bluuebunny/crossref_metadata_2025_split huggingface dataset:
Are Non-animal Systemic Safety Assessments Protective? A Toolbox and Workflow
Authors: Middleton Alistair M , Reynolds Joe , Cable Sophie , Baltazar Maria Teresa , Li Hequn , Bevan Samantha , Carmichael Paul L , Dent Matthew Philip , Hatherell Sarah , Houghton Jade , Kukic Predrag , Liddell Mark , Malcomber Sophie , Nicol Beate , Park Benjamin , Patel Hiral , Scott Sharon , Sparham Chris , Walker Paul , White Andrew 
Published: July 2022

Abstract
An important question in toxicological risk assessment is whether non-animal new approach methodologies (NAMs) can be used to make safety decisions that are protective of human health, without being overly conservative. In this work, we propose a core NAM toolbox and workflow for conducting systemic safety assessments for adult consumers. We also present an approach for evaluating how protective and useful the toolbox and workflow are by benchmarking against historical safety decisions. The toolbox includes physiologically based kinetic (PBK) models to estimate systemic Cmax levels in humans, and 3 bioactivity platforms, comprising high-throughput transcriptomics, a cell stress panel, and in vitro pharmacological profiling, from which points of departure are estimated. A Bayesian model was developed to quantify the uncertainty in the Cmax estimates depending on how the PBK models were parameterized. The feasibility of the evaluation approach was tested using 24 exposure scenarios from 10 chemicals, some of which would be considered high risk from a consumer goods perspective (eg, drugs that are systemically bioactive) and some low risk (eg, existing food or cosmetic ingredients). Using novel protectiveness and utility metrics, it was shown that up to 69% (9/13) of the low risk scenarios could be identified as such using the toolbox, whilst being protective against all (5/5) the high-risk ones. The results demonstrated how robust safety decisions could be made without using animal data. This work will enable a full evaluation to assess how protective and useful the toolbox and workflow are across a broader range of chemical-exposure scenarios.
Genomic epidemiology of seasonal influenza circulation in China during prolonged border closure from 2020 to 2021
Authors: Xie Ruopeng , Adam Dillon C , Edwards Kimberly M , Gurung Shreya , Wei Xiaoman , Cowling Benjamin J , Dhanasekaran Vijaykrishna 
Published: July 2022

Abstract
China experienced a resurgence of seasonal influenza activity throughout 2021 despite intermittent control measures and prolonged international border closure. We show genomic evidence for multiple A(H3N2), A(H1N1), and B/Victoria transmission lineages circulating over 3 years, with the 2021 resurgence mainly driven by two B/Victoria clades. Phylodynamic analysis revealed unsampled ancestry prior to widespread outbreaks in December 2020, showing that influenza lineages can circulate cryptically under non-pharmaceutical interventions enacted against COVID-19. Novel haemagglutinin gene mutations and altered age profiles of infected individuals were observed, and Jiangxi province was identified as a major source for nationwide outbreaks. Following major holiday periods, fluctuations in the effective reproduction number were observed, underscoring the importance of influenza vaccination prior to holiday periods or travel. Extensive heterogeneity in seasonal influenza circulation patterns in China determined by historical strain circulation indicates that a better understanding of demographic patterns is needed for improving effective controls.
Costs of Physician Continuous Professional Development: A Systematic Review
Authors: Cook David A. , Wilkinson John M. , Foo Jonathan 
Published: July 2022

Purpose
An essential yet oft-neglected step in cost evaluations is the selection of resources (ingredients) to include in cost estimates. The ingredients that most influence the cost of physician continuous professional development (CPD) are unknown, as are the relative costs of instructional modalities. This study’s purpose was to estimate the costs of cost ingredients and instructional modalities in physician CPD.

Method
The authors conducted a systematic review in April 2020, searching MEDLINE, Embase, PsycInfo, and the Cochrane Library for comparative cost evaluations of CPD for practicing physicians. Two reviewers, working independently, screened articles for inclusion and extracted information on costs (converted to 2021 U.S. dollars) for each intervention overall, each ingredient, and each modality.

Results
Of 3,338 eligible studies, 62 were included, enumerating costs for 86 discrete training interventions or instructional modalities. The most frequently reported ingredients were faculty time (25 of 86 interventions), materials (24), administrator/staff time (23), and travel (20). Ingredient costs varied widely, ranging from a per-physician median of $4 for postage (10 interventions) to $525 for learner time (13); equipment (9) and faculty time were also relatively expensive (median > $170). Among instructional modalities (≤ 11 interventions per modality), audit and feedback performed by physician learners, computer-based modules, computer-based virtual patients, in-person lectures, and experiences with real patients were relatively expensive (median > $1,000 per physician). Mailed paper materials, video clips, and audit and feedback performed by others were relatively inexpensive (median ≤ $62 per physician). Details regarding ingredient selection (10 of 62 studies), quantitation (10), and pricing (26) were reported infrequently.

