bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase ϵ variants at low dNTP levels
Authors: Barbari Stephanie R , Beach Annette K , Markgren Joel G , Parkash Vimal , Moore Elizabeth A , Johansson Erik , Shcherbakova Polina V 
Published: July 2022

Abstract
Amino acid substitutions in the exonuclease domain of DNA polymerase ϵ (Polϵ) cause ultramutated tumors. Studies in model organisms suggested pathogenic mechanisms distinct from a simple loss of exonuclease. These mechanisms remain unclear for most recurrent Polϵ mutations. Particularly, the highly prevalent V411L variant remained a long-standing puzzle with no detectable mutator effect in yeast despite the unequivocal association with ultramutation in cancers. Using purified four-subunit yeast Polϵ, we assessed the consequences of substitutions mimicking human V411L, S459F, F367S, L424V and D275V. While the effects on exonuclease activity vary widely, all common cancer-associated variants have increased DNA polymerase activity. Notably, the analog of Polϵ-V411L is among the strongest polymerases, and structural analysis suggests defective polymerase-to-exonuclease site switching. We further show that the V411L analog produces a robust mutator phenotype in strains that lack mismatch repair, indicating a high rate of replication errors. Lastly, unlike wild-type and exonuclease-dead Polϵ, hyperactive variants efficiently synthesize DNA at low dNTP concentrations. We propose that this characteristic could promote cancer cell survival and preferential participation of mutator polymerases in replication during metabolic stress. Our results support the notion that polymerase fitness, rather than low fidelity alone, is an important determinant of variant pathogenicity.
Benchmarking computational methods for B-cell receptor reconstruction from single-cell RNA-seq data
Authors: Andreani Tommaso , Slot Linda M , Gabillard Samuel , Strübing Carsten , Reimertz Claus , Yaligara Veeranagouda , Bakker Aleida M , Olfati-Saber Reza , Toes René E M , Scherer Hans U , Augé Franck , Šimaitė Deimantė 
Published: July 2022

AbstractMultiple methods have recently been developed to reconstruct full-length B-cell receptors (BCRs) from single-cell RNA sequencing (scRNA-seq) data. This need emerged from the expansion of scRNA-seq techniques, the increasing interest in antibody-based drug development and the importance of BCR repertoire changes in cancer and autoimmune disease progression. However, a comprehensive assessment of performance-influencing factors such as the sequencing depth, read length or number of somatic hypermutations (SHMs) as well as guidance regarding the choice of methodology is still lacking. In this work, we evaluated the ability of six available methods to reconstruct full-length BCRs using one simulated and three experimental SMART-seq datasets. In addition, we validated that the BCRs assembled in silico recognize their intended targets when expressed as monoclonal antibodies. We observed that methods such as BALDR, BASIC and BRACER showed the best overall performance across the tested datasets and conditions, whereas only BASIC demonstrated acceptable results on very short read libraries. Furthermore, the de novo assembly-based methods BRACER and BALDR were the most accurate in reconstructing BCRs harboring different degrees of SHMs in the variable domain, while TRUST4, MiXCR and BASIC were the fastest. Finally, we propose guidelines to select the best method based on the given data characteristics.
Household inequality and remittances in rural Thailand: a life-cycle perspective
Authors: Disney Richard , McKay Andy , Shabab C Rashaad 
Published: July 2022

AbstractThis article studies the dynamics of income inequality among a panel of rural households in Thailand. In contrast to the many cross-section studies of income inequality, the article exploits a long panel data set to examine lifetime trajectories of household inequality. It finds that income inequality is decreasing over time within cohorts delineated by decennial birth dates of heads of household. This decline in inequality primarily arises from differences in receipt of remittances from adult children of the head of household who live outside the village of origin. On average, poorer households receive remittances from a larger number of children, the annual amount remitted per child is a greater proportion of household income than in richer households, and the importance of remittances in household incomes grows as the head of household ages.
Temporal analysis of Lassa virus infection and transmission in experimentally infected Mastomys natalensis
Authors: Safronetz David , Rosenke Kyle , Meade-White Kimberley , Sloan Angela , Maiga Ousmane , Bane Sidy , Martellaro Cynthia , Scott Dana P , Sogoba Nafomon , Feldmann Heinz 
Published: July 2022

