bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneous pseudobulk simulation enables realistic benchmarking of cell-type deconvolution methods
Authors: Hu Mengying , Chikina Maria 
Published: July 2024

Abstract
Background
Computational cell type deconvolution enables the estimation of cell type abundance from bulk tissues and is important for understanding tissue microenviroment, especially in tumor tissues. With rapid development of deconvolution methods, many benchmarking studies have been published aiming for a comprehensive evaluation for these methods. Benchmarking studies rely on cell-type resolved single-cell RNA-seq data to create simulated pseudobulk datasets by adding individual cells-types in controlled proportions.

Results
In our work, we show that the standard application of this approach, which uses randomly selected single cells, regardless of the intrinsic difference between them, generates synthetic bulk expression values that lack appropriate biological variance. We demonstrate why and how the current bulk simulation pipeline with random cells is unrealistic and propose a heterogeneous simulation strategy as a solution. The heterogeneously simulated bulk samples match up with the variance observed in real bulk datasets and therefore provide concrete benefits for benchmarking in several ways. We demonstrate that conceptual classes of deconvolution methods differ dramatically in their robustness to heterogeneity with reference-free methods performing particularly poorly. For regression-based methods, the heterogeneous simulation provides an explicit framework to disentangle the contributions of reference construction and regression methods to performance. Finally, we perform an extensive benchmark of diverse methods across eight different datasets and find BayesPrism and a hybrid MuSiC/CIBERSORTx approach to be the top performers.

Conclusions
Our heterogeneous bulk simulation method and the entire benchmarking framework is implemented in a user friendly package https://github.com/humengying0907/deconvBenchmarking and https://doi.org/10.5281/zenodo.8206516, enabling further developments in deconvolution methods.
Detecting haplotype-specific transcript variation in long reads with FLAIR2
Authors: Tang Alison D. , Felton Colette , Hrabeta-Robinson Eva , Volden Roger , Vollmers Christopher , Brooks Angela N. 
Published: July 2024

Abstract
Background
RNA-seq has brought forth significant discoveries regarding aberrations in RNA processing, implicating these RNA variants in a variety of diseases. Aberrant splicing and single nucleotide variants (SNVs) in RNA have been demonstrated to alter transcript stability, localization, and function. In particular, the upregulation of ADAR, an enzyme that mediates adenosine-to-inosine editing, has been previously linked to an increase in the invasiveness of lung adenocarcinoma cells and associated with splicing regulation. Despite the functional importance of studying splicing and SNVs, the use of short-read RNA-seq has limited the community’s ability to interrogate both forms of RNA variation simultaneously.

Results
We employ long-read sequencing technology to obtain full-length transcript sequences, elucidating cis-effects of variants on splicing changes at a single molecule level. We develop a computational workflow that augments FLAIR, a tool that calls isoform models expressed in long-read data, to integrate RNA variant calls with the associated isoforms that bear them. We generate nanopore data with high sequence accuracy from H1975 lung adenocarcinoma cells with and without knockdown of ADAR. We apply our workflow to identify key inosine isoform associations to help clarify the prominence of ADAR in tumorigenesis.

Conclusions
Ultimately, we find that a long-read approach provides valuable insight toward characterizing the relationship between RNA variants and splicing patterns.
Effect of norepinephrine and phenylephrine on prothrombotic response in patients undergoing cesarean section under spinal anesthesia: protocol for a randomized, double-blind, controlled study
Authors: Tao Wenhui , Xie Yufang , Ding Wei , Bao Jinfeng , Zhang Ye , Hu Xianwen 
Published: July 2024

Abstract
Background
Norepinephrine and phenylephrine are commonly used vasoactive drugs to treat hypotension during the perioperative period. The increased release of endogenous norepinephrine elicits prothrombotic changes, while parturients are generally in a hypercoagulable state. Therefore, this trial aims to investigate whether there is a disparity between equivalent doses of prophylactic norepinephrine infusion and phenylephrine infusion on prothrombotic response in patients undergoing cesarean section under spinal anesthesia.

Methods
Sixty-six eligible parturients will be recruited for this trial and randomly assigned to the norepinephrine or phenylephrine group. The “study drug” will be administered at a rate of 15 ml/h starting from the intrathecal injection. The primary outcome are plasma coagulation factor VIII activity (FVIII: C), fibrinogen, and D-dimer levels. The secondary outcomes include hemodynamic variables and umbilical artery blood pH value.