Conclusions
Some ingredients, including time, are more important (i.e., contribute more to total costs) than others and should be prioritized in cost evaluations. Data on the relative costs of instructional modalities are insightful but limited. The methods and reporting of cost valuations merit improvement.
COVID-19 in children: epidemic issues and candidate vaccines
Authors: Zhang Peng , Wei Mingwei , Jing Pengfei , Li Zhuopei , Li Jingxin , Zhu Fengcai 
Published: July 2022

Abstract
A large-scale vaccination of coronavirus disease-19 (COVID-19) in adults has been conducted for nearly a year, and there is a growing recognition that immunization for children is also essential. It has been months since emergency use of pediatric COVID-19 vaccine was approved, we reviewed the prevalence and transmission of COVID-19 in children. The prevalence of COVID-19 in children is reduced due to vaccination even in a Delta prevalent period, so an increase in the vaccination rate is needed in children. Although the precise role of children in the transmission requires more research to uncover, they likely played a significant role, according to the available literature. We also described four candidate COVID-19 vaccines for children on their safety and immunogenicity and the impact of severe acute respiratory syndrome coronavirus 2 variants on childhood vaccination. Safety issues on pediatric vaccines post-approval, like adverse events following immunization and adverse events of special interest require studies on long-term and effective regulatory mechanisms.
Research progress in targeted therapy and immunotherapy for gastric cancer
Authors: Li Xuewei , Xu Jun , Xie Jun , Yang Wenhui 
Published: July 2022

Abstract
Gastric cancer (GC) is one of the most common malignant tumors worldwide. Its incidence ranks the 5th among all malignant tumors globally, and it is the 3rd leading cause of death among patients with cancer. Surgical treatment is the first choice in clinical practice. However, targeted therapy, immunotherapy, and other treatment methods have also become research hotspots at home and abroad with the development of individualized precision therapy in recent years, besides traditional radiotherapy and chemotherapy. At present, targeted therapy and immunotherapy are methods used for treating GC, and they have important clinical application value and prospects. This study aimed to review the research progress of targeted therapy and immunotherapy for GC, focusing on its mechanism of action and related important clinical trials, hoping to provide references for the clinical treatment of GC.
Chinese expert consensus on the surgical treatment of primary palmar hyperhidrosis (2021 version)
Authors: Liu Yanguo , Weng Wenhan , Tu Yuanrong , Wang Jun ,   on behalf of Chinese Expert Committee on Palmar Hyperhidrosis
Published: July 2022

Abstract
Primary palmar hyperhidrosis (PPH) is a pathologic condition of excessive sweating on hands that has adverse impacts on patients’ social activity, professional life, and psychological state. Endoscopic thoracic sympathicotomy (ETS) is by far the treatment choice for PPH with the most stable and durable curative effects, but special attention should be given to the side effects of the surgery, especially compensatory hyperhidrosis (CH). This consensus is the second version of the Chinese Expert Consensus on the Surgical Treatment of PPH by the China Expert Committee on Palmar Hyperhidrosis (CECPH), which was published 10 years ago. This consensus emphasizes the need for special attention and careful assessment of the patients’ feelings, as well as their emotional and mental state, and emphasizes that distress due to palmar sweating and the desire for treatment are prerequisites for diagnosis. It also provides a more nuanced delineation of CH and reviews all new attempts to prevent and treat this side effect. New evidence of the epidemiology, pathogenesis of PPH, and indications for surgery were also assessed or recommended.
Dysfunctional gene splicing in glucose metabolism may contribute to Alzheimer's disease
Authors: Deng Shengfeng , Yi Peng , Xu Mingliang , Yi Qian , Feng Jianguo 
Published: July 2022

