bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association between circulating 25-hydroxyvitamin D levels and preeclampsia: a systematic review and dose-response meta-analysis of epidemiologic studies with GRADE assessment
Authors: Rouhani Parisa , Mokhtari Elahe , Lotfi Keyhan , Saneei Parvane 
Published: February 2023

Abstract

Context
Although some studies have examined the connection between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and preeclampsia (PE) risk, the results were inconsistent.

Objective
A dose-response meta-analysis on epidemiologic investigations was conducted to evaluate the relation of 25(OH)D concentration and PE.

Data Source
Electronic databases, including Scopus, MEDLINE (PubMed), the Institute for Scientific Information, Embase, and Google Scholar, were comprehensively search until July 2021.

Data Extraction
A total of 65 observational studies evaluating the link between circulating 25(OH)D concentrations and PE were included. The body of evidence was assessed by the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach.

Data Analysis
Combining 32 effect sizes from 32 prospective studies with 76 394 participants revealed that highest vs lowest circulating 25(OH)D concentrations was significantly related to a 33% reduced risk of PE (relative risk [RR], 0.67; 95%CI, 0.54–0.83). Subgroup analysis by study design revealed that PE risk has significantly decreased in cohort and case-cohort studies (RR, 0.72; 95%CI, 0.61–0.85), and a slight decline was found in nested case-control studies (RR, 0.62; 95%CI, 0.38–1.02). Dose–response analysis in 27 prospective studies with 73 626 participants illustrated that each 10 ng/mL increment in circulating 25(OH)D concentration led to a 14% reduced incidence of PE (RR, 0.86; 95%CI, 0.83–0.90). A U-shaped significant association in nonlinear dose–response analysis was found between 25(OH)D and PE. A significant inverse association was also found between highest vs lowest circulating 25(OH)D concentration and PE in 32 nonprospective studies with 37 477 participants (odd ratio, 0.37; 95%CI, 0.27–0.52). This inverse association was significant in almost all subgroups, based on different covariates.

Conclusion
This meta-analysis of observational investigations showed blood 25(OH)D levels were negatively related to PE risk, in a dose-response manner.

Systematic Review Registration
PROSPERO registration no. CRD42021267486.
A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAFV600E-MutantKRASWild-Type Metastatic Colorectal Cancer
Authors: Tabernero Josep , Van Cutsem Eric , Garralda Elena , Tai David , De Braud Filippo , Geva Ravit , van Bussel Mark T J , Fiorella Dotti Katia , Elez Elena , de Miguel María J , Litwiler Kevin , Murphy Danielle , Edwards Michelle , Morris Van Karlyle 
Published: February 2023

AbstractBackgroundWNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose-­escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions.Patients and MethodsPatients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose–limiting toxicities (DLTs) were observed. Primary endpoints were incidence of DLTs and exposure to WNT974 and encorafenib. Secondary endpoints were anti-tumor activity and safety.ResultsTwenty patients were enrolled (COMBO10, n = 4; COMBO7.5, n = 6; COMBO5, n = 10). DLTs were observed in 4 patients, including grade 3 hypercalcemia (COMBO10, n = 1; COMBO7.5, n = 1), grade 2 dysgeusia (COMBO10, n = 1), and lipase increased (COMBO10, n = 1). A high incidence of bone toxicities (n = 9) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Serious adverse events were reported in 15 patients, most frequently bone fracture, hypercalcemia, and pleural effusion. The overall response rate was 10% and disease control rate 85%; most patients achieved stable disease as their best response.ConclusionConcerns surrounding the safety and lack of preliminary evidence of improved anti-tumor activity of WNT974 + encorafenib + cetuximab, compared with previous encorafenib + cetuximab data, ultimately led to study discontinuation. Phase II was not initiated.Trial registrationClinicalTrials.gov, NCT02278133
Ignorance
Authors: Peels Rik 
Published: February 2023

