bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of a COPD-AssociatedNephronectinFunctional Splicing Genetic Variant in Human Lung TissueviaLong-Read Sequencing
Authors: Saferali Aabida , Wienecke Anastacia N. , Xu Zhonghui , Liu Tao , Sheynkman Gloria M. , Hersh Craig P. , Cho Michael H. , Silverman Edwin K. , Zhou Xiaobo , Wilson Carole L. , Schnapp Lynn M. , Randell Scott H. , Ramos Silvia B.V. , Laederach Alain , Vollmers Christopher , Castaldi Peter J.
Published: February 2025

Background

Identification of COPD disease-causing genes is an important tool for understanding why COPD develops, who is at highest COPD risk, and how new COPD treatments can be developed. Previous COPD genetic studies have identified a highly significant genetic association near nephronectin(NPNT), a gene involved in tissue repair, but the biological mechanisms underlying this association are unknown.

Methods

Splicing quantitative trait locus analysis (sQTL) was performed to identify common genetic variants that alter RNA splicing in lung tissues. These lung sQTL signals were compared to COPD genetic association results near theNPNTgene using colocalization analysis to determine whether genetic risk for COPD in this region may act through altered splicing. Long read sequencing characterized COPD-associated splicing events at isoform-level resolution, and in silico protein structural analysis identified likely functional effects of this alternative splicing.

Results

An established COPD genetic risk variant, rs34712979_A, creates a cryptic splice acceptor site that causes four separate splicing changes imNPNT. The only of these splicing changes that was associated with COPD phenotypes involved a cassette exon (exon 3). Long read RNA sequencing demonstrated that the COPD risk allele causes a shift in isoform usage away from the dominant NPNT Isoform B precursor, which excludes exon 3, to the Isoform A precursor which splices-in exon 3. Alpha-fold protein structural analysis reveals that inclusion of this exon disrupts an EGF-like functional domain in NPNT.

Conclusion

Genetic variants in the nephronectin (NPNT) gene increase COPD risk by changing RNA splicing ofNPNTin the lung.
A Long-Term Follow-Up Study of Sotatercept for Treatment of Pulmonary Arterial Hypertension: Interim Results of SOTERIA
Authors: Preston Ioana R. , Badesch David , Ghofrani Hossein-Ardeschir , Gibbs J. Simon R. , Gomberg-Maitland Mardi , Hoeper Marius M. , Humbert Marc , McLaughlin Vallerie V. , Waxman Aaron B. , Manimaran Solaiappan , Mikhailova Elina , Reddy Madhavi , Lau Anna , de Oliveira Pena Janethe , Souza Rogerio
Published: February 2025

Background

SOTERIA (NCT04796337) is an ongoing open-label study evaluating long-term safety, tolerability, and efficacy of sotatercept in participants with pulmonary arterial hypertension (PAH).

Methods

Eligible adults with PAH on stable background therapy who completed a prior sotatercept study without early discontinuation were enrolled. Participants received subcutaneous sotatercept (≤0.7 mg·kg−1Q3W). Safety and tolerability (primary objective) were assessed by adverse events (AEs), vital signs, and laboratory assessments. Efficacy (secondary objective) was assessed by 6-minute walk distance (6MWD), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, WHO functional class (FC), clinical worsening events, and simplified French risk score (SFRS). The data cutoff date was 08NOV2023.

Results

Altogether, 426 participants were included in the analyses. Mean (sd) duration of exposure to sotatercept and follow-up in SOTERIA was 448.6 (172.93) days (range 21–923 days; 523 patient-years). Of 426 participants, 387 (90.8%) experienced AEs, 15 (3.5%) discontinued treatment, 129 (30.3%) had serious AEs, and 11 (2.6%) had serious AEs related to treatment. There were 12 deaths (2.8%). Among AEs of interest, epistaxis (22.1%) and telangiectasia (16.9%) were the most frequently reported individual events. Twenty-two (5.2%) participants had serious bleeding events, including 2 (0.5%) with serious bleeding leading to death (not related to treatment by investigator judgment). Improvements in 6MWD, NT-proBNP, WHO FC, and SFRS achieved from baseline of SOTERIA were largely maintained at one year, including in the placebo-crossed group.

Conclusion

Interim results of SOTERIA support the favorable benefit-risk of add-on sotatercept treatment in adults with PAH. Follow-up reports from this study will provide additional information on benefit/risk.
Heart Rate response and cardiovascular risk during OSA: an easy biomarker derived from pulse oximetry
Authors: Blanchard Margaux , Imler Théo , Hu Wen-Hsin , Waeber Adrien , Solelhac Geoffroy , Haba-Rubio José , Kerbrat Sandrine , Sabil Abdelkebir , Trzepizur Wojciech , Goupil François , Thomas Audrey , Bailly Sébastien , Azarbarzin Ali , Vollenweider Peter , Marques-Vidal Pedro , Vaucher Julien , Heinzer Raphael , Gagnadoux Frédéric
Published: February 2025

Background

Sleep apnoea specific heart rate response (ΔHR) has been identified as a promising biomarker for stratifying cardiovascular (CV) risk, and predicting positive airway pressure (PAP) benefit in obstructive sleep apnoea (OSA). However, the need for prior manual scoring of respiratory events potentially limits the accessibility and reproducibility of ΔHR. We aimed to evaluate the association of pulse rate response to oxygen desaturations automatically derived from pulse oximetry (ΔHRoxi) with CV risk in OSA.

