bluuebunny/crossref_metadata_2025_split huggingface dataset:
Power and sample sizes estimation in clinical trials with treatment switching in intention-to-treat analysis: a simulation study
Authors: Deng Lejun , Hsu Chih-Yuan , Shyr Yu 
Published: February 2023

Abstract
Background
Treatment switching, also called crossover, is common in clinical trials because of ethical concerns or other reasons. When it occurs and the primary objective is to identify treatment effects, the most widely used intention-to-treat analysis may lead to underpowered trials. Here, we presented an approach to preview power reductions and to estimate sample sizes required to achieve the desired power when treatment switching occurs in the intention-to-treat analysis.

Methods
We proposed a simulation-based approach and developed an R package to perform power and sample sizes estimation in clinical trials with treatment switching.

Results
We simulated a number of randomized trials incorporating treatment switching and investigated the impact of the relative effectiveness of the experimental treatment to the control, the switching probability, the switching time, and the deviation between the assumed and the real distributions for the survival time on power reductions and sample sizes estimation. The switching probability and the switching time are key determinants for significant power decreasing and thus sample sizes surging to maintain the desired power. The sample sizes required in randomized trials absence of treatment switching vary from around four-fifths to one-seventh of the sample sizes required in randomized trials allowing treatment switching as the switching probability increases. The power reductions and sample sizes increase with the decrease of switching time.

Conclusions
The simulation-based approach not only provides a preview for power declining but also calculates the required sample size to achieve an expected power in the intention-to-treat analysis when treatment switching occurs. It will provide researchers and clinicians with useful information before randomized controlled trials are conducted.
Different responses of Japanese encephalitis to weather variables among eight climate subtypes in Gansu, China, 2005–2019
Authors: Li Ruifen , Zhao Xiaohong , Tian Yu , Shi Yanjun , Gu Xueyan , Wang Shuang , Zhang Rui , An Jing , Su Li , Wang Xuxia 
Published: February 2023

AbstractThis study evaluated epidemic temporal aspects of Japanese encephalitis (JE) and investigated the weather threshold of JE response across eight climate subtypes between 2005 and 2019 in Gansu Province, China. Epidemiological data were collected from the China Information System for Disease Control and Prevention (CISDCP). Three epidemic temporal indices [frequency index (α), duration index (β), and intensity index (γ)] were adopted for the comparison of epidemic features among different climate subtypes. In addition, the local indicators of spatial association (LISA) technique was used to detect the hot-spot areas. The category and regression tree (CART) model was used to detect the response threshold of weather variables in hot-spot areas across climate subtypes. Among eight climate subtypes in Gansu, in most hot-spot areas (i.e., high–high clusters), α, β, and γ were detected in the climate subtypes of subtropical winter dry (Cwa), temperate oceanic continental (Cwb), and continental winter dry (Dwa and Dwb). According to the CART analysis, a minimum monthly temperature is required for Japanese encephalitis virus (JEV) transmission, with different threshold values among the climatic subtypes. In temperate climate zones (Cwa and Cwb), this threshold is 19 °C at a 1-month lag. It is lower in continental winter dry climate zones: 18 °C in Dwa (snow climate, dry winter, and hot summer) and 16 °C in Dwb (snow climate, dry winter, and warm summer). Additionally, some areas of the areas with temperate arid (BWk and BSk) had the first JE cases. Further studies to detect whether the climate change influence the JEV’s distribution in Gansu Province are needed.
Peripheral immune cell profiling of double-hit lymphoma by mass cytometry
Authors: Lei Tao , Wu Gongqiang , Xu Yongjin , Zhuang Weihao , Lu Jialiang , Han Shuiyun , Zhuang Yuxin , Dong Xiaowu , Yang Haiyan 
Published: February 2023

