bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-period ground motion simulation and pulse probability distribution characteristics of the Kumamoto MW 7.1 earthquake in Japan
Authors: Ji Zhiwei , Li Zongchao , Zhang Yan , Gao Mengtan , Li Teifei , Sun Jize , Luo Quanbo
Published: September 2024

The 2016 Kumamoto MW 7.1 earthquake in Japan caused severe structural damage. It produced valuable seismic records that offered an opportunity to investigate the characteristics of long-period ground motion and pulse probability distribution. This study works in three main parts. First, we use the finite difference method (FDM) to reproduce the long-period ground motions of the 2016 Kumamoto MW 7.1 earthquake. That provides a crucial foundation for the subsequent phases. We identify velocity pulses within both synthetic and observed waveforms. By rigorously analyzing these pulses, we unveiled a wealth of insights into the characteristics of velocity pulses, strengthening the influence of the rupture directivity effect. In particular, the northeast region of the rupture exhibited a significant concentration of pulsed attributes. Finally, we further focus on establishing statistical relationships between different pulse parameters. The study revealed that the pulse probability distribution model fit well with the observed pulse distribution in the parallel to the fault (FP) and normal to the fault (FN) directions. However, the model also faced challenges in the FN direction due to the mechanism of velocity pulses and altered rupture propagation direction. Crucially, the study established that velocity pulses primarily cluster within a fault distance of less than 30 km, and the relationship between pulse peak value and fault distance followed an exponential trend. The study underscores the imperative of further refining the probability distribution model of velocity pulses, making it more robust and widely applicable. Furthermore, the correlation between velocity pulses and seismic parameters requires further validation through seismic records. This study sets the stage for a deeper understanding of earthquake-induced ground motion and pulse characteristics, contributing to the ongoing efforts in seismic risk assessment.
Coseismic surface ruptures of 20 strike-slip earthquakes measured from geodetic imaging data
Authors: Milliner Chris , Avouac Jean-Philippe , Aati Saif
Published: September 2024

Observations of coseismic surface ruptures are widely used for examining faulting mechanics and kinematics, and in fault displacement hazard analysis. Here, first, we provide new remote sensing observations of 20 historic surface rupturing continental strike-slip earthquakes (6.1 ≤ Mw≤ 7.9). To measure the near-field surface deformation pattern, we have processed a range of raw radar and optical images from satellite and aerial platforms with pixel tracking techniques, and in two cases using standard interferometric synthetic aperture radar (InSAR). We provide a range of observations, including surface displacement maps that constrain at least the horizontal component of surface motion (2D), and for three events the full 3D components. Second, we provide strain invariants for each event, which includes the finite dilatational strain, strain magnitudes, the vorticity, and maximum shear strain. Third, we provide a total of 134 surface fault rupture traces that are mapped manually from the displacement maps. Finally, we provide 2648 measurements of coseismic horizontal fault-parallel surface fault slip that are measured objectively using swath profiles with a function fitting method that we have developed.
OUTREACH: phase 2 study of lisocabtagene maraleucel as outpatient or inpatient treatment at community sites for R/R LBCL
Authors: Linhares Yuliya , Freytes Cesar O. , Cherry Mohamad , Bachier Carlos , Maris Michael , Hoda Daanish , Varela Juan C. , Bellomo Courtney , Cross Scott , Essell James , Fanning Suzanne , Terebelo Howard , Yimer Habte , Courtright Jay , Sharman Jeff P. , Kostic Ana , Vedal Min , Ogasawara Ken , Avilion Ariel , Espinola Ricardo , Yuan Brenda , Mattar Bassam
Published: September 2024

Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB chimeric antigen receptor (CAR) T-cell product approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We present the OUTREACH primary analysis, evaluating the safety and efficacy of outpatient monitoring after liso-cel treatment at community sites in the United States. Adults with R/R LBCL after ≥2 prior lines of therapy received liso-cel. Outpatient vs inpatient monitoring was per investigator discretion. The primary end points were incidences of grade ≥3 cytokine release syndrome (CRS), neurological events (NEs), prolonged cytopenia, and infections. Efficacy was a secondary end point. Eighty-two patients received liso-cel (outpatient monitored, 70%; inpatient monitored, 30%). The median follow-up was 10.6 months (range, 1.0-24.5). In outpatients and inpatients, grade ≥3 CRS occurred in 0% and 0%, NEs in 12% and 4%, infections in 12% and 8%, and prolonged cytopenia in 33% and 32%, respectively. Among outpatients, 25% were never hospitalized after infusion, and 32% were hospitalized ≤72 hours after the day of infusion; the median time to hospitalization was 5.0 days (range, 2-310). The median initial hospitalization duration after liso-cel was 6.0 days (range, 1-28) for outpatients and 15.0 days (range, 3-31) for inpatients. Objective response rate was 80%, complete response rate was 54%, and the median duration of response was 14.75 months (95% confidence interval, 5.0 to not reached). OUTREACH is, to our knowledge, the first and largest study to prospectively assess CAR T-cell therapy with outpatient monitoring in community-based medical centers. Liso-cel demonstrated meaningful efficacy with favorable safety in patients with R/R LBCL. Data support the feasibility of liso-cel administration at community sites with outpatient monitoring. This trial was registered at www.ClinicalTrials.gov as #NCT03744676.
Efficacy and safety of TPO receptor agonists in treatment of ITP associated with predominantly antibody deficiencies
Authors: Soulard Margaux , Galicier Lionel , Mahlaoui Nizar , Fieschi Claire , Deshayes Samuel , Gobert Delphine , Gourguechon Clément , Henique Hélène , Humbert Sebastien , Lacout Carole , Le Calloch Ronan , Michel Marc , Piel-julian Marie-lea , Viallard Jean François , Lescoat Alain , Godeau Bertrand , Perlat Antoinette
Published: September 2024