Abstract
The glucose metabolism is crucial for sustained brain activity as it provides energy and is a carbon source for multiple biomacromolecules; glucose metabolism decreases dramatically in Alzheimer's disease (AD) and may be a fundamental cause for its development. Recent studies reveal that the alternative splicing events of certain genes effectively regulate several processes in glucose metabolism including insulin receptor, insulin-degrading enzyme, pyruvate kinase M, receptor for advanced glycation endproducts, and others, thereby, influencing glucose uptake, glycolysis, and advanced glycation end-products-mediated signaling pathways. Indeed, the discovery of aberrant alternative splicing that changes the proteomic diversity and protein activity in glucose metabolism has been pivotal in our understanding of AD development. In this review, we summarize the alternative splicing events of the glucose metabolism-related genes in AD pathology and highlight the crucial regulatory roles of splicing factors in the alternative splicing process. We also discuss the emerging therapeutic approaches for targeting splicing factors for AD treatment.
A zero-sum game or an interactive frame? Iron competition between bacteria and humans in infection war
Authors: Wu Zhenchao , Shao Jiqi , Zheng Jiajia , Liu Beibei , Li Zhiyuan , Shen Ning 
Published: July 2022

Abstract
Iron is an essential trace element for both humans and bacteria. It plays a vital role in life, such as in redox reactions and electron transport. Strict regulatory mechanisms are necessary to maintain iron homeostasis because both excess and insufficient iron are harmful to life. Competition for iron is a war between humans and bacteria. To grow, reproduce, colonize, and successfully cause infection, pathogens have evolved various mechanisms for iron uptake from humans, principally Fe3+-siderophore and Fe2+-heme transport systems. Humans have many innate immune mechanisms that regulate the distribution of iron and inhibit bacterial iron uptake to help resist bacterial invasion and colonization. Meanwhile, researchers have invented detection test strips and coupled antibiotics with siderophores to create tools that take advantage of this battle for iron, to help eliminate pathogens. In this review, we summarize bacterial and human iron metabolism, competition for iron between humans and bacteria, siderophore sensors, antibiotics coupled with siderophores, and related phenomena. We also discuss how competition for iron can be used for diagnosis and treatment of infection in the future.
The Evolving Story of CNLDO: Serial Photographic Documentation and Parental Perspectives
Authors: Singh Swati , Ali Mohammad Javed 
Published: July 2022

Purpose:
The purpose of this study is to report the temporal sequence of symptomatology of bilateral congenital nasolacrimal duct obstruction and parental perspectives of 2 established lacrimal surgeons studying the natural history of their newborn child.

Methods:
Prospective observational report. Once epiphora was noted, a daily assessment and documentation of several symptoms and signs were initiated using iPhone 11 pro camera. These include epiphora, associated discharge, tear meniscus level, matting of lashes, day-night variation in symptomatology, difficulty in eye-opening upon waking up, conjunctival congestion, periocular changes, especially in the tear trough area and lateral canthus, changes in symptom severity with time, regurgitation on pressure over lacrimal sac area, the fullness of the lacrimal sac area or palpable lacrimal sac swelling, and other associated clinical findings.

Results:
The weekly course of congenital nasolacrimal duct obstruction showed similar patterns in OU, although the phase of severe symptoms was spaced by a 6-week interval between the eyes. The epiphora appeared first, followed by rapidly increasing discharge, the severity of which was alarming to the parents. Periocular skin developed excoriation due to persistent epiphora and cleaning attempts. Focused and regular lacrimal sac compressions resulted in abrupt resolution of epiphora at different time points in each eye. The baby was comfortable when compressions were performed during breastfeeding. Cleaning the discharge regularly can be a daunting task for the new parents. The use of wet ‘eye wipes’ was more effective and comfortable than a cotton bud or cloth piece. Both the parents were lacrimal surgeons, and they did not overtly feel socially embarrassed due to the congenital nasolacrimal duct obstruction, but questions from family and friends were discomforting.

Conclusion:
Parental perspectives of the temporal sequence of congenital nasolacrimal duct obstruction provide better insights into disease management and counseling.
Prognostic scores in post-endoscopic retrograde cholangiopancreatography acute pancreatitis: should we use all, some, or none?
Authors: Macedo Silva Vítor , Freitas Marta , Sousa Magalhães Rui , Cúrdia Gonçalves Tiago , Boal Carvalho Pedro , Rosa Bruno , Cotter José 
Published: July 2022

Background/aims
Acute pancreatitis is the most commonly observed adverse event following endoscopic retrograde cholangiopancreatography (ERCP). Early risk stratification is crucial in the management of these patients, to reduce unfavorable outcomes. Multiple prognostic scores are already used in acute pancreatitis, regardless of its etiology. Scarce data is available for their use specifically on post-ERCP acute pancreatitis (PEP). We aimed to compare the accuracy of different prognostic scores at PEP diagnosis for the prediction of a moderate-to-severe course.

Methods
Cross-sectional study of consecutive ERCPs performed between 2010 and 2020. The final sample included patients with PEP, with the severity graded according to the Atlanta classification. For each patient, different prognostic scores were calculated. Each score’s accuracy for the prediction of a moderate-to-severe course was assessed by analysis of receiving-operating-characteristics (ROC) curves.

Results
From 2012 ERCPs, 102 (5.1%) were complicated by PEP. From these, 34 (1.7% of all ERCPs) were classified as moderate-to-severe. The scores with the best accuracy in predicting a moderate-to-severe course were the BISAP [ area under curve (AUC) = 0.92], Balthazar (AUC = 0.89) and Glasgow-Imrie (AUC = 0.88) scores, with very good to excellent acuities. APACHE II (AUC = 0.81), Marshall score (AUC = 0.81) and PANC3 score (AUC = 0.76) revealed good accuracies. Ranson’s criteria on admission (AUC = 0.70) and HAPS classification (AUC = 0.67) presented less accurate results. Optimal cutoffs for the top scoring classifications were BISAP ≥3 (sensitivity 88.3% and specificity 83.8%), Balthazar ≥2 (sensitivity 84.8% and specificity 85.3%) and Glasgow-Imrie ≥4 (sensitivity 81.0% and specificity 82.6%).

Conclusion
BISAP, Balthazar and Glasgow-Imrie classifications presented the best results for predicting moderate-to-severe PEP, and represent the most useful prognostic scores for risk stratification in this population.
Evaluating of the Quality of Hepatic Diffusion Weighted Imaging Using Multiband Imaging With Variable-Rate Selective Excitation
Authors: Yoshida Naofumi , Nakaura Takeshi , Morita Kosuke , Yoneyama Masami , Inoue Taihei , Tanoue Shota , Uetani Hiroyuki , Oda Seitaro , Nagayama Yasunori , Kidoh Masafumi , Hirai Toshinori 
Published: July 2022

Objective
To assess the image quality of diffusion-weighted imaging (DWI) using multiband (MB) imaging with variable-rate selective excitation (VERSE) and compare it to conventional DWI.

Methods
We retrospectively evaluated hepatic DWI images of patients (n = 76) according to either the conventional method (SENSE, acceleration factor = 2) (n = 38) or fast scanning method (MB imaging with VERSE, acceleration factor = 2 × 2) (n = 38). We also conducted a volunteer study (n = 15) for those scanning methods. During quantitative analysis, the signal-to-noise ratio (SNR), apparent diffusion coefficient values, and contrast in the liver, spleen, and spinal cord were compared between the 2 groups. During qualitative analysis, all images were independently and blindly evaluated by 2 board-certified radiologists. The image contrast, noise, artifacts, and sharpness were assessed, and the performance of classification was measured using receiver operating characteristic curve analysis.

Results
In the retrospective study, the SNRs of the hepatic parenchyma and spinal cord between the 2 protocols were significantly different (liver, 8.9 [interquartile range {IQR}, 7.6–12.2] vs 13.0 [IQR, 10.0–16.7]; P < 0.001 and spinal cord, 6.0 [IQR, 4.7–9.4] vs 4.3 [IQR, 3.8–6.8]; P < 0.02). No significant differences between the 2 protocols in the other retrospective analyses were noted. In the receiver operating characteristic curve analysis, area under the curve was 0.49 (95% confidence intervals, 0.40–0.58).

Conclusion
Multiband VERSE reduced scan time and SNR of hepatic DWI; however, subjective image quality parameters were not significantly impacted.
The imbalance of T-cell immunoglobulin and ITIM domain and CD226 on regulatory T cell in recurrent spontaneous abortion patients
Authors: Li Cui , Ying Chun-Mei , Duan Zhong-Liang 
Published: July 2022

Objective:
To analyze the proportion of peripheral regulatory T cells (Tregs) and the expression of the immune checkpoint molecules T-cell immunoglobulin and ITIM domain (TIGIT) and CD226 on Tregs in patients with recurrent spontaneous abortion (RSA).

Methods:
The proportion of CD3+CD4+CD25+Foxp3+ Tregs and the expression levels of CD226 and TIGIT on Tregs in 30 normal pregnant women and 28 patients with RSA were determined via flow cytometry.

Results:
The proportion of Tregs in the RSA group (4.41% ± 1.54%) was significantly lower than that in the control group (5.27% ± 1.52%, P = 0.0374). Compared with the normal pregnant women, patients with RSA showed decreased TIGIT expression (54.75 ± 9.70% vs. 63.07 ± 12.48%, P = 0.0066) and increased CD226 expression on Tregs (25.59% ± 8.22% vs. 20.46% ± 6.97%, P = 0.0168). The ratio of CD226 to TIGIT in the RSA group (0.48 ± 0.19) was higher than that in the control group (0.34 ± 0.15, P = 0.0027). The proportion of TIGIT+CD226+ Tregs was significantly lower in patients with RSA (9.30% ± 4.95% vs. 13.43% ± 4.72%, P = 0.0020) than in the controls.

Conclusions:
Patients with RSA show a reduced proportion of Tregs and an imbalance in the expression of TIGIT and CD226 on Tregs.
A Novel Microbiome Signature in Gastric Cancer
Authors: Abate Miseker , Vos Elvira , Gonen Mithat , Janjigian Yelena Y. , Schattner Mark , Laszkowska Monika , Tang Laura , Maron Steven B. , Coit Daniel G. , Vardhana Santosh , Vanderbilt Chad , Strong Vivian E. 
Published: July 2022

Objective:The microbiome is hypothesized to have a significant impact on cancer development. In gastric cancer (GC),Helicobacter pyloriis an established class I carcinogen. However, additional organisms in the intratumoral microbiome play an important role in GC pathogenesis and progression. In this study, we characterize the full spectrum of the microbes present within GC and identify distinctions among molecular subtypes.Methods:A microbiome bioinformatics pipeline that is generalizable across multiple next-generation sequencing platforms was developed. Microbial profiles for alpha diversity and enrichment were generated for 2 large, demographically distinct cohorts: (1) internal Memorial Sloan Kettering Cancer Center (MSKCC) and (2) The Cancer Genome Atlas (TCGA) cohorts. A total of 520 GC samples were compared with select tumor-adjacent nonmalignant samples. Microbiome differences among the GC molecular subtypes were identified.Results:Compared with nonmalignant samples, GC had significantly decreased microbial diversity in both MSKCC and TCGA cohorts (P<0.05).Helicobacter,Lactobacillus,Streptococcus,Prevotella, andBacteroideswere significantly more enriched in GC samples when compared with nonmalignant tissue (P<0.05). Microsatellite instability-high GC had distinct microbial enrichment compared with other GC molecular subtypes.Conclusion:Distinct patterns of microbial diversity and species enrichment were identified in patients with GC. Given the varied spectrum of disease progression and treatment response of GC, understanding unique microbial signatures will provide the landscape to explore key microbial targets for therapy.
Determining the Ideal Intraoperative Resting Genital Hiatus Size—Balancing Surgical and Functional Outcomes
Authors: Chang Olivia H. , Yao Meng , Ferrando Cecile A. , Paraiso Marie Fidela R. , Propst Katie 
Published: July 2022

Importance
The intraoperative resting genital hiatus (GH) size can be surgically modified but its relationship to prolapse recurrence is unclear.

Objectives
The objective of this study was to identify the optimal intraoperative resting GH size as it relates to prolapse recurrence and functional outcomes at 1 year.

Study Design
This prospective cohort study was conducted at 2 hospitals from 2019 to 2021. Intraoperative measurements of the resting GH, perineal body, and total vaginal length were collected. The composite primary outcome consisted of anatomic recurrence, subjective recurrence, and/or conservative or surgical retreatment at 1 year. Comparisons of anatomic, functional, and sexual outcomes were compared between patients stratified by the optimal intraoperative GH size identified by receiver operating characteristic curve analysis.

Results
Sixty-eight patients (median age of 63 years) underwent surgery, with 59 (86.8%) presenting for follow-up at 1 year. Based on the 13 patients (22%) with composite recurrence, receiver operating characteristic curve analysis demonstrated an intraoperative resting GH size of 3 cm, had 76.9% sensitivity (confidence interval [CI], 54–99.8%), and 34.8% specificity (CI, 21.0–48.5%) for composite recurrence at 1 year (area under curve = 0.61). Nineteen patients had an intraoperative GH less than 3 cm (32.2%) and 40 had a GH of 3 cm or greater (67.8%). The intraoperative resting GH size was significantly larger in patients with prolapse beyond the hymen at 1 year (4 cm [3.0, 4.0]) compared with those with prolapse at or proximal to the hymen (3.0 cm [2.5, 3.5], P = 0.009).

Conclusions
Intraoperative GH size may not reliably predict composite prolapse recurrence at 1 year, although there was an association between intraoperative resting GH size with prolapse beyond the hymen.