Abstract
Little is known about the temporal patterns of infection and transmission of Lassa virus (LASV) within its natural reservoir (Mastomys natalensis). Here, we characterize infection dynamics and transmissibility of a LASV isolate (Soromba-R) in adult lab-reared M. natalensis originating from Mali. The lab-reared M. natalenesis proved to be highly susceptible to LASV isolates from geographically distinct regions of West Africa via multiple routes of exposure, with 50% infectious doses of &lt; 1 TCID50. Postinoculation, LASV Soromba-R established a systemic infection with no signs of clinical disease. Viral RNA was detected in all nine tissues examined with peak concentrations detected between days 7 and 14 postinfection within most organs. There was an overall trend toward clearance of virus within 40 days of infection in most organs. The exception is lung specimens, which retained positivity throughout the course of the 85-day study. Direct (contact) and indirect (fomite) transmission experiments demonstrated 40% of experimentally infected M. natalensis were capable of transmitting LASV to naïve animals, with peak transmissibility occurring between 28 and 42 days post-inoculation. No differences in patterns of infection or transmission were noted between male and female experimentally infected rodents. Adult lab-reared M. natalensis are highly susceptible to genetically distinct LASV strains developing a temporary asymptomatic infection associated with virus shedding resulting in contact and fomite transmission within a cohort.
A Puzzle with Missing Pieces: Explaining the Effectiveness of World Bank Development Projects
Authors: Ashton Louise , Friedman Jed , Goldemberg Diana , Hussain Mustafa Zakir , Kenyon Thomas , Khan Akib , Zhou Mo 
Published: July 2022

AbstractThe identification of key determinants of aid effectiveness is a long-standing question in the development community. This paper reviews the literature on aid effectiveness at the project level and then extends the inquiry in a variety of dimensions with new data on World Bank investment project financing. It confirms that the country institutional setting and quality of project supervision are associated with project success, as identified previously. However, many aspects of the development project cycle, especially project design, have been difficult to measure and therefore under-investigated. The paper finds that project design, as proxied by the estimated value added of design staff, the presence of prior analytic work, and other specially collected measures, is a significant predictor of ultimate project success. These factors generally grow in predictive importance as the income level of the country rises. The results also indicate that a key determinant of the staff's contribution is their experience with previous World Bank projects, but not other characteristics such as age, education, or country location. Key inputs to the project production process associated with subsequent performance are not captured in routine data systems, although it is feasible to do so. Further, the conceptualization and measurement of the success of project-based aid should be revisited by evaluative bodies to reflect a project's theorized contribution to development outcomes.
The REPAIR Project: A Prospectus for Change Toward Racial Justice in Medical Education and Health Sciences Research: REPAIR Project Steering Committee
Authors:   REPAIR Project Steering Committee
Published: July 2022

Amidst ongoing efforts to address racial injustice, U.S. medical institutions are grappling with the structural roots of anti-Black racism. The REPAIR (REParations and Anti-Institutional Racism) Project is a 3-year strategic initiative at the University of California, San Francisco aiming to address anti-Black racism and augment the presence and voices of people of color in science, medicine, and health care. The REPAIR Project was designed in response to an unmet need for critical dialogue, cross-disciplinary research, and curriculum development addressing structural racism. It offers a framework for thinking and acting to achieve repair in relation to racial injustice and is anchored by 3 concepts—reparations, abolition, and decolonization—which have been deployed as annual themes in academic years 2020–2021, 2021–2022, and 2022–2023, respectively.
The theme of medical reparations builds on the longstanding call for slavery reparations and the paying of debts owed to Black Americans for the harms of slavery. The REPAIR Project focuses on the specific debts owed to Black Americans for racial harm in health care settings. The theme of medical abolition examines the intersections of incarceration, policing, and surveillance in health care and the role of clinicians in furthering or stopping oppressive practices that bind patterns of Black incarceration to health and health care. The theme of decolonizing the health sciences targets “othering” practices entrenched in scientific methodologies that have arisen from colonial-era beliefs and practices around imperialism, including how the colonial-era concept of race contributes to ongoing racial harm.
In this article, the authors describe the REPAIR Project, preliminary outcomes from its first year, and potential future lines of inquiry for medical educators and health sciences researchers. The authors argue that the full damage from slavery and its legacies cannot be undone, but everyone can work in new ways that reduce or eliminate harm.
Learning Together: Co-Learning Among Faculty and Trainees in the Clinical Workplace
Authors: Haddock Lindsey , Rivera Josette , O’Brien Bridget C. 
Published: July 2022