Predominantly antibody deficiencies have an estimated prevalence of >1 in 25 000. Their classical phenotype entails the association of autoimmune manifestations with increased susceptibility to infections. Up to 8% of these patients ultimately develop immune thrombocytopenic purpura (ITP). Reducing the risk for infections and considering nonimmunosuppressive treatments, such as thrombopoietin receptor agonists (TPO-RAs), are important considerations for these patients. This nationwide retrospective case series assessed the outcomes and safety of TPO-RAs as treatment for ITP in adults diagnosed with predominantly antibody deficiencies. Response and complete response to treatment were defined as platelet count reaching 30 × 109/L and 100 × 109/L, respectively. We analyzed data from 28 patients. The median follow-up time after introduction of the first TPO-RAs was 33 months (range, 2 weeks to 10.6 years). After 6 weeks of follow-up, response was achieved in 24 of the 28 patients (85.7%), and among those, 21 patients (75%) displayed a complete response. At the last available follow-up visit, only 7 patients (25%) needed second-line therapies for ITP, and among those, only 5 patients (17.9%) received immunosuppressants. Only 3 patients (10.7%) reported laboratory-confirmed hepatobiliary adverse events of light or mild severity and 3 patients (10.7%) reported thrombotic events. In conclusion, TPO-RAs seemed to be an effective and safe option of treatment in these case series. Our results suggest that eltrombopag or romiplostim should be considered as second-line therapy for ITP related to predominantly antibody deficiencies.
Cycle route uptake and scenario estimation (CRUSE): an approach for developing strategic cycle network planning tools
Authors: Lovelace Robin , Talbot Joey , Vidal-Tortosa Eugeni , Mahfouz Hussein , Brick Elaine , Wright Peter , O’Toole Gary , Brennan Dan , Meade Suzanne
Published: September 2024

This paper describes an approach for developing strategic cycle network planning tools. Based on our experience developing and deploying the Cycle Route Uptake and Scenario Estimation (CRUSE) Tool for Ireland, we outline the underlying methods, including disaggregation of origin–destination data with the open source ‘odjitter’ software, incorporation of additional trip purposes, routing, scenario generation, and development of an intuitive user interface that is tested and used by practitioners. Commissioned by the national infrastructure agency Transport Infrastructure Ireland, CRUSE provides estimates of current and potential future cycling levels under ‘snapshot’ scenarios to inform investment decisions. The publicly available results at https://cruse.bike/ enable planners, engineers, and other stakeholders to make more evidence-based decisions. CRUSE goes beyond previous work by: modeling networks at high spatial resolution; simulating multiple trip purposes (social, shopping, personal utility, recreational, and cycle touring), supplementing official origin–destination datasets on travel for work and education; and providing estimates of ‘quietness’ (a proxy for cyclist comfort and route preference) at the route segment level. Three network types—‘Fastest’, ‘Balanced’, and ‘Quietest’—help plan both arterial and residential cycle networks. Workshops with stakeholders were used to inform the development of the tool. Feedback shows that the tool has a wide range of uses and is already being used in practice to inform urban, inter-urban, and rural cycle network designs. The approach is flexible and open source, allowing the underlying ideas and code to be adapted, supporting more evidence-based and effective cycling policies and interventions internationally.
QTL analysis to identify genes involved in the trade-off between silk protein synthesis and larva-pupa transition in silkworms
Authors: Gao Rui , Li Chunlin , Zhou Ang , Wang Xiachao , Lu Kupeng , Zuo Weidong , Hu Hai , Han Minjin , Tong Xiaoling , Dai Fangyin
Published: September 2024

Background

Insect-based food and feed are increasingly attracting attention. As a domesticated insect, the silkworm (Bombyx mori) has a highly nutritious pupa that can be easily raised in large quantities through large-scale farming, making it a highly promising source of food. The ratio of pupa to cocoon (RPC) refers to the proportion of the weight of the cocoon that is attributed to pupae, and is of significant value for edible utilization, as a higher RPC means a higher ratio of conversion of mulberry leaves to pupa. In silkworm production, there is a trade-off between RPC and cocoon shell ratiao(CSR), which refers the ratio of silk protein to the entire cocoon, during metamorphosis process. Understanding the genetic basis of this balance is crucial for breeding edible strains with a high RPC and further advancing its use as feed.