Abstract
This book rigorously develops a full-blown epistemology of ignorance. It answers questions that are rarely addressed in philosophy; for example, what is ignorance of facts or truths? Is it simply the absence of knowledge, or are things more complex? Can there also be ignorance of entities and ignorance of how to do something? How does ignorance of facts relate to ignorance on some topic, say, quantum mechanics? If one holds a false belief but one also believes one should not hold that belief because it is irrational, does one still count as ignorant? What varieties of ignorance are there? For instance, should we distinguish between disbelief and suspension of judgment and not even being able to grasp a proposition? What is it for groups to be ignorant? And how should we construe degrees of ignorance? This book then shows what difference this epistemology of ignorance makes by applying it to six contemporary debates on sometimes controversial topics in and beyond philosophy: white ignorance, practices of making people ignorant as studied in agnotology, the conditions under which ignorance counts as an excuse, responsibility and particularly culpability for ignorance, educational practices that aim at ignorance, and asserting that one is ignorant. In each case, it turns out that the epistemology of ignorance developed in the first part of the book provides the resources to take the debate important steps further and, in some cases, even to resolve philosophical problems.
Allelic variation of MdMYB123 controls malic acid content by regulating MdMa1 and MdMa11 expression in apple
Authors: Zheng Litong , Liao Liao , Duan Chenbo , Ma Wenfang , Peng Yunjing , Yuan Yangyang , Han Yuepeng , Ma Fengwang , Li Mingjun , Ma Baiquan 
Published: February 2023

Abstract
Acidity is a key determinant of fruit organoleptic quality. Here, a candidate gene for fruit acidity, designated MdMYB123, was identified from a comparative transcriptome study of two Ma1Ma1 apple (Malus domestica) varieties, “Qinguan (QG)” and “Honeycrisp (HC)” with different malic acid content. Sequence analysis identified an A→T SNP, which was located in the last exon, resulting in a truncating mutation, designated mdmyb123. This SNP was significantly associated with fruit malic acid content, accounting for 9.5% of the observed phenotypic variation in apple germplasm. Differential MdMYB123- and mdmyb123-mediated regulation of malic acid accumulation was observed in transgenic apple calli, fruits, and plantlets. Two genes, MdMa1 and MdMa11, were up- and down-regulated in transgenic apple plantlets overexpressing MdMYB123 and mdmyb123, respectively. MdMYB123 could directly bind to the promoter of MdMa1 and MdMa11, and induce their expression. In contrast, mdmyb123 could directly bind to the promoters of MdMa1 and MdMa11, but with no transcriptional activation of both genes. In addition, gene expression analysis in 20 different apple genotypes based on SNP locus from “QG” × “HC” hybrid population confirmed a correlation between A/T SNP with expression levels of MdMa1 and MdMa11. Our finding provides valuable functional validation of MdMYB123 and its role in the transcriptional regulation of both MdMa1 and MdMa11, and apple fruit malic acid accumulation.
A strong culture of clinical research is essential for the training of medical postgraduates in China
Authors: Du Yi , Luo Wenjing 
Published: February 2023

Abstract
Postgraduate medical students are the mainstay of future medical research, and clinical research is one of the most important components of medical research. In recent years, the Chinese government has increased the number of postgraduate students in China. Therefore, the quality of postgraduate training has received widespread attention. This article discusses the advantages and challenges faced by Chinese graduate students when they conduct their clinical research. To address the current misconception that Chinese graduate students only focus on developing their competence in basic biomedical research, the authors call for increased support for clinical research from the Chinese government as well as from schools and teaching hospitals.
Anti-dsDNA IgE induces IL-4 production from basophils, potentially involved in B-cell differentiation in systemic lupus erythematosus
Authors: Fujimoto Sho , Arinobu Yojiro , Miyawaki Kohta , Ayano Masahiro , Mitoma Hiroki , Kimoto Yasutaka , Ono Nobuyuki , Akashi Koichi , Horiuchi Takahiko , Niiro Hiroaki 
Published: February 2023

Abstract

Objectives
Recently, the involvement of basophils and IgE-type autoantibodies in the pathogenesis of SLE has been elucidated using mouse models; however, few studies have been conducted in humans. In this study, the role of basophils and anti-double-stranded DNA (dsDNA) IgE in SLE was examined using human samples.

