bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnostic pitfalls and conundrums in type 1 von Willebrand disease
Authors: Sidonio Robert F. , Lavin Michelle 
Published: December 2022

Abstract
Most people with von Willebrand disease (VWD) have a partial quantitative deficiency of plasma von Willebrand factor (VWF) or type 1 VWD. In contrast to type 2 and type 3 VWD, laboratory assays will not always establish the diagnosis in type 1 VWD. This is because plasma VWF levels in type 1 VWD, especially those with levels closer to 50 IU/dL, overlap with the general population. Assessment is further complicated by increased plasma VWF levels in response to physiologic stressors or aging. Diagnosis of those with type 1 VWD with plasma VWF levels 30 to 50 IU/dL (previously referred to as “low VWF”) requires expert assessment of bleeding phenotype as well as an understanding of the limitations of both bleeding assessment tools (BATs) and laboratory testing. Using the available evidence and highlighting research gaps, we discuss common dilemmas facing providers relating to assessment of adolescents, transition from pediatrics to adult care, and older individuals with type 1 VWD.
What have we learned about the patient's experience of von Willebrand disease? A focus on women
Authors: VanderMeulen Heather , Arya Sumedha , Nersesian Sarah , Philbert Natalie , Sholzberg Michelle 
Published: December 2022

Abstract
Von Willebrand disease (VWD), the most common inherited bleeding disorder (IBD), disproportionately affects females, given the hemostatic challenges they may encounter throughout their lifetimes. Despite this, research about VWD remains grossly underrepresented, particularly compared to hemophilia, which is historically diagnosed in males. Structural sexism, stigmatization of menstrual bleeding, delayed diagnosis, and a lack of timely access to care result in an increased frequency of bleeding events, iron deficiency, iron deficiency anemia, and a decreased quality of life. However, we are only beginning to recognize and acknowledge the magnitude of the burden of this disease. With an increasing number of studies documenting the experiences of women with IBDs and recent international guidelines suggesting changes to optimal management, a paradigm shift in recognition and treatment is taking place. Here, we present a fictional patient case to illustrate one woman's history of bleeding. We review the evidence describing the impact of VWD on quality of life, normalization of vaginal bleeding, diagnostic delays, and the importance of access to multidisciplinary care. Furthermore, we discuss considerations around reproductive decision-making and the intergenerational nature of bleeding, which often renders patients as caregivers. Through incorporating the patient perspective, we argue for an equitable and compassionate path to overcome decades of silence, misrecognition, and dismissal. This path moves toward destigmatization, open dialogue, and timely access to specialized care.
To prophylax or not, and how much and how long? Controversies in VTE prevention for medical inpatients, including COVID-19 inpatients
Authors: Spyropoulos Alex C. 
Published: December 2022

AbstractThe field of thromboprophylaxis for acutely ill medical patients, including those hospitalized for COVID-19, is rapidly evolving both in the inpatient setting and the immediate post–hospital discharge period. Recent data reveal the importance of incorporating holistic thromboembolic outcomes that encompass both venous thromboembolism (VTE) and arterial thromboembolism, as thromboprophylaxis with low-dose direct oral anticoagulants has been shown to reduce major and fatal vascular events, especially against a background of dual pathway inhibition with aspirin. In addition, recent post hoc analyses from randomized trial data have established 5 key bleeding-risk factors that, if removed, reveal a low-bleeding- risk medically ill population and, conversely, key individual risk factors, such as advanced age, a past history of cancer or VTE, an elevated D-dimer, or the use of a validated VTE risk score—the IMPROVE VTE score using established cutoffs—to predict a high-VTE-risk medically ill population that benefits from extended postdischarge thromboprophylaxis. Last, thromboprophylaxis of a high-thrombotic-risk subset of medically ill patients, those with COVID-19, is rapidly evolving, both during hospitalization and post discharge. This article reviews 3 controversial topics in the thromboprophylaxis of hospitalized acutely ill medical patients: (1) clinical relevance of key efficacy and safety outcomes incorporated into randomized trials but not incorporated into relevant antithrombotic guidelines on the topic, (2) the use of individual risk factors or risk models of low-bleeding-risk and high-thrombotic-risk subgroups of medically ill inpatients that benefit from extended thromboprophylaxis, and (3) thromboprophylaxis of hospitalized COVID-19 patients, including extended postdischarge thromboprophylaxis.
Galantamine attenuates autoinflammation in a mouse model of familial mediterranean fever
Authors: Mughrabi Ibrahim T. , Ochani Mahendar , Tanovic Mirza , Wang Ping , Diamond Betty , Sherry Barbara , Pavlov Valentin A. , Ozen Seza , Kastner Daniel L. , Chae Jae Jin , Al-Abed Yousef 
Published: December 2022