Results

Using QTL-seq, we identified a quantitative trait locus (QTL) for the balance between RPC and CSR that is located on chromosome 11 and covers a 9,773,115-bp region. This locus is an artificial selection hot spot that contains ten non-overlapping genomic regions under selection that were involved in the domestication and genetic breeding processes. These regions include 17 genes, nine of which are highly expressed in the silk gland, which is a vital component in the trade-off between RPC and CSR. These genes are annotate with function related with epigenetic modifications and the regulation of DNA replication et al. We identified one and two single nucleotide polymorphisms (SNPs) in the exons of teh KWMTBOMO06541 and KWMTBOMO06485 genes that result in amino acid changes in the protein domains. These SNPs have been strongly selected for during the domestication process. The KWMTBOMO06485 gene encodes the Bombyx mori (Bm) tRNA methyltransferase (BmDnmt2) and its knockout results in a significant change in the trade-off between CSR and RPC in both sexes.

Conclusions

Taken together, our results contribute to a better understanding of the genetic basis of RPC and CSR. The identified QTL and genes that affect RPC can be used for marker-assisted and genomic selection of silkworm strains with a high RPC. This will further enhance the production efficiency of silkworms and of closely-related insects for edible and feed purposes.
Transcriptomic insights into the epigenetic modulation of turnip mosaic virus evolution in Arabidopsis thaliana
Authors: Olmo-Uceda María J. , Ambrós Silvia , Corrêa Régis L. , Elena Santiago F.
Published: September 2024

Background

Plant-virus interaction models propose that a virus’s ability to infect a host genotype depends on the compatibility between virulence and resistance genes. Recently, we conducted an evolution experiment in which lineages of turnip mosaic virus (TuMV) were passaged in Arabidopsis thaliana genotypes carrying mutations in components of the DNA methylation and the histone demethylation epigenetic pathways. All evolved lineages increased infectivity, virulence and viral load in a host genotype-dependent manner.

Results

To better understand the underlying reasons for these evolved relationships, we delved into the transcriptomic responses of mutant and WT plant genotypes in mock conditions and infected with either the ancestral or evolved viruses. Such a comparison allowed us to classify every gene into nine basic expression profiles. Regarding the targets of viral adaptation, our analyses allowed the identification of common viral targets as well as host genotype-specific genes and categories of biological processes. As expected, immune response-related genes were found to be altered upon infection. However, we also noticed the pervasive over-representation of other functional groups, suggesting that viral adaptation was not solely driven by the level of expression of plant resistance genes. In addition, a significant association between the presence of transposable elements within or upstream the differentially expressed genes was observed. Finally, integration of transcriptomic data into a virus-host protein-protein interaction network highlighted the most impactful interactions.

Conclusions

These findings shed extra light on the complex dynamics between plants and viruses, indicating that viral infectivity depends on various factors beyond just the plant’s resistance genes.
Streptokinase reduces Streptococcus dysgalactiae subsp. equisimilis biofilm formation
Authors: Tölken Lea A. , Neufend Janine V. , Oppegaard Oddvar , Methling Karen , Moll Kirsten , Redanz Sylvio , Katsburg Miriam M.D. , Ali Murtadha Q. , Shumba Patience , Kreikemeyer Bernd , Skrede Steinar , Fulde Marcus , Norrby-Teglund Anna , Lalk Michael , Kittang Bård R. , Siemens Nikolai
Published: September 2024

Background

Streptococcus dysgalactiae subspecies equisimilis (SDSE) is increasingly recognized as an emerging cause of invasive diseases including necrotizing soft tissue infections (NSTIs). In contrast to the closely related Streptococcus pyogenes, SDSE infections mainly affect older and comorbid patients. Biofilm formation has been demonstrated in soft tissue biopsies of S. pyogenes NSTI cases.

Results

Here, we show that bacterial aggregations indicative of biofilms are also present in SDSE NSTI. Although streptokinase (Ska) activity and biofilm formation did not correlate in a diverse set of clinical SDSE isolates, addition of exogenous Ska at an early time point prevented biofilm formation for selected strains. Deletion of ska in SDSE S118 strain resulted in increased biofilm forming capacity. Ska-deficient mutant strain was characterized by a higher metabolic activity and consequent metabolome profiling of biofilms identified higher deposition of a wide range of metabolites as compared to the wild-type.

Conclusions

Our results argue that Ska suppresses biofilm formation in SDSE independent of its original plasminogen converting activity. However, the impact of biofilms and its consequences for patient outcomes in streptococcal NSTIs remain to be elucidated.
Discovery of a conserved translationally repressive upstream open reading frame within the iron-deficiency response regulator IDEF2
Authors: Carey-Fung Oscar , Beasley Jesse T. , Broad Ronan C. , Hellens Roger P. , Johnson Alexander A. T.
Published: September 2024

Background

Iron (Fe) deficiency affects 30–50% of the world’s population. Genetic biofortification of staple crops is a promising strategy for improving human nutrition, but the number of effective precision breeding targets for Fe biofortification is small. Upstream open reading frames (uORFs) are cis-regulatory elements within the 5’ leader sequence (LS) of genes that generally repress translation of the main open reading frame (mORF).