Methods
The correlation between disease activity and serum levels of anti-dsDNA IgE in SLE was evaluated using enzyme-linked immunosorbent assay. Cytokines produced by IgE-stimulated basophils from healthy subjects were assessed using RNA sequences. The interaction of basophils and B cells to promote B cell differentiation was investigated using a co-culture system. The ability of basophils from patients with SLE with anti-dsDNA IgE to create cytokines that may be involved in B cell differentiation in response to dsDNA was examined using real-time PCR.

Results
Anti-dsDNA IgE levels in the serum of patients with SLE correlated with disease activity. Healthy donor basophils produced IL-3, IL-4 and TGF-β1 after anti-IgE stimulation. Co-culture of B cells with anti-IgE-stimulated basophils increased plasmablasts which were cancelled by neutralizing IL-4. After encountering the antigen, basophils released IL-4 more quickly than follicular helper T cells. Basophils isolated from patients with anti-dsDNA IgE promoted IL-4 expression by adding dsDNA.

Conclusions
These results suggest that basophils contribute to the pathogenesis of SLE by promoting B cell differentiation via dsDNA-specific IgE in patients similar to the process described in mouse models.
DETERMINATION OF RADON ACTIVITY CONCENTRATIONS IN SOME WELL WATERS NEAR THE AKŞEHIR-SIMAV FAULT SYSTEM AND ESTIMATION OF MEAN ANNUAL EFFECTIVE DOSES
Authors: Sandıkcıoğlu Gümüş Ayla 
Published: February 2023

AbstractRadon concentrations were measured in four-well and spring water, which is used as drinking water, in the villages and districts of Afyonkarahisar province near Akşehir-Simav fault system for 24 month period, and the annual average effective dose amounts were calculated. In addition, the relationship between the average radon concentration results of potable water wells and the distance of the wells to the fault was examined for the first time in this region. Mean radon concentrations were measured between 1.9 ± 0.3 and 11.9 ± 0.5 Bql−1. The annual effective dose values were calculated between 11 ± 1.7 and 70.1 ± 2.8 μSvy−1 for infants, 4.0 ± 0.6 and 25.7 ± 1.0 μSvy−1 for children and 4.8 ± 0.7 and 30.5 ± 1.2 μSvy−1 for adults. In addition, the effect of the distance of the wells from the fault on the mean radon concentrations was also investigated. The regression coefficient (R2) was calculated as 0.85. The average radon concentration was observed higher in the water wells close to the fault. The highest mean radon concentration was measured in well no. 4, closest to the fault and 1.07 km away.
Seroprevalence of hepatitis E virus after pediatric liver transplantation
Authors: Getsuwan Songpon , Pasomsub Ekawat , Yutthanakarnwikom Pichet , Tongsook Chutatip , Butsriphum Napapat , Tanpowpong Pornthep , Janchompoo Pareena , Treepongkaruna Suporn , Lertudomphonwanit Chatmanee 
Published: February 2023

AbstractBackgroundSoutheast Asia is the endemic area of hepatitis E virus (HEV) infection. We aimed to determine the seroprevalence of the virus, its association, and the prevalence of chronic infection after pediatric liver transplantation (LT).MethodsA cross-sectional study was performed in Bangkok, Thailand. Patients aged &lt;18 years who had LT for &gt;2 years underwent serologic and real-time polymerase chain reaction (rt-PCR) tests. Acute HEV infection was defined by the presence of positive anti-HEV immunoglobulin (Ig)M and HEV viremia from the rt-PCR. If the viremia persisted for &gt;6 months, chronic HEV infection was diagnosed.ResultsA total of 101 patients had a median age of 8.4 years [interqartile range (IQR): 5.8–11.7]. The seroprevalence of anti-HEV IgG and IgM was 15% and 4%, respectively. Positive IgM and/or IgG were associated with a history of elevated transaminases with an unknown cause after LT (p = 0.04 and p = 0.01, respectively). The presence of HEV IgM was associated with a history of elevated transaminases with an unknown cause within 6 months (p = 0.01). The two patients (2%) diagnosed with chronic HEV infection did not fully respond to the reduction of immunosuppression but responded well to ribavirin treatment.ConclusionsSeroprevalence of HEV among pediatric LT recipients was not rare in Southeast Asia. Since HEV seropositivity was associated with elevated transaminases of an unknown cause, investigation for the virus should be offered in LT children with hepatitis after excluding other etiologies. Pediatric LT recipients with chronic HEV infection may receive a benefit from a specific antiviral treatment.
Sharps Injuries Among Medical Trainees and Attending Physicians
Authors: Kasteler Stephen D. , Reid Michelle , Lee Peter C. , Sparer-Fine Emily , Laramie Angela K. 
Published: February 2023