AbstractBackgroundDouble-hit or Triple-hit lymphoma (DHL/THL) is a subset of high-grade B cell lymphoma harboring rearrangements ofMYCandBCL2and/orBCL6, and usually associate with aggressive profile, while current therapies tend to provide poor clinical outcomes and eventually relapsed. Further explorations of DHL at cellular and molecular levels are in demand to offer guidance for clinical activity.MethodsWe collected the peripheral blood of DHL patients and diffused large B cell lymphoma (DLBCL) patients from single institute and converted them into PBMC samples. Mass cytometry was then performed to characterize these samples by 42 antibody markers with samples of healthy people as control. We divided the immune cell subtypes based on the expression profile of surface antigens, and the proportion of each cell subtype was also analyzed. By comparing the data of the DLBCL group and the healthy group, we figured out the distinguished immune cell subtypes of DHL patients according to their abundance and marker expression level. We further analyzed the heterogeneity of DHL samples by pairwise comparison based on clinical characteristics.ResultsWe found double-positive T cells (DPT) cells were in a significantly high percentage in DHL patients, whereas the ratio of double-negative T cells (DNT) was largely reduced in patients. Besides, CD38 was uniquely expressed at a high level on some naïve B cells of DHL patients, which could be a marker for the diagnosis of DHL (distinguishing from DLBCL), or even be a drug target for the treatment of DHL. In addition, we illustrated the heterogeneity of DHL patients in terms of immune cell landscape, and highlightedTP53as a major factor that contributes to the heterogeneity of the T cells profile.ConclusionOur study demonstrated the distinct peripheral immune cell profile of DHL patients by contrast to DLBCL patients and healthy people, as well as the heterogeneity within the DHL group, which could provide valuable guidance for the diagnosis and treatment of DHL.
First nosocomial infections in children supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO)
Authors: Cousin Vladimir L. , Rodriguez-Vigouroux Robert , Karam Oliver , Rimensberger Peter , Posfay-Barbe Klara M. 
Published: February 2023

Abstract
Background
Veno-arterial Extracorporeal Membrane Oxygenation (VA-ECMO) is a standard procedure for patient with refractory shock in Pediatric Intensive Care Unit (PICU). There is a paucity of data on the time relationship between VA-ECMO support, nosocomial infection occurrence, and PICU length of stay (LOS). The aim of this study was to determine the characteristics and impact of ECMO-related infections.

Methods
This is a retrospective study from 01/2008 to 12/2014, enrolling children with a VA-ECMO support for > 6 h. We recorded the first PICU infection during the VA-ECMO run, defined as a positive microbiological sample with clinical signs of infection or clinical signs of severe infection without positive sample.

Results
During the study period, 41 patients (25/41 male) were included, with a median age of 41.2 months (IQR 12.9–89.9) and a 53% mortality rate. Median time on VA-ECMO was 4.2 d (IQR 2–7.1), median PICU LOS was 14.7 d (IQR 4,7–26,9). Overall, 34% patients developed an infection, with an incidence of 60/1000 VA-ECMO days. Median time to first infection was 4 d (IQR 3–5), with Pseudomonas spp. being the most commonly detected microorganism (42%). Infected sites were ventilator-associated pneumonia (9/14), sternotomy infection (2/14), bloodstream (2/14) and urinary tract infections (1/14). Longer VA-ECMO support (> 5 d) (OR 5.9 (CI 95% 1.4–24.6; p = 0.01) and longer PICU stay (> 14 d) (OR 12 (95% CI 2.2–65.5; p = 0.004) were associated with infection.

Conclusion
In this single-center study, we underlined the high proportion and early occurrence of infections in patient on VA-ECMO, mostly in the first week. As infection was an early event, it may prolong the duration of VA-ECMO support and PICU LOS. Further research is needed to better understand the impact of infections on VA-ECMO and develop prevention strategies.
Feto-placental endothelial dysfunction in Gestational Diabetes Mellitus under dietary or insulin therapy
Authors: Wang Jing-Jing , Wang Xi , Li Qian , Huang Hua , Zheng Qiao-Ling , Yao Qin , Zhang Jun 
Published: February 2023

Abstract
Objective
Gestational diabetes mellitus (GDM) is a serious complication in pregnancy. Despite controlling the plasma glucose levels with dietary intervention (GDM-D) or insulin therapy (GDM-I), children born of diabetic mothers suffer more long-term complications from childhood to early adulthood. Placental circulation and nutrient exchange play a vital role in fetal development. Additionally, placental endothelial function is an indicator of vascular health, and plays an important role in maintaining placental circulation for nutrient exchange. This study was conducted to assess changes in fetal endothelial dysfunction in GDM under different interventions during pregnancy.