Results

We aligned publicly available rice (Oryza sativa L.) ribo-seq datasets and transcriptomes to identify putative uORFs within important Fe homeostasis genes. A dual luciferase assay (DLA) was used to determine whether these uORFs cause repression of mORF translation and pinpoint LS regions that can be mutated for mORF derepression. A translationally repressive uORF region was identified in two positive regulators of the Fe-deficiency response: IDEF1 and IDEF2. The IDEF2-uORF peptide was highly conserved among monocots and a mutation series in the 5’ LS of the wheat (Triticum aestivum L.) TaIDEF2-A1 gene demonstrated variable mORF derepression.

Conclusions

Together these results reveal a possible regulatory mechanism by which IDEF2 transcription factors modulate the Fe deficiency response in monocots, and highlight novel precision breeding targets to improve crop nutrition and abiotic stress tolerance.
Reframing conceptualizations of primary care involvement in opioid use disorder treatment
Authors: Chiu Kellia , Sud Abhimanyu
Published: September 2024

Background

Opioid-related harms and opioid use disorder (OUD) are health priorities requiring urgent policy responses. There have been many calls for improved OUD care in primary care, as well as increasing involvement of primary care providers in countries like Canada and Australia, which have been experiencing high rates of opioid-related harms.

Methods

Using Starfield’s 4Cs conceptualization of primary care functions, we examined how and why primary care systems may be suited towards, or pose challenges to providing OUD care, and identified health system opportunities to address these challenges. We conducted 14 semi-structured interviews with 16 key informants with experience in opioid use policy in Canada and Australia.

Results

Primary care was identified to be an ideal setting for OUD care delivery due to its potential as the first point of contact in the health system; the opportunity to offer other health services to people with OUD; and the ability to coordinate care with other health providers (e.g. specialists, social workers) and thus also provide care continuity. However, challenges include a lack of resources and support for chronic disease management more broadly in primary care, and the prevailing model of OUD treatment, where addictions care is not seen as part of comprehensive primary care. Additionally, the highly regulated OUD policy landscape is also a barrier, manifesting as a ‘regulatory cascade’ in which restrictive oversight of OUD treatment passes from regulators to health providers to patients, normalizing the overly restrictive nature and inaccessibility of OUD care.

Conclusions

While primary care is an essential arena for providing OUD care, existing sociocultural, political, health professional, and health system factors have led to the current model of care that limits primary care involvement. Addressing this may involve structurally embedding OUD care into primary care and strengthening primary care in general.
Mutational signatures in 175 Chinese gastric cancer patients
Authors: Liu Fatao , Hu Nan , Jiang Kewei , Liu Huaitian , Wang Mingyi , Hu Ying , Zhang Tongwu , Wu Ho-Hsiang , Yang Howard , Weng Hao , Dong Ping , Giffen Carol , Zhu Bin , Lee Maxwell P. , Abnet Christian C. , Taylor Philip R. , Liu Yun , Liu Yingbin , Goldstein Alisa M.
Published: September 2024

Background

Gastric cancer (GC), a molecularly heterogeneous disease, is the third leading cause of cancer death worldwide. The majority of GC cases worldwide occur in East Asia, predominantly China. Mutational Signature Framework offers an elegant approach to identify mutational processes present in tumors.

Methods

To identify mutational signature patterns, we conducted whole exome sequencing (WES) analysis in Chinese patients with GC. Mutect2 and MutsigCV were used to identify significantly mutated genes in 175 Chinese GC cases using paired tumor-normal tissues. We investigated mutational signatures using Catalogue of Somatic Mutations in Cancer (COSMIC) Version 2 (V2) and Version 3 (V3).

Results

We identified 104 mutated genes with P < 0.01. Seven genes (OR6B1, B2M, ELF3, RHOA, RPL22, TP53, ARIDIA) had q < 0.0001, including six previously associated with GC. Mutational signatures (COSMIC-V3) observed include 14 single base substitutions (SBS), one doublet base substitution (DBS) Signature A, and one InDel (ID2). The most frequent SBS signatures (SBS05, SBS01, SBS15, SBS20, SBS40) were also observed in 254 White GC cases from The Cancer Genome Atlas (TCGA) Project. However, SBS01 and SBS20 showed significant differences between Whites vs. All Asians (19.3% vs. 11.3% for SBS 1 (P = 0.012) and 11.4% vs. 5.9% for SBS20 (P = 0.025), respectively). Using COSMIC V2, signatures 6, 15, and 1 were the most frequent in Chinese GC cases. Further, most Chinese GC cases carried multiple signatures.

Conclusions

This effort represents the most detailed mutational signatures analysis of GC cases from China to date. Results hold promise for new insights in understanding risk and prognosis factors in GC.
Midwifery students’ satisfaction with simulation-based education and associated factors among governmental universities in Amhara region, Ethiopia 2022
Authors: Gebrekidan Fiker Chane , Aweke Amlaku Mulat , Gella Getahun Belay , Bekele Yibeltal Alemu
Published: September 2024

Background

Simulation is a method of learning in which the learner experiences a simulated situation instead of being physically present in the clinical area. Exposing students to simulation-based education improves learners’ clinical competence and ability to make decisions, which are crucial for today’s health workforce. When given the proper circumstances, such as receiving feedback on their performance, having the chance for repeated practice, and having simulation as a core component of the curriculum, simulated instruction greatly aids in learning. Although previous studies have been conducted in this area, there are gaps in determining the factors related to their learning environment and design characteristics.