Abstract
Background
Autoinflammatory diseases, a diverse group of inherited conditions characterized by excessive innate immune activation, have limited therapeutic options. Neuroimmune circuits of the inflammatory reflex control innate immune overactivation and can be stimulated to treat disease using the acetylcholinesterase inhibitor galantamine.

Methods
We tested the efficacy of galantamine in a rodent model of the prototypical autoinflammatory disease familial Mediterranean fever (FMF). Multiple chronic disease markers were evaluated in animals that received long-term galantamine treatment compared to vehicle.

Results
Long-term treatment with galantamine attenuated the associated splenomegaly and anemia which are characteristic features of this disease. Further, treatment reduced inflammatory cell infiltration into affected organs and a subcutaneous air pouch.

Conclusions
These findings suggest that galantamine attenuates chronic inflammation in this mouse model of FMF. Further research is warranted to explore the therapeutic potential of galantamine in FMF and other autoinflammatory diseases.
Mid-term results of subcapital realignment of chronic slipped capital femoral epiphysis using surgical hip dislocation: a prospective case series
Authors: Abosalem Ahmed Abdelazim , Sakr Samy Abdel-Hady , Mesregah Mohamed Kamal , Zayda Ahmed Ibrahim 
Published: December 2022

Abstract
Background
Slipped capital femoral epiphysis (SCFE) requires surgical treatment when diagnosed. The surgical management of moderate to severe SCFE remains an area of controversy among pediatric orthopedic surgeons. The severity of slippage, the viability of the femoral epiphysis, and the method of surgical management determine the long-term clinical and radiographical outcome. This study sought to evaluate the mid-term results of subcapital realignment of chronic stable slipped femoral epiphysis with open physis using surgical hip dislocation.

Materials and methods
This study was a prospective case series of adolescents with moderate or severe degrees of chronic SCFE who had undergone subcapital osteotomy using the surgical hip dislocation technique. The Harris Hip Score (HHS) was used to assess functional outcomes at 6 years of follow-up. A HHS of ≥ 80 points was considered satisfactory. Postoperative radiological outcomes were evaluated using epiphyseal-shaft angles and alpha angles. Postoperative complications were observed.

Results
This study included 40 patients, 32 (80%) males and 8 (20%) females, with a mean age of 14.1 ± 1.8 years. There was a statistically significant improvement in the mean HHS from 45 ± 12.3 preoperatively to 91.8 ± 11.6 points at 6 years of follow-up. The mean epiphyseal-shaft angle reduced from 60.5 ± 15.3° preoperatively to 10.3 ± 2.4° postoperatively, P < 0.001. The mean alpha angle reduced from 72.5 ± 10.1° preoperatively to 40.4 ± 6.4°, P < 0.001. Four (10%) patients showed femoral head avascular necrosis (AVN).

Conclusions
Subcapital realignment of chronic SCFE can achieve satisfactory clinical and radiological outcomes, but femoral head AVN remains a risk.
Level of evidence Level IV.
EasySMPC: a simple but powerful no-code tool for practical secure multiparty computation
Authors: Wirth Felix Nikolaus , Kussel Tobias , Müller Armin , Hamacher Kay , Prasser Fabian 
Published: December 2022

Abstract
Background
Modern biomedical research is data-driven and relies heavily on the re-use and sharing of data. Biomedical data, however, is subject to strict data protection requirements. Due to the complexity of the data required and the scale of data use, obtaining informed consent is often infeasible. Other methods, such as anonymization or federation, in turn have their own limitations. Secure multi-party computation (SMPC) is a cryptographic technology for distributed calculations, which brings formally provable security and privacy guarantees and can be used to implement a wide-range of analytical approaches. As a relatively new technology, SMPC is still rarely used in real-world biomedical data sharing activities due to several barriers, including its technical complexity and lack of usability.

