally validated. The Boruta algorithm was used to select variables. Then, eight machine learning algorithms were used to construct prediction models for acute kidney injury (AKI) occurrence in intensive care unit (ICU) patients. A new stacked ensemble model was developed using the Stacking ensemble method. Model evaluation was performed using area under the receiver operating characteristic curve (AUC), precision-recall (PR) curve, accuracy, recall and F1 score. The Shapley additive explanation (SHAP) method was used to explain the models.

Main outcome measures

AKI in patients with acute pancreatitis complicated by sepsis.

Results

The final study included 1295 patients with acute pancreatitis complicated by sepsis, among whom 893 cases (68.9%) developed acute kidney injury. We established eight base models, including Logit, SVM, CatBoost, RF, XGBoost, LightGBM, AdaBoost and MLP, as well as a stacked ensemble model called Multimodel. Among all models, Multimodel had an AUC value of 0.853 (95% CI: 0.792 to 0.896) in the internal validation dataset and 0.802 (95% CI: 0.732 to 0.861) in the external validation dataset. This model demonstrated the best predictive performance in terms of discrimination and clinical application.

Conclusion

The stack ensemble model developed by us achieved AUC values of 0.853 and 0.802 in internal and external validation cohorts respectively and also demonstrated excellent performance in other metrics. It serves as a reliable tool for predicting AKI in patients with acute pancreatitis complicated by sepsis.
Developing evaluation metrics to measure the US national institute of health plans to enhance diverse perspectives: a protocol for a consensus-based study
Authors: Levites Strekalova Yulia A , Jain Sanjay , Sarder Pinaki
Published: February 2025

Introduction

The diversity of participating investigators representing diverse disciplines, career stages, stakeholder groups, regions and types of institutions is essential for the success of large-scale research programmes. In 2021, the National Institutes of Health introduced a requirement for some of its large grants to include a separate section that describes the project’s plan for enhancing diverse perspectives (PEDPs). Our project aims to develop consensus-based PEDP evaluation metrics and instruments that can be systematically and sustainably collected across the projects.

Methods and analysis

Evaluation work is organised into three objectives. First, shared knowledge about PEDP infrastructures, activities and outcomes will be elicited through the review of the PEDP texts of funded projects, with 15 as the target sample size. Data will be analysed using a cultural domain analysis approach and assessed for recurrence and salience of PEDP metrics. Second, consensus-based evaluation metrics will be developed using a three-round Delphi method. The descriptive statistics (mean, SD and IQR) and cultural consensus analyses will be applied to the first and last rounds of the Delphi survey. Third, metrics will be piloted for implementation and validation within one of the Human BioMolecular Atlas Programme sites. Work will be completed by Fall 2025.

Ethics and dissemination

The long-term goal of the effort reported in this paper is to develop PEDP common metrics that are generalisable and feasible across diverse projects. This rigorous, focused evaluation development effort aims to inform scientific practices and policies around implementing the plans to enhance diverse perspectives.
Tebipenem pivoxil as an alternative to ceftriaxone for clinically non-responding children with shigellosis: a randomised non-inferiority trial protocol
Authors: Nuzhat Sharika , Islam Md Ridwan , Das Subhasish , Bashar Syed Jayedul , Pavlinac Patricia B , Arnold Samuel L , Newlands Amy , Gibson Rachel , Alvaro Elena Fernandez , Addo Juliet , Khanam Farhana , Ahmed Dilruba , Chisti Md Jobayer , Qadri Firdausi , Ahmed Tahmeed
Published: February 2025

Introduction

Shigellosis is the second leading cause of diarrhoeal deaths among children worldwide. Oral azithromycin and intravenous ceftriaxone are the recommended first-line and second-line therapies for shigellosis in Bangladesh, respectively, but growing antibiotic resistance will require new antibiotic options. Tebipenem pivoxil, an orally administered carbapenem antibiotic with activity against many strains of antibiotic-resistant bacteria, may be a viable option.