Method

An institution-based cross-sectional study was conducted on 413 midwifery students in Amhara region universities from August 1–30, 2022. Study participants were selected via a simple random sampling technique. Data were collected from third and fourth-year undergraduate midwifery students through a self-administered questionnaire. Epi Data version 4.6 and Statistical Package for Social Sciences version 26 were used for data entry and analysis, respectively. Bivariable and multivariable logistic regression analyses were employed; a P-value of less than 0.05 was considered statistically significant in the study.

Result

This study revealed that 84.7% (95% CI: 81.1–88.3) of midwifery students in Amhara region universities were satisfied with simulation-based education. Year of study [AOR: 2.936; 95% CI (1.531–5.631)], adequate support [AOR: 2.903; 95% CI (1.217–6.922)], availability of instructors [AOR = 2.861, 95% CI (1.078–7.591)], and provision of checklists [AOR: 2.326; 95% CI (1.143–4.734)] were found to be statistically significant variables.

Conclusion

This study revealed undergraduate midwifery students were more satisfied with simulation-based education compared with previous studies conducted in Ethiopia. Predictor variables such as year of study, support, instructor availability, and provision of checklists were significantly associated with student satisfaction. Hence, midwifery departments should strengthen the support given by staff, encourage their instructors to be available during simulations, improve the utilization and provision of checklists to students as much as possible.
Longitudinal study of association between quality of life and grit in internal medicine residents in Ramathibodi Hospital
Authors: Kitthavorn Pattarapol , Srisuma Sahaphume , Hongsanguansri Sirichai , Morasert Thotsaporn
Published: September 2024

Background

Grit refers to a combination of perseverance and passion, which is essential for long-term success. Grit is associated with higher education attainment and a lower likelihood of burnout. Understanding how grit evolves during internal medicine residency training is important for providing better support to residents. The primary objective of the current study was to evaluate potential changes in the level of grit throughout the training program and investigate the association between grit and stress levels, quality of life (QoL), and satisfaction of learning scores.

Methods

We conducted a prospective study involving internal medicine residents enrolled in training programs from July 2022 to July 2023, except for the second-third-year residents of dermatology and neurology programs and the third-year residents of haematology and oncology programs, which are not part of the same training regimen. Data collection was conducted using questionnaires at the beginning of the training year and every three months until the end. Collected data included age, gender, habitat, working experience, financial burden, marital status, rotations, grit scores, QoL, stress score, and satisfaction of learning score during each trimester. Changes in grit over the year were examined using repeated measures analysis of variance adjusted by training program, financial status, working experience, habitat, marital status, and age. We performed multivariable linear regression models to explore associations between grit and the following domains: QoL, ST-5, and SoLs.

Results

Of 122 internal medicine residents in all three years of training, one resident dropped out during training, and another declined to participate. A total of 120 residents were included. Grit did not significantly change over time. Subgroup analysis of the first-year resident group revealed that grit significantly decreased (P = 0.049). Multivariable analysis revealed that grit was positively associated with QoL (β = 0.01, P < 0.001) and satisfaction of learning score (β = 0.07, P < 0.001) but inversely associated with stress score (β = − 0.04, P < 0.001).

Conclusions

Of all residents, grit did not change over a year. However, only the first-year residents reported a decrease in grit during a training year. Throughout first-year residents’ internal medicine residency training, grit was positively associated with QoL and satisfaction of learning score but negatively associated with stress level. These findings suggest the need for targeted interventions to support first-year residents and enhance their resilience throughout training.
Dissemination and outcome reporting bias in clinical malaria intervention trials: a cross-sectional analysis
Authors: Pool Lydia , Ruiz del Portal Luyten Claire , van der Pluijm Rob W. , Soentjens Patrick , Hanscheid Thomas , Grobusch Martin P. , Visser Benjamin J.
Published: September 2024

Background

Dissemination and outcome reporting biases are a significant problem in clinical research, with far-reaching implications for both scientific understanding and clinical decision-making. This study investigates the prevalence of dissemination- and outcome reporting biases in registered interventional malaria research.

Methods

All malaria interventional trials registered on ClinicalTrials.gov from 2010 to 2020 were identified. Subsequently, publications that matched the registration were searched. The primary outcome measures were the percentage of registered studies that resulted in subsequent publication of study results, the concordance between registered outcomes, and reported outcomes. Secondary outcomes were compliance with WHO standards for timely publication (issued in 2017) of summary study results in the respective trial registry (within 12 months of study completion) or peer-reviewed publication (within 24 months of study completion) was evaluated.