Results
To overcome these barriers, we have developed the tool EasySMPC, which is implemented in Java as a cross-platform, stand-alone desktop application provided as open-source software. The tool makes use of the SMPC method Arithmetic Secret Sharing, which allows to securely sum up pre-defined sets of variables among different parties in two rounds of communication (input sharing and output reconstruction) and integrates this method into a graphical user interface. No additional software services need to be set up or configured, as EasySMPC uses the most widespread digital communication channel available: e-mails. No cryptographic keys need to be exchanged between the parties and e-mails are exchanged automatically by the software. To demonstrate the practicability of our solution, we evaluated its performance in a wide range of data sharing scenarios. The results of our evaluation show that our approach is scalable (summing up 10,000 variables between 20 parties takes less than 300 s) and that the number of participants is the essential factor.

Conclusions
We have developed an easy-to-use “no-code solution” for performing secure joint calculations on biomedical data using SMPC protocols, which is suitable for use by scientists without IT expertise and which has no special infrastructure requirements. We believe that innovative approaches to data sharing with SMPC are needed to foster the translation of complex protocols into practice.
Transcriptome analysis and cytochrome P450 monooxygenase reveal the molecular mechanism of Bisphenol A degradation by Pseudomonas putida strain YC-AE1
Authors: Eltoukhy Adel , Jia Yang , Lamraoui Imane , Abo-Kadoum M. A. , Atta Omar Mohammad , Nahurira Ruth , Wang Junhuan , Yan Yanchun 
Published: December 2022

Abstract
Background
Bisphenol A (BPA) is a rapid spreading organic pollutant that widely used in many industries especially as a plasticizer in polycarbonate plastic and epoxy resins. BPA reported as a prominent endocrine disruptor compound that possesses estrogenic activity and fulminant toxicity. Pseudomonas putida YC-AE1 was isolated in our previous study and exerted a strong degradation capacity toward BPA at high concentrations; however, the molecular degradation mechanism is still enigmatic.

Results
We employed RNA sequencing to analyze the differentially expressed genes (DEGs) in the YC-AE1 strain upon BPA induction. Out of 1229 differentially expressed genes, 725 genes were positively regulated, and 504 genes were down-regulated. The pathways of microbial metabolism in diverse environments were significantly enriched among DEGs based on KEGG enrichment analysis. qRT-PCR confirm the involvement of BPA degradation relevant genes in accordance with RNA Seq data. The degradation pathway of BPA in YC-AE1 was proposed with specific enzymes and encoded genes. The role of cytochrome P450 (CYP450) in BPA degradation was further verified. Sever decrease in BPA degradation was recorded by YC-AE1 in the presence of CYP450 inhibitor. Subsequently, CYP450bisdB deficient YC-AE1 strain △ bisdB lost its ability toward BPA transformation comparing with the wild type. Furthermore, Transformation of E. coli with pET-32a-bisdAB empowers it to degrade 66 mg l−1 of BPA after 24 h. Altogether, the results showed the role of CYP450 in biodegradation of BPA by YC-AE1.

Conclusion
In this study we propose the molecular basis and the potential role of YC-AE1cytochrome P450 monooxygenase in BPA catabolism.
Sodium formononetin-3'-sulphonate alleviates cerebral ischemia–reperfusion injury in rats via suppressing endoplasmic reticulum stress-mediated apoptosis
Authors: Bai Yue , He Zhiwei , Duan Weisong , Gu He , Wu Kefeng , Yuan Wei , Liu Wenkang , Huang Huaipeng , Li Yanan 
Published: December 2022

Abstract
Background
Sodium formononetin-3ʹ-sulphonate (Sul-F) may alleviate I/R injury in vivo with uncertain mechanism. Endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of cerebral ischemia‐reperfusion (I/R) injury. Our aim is to figure out the effect of Sul-F on cerebral I/R injury and to verify whether it works through suppressing ER stress-mediated apoptosis.