Purpose
Sharps injuries are a particularly concerning occupational hazard faced by physicians and are largely preventable. This study compared the proportion and rate of sharps injuries among medical trainees with those among attending physicians by sharps injury characteristics.

Method
The authors used data reported to the Massachusetts Sharps Injury Surveillance System from 2002–2018. Sharps injury characteristics examined were department where injury occurred, device, purpose or procedure for which device was used or intended, presence of sharps injury prevention feature, who was holding the device, and how and when the injury occurred. Global chi-square was used to assess differences in the percent distribution of sharps injury characteristics between physician groups. Joinpoint regression was used to evaluate trends in injury rates among trainees and attendings.

Results
From 2002–2018, 17,565 sharps injuries among physicians were reported to the surveillance system, 10,525 of which occurred among trainees. For attendings and trainees combined, sharps injuries occurred most in operating and procedure rooms and most often involved suture needles. Significant differences in sharps injuries were found between trainees and attendings with respect to department, device, and intended purpose or procedure. Sharps without engineered sharps injury protections accounted for approximately 4.4 times as many injuries (13,355, 76.0%) as those with protections (3,008, 17.1%). Among trainees, sharps injuries were highest in the first quarter of the academic year and decreased over time, while sharps injuries among attendings had a very slight, significant increase.

Conclusions
Sharps injuries are an ongoing occupational hazard faced by physicians, particularly during clinical training. Further research is needed to elucidate the etiology of the observed injury patterns during the academic year. Medical training programs need to implement a multipronged approach to prevent sharps injuries, including increased use of devices with sharps injury prevention features and robust training on safe handling of sharps.
Beyond Compliance: Growth as the Guiding Value in Undergraduate Medical Education
Authors: Woodruff James N. , Lee Wei Wei , Vela Monica , Davidson Arnold I. 
Published: February 2023

Adhering to the paradigm of the natural sciences, much of undergraduate medical education (UME) in the United States remains committed to objectivity, compliance, and standardization in its approach to teaching, evaluation, student affairs, and accreditation practices. The authors argue that, while these simple and complicated problem solving (SCPS) approaches may be valid for some highly controlled environments of UME, they lack rigor in complex, real-world environments where optimal care and education is not standardized but is tailored to context and individual needs. This argument is supported by evidence that “systems” approaches, characterized by complex problem solving (CPS, differentiated from complicated problem solving), lead to better outcomes in patient care and student academic performance. Examples of interventions implemented at the University of Chicago Pritzker School of Medicine from 2011 to 2021 further illustrate this point.
Interventions in student well-being that emphasize personal and professional growth have led to student satisfaction that is 20% higher than the national average on the Association of American Medical Colleges Graduation Questionnaire (GQ). Career advising interventions that augment the use of adaptive behaviors in place of rules and guidelines have yielded 30% fewer residency applications per student than the national average while simultaneously yielding residency “unmatched” rates that are one-third of the national average. Regarding diversity, equity, and inclusion, an emphasis on civil discourse around real-world problems has been associated with student attitudes toward diversity that are 40% more favorable than the national average on the GQ. In addition, there has been an increase in the number of matriculating students who are underrepresented in medicine to 35% of the incoming class. The article concludes with a review of philosophic barriers to incorporating the CPS paradigm into UME and of notable pedagogic differences between CPS and SCPS approaches.
Medical Disruptions During Center-Based Cardiac Rehabilitation
Authors: Khong Anthony , Liu Nina , Giancaterino Shaun , Junker Margaret , Labiak Rachel , Cortez-Toledo Elizabeth , Fausto Alejandra Galina Bernal , Andrade Humberto , Chen Christopher , López Javier E. 
Published: February 2023

Purpose:
The purpose of this study is to show that with remote and virtual cardiac rehabilitation (CR) care models rapidly emerging, CR core components must be maintained to prioritize safety and effectiveness. Currently, there is a paucity of data on medical disruptions in phase 2 center-based CR (cCR). This study aimed to characterize the frequency and types of unplanned medical disruptions.