Discussion
Our study is the first trial comparing the effect of norepinephrine and phenylephrine on prothrombotic response in patients undergoing cesarean section under spinal anesthesia. Positive or negative results will all help us better understand the impact of vasoactive drugs on patients. If there are any differences, this trial will provide new evidence for maternal choice of vasoactive medications in the perioperative period.

Trial registration
Chinese Clinical Trial Registry ChiCTR2300077164. Registered on 1 November 2023. https://www.chictr.org.cn/.
Effect of esketamine combined with dexmedetomidine on delirium in sedation for mechanically ventilated ICU patients: protocol for a nested substudy within a randomized controlled trial
Authors: Zhang Wenhui , You Jinjin , Hu Jing , Chen Xiangding , Wang Han , Li Nan , Wei Chen , Tang Wanchun , Zuo Xiangrong 
Published: July 2024

Abstract
Background
Use of sedatives and analgesics is associated with the occurrence of delirium in critically ill patients receiving mechanical ventilation. Dexmedetomidine reduces the occurrence of delirium but may cause hypotension, bradycardia, and insufficient sedation. This substudy aims to determine whether the combination of esketamine with dexmedetomidine can reduce the side effects and risk of delirium than dexmedetomidine alone in mechanically ventilated patients.

Methods
This single-center, randomized, active-controlled, superiority trial will be conducted at The First Affiliated Hospital of Nanjing Medical University. A total of 134 mechanically ventilated patients will be recruited and randomized to receive either dexmedetomidine alone or esketamine combined with dexmedetomidine, until extubation or for a maximum of 14 days. The primary outcome is the occurrence of delirium, while the second outcomes include the number of delirium-free days; subtype, severity, and duration of delirium; time to first onset of delirium; total dose of vasopressors and antipsychotics; duration of mechanical ventilation; ICU and hospital length of stay (LOS); accidental extubation, re-intubation, re-admission; and mortality in the ICU at 14 and 28 days.

Discussion
There is an urgent need for a new combination regimen of dexmedetomidine due to its evident side effects. The combination of esketamine and dexmedetomidine has been applied throughout the perioperative period. However, there is still a lack of evidence on the effects of this regimen on delirium in mechanically ventilated ICU patients. This substudy will evaluate the effects of the combination of esketamine and dexmedetomidine in reducing the risk of delirium for mechanically ventilated patients in ICU, thus providing evidence of this combination to improve the short-term prognosis. The study protocol has obtained approval from the Medical Ethics Committee (ID: 2022-SR-450).

Trial registration
ClinicalTrials.gov: NCT05466708, registered on 20 July 2022.
Biofeedback combined with percutaneous electrical pudendal nerve stimulation for the treatment of low anterior rectal resection syndrome: a study protocol for a randomized controlled trial
Authors: Cao Gaoyang , Zhang Xinjie , Wang Fei , Man Da , Wu Lijie , Pan Xuchu , Chen Shan 
Published: July 2024

Abstract
Background
Low anterior resection syndrome (LARS) is a distressing condition that affects approximately 25–80% of patients following surgery for rectal cancer. LARS is characterized by debilitating bowel dysfunction symptoms, including fecal incontinence, urgent bowel movements, and increased frequency of bowel movements. Although biofeedback therapy has demonstrated effectiveness in improving postoperative rectal control, the research results have not fulfilled expectations. Recent research has highlighted that stimulating the pudendal perineal nerves has a superior impact on enhancing pelvic floor muscle function than biofeedback alone. Hence, this study aims to evaluate the efficacy of a combined approach integrating biofeedback with percutaneous electrical pudendal nerve stimulation (B-PEPNS) in patients with LARS through a randomized controlled trial (RCT).

Methods and analysis
In this two-armed multicenter RCT, 242 participants with LARS after rectal surgery will be randomly assigned to undergo B-PEPNS (intervention group) or biofeedback (control group). Over 4 weeks, each participant will undergo 20 treatment sessions. The primary outcome will be the LARS score. The secondary outcomes will be anorectal manometry and pelvic floor muscle electromyography findings and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scores. Data will be collected at baseline, post-intervention (1 month), and follow-up (6 months).

Discussion
We anticipate that this study will contribute further evidence regarding the efficacy of B-PEPNS in alleviating LARS symptoms and enhancing the quality of life for patients following rectal cancer surgery.