Methods
The primary human umbilical vein endothelial cells (HUVECs) were obtained from normal pregnant women (n = 11), GDM-D (n = 14), and GDM-I (n = 12) patients. LC-MS/MS was used to identify differentially expressed proteins in primary HUVECs among the three groups, after which Bioinformatics analysis was performed. Glucose uptake, ATP level, apoptosis, and differentially expressed proteins were assessed to investigate changes in energy metabolism.

Results
A total of 8174 quantifiable proteins were detected, and 142 differentially expressed proteins were identified after comparing patients with GDM-D/GDM-I and healthy controls. Of the 142, 64 proteins were upregulated while 77 were downregulated. Bioinformatics analysis revealed that the differentially expressed proteins were involved in multiple biological processes and signaling pathways related to cellular processes, biological regulation, and metabolic processes. According to the results from KEGG analysis, there were changes in the PI3K/AKT signaling pathway after comparing the three groups. In addition, there was a decrease in glucose uptake in the GDM-I (P < 0.01) group. In GDM-I, there was a significant decrease in the levels of glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3). Moreover, glucose uptake was significantly decreased in GDM-I, although in GDM-D, there was only a decrease in the levels of GLUT1. ATP levels decreased in GDM-I (P < 0.05) and apoptosis occurred in both the GDM-D and GDM-I groups. Compared to the normal controls, the levels of phosphate AKT and phosphate AMPK over total AKT and AMPK were reduced in the GDM-I group.

Conclusion
In summary, endothelial dysfunction occurred in pregnancies with GDM even though the plasma glucose levels were controlled, and this dysfunction might be related to the degree of glucose tolerance. The energy dysfunction might be related to the regulation of the AKT/AMPK/mTOR signaling pathway.
A novel ex vivo perfusion-based mandibular pig model for dental product testing and training
Authors: van Erk Machteld , Lomme Roger M. L. M. , Roozen Edwin A. , van Oirschot Bart A. J. A. , van Goor Harry 
Published: February 2023

Abstract
Background
A translational ex vivo perfusion-based mandibular pig model was developed as an alternative to animal experiments, for initial assessment of biomaterials in dental and maxillofacial surgery and training. This study aimed to assess the face and content validity of the novel perfusion-based model.

Methods
Cadaveric porcine heads were connected to an organ assist perfusion device for blood circulation and tissue oxygenation. Dental professionals and dental trainees performed a surgical procedure on the mandibula resembling a submandibular extraoral incision to create bone defects. The bone defects were filled and covered with a commercial barrier membrane. All participants completed a questionnaire using a 5-point Likert scale to assess the face and content validity of the model. Validation data between the two groups of participants were compared with Mann–Whitney U test.

Results
Ten dental professionals and seven trainees evaluated the model for face and content validity. Participants reported model realism, with a mean face validity score of 3.9 ± 1.0 and a content validity of 4.1 ± 0.8. No significant differences were found for overall face and content validity between experts and trainees.

Conclusion
We established face and content validity in a novel perfusion-based mandibular surgery model. This model can be used as an alternative for animal studies evaluating new biomaterials and related dental and maxillofacial surgical procedural training.
Risk of cardiometabolic outcomes among women with a history of pelvic inflammatory disease: a retrospective matched cohort study from the UK
Authors: Okoth Kelvin , Thomas G. Neil , Nirantharakumar Krishnarajah , Adderley Nicola J. 
Published: February 2023

Abstract
Introduction
To describe the incidence and prevalence of pelvic inflammatory disease (PID) and to estimate the risk of cardiometabolic outcomes among women with PID compared to women without PID.

Methods
A UK retrospective matched cohort study using data from The Health Improvement Network. To assess cardiometabolic risk, women (aged ≥ 16 years) with PID were compared to matched controls without PID. Annual prevalence and incidence of PID (1998–2017) were estimated among women aged 16–50 years using annual cross-sectional and cohort analyses, respectively. Adjusted hazard ratios (aHR) and 95% CI for cardiometabolic outcomes were estimated using Cox proportional hazards models. The primary outcome was composite cardiovascular disease (CVD) and its subtypes, including ischaemic heart disease (IHD), heart failure (HF) and cerebrovascular disease. Secondary outcomes were hypertension, and type 2 diabetes mellitus (T2DM).