Methods:
We reviewed 5038 consecutive sessions from 251 patients enrolled in cCR program from October 2018 to September 2021. Quantification of events was normalized to sessions to control for multiple disruptions that occurred to a single patient. A multivariate logistical regression model was used to predict comorbid risk factors for disruptions.

Results:
Fifty percent of patients experienced one or more disruptions during cCR. Glycemic events (71%) and blood pressure (12%) abnormalities accounted for most of these while symptomatic arrhythmias (8%) and chest pain (7%) were less frequent. Sixty-six percent of events occurred within the first 12 wk. The regression model showed that a diagnosis of diabetes mellitus was the strongest predictor for disruptions (OR = 2.66: 95% CI, 1.57-4.52; P < .0001).

Conclusions:
Medical disruptions were frequent during cCR, with glycemic events being most common and occurring early. A diagnosis of diabetes mellitus was a strong independent risk factor for events. This appraisal suggests that patients living with diabetes mellitus, particularly those on insulin, need to be the highest priority for monitoring and planning and suggests that a hybrid care model may be beneficial in this population.
Conundrums of choice of ‘normal’ kidney tissue for single cell studies
Authors: Jain Sanjay 
Published: February 2023

Purpose of review
Defining molecular changes in key kidney cell types across lifespan and in disease states is essential to understand the pathogenetic basis of disease progression and targeted therapies. Various single cell approaches are being applied to define disease associated molecular signatures. Key considerations include the choice of reference tissue or ‘normal’ for comparison to diseased human specimens and a benchmark reference atlas. We provide an overview of select single cell technologies, key considerations for experimental design, quality control, choices and challenges associated with assay type and source for reference tissue.

Recent findings
Several initiatives including Kidney Precision Medicine Project, Human Biomolecular Molecular Atlas Project, Genitourinary Disease Molecular Anatomy Project, ReBuilding a Kidney consortium, Human Cell Atlas and Chan Zuckerburg Initiative are generating single cell atlases of ‘normal’ or disease kidney. Different sources of kidney tissue are used as reference. Signatures of injury, resident pathology and procurement associated biological and technical artifacts have been identified in human kidney reference tissue.

Summary
Committing to a particular reference or ‘normal’ tissue has significant implications in interpretation of data from disease samples or in ageing. Voluntarily donated kidney tissue from healthy individuals is generally unfeasible. Having reference datasets for different types of ‘normal’ tissue can aid in mitigating the confounds of choice of reference tissue and sampling biases.
The expanding spectrum and utility of antigens in membranous nephropathy
Authors: Miller Paul , Caza Tiffany 
Published: February 2023

Purpose of review
Multiple antigenic targets were discovered in membranous nephropathy, representing distinct autoimmune diseases with a similar morphologic pattern of injury. An overview of recent developments, including antigen types, clinical associations, serologic monitoring, and advancements in understanding disease pathogenesis are provided.

Recent findings
Several new antigenic targets have defined subtypes of membranous nephropathy, including Neural epidermal growth factor-like 1, protocadherin 7, HTRA1, FAT1, SEMA3B, NTNG1, NCAM1, exostosin 1/2, transforming growth factor beta receptor 3, CNTN1, proprotein convertase subtilisin/kexin type 6, and neuron-derived neurotrophic factor. Autoantigens in membranous nephropathy may demonstrate unique clinical associations, assisting the nephrologist to identify potential disease etiologies and triggers, such as autoimmune disease, cancer, medications, and infections.

Summary
We are entering an exciting era for which an antigen-based approach will further define subtypes of membranous nephropathy, allow for development of noninvasive diagnostics, and improve care for patients.