Results
The cerebral lesions of middle cerebral artery occlusion (MCAO) model in SD rats were aggravated after 24 h of reperfusion, including impaired neurological function, increased infarct volume, intensified inflammatory response and poor cell morphology. After intervention, the edaravone (EDA, 3 mg/kg) group and Sul-F high-dose (Sul-F-H, 80 mg/kg) group significantly alleviated I/R injury via decreasing neurological score, infarct volume and the serum levels of inflammatory factors (TNF-α, IL-1β and IL-6), as well as alleviating pathological injury. Furthermore, the ER stress level and apoptosis rate were elevated in the ischemic penumbra of MCAO group, and were significantly blocked by EDA and Sul-F-H. In addition, EDA and Sul-F-H significantly down-regulated the ER stress related PERK/eIF2α/ATF4 and IRE1 signal pathways, which led to reduced cell apoptosis rate compared with the MCAO group. Furthermore, there was no difference between the EDA and Sul-F-H group in terms of therapeutic effect on cerebral I/R injury, indicating a therapeutic potential of Sul-F for ischemic stroke.

Conclusions
Sul-F-H can significantly protects against cerebral I/R injury through inhibiting ER stress-mediated apoptosis in the ischemic penumbra, which might be a novel therapeutic target for ischemic stroke.
Comprehensive identification and expression analyses of the SnRK gene family in Casuarina equisetifolia in response to salt stress
Authors: Ai Di , Wang Yujiao , Wei Yongcheng , Zhang Jie , Meng Jingxiang , Zhang Yong 
Published: December 2022

Abstract
Background
Sucrose nonfermenting-1 (SNF1)-related protein kinases (SnRKs) play crucial roles in plant signaling pathways and stress adaptive responses by activating protein phosphorylation pathways. However, there have been no comprehensive studies of the SnRK gene family in the widely planted salt-tolerant tree species Casuarina equisetifolia. Here, we comprehensively analyze this gene family in C. equisetifolia using genome-wide identification, characterization, and profiling of expression changes in response to salt stress.

Results
A total of 26 CeqSnRK genes were identified, which were divided into three subfamilies (SnRK1, SnRK2, and SnRK3). The intron–exon structures and protein‑motif compositions were similar within each subgroup but differed among groups. Ka/Ks ratio analysis indicated that the CeqSnRK family has undergone purifying selection, and cis-regulatory element analysis suggested that these genes may be involved in plant development and responses to various environmental stresses. A heat map was generated using quantitative real‑time PCR (RT-qPCR) data from 26 CeqSnRK genes, suggesting that they were expressed in different tissues. We also examined the expression of all CeqSnRK genes under exposure to different salt concentrations using RT-qPCR, finding that most CeqSnRK genes were regulated by different salt treatments. Moreover, co-expression network analysis revealed synergistic effects among CeqSnRK genes.

Conclusions
Several CeqSnRK genes (CeqSnRK3.7, CeqSnRK3.16, CeqSnRK3.17) were up-regulated following salt treatment. Among them, CeqSnRK3.16 expression was significantly up-regulated under various salt treatments, identifying this as a candidate gene salt stress tolerance gene. In addition, CeqSnRK3.16 showed significant expression change correlations with multiple genes under salt stress, indicating that it might exhibit synergistic effects with other genes in response to salt stress. This comprehensive analysis will provide a theoretical reference for CeqSnRK gene functional verification and the role of these genes in salt tolerance.
Coronary calcium density in relation to coronary heart disease and cardiovascular disease in adults with diabetes or metabolic syndrome: the Multi-ethnic Study of Atherosclerosis (MESA)
Authors: Zhao Yanglu , Malik Shaista , Criqui Michael H. , Allison Matthew A. , Budoff Matthew J. , Sandfort Veit , Wong Nathan D. 
Published: December 2022

Abstract
Background
Coronary artery calcium (CAC) density is inversely associated with coronary heart disease (CHD) and cardiovascular disease (CVD) risk. We examined this relation in those with diabetes mellitus (DM) or metabolic syndrome (MetS).

Methods
We studied 3,818 participants with non-zero CAC scores from the Multiethnic Study of Atherosclerosis and classified them as DM, MetS (without DM) or neither DM/MetS. Risk factor-adjusted CAC density was calculated and examined in relation to incident CHD and CVD events over a median follow-up of 15 years among these three disease groups.