Results
Among the 715 recorded composite CVD events, the crude incidence rate per 1000 person-years was 1.5 among women with history of PID compared to 1.3 in matched controls. Compared to women without PID (N = 73,769), the aHRs for cardiometabolic outcomes among women with PID (N = 19,804) were: composite CVD 1.10 (95% CI 0.93–1.30); IHD 1.19 (95% CI 0.93–1.53); cerebrovascular disease 1.13 (95% CI 0.90–1.43); HF 0.92 (95% CI 0.62–1.35) hypertension 1.10 (95% CI 1.01–1.20); and T2DM 1.25 (95% CI 1.09–1.43). The prevalence (per 10,000 population) of PID was 396.5 in 1998 and 237 in 2017. The incidence (per 10,000 person-years) of PID was 32.4 in 1998 and 7.9 in 2017.

Conclusion
There was no excess risk of composite CVD or its subtypes among women with history of PID compared to matched controls. Findings from our study suggest that history of PID was associated with an increased risk of hypertension and type 2 diabetes mellitus, two major risk factors for CVD. Additional studies are required to support these findings.
The conundrums of the reasonable patient standard in English medical law
Authors: Kwok Kelvin Hiu Fai , Ip Eric C. , Lee Shing Fung 
Published: February 2023

Abstract
Background
In its 2015 decision in Montgomery v. Lanarkshire Health Board, the Supreme Court of the United Kingdom overruled the long-standing, paternalistic prudent doctor standard of care in favour of a new reasonable patient standard which obligates doctors to make their patients aware of all material risks of the recommended treatment and of any reasonable alternative treatment. This landmark judgment has been of interest to the rest of the common law world. A judicial trend of invoking Montgomery to impose more stringent requirements on doctors is discernible in subsequent decisions since then.

Main body
In this narrative review, without questioning the idea that properly informed patients should play a more active role in procedures affecting their own health in furtherance of their autonomy, safety, and consumer rights, we identify and analyse, with the aid of realistic clinical thought experiments, three practical conundrums that the Montgomery standard may inflict on the daily work of doctors, unfairly exposing them to arbitrary legal risks.

Conclusions
These conundrums pertain to the ascertainment of the risks that must be disclosed to the patient under the test of ‘materiality’; the legal uncertainty as to the scope of the exceptions; and the actual ability of doctors to cope with the pressures of time. These conundrums offer ripe opportunities to rethink the proper role of judicially developed medical law in modern health care practice.
Patients acceptance and comprehension to written and verbal consent (PAC–VC)
Authors: Kashur Rabia , Ezekowitz Justin , Kimber Shane , Welsh Robert C. 
Published: February 2023

Abstract
Background
Acute myocardial infarction (AMI) research is challenging as it requires enrollment of acutely ill patients. Patients are generally in a suboptimal state for providing informed consent. Patients’ understanding to verbal assents have not been previously examined in AMI research. Patients Acceptance and Comprehension to Written and Verbal Consent (PAC–VC) compared patients’ understanding and attitudes to verbal and written consents in AMI RCTs.

Methods
PAC–VC recruited patients from 3 AMI trials using both verbal N = 12 and written N = 6 consents. We compared patients’ understanding using two survey questionnaires. The first questionnaire used open-ended questions with multiple choice answers. The second questionnaire used a 5-point Likert scale to measure patients understanding and attitudes to the consent process. Overall answers average scores were categorized into three groups: Adequate understanding (71–100) %, Partial understanding (41–70)% and Inadequate understanding (0–40)%.

Results
Responses showed patients with verbal assent had adequate understanding to most components of informed consent, close to those of written consent. Most patients did not read written information entirely and believed that it is not important to make a final decision. Patients favoured to have written information be part of the consent but not necessarily presented during the initial consent process. Patients felt less pressured in the verbal assent arm than those of written consent.