Results

A total of 579 trials were identified on ClinicalTrials.gov, of which 544 met the inclusion criteria. Notably, almost 36.6% of these trials (199/544) were registered retrospectively, with 129 (23.7%) registered after the first patient enrolment and 70 (12.9%) following study completion. Publications were identified for 351 out of 544 registered trials (64.5%), involving 1,526,081 study participants. Conversely, publications were not found for 193 of the 544 registrations (35.5%), which aimed to enrol 417,922 study participants. Among these 544 registrations, 444 (81.6%) did not meet the WHO standard to post summary results within 12 months of primary study completion (the last visit of the last subject for collection of data on the primary outcome), while 386 out of 544 registrations (71.0%) failed to publish their results in a peer-reviewed journal within 24 months of primary study completion. Discrepancies were noted in the reported primary outcomes compared to the registered primary outcomes in 47.6% (222/466) of the published trials, and an even higher discordance rate of 73.2% (341/466 publications) for secondary outcomes.

Conclusions

Non-dissemination remains a significant issue in interventional malaria research, with most trials failing to meet WHO standards for timely dissemination of summary results and peer-reviewed journal publications. Additionally, outcome reporting bias is highly prevalent across malaria publications. To address these challenges, it is crucial to implement strategies that enhance the timely reporting of research findings and reduce both non-dissemination and outcome reporting bias.
Revisiting a decade of inequality in healthcare financial burden in Cambodia, 2009–19: trends, determinants and decomposition
Authors: Fernandes Antunes Adélio , Jithitikulchai Theepakorn , Hohmann Juergen , Flessa Steffen
Published: September 2024

Background

Out-of-pocket healthcare expenditure (OOPHE) without adequate social protection often translates to inequitable financial burden and utilization of services. Recent publications highlighted Cambodia’s progress towards Universal Health Coverage (UHC) with reduced incidence of catastrophic health expenditure (CHE) and improvements in its distribution. However, departing from standard CHE measurement methods suggests a different storyline on trends and inequality in the country.

Objective

This study revisits the distribution and impact of OOPHE and its financial burden from 2009–19, employing alternative socio-economic and economic shock metrics. It also identifies determinants of the financial burden and evaluates inequality-contributing and -mitigating factors from 2014–19, including coping mechanisms, free healthcare, and OOPHE financing sources.

Methods

Data from the Cambodian Socio-Economic Surveys of 2009, 2014, and 2019 were utilized. An alternative measure to CHE is proposed: Excessive financial burden (EFB). A household was considered under EFB when its OOPHE surpassed 10% or 25% of total consumption, excluding healthcare costs. A polychoric wealth index was used to rank households and measure EFB inequality using the Erreygers Concentration Index. Inequality shifts from 2014–19 were decomposed using the Recentered Influence Function regression followed by the Oaxaca-Blinder method. Determinants of financial burden levels were assessed through zero-inflated ordered logit regression.

Results

Between 2009–19, EFB incidence increased from 10.95% to 17.92% at the 10% threshold, and from 4.41% to 7.29% at the 25% threshold. EFB was systematically concentrated among the poorest households, with inequality sharply rising over time, and nearly a quarter of the poorest households facing EFB at the 10% threshold. The main determinants of financial burden were geographic location, household size, age and education of household head, social health protection coverage, disease prevalence, hospitalization, and coping strategies. Urbanization, biased disease burdens, and preventive care were key in explaining the evolution of inequality.

Conclusion

More efforts are needed to expand social protection, but monitoring those through standard measures such as CHE has masked inequality and the burden of the poor. The financial burden across the population has risen and become more unequal over the past decade despite expansion and improvements in social health protection schemes. Health Equity funds have, to some extent, mitigated inequality over time. However, their slow expansion and the reduced reliance on coping strategies to finance OOPHE could not outbalance inequality.
European health regulations reduce registry-based research
Authors: Brück Oscar , Sanmark Enni , Ponkilainen Ville , Bützow Alexander , Reito Aleksi , Kauppila Joonas H. , Kuitunen Ilari
Published: September 2024

Background

The European Health Data Space (EHDS) regulation has been proposed to harmonize health data processing. Given its parallels with the Act on Secondary Use of Health and Social Data (Secondary Use Act) implemented in Finland in 2020, this study examines the consequences of heightened privacy constraints on registry-based medical research.

Methods

We collected study permit counts approved by university hospitals in Finland in 2014–2023 and the data authority Findata in 2020‒2023. The changes in the study permit counts were analysed before and after the implementation of the General Data Protection Regulation (GDPR) and the Secondary Use Act. By fitting a linear regression model, we estimated the deficit in study counts following the Secondary Use Act.

Results

Between 2020 and 2023, a median of 5.5% fewer data permits were approved annually by Finnish university hospitals. On the basis of linear regression modelling, we estimated a reduction of 46.9% in new data permits nationally in 2023 compared with the expected count. Similar changes were neither observed after the implementation of the GDPR nor in permit counts of other medical research types, confirming that the deficit was caused by the Secondary Use Act.