Methods

ΔHRoxiand ΔHR were measured in OSA patients from theIRSR Pays de la Loire Sleep Cohort(PLSC;n=5,002) and theHypnoLauscohort (n=1,307). The primary outcome was major adverse CV events (MACEs), a composite of mortality, stroke, and cardiac diseases. Cox regressions analyses were conducted to evaluate the association of ΔHRoxiand ΔHR categorized into low, midrange and high categories, with MACEs.

Results

MACEs occured in 768 patients fromPLSCand 87 patients fromHypnoLaus(median follow-up: 8.0 and 7.5 years respectively). Multivariable Cox models showed that subjects with high ΔHRoxi(vs midrange) had higher risk of MACEs inPLSC(hazard ratio, HR: 1.42 [95% CI:1.18–1.71]) andHypnoLaus(HR: 1.72 [1.03–2.87]). Similar findings were observed for high ΔHR. Among 2,718 patients fromPLSCtreated with PAP, the association of PAP adherence (PAP use ≥4 h/night, vs non adherence) with MACEs was modified by baseline ΔHR and ΔHRoxi(p for interaction<0.05).

Conclusions

ΔHRoxicould constitute a reliable and easy to measure biomarker for stratifying CV risk and predicting CV benefit of PAP in OSA.
Incident tuberculosis in people with HIV across Europe from 2012–2022: incidence rates, risk factors, and regional differences in a multicentre cohort study
Authors: Kraef Christian , Roen Ashley , Podlekareva Daria , Bakowska Elzbieta , Nemeth Johannes , Knappik Michael , Payen Marie-Christine , Wit Ferdinand , Mussini Christina , d'Arminio Monforte Antonella , Castagna Antonella , Chkhartishvili Nikoloz , Neesgaard Bastian , Jaschinski Nadine , Anne Alain Volny , Borodulina Elena , Ballief Marie , Wallner Elmar , Israelski Dennis , Garges Harmony , Mocroft Amanda , Kirk Ole ,   the RESPOND Study Group
Published: February 2025

Background

Tuberculosis remains the leading cause of death among people with HIV. The aim of this study was to describe the incidence of tuberculosis (TB), explore risk factors and to calculate their population attributable fractions (PAF) in people with HIV across Europe, stratified by region.

Method

Longitudinal study of people with HIV aged>18 years with follow-up from either 1/1/2012, or cohort enrolment, until date of TB diagnosis, last visit, death, or 31/12/2022. Factors associated with TB, in particular antiretroviral therapy status and smoking, were analysed using multivariable Poisson regression.

Results

A total of 38 837 participants with HIV with a median follow-up of 7.7 (4.3–10.4) years. Overall, 306 TB cases were diagnosed during 275 811 person-years of follow-up (PYFU; incidence rate (IR) 1.03/1000 PYFU, 95% CI 0.91–1.11). 3.3% (n=81/2428) participants had incident TB in Eastern Europe (IR 6.13, 4.93–7.62). Overall, the IR decreased from 2.03 (1.53–2.68) in 2012 to 0.44 (0.20–0.97) in 2022. Modifiable risk factors were smoking (adjusted incidence rate ratio 2.94; 95%CI1.62–5.34) and not receiving antiretroviral therapy (versuson; 3.29; 2.36–4.58). A history of TB pre-baseline increased the risk of recurrence (aIRR 7.77; 95%CI 4.09–14.74). The PAF for not receiving antiretroviral therapy was 34.6% in Non-Eastern Europe and 31.2% in Eastern Europe.

Conclusions

TB incidence has been decreasing among people with HIV, but remains more frequent in Eastern Europe. Improvement of antiretroviral therapy-coverage and adherence and a focus on non-communicable disease risk factors such as smoking could reduce the incidence of TB.
Post-Hospitalisation COVID-19 Rehabilitation (PHOSP-R): A randomised controlled trial of exercise-based rehabilitation
Authors: Daynes Enya , Evans Rachael A , Greening Neil J , Bishop Nicolette C , Yates Thomas , Lozano-Rojas Daniel , Ntotsis Kimon , Richardson Matthew , Baldwin Molly M , Hamrouni Malik , Hume Emily , McAuley Hamish , Mills George , Megaritis Dimitrios , Roberts Matthew , Bolton Charlotte E , Chalmers James D , Chalder Trudie , Docherty Annemarie B , Elneima Omer , Harrison Ewen M , Harris Victoria C , Ho Ling p , Horsley Alex , Houchen-Wolloff Linzy , Leavy Olivia C , Marks Michael , Poinasamy Krishna , Quint Jennifer K , Raman Betty , Saunders Ruth M , Shikotra Aarti , Singapuri Amisha , Sereno Marco , Terry Sarah , Wain Louise V , Man William D-C , Echevarria Carlos , Vogiatzis Ioannis , Brightling Christopher , Singh Sally J
Published: February 2025

Objective

Post-COVID syndrome involves prolonged symptoms with multi-system and functional impairment lasting at least 12 weeks after acute COVID-19. We aimed to determine the efficacy of exercise-based rehabilitation interventions, either face-to-face or remote, compared to usual care in individuals experiencing Post-COVID syndrome following a hospitalisation of acute COVID-19.

Design

This single-blind randomised controlled trial compared two COVID exercise-based rehabilitation interventions (face-to-face or remote) to usual care in participants with Post-COVID syndrome following a hospitalisation. The interventions were either a face-to-face or remote eight-week program of individually prescribed exercise and education. The primary outcome was the change in Incremental Shuttle Walking Test (ISWT) following eight weeks of intervention (either face-to-face or remote) compared to usual care. Other secondary outcomes were measured including health related quality of life (HRQoL), and exploratory outcomes included lymphocyte immunotyping.

Results

181 participants (55% male, mean [sd] age 59 [12] years, length of hospital stay 12 [19] days) were randomised. There was an improvement in the ISWT distance following face-to-face rehabilitation (mean 52 [95% CI 19 to 85]m, p=0·002) and remote rehabilitation (mean 34 [95% CI 1 to 66]m, p=0·047) compared to usual care alone. There were no differences between groups for HRQoL of self-reported symptoms. Analysis of immune markers revealed significant increases in naïve and memory CD8+ T cells following face-to-face rehabilitation versus usual care alone (p<0·001, n=31).

Conclusion

Exercise-based rehabilitation improved short-term exercise capacity in Post-COVID syndrome following an acute hospitalisation and showed potential for beneficial immunomodulatory effects.
Relevance of telemonitoring algorithms for the management of home noninvasive ventilation
Authors: Bianquis Clara , El Husseini Kinan , Razakamanantsoa Léa , Kerfourn Adrien , Fresnel Emeline , Borel Jean-Christian , Cuvelier Antoine , Dupuis Johan , Gagnadoux Frédéric , Morélot-Panzini Capucine , Gonzalez-Bermejo Jesus , Muir Jean-François , Prigent Arnaud , Rabec Claudio , Trzepizur Wojciech , Winck Joao , Murphy Patrick Brian , Patout Maxime
Published: February 2025

Background

The increasing number of patients requiring home noninvasive ventilation (HNIV) is a challenge for our healthcare system. Telemonitoring may be used to facilitate the management of HNIV patients. We aimed to assess the ability of telemonitoring algorithms to identify patients not adequately ventilated. Our secondary aim was to assess the consequences related to these algorithms, including costs.

Methods

Eleven HNIV experts each provided an algorithm to identify patients with suboptimal ventilation. Each algorithm was tested using real-life data from a cohort of patients over a 90-day period.

Inadequate HNIV was defined as the presence of at least one criterion amongst the following: uncontrolled hypoventilation, daily adherence <4 h·day−1, HNIV related severe side effect, a residual event index>10/h.

Results

One hundred patients were included in the cohort. According to our criteria, HNIV was considered as inadequate in 66 (66%) patients, without difference between underlying respiratory disease. Telemonitoring algorithms correctly classified patients in 65 [52–66] % of cases. They had a global sensitivity of 78 [37–95] %, a specificity of 40 [19–78] %, a positive predictive value of 72 [65–77] % and a negative predictive value of 45 [37–51] %.

Applying telemonitoring algorithms resulted in 127 [84–238] alerts across the study population with a median cost increase of €2064 [952–6262].

Conclusion

Telemonitoring algorithms have poor diagnostic performances in identifying inadequately ventilated patient. They increase workload for healthcare workers and costs.
The impact of bronchoscopic lung volume reduction with endobronchial valves with or without pulmonary rehabilitation on symptoms of fatigue, anxiety and depression: a multicentre randomised controlled trial
Authors: Posthuma Rein , van der Molen Marieke C. , Vaes Anouk W. , Hartman Jorine E. , Spruit Martijn A. , Slebos Dirk-Jan , Vanfleteren Lowie E.G.W.
Published: February 2025

Background

Bronchoscopic lung volume reduction using one-way endobronchial valves (BLVR-EBV) improves exercise capacity and quality of life in patients with severe emphysema. However, its effect on symptoms of fatigue, anxiety and depression is unclear. Furthermore, if the combination of pulmonary rehabilitation (PR) and BLVR-EBV yields additional impact on these symptoms remains unknown. We hypothesized that BLVR-EBV would reduce symptoms of fatigue, anxiety and depression and that the combination of BLVR-EBV with PR would lead to additional reduction when compared to BLVR-EBV alone.

Methods

The SoLVE study (NCT03474471) was a prospective multicentre randomised controlled trial to examine the impact and optimal timing of PR on exercise physiology and patient reported outcomes in patients receiving BLVR-EBV treatment. Subjects were randomised into three groups: PR before BLVR-EBV, PR after BLVR-EBV and BLVR-EBV alone.

Fatigue severity was assessed using the Checklist Individual Strength fatigue subscale (CIS-fatigue). The Hospital Anxiety and Depression Scale evaluated symptoms of anxiety (HADS-A) and depression (HADS-D).

Results

Ninety-seven participants were included. After 6-months follow-up the overall mean change after BLVR-EBV with or without PR was −8.2±10.6 points on CIS-fatigue score, −2.2±2.9 points on HADS-A and −2.3±3.0 points on HADS-D (p<0.001). No significant differences were observed between groups for changes in CIS-fatigue, HADS-A and HADS-D.

Conclusion

BLVR-EBV is an effective intervention to improve symptoms of fatigue, anxiety and depression. The combination of PR and BLVR-EBV did not result in additional improvement when compared to BLVR-EBV alone.
Clinical and prognostic role of tricuspid regurgitation in incident patients with pulmonary arterial hypertension
Authors: Ghio Stefano , Moschella Martina Marialaura , Baccelli Andrea , Savonitto Giulio , Maldera Martina , Haji Gulam , Davies Rachel , Howard Luke , Lo Giudice Francesco
Published: February 2025

Question addressed by the study

The clinical and prognostic role of tricuspid valve regurgitation (TR) in patients with pulmonary arterial hypertension (PAH) is still underappreciated. The main objective of the present study was to assess the prognostic value of TR in incident PAH patients.

Methods

Consecutive incident PAH patients were enrolled from 2011 to 2021. Patients underwent right heart catheterization (RHC), CPET, echocardiography including the degree of TR, tricuspid annular plane systolic excursion (TAPSE), ratio of TAPSE to pulmonary artery pressure (TAPSE/PASP), right ventricular (RV) areas, right atrial area. The primary endpoint of survival analysis was all-cause death.

Results

Compared to patients with mild TR or no TR, those with TR of moderate degree or more had a worse TAPSE and TAPSE/PASP, similar RV areas at echocardiography, worse peak VO2 at CPET, higher right atrial pressure and pulmonary vascular resistance at RHC. TR of moderate degree or more was the only echocardiographic parameter associated with poor survival at Cox regression analyses, (HR 3.34, 95%CI 1.73–6.45, p <0.001). The assessment of TR severity was crucial to determine the prognosis of patients who would have been categorized as low risk based on normal values of TAPSE or TAPSE/PASP values.

Answer to the question

In treatment-naive PAH patients, TR is an important echocardiographic prognostic indicator. In particular, as an emerging concept, assessment of severity of TR is critical to stratify the prognosis of patients who would have been considered at low risk based on normal values of TAPSE or of TAPSE/PASP.
Long-term PM2.5exposure impairs lung growth and increases airway inflammation in Taiwanese school children
Authors: Tsai Yi-Giien , Wang Jiu-Yao , Yang Kuender D. , Yang Hsiao-Yu , Yeh Yen-Po , Chang Yu-Jun , Lee Jui Huan , Wang Shu-Li , Huang Shau-Ku , Chan Chang-Chuan
Published: February 2025

Rationale

Prolonged exposure to fine particulate matter (PM2.5) may aggravate asthma, impair lung development, and increase airway inflammation.

Objective

This study investigated the impact of long-term PM2.5exposure on respiratory health, lung function growth, and fractional exhaled nitric oxide (FENO) in a large longitudinal cohort of school children.

Methods

A total of 6120 elementary school children residing in townships near coal-fired power plants in Taiwan were prospectively enrolled from 2016 to 2018. Baseline and follow-up data on asthmatic symptoms, spirometry, FENO, and environmental factors were collected. Annual PM2.5exposure was estimated using land-use regression models based on school and home addresses, and associations were adjusted for SO2and NO2.

Results

The final analysis included 5364 children and revealed that a 1 μg·m−3increase in annual PM2.5exposure was associated with higher odds of current wheezing (OR=1.07), “ever” wheeze (OR=1.03), diagnosed asthma (OR=1.03), and exercise-induced wheeze (OR=1.04) (p<0.05). Each unit increase in PM2.5exposure was associated with a decrease of 7 mLin FEV1, 5 mLin FVC, and a 0.479 ppb rise in FENO after adjusting for potential confounders (p<0.05). Among 207 new-onset wheezing patients, increased PM2.5exposure significantly decreased FEV1 by 13 mLand FVC by 15 ml, while increasing FENO levels by 0.847 ppb (p<0.05).

Conclusions

Long-term PM2.5exposure significantly increases the risk of asthma symptoms, impedes lung growth, and triggers airway inflammation, particularly affecting children with new-onset wheezing in community settings.
Possible therapeutic effect on nocturia after radical prostatectomy by OnabotulinumtoxinA injection: a case series
Authors: Imasato Naoki , Yajima Shugo , Ogasawara Ryo Andy , Hirose Kohei , Sekiya Ken , Katsumura Sao , Kataoka Madoka , Nakanishi Yasukazu , Masuda Hitoshi
Published: February 2025

Background

Intravesical onabotulinumtoxinA (BTX-A) injection is an established treatment for overactive bladder (OAB) in patients who do not respond to conventional medical therapy. This study aimed to evaluate the safety and efficacy of BTX-A injections in patients with urinary dysfunction after radical prostatectomy (RP).

Methods

This retrospective case series included 11 post-RP patients with urinary dysfunction　who received intravesical BTX-A injections and were followed-up for 12 months. We measured and analyzed the efficacy of BTX-A treatment using the Overactive Bladder Symptom Score (OABSS), International Prostate Symptom Score (IPSS), quality of life score, and number of pad sheets used before and after intravesical BTX-A injection.

Results

Following BTX-A injections, significant improvements were observed in the OABSS Q2 score, which evaluates nocturia. The median (IQR) OABSS Q2 score improved from 3.0 (2.0–3.0) at baseline to 1.0 (1.0–2.0, p = 0.012) at 3 months. Similarly, the IPSS Q7 score showed notable changes. The baseline median (IQR) was 3.0 (2.0–4.0), which significantly reduced to 2.0 (2.0–2.5, p = 0.036) at 1 month. Further improvement was observed at 3 months, with a median (IQR) of 2.0 (1.0–2.5, p = 0.021). There were no statistically significant differences in the other categories. There were no statistically significant differences among the other categories.

Conclusion

Intravesical BTX-A injections significantly improved nocturia without complications in post-RP patients. This treatment represents a potential therapeutic option for managing refractory nocturia after RP.
A systematic review of mediation analysis frameworks in studies examining the determinants of cardiometabolic outcomes in people living with HIV
Authors: Ebasone Peter Vanes , Peer Nasheeta , Dzudie Anastase , Foaleng Merveille , Melpsa Johney , Kengne Andre Pascal
Published: February 2025

Introduction

Mediation analysis provides a more flexible mechanistic view of the causal relationship between HIV-related factors and cardiometabolic diseases. However, there is limited evidence on how mediation analysis is implemented in this specific research area. We aimed to describe the frameworks used in mediation analysis and examine how these analyses are conducted and reported in studies focusing on cardiometabolic outcomes among people living with HIV (PLWH).

Methods

Following the PRISMA 2020 Guidelines, we comprehensively searched Medline, CINAHL, Africa-Wide Information and SCOPUS to identify observational studies that employed mediation analysis before October 2023. Two reviewers independently screened studies for eligibility. One reviewer performed data extraction, and two others reviewed the extracted information.

Results

Nine studies met the inclusion criteria, predominantly focusing on the mediation effects of weight and obesity-related factors on the relationship between HIV serostatus, ART, and cardiometabolic outcomes. The review revealed a diverse application of both traditional and causal mediation frameworks. However, inconsistencies and gaps in reporting were noted, particularly in handling missing data, detailing identifiability assumptions, and the use of sensitivity analyses.

Conclusion

While some studies of cardiometabolic risks among PLWH have embraced causal mediation frameworks, their overall application remains limited. In addition, we identified notable inconsistencies and gaps in reporting practices. To advance the field, researchers should not only integrate more rigorous causal mediation methods but also closely follow established reporting guidelines, such as the AGReMA Statement, to ensure greater transparency, reliability, and impact of future research.
Supporting Educational Excellence in Diversity (SEED): faculty development and allyship
Authors: Chadha Puja , Kang Esther H. , Ngo Victoria , Jorrin Rebecca , Kochai Khoban , Ackerman-Barger Kupiri , Ton Hendry
Published: February 2025

Introduction

Bias, privilege, microaggressions, and other forms of mistreatment negatively impact students’ learning, professional development, wellness, and identity. Supporting Educational Excellence in Diversity (SEED) is an innovative faculty development curriculum co-founded and co-designed by medical students/trainees. SEED is unique given it provides vital yet practical communication tools and strategies to support cultural humility when navigating critical conversations related to diversity, inclusion, and harm.

Objective

This curriculum helps faculty to identify, redress, and prevent mistreatment within clinical and non-clinical learning environments while cultivating cultural humility.

Methods

SEED incorporated a sequential hybrid model approach through the use of interactive online modules, virtual asynchronous self-reflection assignments, followed by in-person discussions with role-play opportunities. Using novel tools, it taught faculty core knowledge and strategies to facilitate discussions in navigating harms related to diversity and inclusion. Authors measured impact via self-reported, de-identified pre-and-post questionnaires.

Results

An idependent t-test analysis pre-post-test study of 67 faculty participants revealed statistically significant (P < .001) differences from pre to post on all items with one item statistically significant at a p < .05. The overall effect size was 1.65 showing significant improvement in participants’ self-perceived ability to identify and address microaggressions, privilege, sources of bias, and related harm in the clinical and learning environments. These improvements were identified within themselves, faculty peers, teaching curricula, and teaching modalities. SEED was adopted health system-wide through customized departmental faculty offerings given the statistically and practically significant change in learning, awareness, and attitudes for respondents. SEED is currently under consideration as a maintenance of certification self-assessment course by a national board.

Conclusion

The innovative SEED faculty development curriculum was co-created and designed by students/trainees. SEED shows promising results in improving participants’ foundational learning in promoting inclusive change to enhance learning environments for healthcare trainees. SEED is unique in providing vital yet practical communication tools and strategies to support cultural humility when navigating critical conversations related to diversity, inclusion, and harm.
A non-structural protein 1 substitution of dengue virus enhances viral replication by interfering with the antiviral signaling pathway
Authors: Hee Jing-Ru , Cheng Dayna , Chen Yu-Hong , Wang Sheng-Hsuan , Chao Chiao-Hsuan , Huang Sheng-Wen , Ling Pin , Wan Shu-Wen , Chang Chih-Peng , Chu Justin Jang Hann , Yeh Trai-Ming , Wang Jen-Ren
Published: February 2025

Background

The largest dengue virus 2 (DENV2) outbreak occurred in Taiwan in 2015, resulting in many fatalities. We therefore aim to identify crucial genetic variations which determine the virulence of the 2015 Taiwan outbreak strains.

Methods

We compared the 2015 Taiwan DENV2 sequences to the pre-2015 sequences. Reverse genetics (rg) viruses with substitutions were produced and the viral growth kinetics were investigated. We treated A549 cells with interferon (IFN) to determine the interferon-stimulated genes (ISGs) expression and STAT1 phosphorylation in the rg viral infection and plasmid transfection systems. IFN and pro-inflammatory cytokines levels were measured upon DENV infection using ELISA.

Results

The rgNS1-K272R mutant showed faster replication in IFN-I producing cells compared to wildtype (WT) virus. Results revealed that NS1-K272R substitution contributed to higher soluble NS1 secretion and evade the antiviral response by suppressing the expression of ISGs and STAT1 phosphorylation compared to NS1-WT. Infection with rgNS1-K272R induced higher secretion of pro-inflammatory cytokines through the activation of canonical nuclear factor-kappa B (NF-κB) signaling pathway.

Conclusions

Our results revealed that the DENV NS1 amino acid substitution affects the NS1 ability in immune evasion, which may contribute to the largest dengue outbreak in Taiwan since the 1990s.
The zinc finger protein ZFP36L2 inhibits flavivirus infection via the 5′-3′ XRN1-mediated RNA decay pathway in the replication complexes
Authors: Lin Ren-Jye , Lin Li-Hsiung , Chen Zih-Ping , Liu Bing-Cheng , Ko Pin-Chen , Liao Ching-Len
Published: February 2025

Background

The zinc finger protein 36-like (ZFP36L) family is a CCCH-type group consisting of RNA-binding proteins, i.e., ZFP36L1 and ZFP36L2, which regulate cellular mRNA through the RNA decay pathway. ZFP36L1 combats flavivirus infections through the 5′-3′ XRN1 and 3′-5′ RNA exosome decay pathways. The present study clarified the role of human ZFP36L2 in the defense response of the host against flavivirus infection.

Methods

Cell lines with overexpression or knockdown of ZFP36L2 were established using lentiviral vectors carrying genes for overexpression and short-hairpin RNA targeting specific genes, respectively. A plaque assay was employed to determine the viral titer. Immunofluorescence and real-time quantitative polymerase chain reaction were used to measure the viral RNA levels. The in vitro-transcribed RNA transcript derived from a replication-dead Japanese encephalitis virus (JEV) replicon containing the renilla luciferase reporter gene (J-R2A-NS5mt) was used to assess the stability of the flavivirus RNA. An RNA immunoprecipitation assay was used to detect the protein–RNA binding ability. Confocal microscopic images were captured to analyze protein colocalization.

Results

ZFP36L2 served as an innate host defender against JEV and dengue virus. ZFP36L2 inhibited flavivirus infection solely through the 5′-3′ XRN1 RNA decay pathway, whereas ZFP36L1 inhibited JEV infection via the 5′-3′ XRN1 and 3′-5′ RNA exosome RNA decay pathways. The direct binding between viral RNA and ZFP36L2 via its CCCH-type zinc finger motifs facilitated the degradation of flavivirus RNA mediated by 5′-3′ XRN1. Furthermore, ZFP36L2 was localized in processing bodies (PBs), which participate in the 5′-3′ XRN1-mediated RNA decay pathway. Nonetheless, the disruption of PBs did not affect the antiviral activity of ZFP36L2, suggesting that its localization is not essential for the function of the protein. Interestingly, the colocalization of ZFP36L2 and XRN1 with viral RNA and NS3 revealed that the antiviral activity of ZFP36L2 occurred within the replication complexes (RCs).

Conclusions

In summary, ZFP36L2 bound to and degraded viral RNA through the XRN1-mediated RNA decay pathway in the RCs, thereby inhibiting flavivirus replication. These findings provide valuable insights into the diverse antiviral mechanisms of the ZFP36-like family of proteins in the innate immune response against flavivirus infection.
A novel recombinant PHB production platform in filamentous cyanobacteria avoiding nitrogen starvation while preserving cell viability
Authors: Fink Phillipp , Menzel Claudia , Kwon Jong-Hee , Forchhammer Karl
Published: February 2025

During the past decades, the importance of developing sustainable, carbon dioxide (CO2)-neutral and biodegradable alternatives to conventional plastic has become evident in the context of global pollution issues. Therefore, heterotrophic bacteria such as Cupriavidus sp. have been intensively explored for the synthesis of the biodegradable polymer polyhydroxybutyrate (PHB). PHB is also naturally produced by a variety of phototrophic cyanobacteria, which only need sunlight and CO2, thereby allowing a CO2 negative, eco-friendly synthesis of this polymer. However, a major drawback of the use of cyanobacteria is the need of a two-stage production process, since relevant amount of PHB synthesis only occurs after transferring the cultures to conditions of nitrogen starvation, which hinders continuous, large-scale production.

This study aimed at generating, by means of genetic engineering, a cyanobacterium that continuously produces PHB in large amounts. We choose a genetically amenable filamentous cyanobacterium of the genus Nostoc sp., which is a diazotrophic cyanobacterium, capable of atmospheric nitrogen (N2) fixation but naturally does not produce PHB. We transformed this Nostoc strain with various constructs containing the constitutive promotor P
psbA
and the PHB synthesis operon phaC1AB from Cupriavidus necator H16. In fact, while the transformants initially produced PHB, the PHB-producing strains rapidly lost cell viability. Therefore, we next attempted further optimization of the biosynthetic gene cluster. The PHB operon was expanded with phasin gene phaP1 from Cupriavidus necator H16 in combination with the native intergenic region of apcBA from Nostoc sp. 7120. Finally, we succeeded in stabilized PHB production, whilst simultaneously avoiding decreasing cell viability. In conclusion, the recombinant Nostoc strain constructed in the present work constitutes the first example of a continuous and stable PHB production platform in cyanobacteria, which has been decoupled from nitrogen starvation and, hence, harbours great potential for sustainable, industrial PHB production.
Use of TikTok by nutrition healthcare professionals: a pilot analysis of the Italian context
Authors: Scaioli Giacomo , Bert Fabrizio , Durbano Alessandro , Pivi Alex , Lo Moro Giuseppina , Siliquini Roberta
Published: February 2025

Aim

Social Media (SM) has become a leading source for health information dissemination. TikTok, one of the newest SMs, became very popular in the last three years. Many healthcare professionals became content creators and science communicators on this SM, and one of the most popular topics is food and nutrition. The present study aims to analyze how nutrition professionals communicate through TikTok and assess the characteristics of their accounts and videos.

Methods

The study includes 53 Italian health professionals active on TikTok, selected through a search on this SM using nutrition-related keywords. Each tiktoker's characteristics of their last ten videos were described through an ad-hoc checklist. Multilevel multivariable linear regression models were performed to identify factors that could be associated with higher video popularity.

Results

A total of 67.7% of the tiktokers were female; 54% were under 30 years old. The median number of likes for each video was 300 (IQR 75–1070). The linguistic register was 'informal' in 70.7% of the videos. In 67.3%, the topic was 'diet-related' (videos relating to nutrition and nutritional choices). Multivariable multilevel linear regression models showed that 'diet-related' topics were associated with more likes (adj Coeff. 1111.62, p = 0.048) and comments (adj Coeff. 12.09, p = 0.036).

Conclusions

TikTok might be an impactful source for health promotion on food and nutrition topics. The popularity of diet-related videos underlines the potential of this SM for increasing knowledge and skills about healthy diets and good nutritional habits, especially for an audience of adolescents.
Opportunities and challenges to delivering a trial for depressive symptoms in primary care during the COVID-19 pandemic: insights from the Alpha-Stim-D randomised controlled trial
Authors: Patel Shireen , Patel Priya , Boutry Clement , Guo Boliang , Butler Deborah , Higton Fred , McNaughton Rebecca , Briley Paul M. , Griffiths Christopher , Nixon Neil , Prasad Vibhore , Sayal Kapil , Smart David , Zafar Azhar , Kai Joe , Morriss Richard
Published: February 2025

Background

Randomised controlled trials (RCTs) are widely regarded as the most powerful research design for evidence-based practice. However, recruiting to RCTs can be challenging resulting in heightened costs and delays in research completion and implementation. Enabling successful recruitment is crucial in mental health research. Despite the increase in the use of remote recruitment strategies and digital health interventions, there is limited evidence on methods to improve recruitment to remotely delivered mental health trials. The paper outlines practical examples and recommendations on how to successfully recruit participants to remotely delivered mental health trials.

Methods

The Alpha Stim-D Trial was a multi-centre double-blind randomised controlled trial, for people aged 16 years upwards, addressing depressive symptoms in primary care. Despite a 6-month delay in beginning recruitment due to the COVID-19 pandemic, the trial met the recruitment target within the timeframe and achieved high retention rates. Several strategies were implemented to improve recruitment; some of these were adapted in response to the COVID-19 pandemic. This included adapting the original in-person recruitment strategies. Subsequently, systematic recruitment using postal invitations from criteria-specific search of the sites’ electronic health records was added to opportunistic recruitment to increase referrals in response to sub-target recruitment whilst also reducing the burden on referring sites. Throughout the recruitment process, the research team collaborated with key stakeholders, such as primary care clinicians and the project’s Patient and Public Involvement and Engagement (PPI/E) representatives, who gave advice on recruitment strategies. Furthermore, the study researchers played a key role in communicating with participants and building rapport from study introduction to data collection.

Conclusions

Our findings suggest that trial processes can influence recruitment; therefore, consideration and a regular review of the recruitment figures and strategies is important. Recruitment of participants can be maximised by utilising remote approaches, which reduce the burden and amount of time required by referring sites and allow the research team to reach more participants whilst providing participants and researchers with more flexibility. Effectively communicating and working collaboratively with key stakeholders throughout the trial process, as well as building rapport with participants, may also improve recruitment rates.
Distinctive autophagy/mitophagy biomarker profiles in frontotemporal lobar degeneration and Alzheimer’s disease
Authors: Veverová Kateřina , Katonová Alžběta , Horáková Hana , Laczó Jan , Angelucci Francesco , Hort Jakub , Lautrup Sofie , Fang Evandro Fei , Vyhnálek Martin
Published: February 2025

Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer’s disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile).

Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.
Diastolic Versus Systolic or Mean Intraoperative Hypotension as Predictive of Perioperative Myocardial Injury in a White-Box Machine-Learning Model
Authors: Valadkhani Arman , Gupta Anil , Cauli Giordano , Nordström Johan L. , Rohi Ayda , Tufexis Panos , Hällsjö Sander Caroline , Jacobsson Martin , Bell Max
Published: February 2025

BACKGROUND:

Intraoperative hypotension (IOH) and tachycardia are associated with perioperative myocardial injury (PMI), and thereby increased postoperative mortality. Patients undergoing vascular surgery are specifically at risk of developing cardiac complications. This study aimed to explore the association between different thresholds for IOH and tachycardia, and PMI. It also aimed to explore which threshold for IOH and tachycardia best predicts PMI.

METHODS:

In this single-center prospective observational study, high-sensitivity cardiac troponin T was measured preoperatively and at 4, 24, and 48 hours after vascular surgery. Absolute and relative thresholds were used to define intraoperative systolic, mean, and diastolic arterial hypotension, measured every 15 seconds by invasive arterial pressure monitoring and heart rate using the Philips IntelliVue X3 monitor. Decision tree machine-learning (ML) models were used to explore which thresholds for IOH and tachycardia best predict PMI. Clinical utility and transparency were prioritized over maximizing the performance of the ML model and therefore a white-box model was used.

RESULTS:

In all, 498 patients were included in the study. Ninety-nine patients (20%) had PMI. Significant associations were found between IOH and PMI using both absolute and relative thresholds for systolic, mean, and diastolic arterial pressure. Absolute thresholds based on diastolic arterial pressure had the strongest correlation with PMI and yielded greater statistical significance. The threshold that was most predictive of PMI was an absolute diastolic arterial pressure <44 mm Hg. The prediction model with the absolute threshold of diastolic arterial pressure <44 mm Hg had a macro average F1 score of 0.67 and a weighted average F1 score of 0.76. No association was found between tachycardia and PMI.

CONCLUSIONS:

We found that an absolute, not relative, IOH threshold based on diastolic arterial pressure, and not systolic or mean arterial pressure, or tachycardia, was most predictive of PMI.
Expulsion as Decolonization
Authors: Serunkuma Yusuf K.
Published: February 2025

Despite more than a hundred years in Uganda, ethnic Indian Ugandans have struggled to integrate into a space historically renowned for naturalizing visitors. As the Mabira Forest Protests of 2007 demonstrated, Indian-Ugandans have sustained the image of a ‘loathed exploitative settler’ among their native compatriots. Despite this image having a specific colonial history, this article contends that the persistence of anti-Indian sentiments—and the ire and violence—is not simply a “legacy of colonialism” or evidence of natives’ xenophobia. It is rather a product of closed Indian cultural practices, and state sanctioned economic privileging of Indian-Asian businessmen, which combine to effectively alienate the entire community from other Ugandans. If the 1972 Indian expulsion was understood through the lens of decolonization, the abundance of the conditions that led to 1972, renders another expulsion possible. To make these contentions, this article provides context on the nature and scale of anti-Asian public sentiments in Uganda by drawing on sources from the mainstream and popular media that narrate and analyze the often-suspicious economic dealings of prominent Indian-Ugandans. Prominent among others is the subject of “repossession” of expropriated Indian properties. The article revisits the 2007 Mabira Forest protests to demonstrate controversies, connections, and possibilities of re-expulsion as the ingredients of 1972 abound.
The Gap Which Separates: Simultaneity, Disparity, and Audiovisual-Linking Technologies in “Southeast Asian Contemporary Art”
Authors: Nelson Roger
Published: February 2025

How have artists and curators working in “Southeast Asia” imagined the contemporaneity between this region and the rest of the world, and how has this imagining been affected by twenty-first-century advances in technology and globalization? This essay approaches these questions through a discussion of recent artistic and curatorial practices that engage with simultaneity. The essay proposes that simultaneity is an important and recurrent concern for artists and curators that has been underexplored within art historical and related discourses. The essay centers on a close reading of two projects, conceived fifteen years apart, that reflect the radical transformations of technologies that took place within that period. One project, Calling Cambodia (1998–99) by the Faculty of Plastic Arts at the Royal University of Fine Arts, Phnom Penh, proposed—yet, due to technological constraints, failed—to place Phnom Penh in live video contact with Fukuoka during a major art exhibition in the Japanese city, which was also the first instance of Cambodia's entrance into new Asian and global circuits of contemporary art. A second project, Leak Light Time Heat (2014) by collaborating artists Enzo Camacho and Ami Lien, addresses Manila's real-time service provision for United States customers through call centers.
The formation of chaperone-rich GET bodies depends on the tetratricopeptide repeat region of Sgt2 and is reversed by NADH
Authors: Jennrich Jonas , Farkas Ákos , Urlaub Henning , Schwappach Blanche , Bohnsack Katherine E.
Published: February 2025

The guided-entry of tail-anchored proteins (GET) pathway is a post-translational targeting route to the endoplasmic reticulum. Upon glucose withdrawal, the soluble GET proteins re-localize to dynamic cytosolic foci, here termed GET bodies. Our data reveal that the pre-targeting complex components, Sgt2 and the Get4-Get5 heterodimer, and the Get3 ATPase play important roles in the assembly of these structures. More specifically, the TPR region of Sgt2 is required as a GET body scaffold. Systematic compositional analyses of GET bodies reveal their chaperone-rich nature and the presence of numerous proteins involved in metabolic processes. Temporal analyses of GET body assembly demonstrate the sequential recruitment of different chaperones, and we discover the requirement of Sis1 and Sti1 for maintaining the dynamic properties of these structures. In vivo, NADH derived from the oxidation of ethanol to acetaldehyde can induce GET body disassembly in a reaction depending on the alcohol dehydrogenase Adh2 and in vitro, addition of NADH resolves GET bodies. This suggests a mechanistic basis for their formation and disassembly in response to the metabolic shift caused by glucose withdrawal and re-addition.