Conclusion
Patients had adequate understanding to most components of verbal assent and comparable to those of written consent. Utilizing verbal assents in the acute care setting should be further assessed in larger trials.
Dignity at stake – relatives’ experiences of influencing dignified care in nursing homes
Authors: Hartviksen Trude Anita , Aspfors Jessica , Uhrenfeldt Lisbeth 
Published: February 2023

Abstract
Background
Dignity, in the care of older nursing home residents, has been an increasingly part of the public discourse the recent years. Despite a growing body of knowledge about dignity and indignity in nursing homes, we have less knowledge of how relatives experience their role in this context. This study is a follow-up to a previous study in nursing homes, which gave rise to concern about the relatives’ descriptions of residents’ dignity. The aim of this current study is to critically discuss relatives’ experiences of influencing the dignified care of residents of nursing homes.

Methods
Methodologically, the study is informed by a critical hermeneutic stance, where the analysis is guided by a qualitative interpretive approach and a humanizing framework. This is a secondary analysis that includes data from five semi-structured focus groups from a previous study. The participants were 18 relatives of 16 residents living in two nursing homes in rural northern Norway.

Results
The main theme in this study, preventing missed care when dignity is at stake, is identified when relatives of nursing homes experience that they are able to influence dignified care by (a) pinpointing to prevent missed care and (b) compensating when dignity is threatened.

Conclusions
Despite their stated good intentions to safeguard dignity, relatives of nursing homes experience being alienated in their attempts to change what they describe as undignified and unacceptable practice into dignified care. The relatives’ observations of dignity and indignity are, contrary to what national and international regulations require, not mapped and/or used in any form of systematic quality improvement work. This indicates that knowledge-based practice in nursing homes, including the active application of user and relative knowledge, has untapped potential to contribute to quality improvement towards dignified care.
Krüppel-like factor 9 (KLF9) links hormone dysregulation and circadian disruption to breast cancer pathogenesis
Authors: Ybañez Weand S. , Bagamasbad Pia D. 
Published: February 2023

Abstract
Background
Circadian disruption is an emerging driver of breast cancer (BCa), with epidemiological studies linking shift work and chronic jet lag to increased BCa risk. Indeed, several clock genes participate in the gating of mitotic entry, regulation of DNA damage response, and epithelial-to-mesenchymal transition, thus impacting BCa etiology. Dysregulated estrogen (17β-estradiol, E2) and glucocorticoid (GC) signaling prevalent in BCa may further contribute to clock desynchrony by directly regulating the expression and cycling dynamics of genes comprising the local breast oscillator. In this study, we investigated the tumor suppressor gene, Krüppel-like factor 9 (KLF9), as an important point of crosstalk between hormone signaling and the circadian molecular network, and further examine its functional role in BCa.

Methods
Through meta-analysis of publicly available RNA- and ChIP-sequencing datasets from BCa tumor samples and cell lines, and gene expression analysis by RT-qPCR and enhancer- reporter assays, we elucidated the molecular mechanism behind the clock and hormone regulation of KLF9. Lentiviral knockdown and overexpression of KLF9 in three distinct breast epithelial cell lines (MCF10A, MCF7 and MDA-MB-231) was generated to demonstrate the role of KLF9 in orthogonal assays on breast epithelial survival, proliferation, apoptosis, and migration.

Results
We determined that KLF9 is a direct GC receptor target in mammary epithelial cells, and that induction is likely mediated through coordinate transcriptional activation from multiple GC-responsive enhancers in the KLF9 locus. More interestingly, rhythmic expression of KLF9 in MCF10A cells was abolished in the highly aggressive MDA-MB-231 line. In turn, forced expression of KLF9 altered the baseline and GC/E2-responsive expression of several clock genes, indicating that KLF9 may function as a regulator of the core clock machinery. Characterization of the role of KLF9 using complementary cancer hallmark assays in the context of the hormone-circadian axis revealed that KLF9 plays a tumor-suppressive role in BCa regardless of molecular subtype. KLF9 potentiated the anti-tumorigenic effects of GC in E2 receptor + luminal MCF7 cells, while it restrained GC-enhanced oncogenicity in triple-negative MCF10A and MDA-MB-231 cells.

Conclusions
Taken together, our findings support that dysregulation of KLF9 expression and oscillation in BCa impinges on circadian network dynamics, thus ultimately affecting the BCa oncogenic landscape.