Purpose
Studies of workplace learning largely focus on how individuals (clinicians and trainees) learn in the clinical workplace. By focusing on individuals, these studies miss opportunities to explore the co-constructive nature of learning that may result in clinician–educators and trainees learning alongside each other (co-learning). The purpose of this study was to explore whether and how co-learning occurs in the workplace and what value co-learning holds.

Method
Using a constructivist grounded theory approach, the authors interviewed 34 faculty clinician–educators from 10 specialties at one academic institution to explore whether and how co-learning occurred in their practice and how faculty perceived its value for faculty and for trainees. Interviews were conducted and recorded June to December 2019. Through iterative analysis, the authors refined a conceptual model of co-learning.

Results
In a 3-part model of co-learning derived from faculty interviews, faculty and trainees jointly identify learning opportunities during work-related activities and choose learning strategies for learning that lead to interpretation and construction of meaning; these activities produce learning outcomes, such as understanding or insight. The model also accounts for asymmetry in experience and position between faculty and trainees. All faculty participants valued co-learning and elucidated barriers and facilitators to using it in the workplace. How faculty managed asymmetries shaped the nature of the co-learning. When faculty worked to lessen asymmetry between teacher and trainee, co-learning was often collaborative.

Conclusions
The model of co-learning makes explicit the concept of asymmetry in workplace learning and aids consideration of how related dynamics affect the nature of learning. Faculty must be intentional in managing asymmetries to fully leverage learning opportunities afforded by the workplace.
Application of Bayesian Methods to Help Interpret the VANCO Trial Results
Authors: O'Hara Nathan N. , Castillo Renan C. , Carlini Anthony R. , Joshi Manjari , Murray Clinton K. , Allen Lauren E. , Huang Yanjie , Gary Joshua L. , Bosse Michael J. , Obremskey William T. , McKinley Todd O. , Schmidt Andrew H. , O'Toole Robert V. ,   and METRC
Published: July 2022

Objective:
To determine whether a Bayesian analysis changes the results of the VANCO trial.

Design:
A secondary analysis of a randomized clinical trial using Bayesian methods.

Setting:
Thirty-six US trauma centers.

Patients:
Patients ages 18–80 years with a tibial plateau or pilon fracture deemed high risk of infection and definitively treated with plate and screw fixation.

Intervention:
Patients were randomly allocated to receive 1000 mg of intrawound vancomycin powder at their definitive fixation or to a control group that received no topical antibiotics.

Main Outcome Measurements:
A deep surgical site infection requiring operative treatment within 6 months of definitive fixation. Secondary outcomes included gram-positive and gram-negative–only deep surgical site infections.

Results:
Of the 980 patients randomized, 874 (89%) had at least 140 days of follow-up and were included in this Bayesian analysis. The estimated probability that intrawound vancomycin powder reduces the risk of a deep surgical site infection is >98% [relative risk (RR), 0.66; 95% credible interval (CrI), 0.46–0.98]. There is a >99% chance intrawound vancomycin powder reduces gram-positive infections and an 80% chance the magnitude of this risk reduction exceeds 35% (RR, 0.52; 95% CrI, 0.33–0.84) exists. It is unlikely (44%) that intrawound vancomycin powder prevents gram-negative surgical site infections (RR, 1.06; 95% CrI, 0.48–2.45).