Results
Adjusted CAC density was 2.54, 2.61 and 2.69 among those with DM, MetS or neither DM/MetS. Hazard ratios (HRs) for CHD per 1 SD increase of CAC density was 0.91 (95% CI: 0.72–1.16), 0.70 (95% CI: 0.56–0.87) and 0.79 (95% CI: 0.66–0.95) for those with DM, MetS or neither DM/MetS groups and were 0.77 (95% CI: 0.64–0.94), 0.83 (95% CI: 0.70–0.99) and 0.82 (95% CI: 0.71–0.95) for CVD, respectively. Adjustment for CAC density increased the HRs of CAC volume for CHD/CVD events. Compared to prediction models with or without single CAC measures, c-statistics of models with CAC volume and density were the highest ranging 0.67–0.72.

Conclusion
CAC density is lower among patients with DM or MetS than those with neither DM/MetS and is inversely associated with future CHD/CVD risk among them. Including CAC density in risk assessment among those with MetS may improve prediction of CHD and CVD.
Care and support networks of community-dwelling frail individuals in North West London: a comparison of patient and healthcare workers’ perceptions
Authors: Sunkersing David , Martin Finbarr C. , Sullivan Paul , Bell Derek 
Published: December 2022

Abstract
Background
Evidence suggests that successful assessment and care for frail individuals requires integrated and collaborative care and support across and within settings. Understanding the care and support networks of a frail individual could therefore prove useful in understanding need and designing support. This study explored the care and support networks of community-dwelling older people accessing a falls prevention service as a marker of likely frailty, by describing and comparing the individuals’ networks as perceived by themselves and as perceived by healthcare providers involved in their care.

Methods
A convenience sample of 16 patients and 16 associated healthcare professionals were recruited from a community-based NHS ‘Falls Group’ programme within North-West London. Individual (i.e., one on one) semi-structured interviews were conducted to establish an individual’s perceived network. Principles of quantitative social network analysis (SNA) helped identify the structural characteristics of the networks; qualitative SNA and a thematic analysis aided data interpretation.

Results
All reported care and support networks showed a high contribution level from family and friends and healthcare professionals. In patient-reported networks, ‘contribution level’ was often related to the ‘frequency’ and ‘helpfulness’ of interaction. In healthcare professional reported networks, the reported frequency of interaction as detailed in patient records was used to ascertain ‘contribution level’.

Conclusion
This study emphasises the importance of the role of informal carers and friends along with healthcare professionals in the care of individuals living with frailty. There was congruence in the makeup of ‘patient’ and ‘provider’ reported networks, but more prominence of helper/carers in patients’ reports. These findings also highlight the multidisciplinary makeup of a care and support network, which could be targeted by healthcare professionals to support the care of frail individuals.
A comparison of clinical development pathways to advance tuberculosis regimen development
Authors: Chang V. , Phillips P. P. J. , Imperial M. Z. , Nahid P. , Savic R. M. 
Published: December 2022

Abstract
Background
Current tuberculosis (TB) regimen development pathways are slow and in urgent need of innovation. We investigated novel phase IIc and seamless phase II/III trials utilizing multi-arm multi-stage and Bayesian response adaptive randomization trial designs to select promising combination regimens in a platform adaptive trial.

Methods
Clinical trial simulation tools were built using predictive and validated parametric survival models of time to culture conversion (intermediate endpoint) and time to TB-related unfavorable outcome (final endpoint). This integrative clinical trial simulation tool was used to explore and optimize design parameters for aforementioned trial designs.

Results
Both multi-arm multi-stage and Bayesian response adaptive randomization designs were able to reliably graduate desirable regimens in ≥ 95% of trial simulations and reliably stop suboptimal regimens in ≥ 90% of trial simulations. Overall, adaptive phase IIc designs reduced patient enrollment by 17% and 25% with multi-arm multi-stage and Bayesian response adaptive randomization designs respectively compared to the conventional sequential approach, while seamless designs reduced study duration by 2.6 and 3.5 years respectively (typically ≥ 8.5 years for standard sequential approach).

Conclusions
In this study, we demonstrate that adaptive trial designs are suitable for TB regimen development, and we provide plausible design parameters for a platform adaptive trial. Ultimately trial design and specification of design parameters will depend on clinical trial objectives. To support decision-making for clinical trial designs in contemporary TB regimen development, we provide a flexible clinical trial simulation tool that can be used to explore and optimize design features and parameters.