Methods

A phase IIb randomised controlled trial was planned to determine the efficacy and safety of oral tebipenem pivoxil, compared with intravenous ceftriaxone, for children with
Shigella
diarrhoea unresponsive to the first-line antibiotic therapy. We will enrol 132 children in the trial (66 in each arm). Children from Bangladesh aged 24–59 months suspected of having
Shigella
diarrhoea, with no clinical improvement within 48 hours of starting first-line therapy, will be randomised to a 3-day course of intravenous ceftriaxone (50 mg/kg, once a day) or a 3-day course of oral tebipenem pivoxil (4 mg/kg, three times a day). The children will be evaluated for key clinical, microbiological and safety outcomes during the subsequent 30-day period. Clinically, failure at day 3 will be defined as the presence of fever (axillary temperature ≥38°C), diarrhoea (three or more abnormally loose or watery stools in the last 24 hours), blood in stool, or abdominal pain/tenderness at day 3 of follow-up or death or hospitalisation prior to day 3. It is hypothesised that children treated with tebipenem pivoxil will have no worse clinical and microbiological failure rates compared with ceftriaxone.

Ethics and dissemination

This study protocol was approved by the institutional review board of the International Centre for Diarrhoeal Disease Research, Bangladesh, which comprises a research review committee and an ethics review committee. In addition, the use of tebipenem pivoxil in shigellosis was approved by the Directorate General of Drug Administration of Bangladesh.

Trial registration number

NCT05121974
.
Efficacy of synovectomy in the treatment of femoral head osteonecrosis with vascularised fibular grafting in Shanghai: a protocol for SYNERGY-VGF trial
Authors: Fu Kai , Zheng Wei , Cai Qianying , Peng Hao , He Haiyan , Zhu Daoyu , Jiang Chenyi , Wang Zehao , Ding Peng , Yin Jimin , Jin Dongxu , Zhang Changqing , Gao Youshui
Published: February 2025

Background

Osteonecrosis of the femoral head (ONFH) is characterised by progressive bone death, leading to joint incongruity and eventual osteoarthritis. Various interventions have been explored to forestall disease progression and delay total hip arthroplasty (THA). Free vascularised fibula grafting (FVFG) has shown promise, particularly in the precollapse stages of ONFH. However, the potential benefits of combining synovectomy with FVFG to address synovitis in ONFH have not been systematically studied. This trial seeks to compare outcomes between patients undergoing FVFG with and without synovectomy.

Methods and analysis

The trial is a randomised, single-centre, parallel-group trial comparing FVFG with synovectomy versus FVFG alone in patients with ONFH and synovitis. 90 participants will be randomised into two groups: synovectomy (n=45) and non-synovectomy (n=45). The primary outcome is the Harris Hip Score (HHS) change at 12 months post surgery. Secondary outcomes include HHS, Numeric Rating Scale (NRS) for pain, Depression Anxiety Stress Scales-21 (DASS-21), and EQ-5D scale assessments at intervals up to 12 months post randomisation.

Ethics and dissemination

This trial was approved by the Human Research Ethics Committee of Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine prior to patient recruitment (approval number: 2023-076). Results from this trial will be published in peer-reviewed journals. Results will also be presented at international conferences.

Trial registration number

Chinese Clinical Trial Registry (ChiCTR) Identifier: ChiCTR2300073385. Prospectively registered on 10 July 2023.
Role of the collagen scaffold in preventing intrauterine adhesion from recurrence after adhesiolysis: protocol for a multicentre, randomised, controlled, parallel-group, open-label, superiority clinical trial
Authors: Li Taishun , Wang Huiyan , Xu Biyun , Zhu Hui , Hu Yali
Published: February 2025

Introduction

Intrauterine adhesions (IUAs) are one of the most common causes of uterine infertility. Hysteroscopic adhesiolysis is the primary treatment for IUA, but the rate of IUA recurrence is high in moderate to severe cases. While traditional guidelines recommend placing a non-copper stainless steel intrauterine device (IUD) into the uterine cavity after adhesiolysis to prevent readhesion, the preventive effect is uncertain. Our preliminary trials suggested that the collagen scaffold was more effective in moderate cases. This study aims to assess the efficacy and safety of a collagen scaffold versus IUD in preventing readhesion after hysteroscopic adhesiolysis in patients with moderate IUA.

Methods and analysis

This multicentre, open-label, randomised controlled trial evaluates the efficacy and safety of a collagen scaffold compared with an IUD in preventing readhesion after hysteroscopic adhesiolysis in women with moderate IUA. This trial will be conducted at six teaching hospitals and plans to enrol 200 participants. The primary outcome is the non-recurrence rate of IUA 2 months after adhesiolysis. Secondary endpoints include changes in American Fertility Society scores before and after surgery and postoperative menstrual blood volume. The 95% CIs for the difference in non-recurrence rates between the two groups will be calculated. If the lower limit of this interval exceeds the superiority threshold of zero, the conclusion of superiority is confirmed.