Conclusions

This study highlights concerns related to data privacy laws for registry-based medical research and future patient care.
Challenges in the diagnosis of fibrodysplasia ossificans progressiva with the ACVR1 mutation (c.774G > C, p.R258S): a case report and review of literature
Authors: Yang Siqi , Cui Rongrong , Li Jialin , Dai Ruchun
Published: September 2024

The diagnosis of fibrodysplasia ossificans progressiva is missed or delayed because of its insidious precursors, especially in uncharacteristic cases. Fibrodysplasia ossificans progressiva, which mostly displayed the mutation c.617G > A, p.R206H, is characterized by congenital malformation of the great toe and progressive extra-skeletal ossification of ligaments, tendons and muscles. The mutation c.774G > C, p.R258S (HGVS: NC_000002.11:g.158626896 C > G) in activin A receptor type I is an infrequent etiology of fibrodysplasia ossificans progressiva and can present different clinical features. Awareness of these multiple clinical features will help endocrinologists in the early diagnosis of fibrodysplasia ossificans progressiva. We report a case of fibrodysplasia ossificans progressiva with the activin A receptor type I mutation c.774G > C, p.R258S, which was diagnosed before its ossifying period.
Probing the orthogonality and robustness of the mammalian RNA-binding protein Musashi-1 in Escherichia coli
Authors: Dolcemascolo Roswitha , Ruiz Raúl , Baldanta Sara , Goiriz Lucas , Heras-Hernández María , Montagud-Martínez Roser , Rodrigo Guillermo
Published: September 2024

RNA recognition motifs (RRMs) are widespread RNA-binding protein domains in eukaryotes, which represent promising synthetic biology tools due to their compact structure and efficient activity. Yet, their use in prokaryotes is limited and their functionality poorly characterized. Recently, we repurposed a mammalian Musashi protein containing two RRMs as a translation regulator in Escherichia coli. Here, employing high-throughput RNA sequencing, we explored the impact of Musashi expression on the transcriptomic and translatomic profiles of E. coli, revealing certain metabolic interference, induction of post-transcriptional regulatory processes, and spurious protein-RNA interactions. Engineered Musashi protein mutants displayed compromised regulatory activity, emphasizing the importance of both RRMs for specific and sensitive RNA binding. We found that a mutation known to impede allosteric regulation led to similar translation control activity. Evolutionary experiments disclosed a loss of function of the synthetic circuit in about 40 generations, with the gene coding for the Musashi protein showing a stability comparable to other heterologous genes. Overall, this work expands our understanding of RRMs for post-transcriptional regulation in prokaryotes and highlight their potential for biotechnological and biomedical applications.
HIF-1α-HPRT1 axis promotes tumorigenesis and gefitinib resistance by enhancing purine metabolism in EGFR-mutant lung adenocarcinoma
Authors: Geng Pengyu , Ye Fei , Dou Peng , Hu Chunxiu , He Jiarui , Zhao Jinhui , Li Qi , Bao Miao , Li Xiangnan , Liu Xinyu , Xu Guowang
Published: September 2024

Background

The mutations of oncogenic epidermal growth factor receptor (EGFR) is an important cause of lung adenocarcinoma (LUAD) malignance. It has been knowm that metabolic reprogramming is an important hallmark of malignant tumors, and purine metabolism is a key metabolic pathway for tumor progression and drug resistance, but its relationship with the EGFR-mutant LUAD is unclear.

Methods

Metabolic reprogramming was studied through capillary electrophoresis-time of flight mass spectrometry (CE-TOF/MS)-based metabolic profiling analysis. Cell proliferation in vitro was evaluated by EdU staining and cell cycle assay. Tumorigenicity in vivo was tested by subcutaneous tumor formation experiment in nude mice. The binding of hypoxia-inducible factor-1 alpha (HIF-1α) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) was detected by DNA pull‑down assay and Chromatin immunoprecipitation (ChIP) assays. HIF-1α, HPRT1, DNA damage and cell apoptosis related genes were examined by western blot. In addition, RNA sequencing, mass spectrometry and bioinformatics analysis were performed.

Results

We found that mutated EGFR (muEGFR) upregulates HPRT1 to promote purine metabolism and tumorigenesis of EGFR-mutant LUAD. Mechanistically, muEGFR increases HIF-1α expression through protein stability. Meanwhile, up-regulated HIF-1α bound to the promoter of HPRT1 and transcriptionally activates HPRT1 expression, enhancing purine metabolism to maintain rapid tumor cell proliferation in EGFR-mutant LUAD. Further, gefitinib inhibited the synthesis of purine nucleotides, and HPRT1 inhibition increased the sensitivity of gefitinib to EGFR-mutant LUAD.

Conclusions

Our study reveals that muEGFR-HIF-1α-HPRT1 axis plays a key role in EGFR-mutant LUAD and provides a new strategy-inhibiting purine metabolism for treating EGFR-mutant LUAD.
Dynamic glycolytic reprogramming effects on dendritic cells in pancreatic ductal adenocarcinoma
Authors: Zhang Bo , Ohuchida Kenoki , Tsutsumi Chikanori , Shimada Yuki , Mochida Yuki , Oyama Koki , Iwamoto Chika , Sheng Nan , Fei Shuang , Shindo Koji , Ikenaga Naoki , Nakata Kohei , Oda Yoshinao , Nakamura Masafumi
Published: September 2024

Background

Pancreatic ductal adenocarcinoma tumors exhibit resistance to chemotherapy, targeted therapies, and even immunotherapy. Dendritic cells use glucose to support their effector functions and play a key role in anti-tumor immunity by promoting cytotoxic CD8+ T cell activity. However, the effects of glucose and lactate levels on dendritic cells in pancreatic ductal adenocarcinoma are unclear. In this study, we aimed to clarify how glucose and lactate can impact the dendritic cell antigen-presenting function and elucidate the relevant mechanisms.