Trial registration
Chinese Clincal Trials Register ChiCTR2300078101. Registered 28 November 2023.
Predicting functional movement capacity in adults: the effect of range of motion and isometric strength
Authors: Özkan Mazhar , Canli Umut , Alwhaibi Reem , Ustaömer Kübra , Karaçam Aydın , Orhan Bekir Erhan , Bohn Lucimere , Sivrikaya Kenan , Sönmeyenmakas Aytekin , Gonzalez Pablo Prieto 
Published: July 2024

AbstractThe aim of the study was to determine the role of isometric strength and range of motion in predicting Functional Movement Screen (FMS) scores of adults. A total of 120 participants (age = 34.62 ± 11.82 years; height = 170.56 ± 9.63 cm; weight = 73.62 ± 15.39 kg) volunteered to participate in the study. Anthropometric measurements were performed, including height, body weight, muscle mass, and body fat. Following this, the ranges of motion of the shoulder, hip, knee, and ankle joints were measured sequentially. Isometric strength and FMS tests were then performed. Hip extension isometric strength explained 23% of the variation in FMStotal. The common effect of knee flexion, shoulder flexion, and dorsiflexion joint range of motion explained 34% of the change in FMStotal (F (3−116) = 20.375, p < 0.001). A significant relationship (R = 0.658, R2 = 0.413) was found between hip extension isometric strength, knee flexion, shoulder flexion, and dorsiflexion range of motion and FMStotal (F (4−115) = 21.952, p < 0.001). The common effect of all these variables explains 43% of the change in FMStotal. The results indicate that the FMS test scores, which are utilized to evaluate the risk of injury in sedentary adults, can be significantly predicted by the effect of hip extension isometric strength and parameters related to knee flexion, shoulder flexion, and dorsiflexion joint range of motion. At this time, it is advised that range of motion and isometric strength be taken into account when determining a person’s functional movement capacity.
Evaluation of frailty in geriatric patients undergoing cardiac rehabilitation after cardiac procedure: results of a prospective, cross-sectional study
Authors: Steinmetz Carolin , Krause Laura , Sulejmanovic Samra , Kaumkötter Sabrina , Hartog Johanneke , Scheenstra Bart , Stefan Flohr , Mengden Thomas , Grefe Clemens , Knoglinger Ernst , Reiss Nils , Bjarnason-Wehrens Birna , Schmidt Thomas , Sadlonova Monika , von Arnim Christine A. F. , Heinemann Stephanie 
Published: July 2024

Abstract
Background
Frailty is an indicator of a decline in quality of life and functional capacity in cardiac rehabilitation (CR) patients. Currently, there is no standardized assessment tool for frailty used in CR. The aim of this study was to determine if the Clinical Frailty Scale (CFS) is feasible for assessing frailty in CR.

Methods
Prospective, cross-sectional study within the framework of the ongoing multicenter prehabilitation study "PRECOVERY". Patients ≥75 years undergoing CR after cardiac procedure (n=122) were recruited in four German inpatient CR facilities. Assessments included: CFS, Katz-Index, hand grip strength (HGS), Short Physical Performance Battery (SPPB) and six-minute-walk test (6MWT). Outcomes were frailty (CFS≥4) and the correlation of frailty with assessments of functional capacity, activities of daily living and clinical parameters. Statistical analysis included descriptive statistics and correlations, using the spearman correlation coefficient and chi-square test to test for significance.

Results
Data from 101 patients (79.9±4.0 years; 63% male) were analyzed. The mean CFS score was 3.2±1.4; 41.6% were defined as frail (CFS≥4). The mean time required to assess the CFS was 0.20 minutes. The findings show that CFS correlates significantly (p<0.001) with the following factors: Katz-Index, HGS, SPPB-Score and 6MWT (r≤-0.575). In addition, CFS correlated with small to moderate effects with co-morbidities (r=0.250), as-needed medications and need for nursing assistance (r≤0.248).

Conclusions
The CFS assessment can be performed in under one minute and it correlates significantly with assessments of functional capacity, activities of daily living and clinical parameters in the CR setting.