Ethics and dissemination

This study has received approval from the ethics committee of the Affiliated Drum Tower Hospital of Nanjing University Medical School (2022-491-02) and the ethics committees of the participating centres. Written informed consent will be obtained from each participant before starting any study procedures. The results of this trial will be published in a peer-reviewed journal.

Trial registration number

ChiCTR2300068271.
Comparison of remimazolam-based and propofol-based general anaesthesia on postoperative quality of recovery in patients undergoing laparoscopic sleeve gastrectomy: protocol for a prospective, randomised, parallel-group, non-inferiority trial
Authors: An Dong-jiao , Wang Jing , Ren Chuning , Zhao Yanjun , Wei Changwei , Wu Anshi
Published: February 2025

Introduction

Remimazolam is a novel short-acting benzodiazepine that exhibits sedative and hypnotic properties without compromising respiratory function and while maintaining haemodynamic stability. Its safety and efficacy have been demonstrated to be non-inferior to those of propofol in the context of general anaesthesia. Nevertheless, the non-inferiority in terms of postoperative recovery quality in obese patients has not been established. Thus, we conducted a prospective, randomised, parallel-group, non-inferiority study to compare remimazolam-based general anaesthesia with propofol-based general anaesthesia on the postoperative quality of recovery (QoR) in patients undergoing laparoscopic sleeve gastrectomy.

Methods and analysis

All participants meeting the included criteria will be enrolled after signing an informed consent form. Patients will be randomly allocated to either the propofol group (n=63; induction and maintenance with propofol) or the remimazolam group (n=63; induction and maintenance with remimazolam). The primary endpoint of the study is the 15-item QoR Scale assessed at 24 hours postoperatively. Secondary endpoints include the doses of anaesthetic required for loss of consciousness (LOC), the time to LOC, the time to recovery of consciousness, the total amount of anaesthetic administered during the surgery and the incidence of hypotension and bradycardia. Additionally, postoperative profiles of pain, nausea and vomiting, delirium, intraoperative awareness, adverse events and patient satisfaction will be collected. Statistical analyses will be performed using IBM SPSS Statistics V.26.0 and GraphPad Prism V.5.01. Statistical significance is set at two-sided p values<0.05.

Ethics and dissemination

Ethical approval was obtained from the ethics committees of Beijing Chaoyang Hospital, Capital Medical University (No. 2023ke715-1). The findings will be disseminated in peer-reviewed publications.

Trial registration number

ChiCTR2400083700.
What are the lived experiences of patients with cancer and their families in northern Ghana? A qualitative study using narrative interview and creative task approach
Authors: Tuck Chloe Zabrina , Akparibo Robert , Gray Laura A , Suraj Hamza , Iddrisu Abdul-Rashid Timtoni , Abane Tampuri Rahman , Deedat Alhassan Ahmed , Aryeetey Richmond Nii Okai , Abubakari Braimah Baba , Azure Amos , Cooper Richard
Published: February 2025

Objectives

Cancer poses a major burden in Ghana that is exacerbated by poor engagement with biomedical treatment. The reasons for this are not well understood for most cancers and in northern Ghana.

Design

This research took combined narrative interviews with a creative task that was analysed through reflexive thematic analysis.

Setting

A tertiary treatment centre in northern Ghana.

Participants

15 adult (>18 years) patients or their relatives who had been diagnosed and/or treated for cancer within the last 2 years.

Results

The thematic analysis highlighted the psychological burden of cancer and ways participants cope and find meaning, including through religion, trust in biomedical treatment, and occupation and social support. The findings stress the negative impact of the financial burden, shame, worry and the spiralling poverty this causes.

The creative task was found to be resonant, emotive and more humanising, which is anticipated to be more effective when communicating with policy-makers and community members. The findings provide rich contextual insights to understand patients’ and relatives’ perspectives and frame their experiences within what was important to them.

Conclusions

Together the research has identified a critical need for policy to consider the psychosocial, occupational, spiritual and financial needs of patients with cancer in northern Ghana. It has demonstrated narrative interviews with graphical elicitation as an effective approach to discuss sensitive topics for findings that can engage stakeholders and inform holistic cancer service design.