Conclusions:
There is a high probability (>98%) that intrawound vancomycin powder reduces deep surgical site infections in patients with tibial plateau or pilon fractures at high risk of infection and even more likely it reduces deep infections with gram-positive pathogens (>99%).

Level of Evidence:
Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Burden of pancreatitis and associated risk factors in China, 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019
Authors: Han Ke , Chen Shimin , Song Yang , Du Chen , Gao Fei , Liu Shaohua , He Yao , Chai Ningli , Linghu Enqiang , Liu Miao 
Published: July 2022

Abstract

Background:
Pancreatitis is a common disease of the digestive system. Acute pancreatitis is one of the most common reasons for gastrointestinal hospital admission, and chronic pancreatitis significantly reduces quality of life. However, national epidemiological data on pancreatitis in China are lacking. This study aimed to quantify the disease burden of pancreatitis in China from 1990 to 2019.

Methods:
This study was based on the Global Burden of Disease Study 2019 dataset. Age-standardized rates of incidence (ASIR), prevalence (ASPR), mortality (ASMR), and disability-adjusted life years (DALYs) were used to describe the disease burden of pancreatitis, and estimated annual percentage change (EAPC) was used to indicate the average change in age-standardized rates. We also described the trend of pancreatitis-related mortality and DALYs, which are attributable to alcohol use by age and sex.

Results:
From 1990 to 2019, the ASIR, ASPR, ASMR, and age-standardized DALYs of pancreatitis in China decreased by 10.90, 1.50, 0.49, and 15.54 per 100,000, respectively, with EAPCs of −1.35 (95% uncertainty interval [UI]: −1.67, −1.02) and −0.37 (95% UI: −0.43, −0.31), −2.01 (95% UI: −2.07, −1.94) and −2.32 (95% UI: −2.37, −2.28), respectively. Recently, the numbers of incident and prevalent cases have risen, with estimates of 380,018 (95% UI: 308,669–462,767) and 493,765 (95% UI: 416,705–578,675), respectively, in 2019. Among men, the disease burden of pancreatitis was more severe than among women, and with variances in the distribution among different age groups. Age-standardized DALYs caused by alcohol-related pancreatitis have gradually worsened in the past decade, accounting for 34.09% of the total in 2019.

Conclusions:
The disease burden of pancreatitis in China has declined in the past 30 years, but the exacerbation of population aging poses a challenge to prevention and control of pancreatitis. Alcohol use has gradually become an important factor in the disease burden of pancreatitis in recent years.
Treating non-small cell lung cancer by targeting the PI3K signaling pathway
Authors: Jiang Lin , Zhang Jingbo , Xu Yan , Xu Heng , Wang Mengzhao 
Published: July 2022

Abstract
The phosphosphatidylinositol-3-kinase (PI3K) signaling pathway is one of the most important intracellular signal transduction pathways affecting cell functions, such as apoptosis, translation, metabolism, and angiogenesis. Lung cancer is a malignant tumor with the highest morbidity and mortality rates in the world. It can be divided into two groups, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for >85% of all lung cancers. There are currently many clinical treatment options for NSCLC; however, traditional methods such as surgery, chemotherapy, and radiotherapy have not been able to provide patients with good survival benefits. The emergence of molecular target therapy has improved the survival and prognosis of patients with NSCLC. In recent years, there have been an increasing number of studies on NSCLC and PI3K signaling pathways. Inhibitors of various parts of the PI3K pathway have appeared in various phases of clinical trials with NSCLC as an indication. This article focuses on the role of the PI3K signaling pathway in the occurrence and development of NSCLC and summarizes the current clinical research progress and possible development strategies.
Gut microbiota: a new insight into neurological diseases
Authors: Liu Lanxiang , Wang Haiyang , Chen Xueyi , Xie Peng 
Published: July 2022

Abstract
In the last decade, it has become increasingly recognized that a balanced gut microbiota plays an important role in maintaining the health of the host. Numerous clinical and preclinical studies have shown that changes in gut microbiota composition are associated with a variety of neurological diseases, e.g., Parkinson's disease, Alzheimer's disease, and myasthenia gravis. However, the underlying molecular mechanisms are complex and remain unclear. Behavioral phenotypes can be transmitted from humans to animals through gut microbiota transplantation, indicating that the gut microbiota may be an important regulator of neurological diseases. However, further research is required to determine whether animal-based findings can be extended to humans and to elucidate the relevant potential mechanisms by which the gut microbiota regulates neurological diseases. Such investigations may aid in the development of new microbiota-based strategies for diagnosis and treatment and improve the clinical management of neurological disorders. In this review, we describe the dysbiosis of gut microbiota and the corresponding mechanisms in common neurological diseases, and discuss the potential roles that the intestinal microbiome may play in the diagnosis and treatment of neurological disorders.
Recurrent PTPN14 Mutations in Trichilemmoma: Evidence for Distinct Pathways of Molecular Pathogenesis
Authors: Russell-Goldman Eleanor , Dong Fei , Hanna John 
Published: July 2022

Abstract:
Trichilemmoma is a benign cutaneous neoplasm that recapitulates the outer root sheath of the hair follicle. Trichilemmomas may occur sporadically or in association with Cowden syndrome, which is characterized by germline mutations in the lipid phosphatase PTEN (phosphatase and tensin homolog on chromosome 10). Interestingly, most sporadic trichilemmomas do not show PTEN aberrations, but rather activating mutations in HRAS. Despite these important advances, a comprehensive genetic analysis of trichilemmoma has not been reported. Here, we used a next-generation DNA sequencing platform to study 9 sporadic trichilemmoma cases. Seven cases (7/9; 78%) harbored activating mutations in HRAS, consistent with previous findings. Unexpectedly, we identified recurrent mutations in the tyrosine phosphatase PTPN14 (protein tyrosine phosphatase nonreceptor type 14) in 4 cases (4/9; 44%). Three of these cases also harbored HRAS mutations, whereas one case occurred in the absence of a HRAS mutation and showed evidence of biallelic inactivation of PTPN14. Finally, one case (1/9; 11%) showed biallelic inactivation of PTEN in the absence of a HRAS (or PTPN14) mutation. These data suggest at least 3 distinct pathways of molecular pathogenesis in sporadic trichilemmoma and identify PTPN14 as a potentially important contributor to trichilemmoma biology.
Virtual Reality Improves Patient Experience and Anxiety During In-office Carpal Tunnel Release
Authors: Miller McKenzie B. , Gabel Shelley A. , Gluf-Magar Lindsay C. , Haan Pam S. , Lin Judith C. , Clarkson James H. W. 
Published: July 2022

Background:
This study examined how wide- awake local anesthesia no tourniquet (WALANT) surgery in the office versus the standard operating room (OR) impacts patient experience, and the effect wide awake virtual reality (WAVR) has in conjunction with WALANT on patient experience.

Methods:
This is a patient-reported outcome study of patients undergoing carpal tunnel release by a single surgeon between August 2017 and March 2021. Patients were classified by location; traditional OR versus WALANT in-office. In-office patients were further classified by whether they chose to use WAVR or not. Patients rated overall experience, enjoyability, and anxiety using a Likert scale (1–7).

Results:
The online survey had a 44.8% response rate. OR patients were twice as likely to report a neutral or negative experience (23% versus 11%, P = 0.03), significantly lower enjoyment scores (44% versus 20%, P = 0.0007)‚ and higher anxiety (42% versus 26%, P = 0.04) compared with office-based WALANT patients. With the addition of WAVR, office patients reported higher enjoyment than those who did not use WAVR (85% versus 73%, P = 0.05). Patients reporting an anxiety disorder were more likely to choose WAVR when compared with patients without anxiety disorder (73.8% versus 56.4%). When they chose WAVR, they had greater anxiolysis (79% versus 47%, P = 0.01)‚ and increased enjoyment (90% versus 59%, P = 0.005).

Conclusions:
This study demonstrates improved patient experience in the office setting, further amplified by WAVR. Preexisting anxiety disorder is a positive predictive variable toward the patients’ choice to use WAVR.