Trial registration
German Clinical Trials Register (DRKS; http:// www. drks. de; DRKS00032256). Retrospectively registered on 13 July 2023.
Vitamin D levels and bone mineral density of middle-aged premenopausal female football and volleyball players in Japan: a cross-sectional study
Authors: Sakamoto Kimiko , Miyamori Takayuki , Someya Yuki , Nagao Masashi , Ishihara Yoshihiko , Kobayashi Yohei , Shimasaki Yu , Imai Junko , Ono Takeshi , Ikeda Hiroshi , Tashima Kohzo , Yoshimura Masafumi 
Published: July 2024

Abstract
Background
The number of football teams in senior categories has increased. As outdoor sports entail players being exposed to sunlight, playing football may contribute to maintaining vitamin D stores and body mineral density while preventing osteoporosis. This study aimed to determine the bone mineral density and vitamin D levels in middle-aged premenopausal female football players.

Methods
Participants were premenopausal females in their 40s. We evaluated bone mineral density of the second to the fourth lumbar vertebrae and femoral neck, serum 25-hydroxy vitamin D (25-OHD) levels, which is an indicator of vitamin D stores, and body composition. In addition, we administered a questionnaire survey on exercise habits and lifestyle. Ninety-two participants were categorised into three groups: the football group (n = 27), volleyball group (n = 40), and non-exercise group (n = 25).

Results
Bone mineral density was higher in the football and volleyball groups than in the non-exercise group (P < 0.01). The volleyball group had a significantly higher bone mineral density of the lumbar spine and femoral neck than the non-exercise group (P < 0.01). The football group had a significantly higher bone mineral density of the femoral neck than the non-exercise group (P < 0.01). Although the football group had played fewer years than the volleyball group (P < 0.01), serum 25-OHD levels were the highest in the football group and were significantly higher than those in the volleyball and non-exercise groups (P < 0.01).

Conclusions
Middle-aged premenopausal football players had higher body vitamin D levels and bone mineral densities than non-active females. These results suggest that playing football may contribute to the prevention of osteoporosis.

Trial registration
UMIN Clinical Trials Registry UMIN000054235. 2024/04/23. Retrospectively registered.
Using clotted, pelleted blood samples for direct molecular detection of Bartonella spp. in small mammal wildlife surveillance studies
Authors: Jeeves Simon P. , Fernando Champika , Kotwa Jonathon D. , Mubareka Samira , Hill Janet E. , Jardine Claire M. 
Published: July 2024

Abstract
Objective
Bartonella are emerging bacterial zoonotic pathogens. Utilization of clotted blood samples for surveillance of these bacteria in wildlife has begun to supersede the use of tissues; however, the efficacy of these samples has not been fully investigated. Our objective was to compare the efficacy of spleen and blood samples for DNA extraction and direct detection of Bartonella spp. via qPCR. In addition, we present a protocol for improved DNA extraction from clotted, pelleted (i.e., centrifuged) blood samples obtained from wild small mammals.

Results
DNA concentrations from kit-extracted blood clot samples were low and A260/A280 absorbance ratios indicated high impurity. Kit-based DNA extraction of spleen samples was efficient and produced ample DNA concentrations of good quality. We developed an in-house extraction method for the blood clots which resulted in apposite DNA quality when compared to spleen samples extracted via MagMAX DNA Ultra 2.0 kit. We detected Bartonella in 9/30 (30.0%) kit-extracted spleen DNA samples and 11/30 (36.7%) in-house-extracted blood clot samples using PCR. Our results suggest that kit-based methods may be less suitable for DNA extraction from blood clots, and that blood clot samples may be superior to tissues for Bartonella detection.
Inappropriate treatment of pulmonary aspergillosis caused by Aspergillus flavus in susceptible pediatric patients: a case series
Authors: Hosseinikargar Neginsadat , Zarrinfar Hossein , Seyedi Seyed Javad , Mojtahedi Seyedeh Sabereh 
Published: July 2024

Abstract
Background
Pulmonary aspergillosis is a prevalent opportunistic fungal infection that can lead to mortality in pediatric patients with underlying immunosuppression. Appropriate and timely treatment of pulmonary aspergillosis can play a crucial role in reducing mortality among children admitted with suspected infections.

Case presentation
The present study reports three cases of inappropriate treatment of pulmonary aspergillosis caused by Aspergillus flavus in two Iranian pediatric patients under investigation and one Afghan patient. Unfortunately, two of them died. The cases involved patients aged 9, 1.5, and 3 years. They had been diagnosed with pulmonary disorders, presenting nonspecific clinical signs and radiographic images suggestive of pneumonia. The identification of A. flavus was confirmed through DNA sequencing of the calmodulin (CaM) region.

Conclusion
A. flavus was the most prevalent cause of pulmonary aspergillosis in pediatric patients. Early diagnosis and accurate antifungal treatment of pulmonary aspergillosis could be crucial in reducing the mortality rate and also have significant potential for preventing other complications among children. Moreover, antifungal prophylaxis seems to be essential for enhancing survival in these patients.
Maximum likelihood inference for a class of discrete-time Markov switching time series models with multiple delays
Authors: Martínez-Ordoñez José. A. , López-Santiago Javier , Miguez Joaquín 
Published: July 2024

AbstractAutoregressive Markov switching (ARMS) time series models are used to represent real-world signals whose dynamics may change over time. They have found application in many areas of the natural and social sciences, as well as in engineering. In general, inference in this kind of systems involves two problems: (a) detecting the number of distinct dynamical models that the signal may adopt and (b) estimating any unknown parameters in these models. In this paper, we introduce a new class of nonlinear ARMS time series models with delays that includes, among others, many systems resulting from the discretisation of stochastic delay differential equations (DDEs). Remarkably, this class includes cases in which the discretisation time grid is not necessarily aligned with the delays of the DDE, resulting in discrete-time ARMS models with real (non-integer) delays. The incorporation of real, possibly long, delays is a key departure compared to typical ARMS models in the literature. We describe methods for the maximum likelihood detection of the number of dynamical modes and the estimation of unknown parameters (including the possibly non-integer delays) and illustrate their application with a nonlinear ARMS model of El Niño–southern oscillation (ENSO) phenomenon.
Effectiveness of exercise training on arterial stiffness and blood pressure among postmenopausal women: a systematic review and meta-analysis
Authors: Yang Deshuang , Tao Shiyi , Shao Mingjing , Huang Li , Xiao Xiang , Zhang Jin , Yao Ruiqi , Sun Ziyi 
Published: July 2024

Abstract
Background
The acute and long-term benefits of exercise training on cardiovascular health have been well established. The systematic review and meta-analysis aimed to systematically assess the effectiveness of exercise training on arterial stiffness and blood pressure among postmenopausal women with elevated blood pressure.

Methods
A comprehensive search was conducted on PubMed, Embase, Web of Science, ProQuest, Cochrane Library, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov website from inception to September 30, 2023, to identify the randomized controlled trials (RCTs), which evaluated the effectiveness of exercise training on arterial stiffness and blood pressure in postmenopausal women. Standardized mean differences (SMD), weighted mean differences (WMD), and 95% confidence intervals (95% CIs) were calculated using random/fixed effects models. Quality assessment was performed using the modified Jadad scale and the Cochrane Risk of Bias Tool. Sensitivity analysis and subgroup analysis were conducted based on drug dosage, treatment duration, and age of administration to further explore potential heterogeneity. Funnel plots were performed to assess publication bias and Begg’s regression test was carried out for funnel plot asymmetry.

Results
Twenty-two RCTs involving 1978 participants were included in the quantitative analysis. The mean quality of eligible studies was 4.2 out of 7 based on the modified Jadad scale. The results indicated that exercise training had a significant effect on reducing brachial-ankle pulse wave velocity [MD = − 0.69, 95%CI (− 1.11, − 0.27), P = 0.001], decreasing augmentation index (AIx) [MD = − 6.00, 95%CI (− 6.39, − 5.61), P < 0.00001] and AIx normalized to a heart rate of 75 beats per minute (AIx@75%) [MD = − 7.01, 95%CI − 7.91 to − 6.12, P < 0.00001], lowering systolic blood pressure [MD = − 6.19, 95%CI − 9.24 to − 3.15, P < 0.0001], diastolic blood pressure [MD = − 3.57, 95%CI (− 6.10, − 1.03), P = 0.006) and pulse pressure [MD = − 8.52, 95%CI (− 16.27, − 0.76), P = 0.03]. Subgroup analysis revealed that baseline blood pressure levels had a large impact on the effect of exercise training.

Conclusions
The systematic review and meta-analysis suggested that exercise training may ameliorate arterial stiffness and reduce blood pressure in postmenopausal women with elevated blood pressure. However, the optimal mode of exercise training that improves arterial stiffness and blood pressure in this population requires further investigation.

Systematic review registration
PROSPERO CRD42021211268