Methods

Glycolytic activity and immune cell infiltration in pancreatic ductal adenocarcinoma were evaluated using patient-derived organoids and resected specimens. Cell lines with increased or decreased glycolysis were established from KPC mice. Flow cytometry and single-cell RNA sequencing were used to evaluate the impacts on the tumor microenvironment. The effects of glucose and lactate on the bone marrow-derived dendritic cell antigen-presenting function were detected by flow cytometry.

Results

The pancreatic ductal adenocarcinoma tumor microenvironment exhibited low glucose and high lactate concentrations from varying levels of glycolytic activity in cancer cells. In mouse transplantation models, tumors with increased glycolysis showed enhanced myeloid-derived suppressor cell infiltration and reduced dendritic cell and CD8+ T cell infiltration, whereas tumors with decreased glycolysis displayed the opposite trends. In three-dimensional co-culture, increased glycolysis in cancer cells suppressed the antigen-presenting function of bone marrow-derived dendritic cells. In addition, low-glucose and high-lactate media inhibited the antigen-presenting and mitochondrial functions of bone marrow-derived dendritic cells.

Conclusions

Our study demonstrates the impact of dynamic glycolytic reprogramming on the composition of immune cells in the tumor microenvironment of pancreatic ductal adenocarcinoma, especially on the antigen-presenting function of dendritic cells.
The epidemiology and outcomes of hospitalized drowning in Thai children: a national data analysis 2015–2019
Authors: Niamsanit Sirapoom , Uppala Rattapon , Sitthikarnkha Phanthila , Techasatian Leelawadee , Saengnipanthkul Suchaorn , Thepsuthammarat Kaewjai , Sutra Sumitr
Published: September 2024

Background

Drowning remains a common cause of death among children. However, the epidemiology and impact of drowning in Thailand was underexplored. This study aimed to analyze the epidemiology and clinical outcomes of pediatric drowning in Thailand and to determine the factors associated with the need for intubation and mortality.

Methods

Data derived from the Thai healthcare delivery system for the period between 2015 and 2019 were used to examine the monthly admissions, mortality rates, length of hospital stay, and the number of patients who received endotracheal intubation. Multivariate logistic regression analysis was employed to identify the risk factors associated with the need for intubation and mortality.

Results

Of the 4,911, 58.8% were under six years old, 63.5% were male, and 31.2% were from the Northeastern region. The majority drowned during April, which is the summer season in Thailand. Among these patients, 28.8% required intubation, with the highest proportion found in the 6-<12 years age group (35.9%). The independent risk factors for intubation were metabolic acidosis (adjusted odd ratio [aOR] 9.74; 95% confidence interval [CI] 7.14–13.29; p < 0.001) and pulmonary edema (aOR 5.82; 95%CI 3.92–8.65; p < 0.001). The overall mortality rate due to drowning was 12.6%. Factors significantly associated with mortality included in-hospital cardiac arrest (aOR 4.43; 95%CI 2.78–7.06; p < 0.001), and the presence of drowning-related complications, particularly renal failure (aOR 7.13; 95%CI 3.93–12.94; p < 0.001).

Conclusion

Drowning admissions and mortality were highest among male children under six years old, occurring mainly during the summer season. Significant factors associated with intubation requirement included metabolic acidosis and pulmonary edema. The mortality was significantly associated with in-hospital cardiac arrest and drowning-related complications, particularly renal failure.

Trial registration

This is an observational study, does not include any intervention, and has therefore not been registered.
Acute exposure to mercury drives changes in gene expression in Drosophila melanogaster
Authors: Sanderson Brian J. , Sims-West Dylan J. , Macdonald Stuart J.
Published: September 2024

Objective

We quantified the effect of acute exposure to a high dosage of inorganic mercury on gene expression in Drosophila melanogaster using RNA-sequencing of whole adult females.

Results

We found 119 genes with higher gene expression following treatment (including all 5 Drosophila metallothionine genes and a number of heat shock protein genes), and 31 with lower expression (several of which are involved in egg formation). Our results highlight biological processes and genetic pathways impacted by exposure to this toxic metal, and provide motivation for future studies to understand the genetic basis of response to mercury.
Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling
Authors: Shaw Nicole C. , Chen Kevin , Farley Kathryn O. , Hedges Mitchell , Forbes Catherine , Baynam Gareth , Lassmann Timo , Fear Vanessa S.
Published: September 2024

Background

SETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate the functional effects of three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain.

Methods

Genetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes.

Results

The data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype.

Limitations

The study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids.

Conclusions

We developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype.