bluuebunny/crossref_metadata_2025_split huggingface dataset:
Consensus-based approach to managing opioids, including opioid misuse and opioid use disorder, in patients with serious illness: protocol for a modified Delphi process
Authors: King Caroline , Arnold Robert , Dao Emily , Kapo Jennifer , Liebschutz Jane , Meier Diane , Paice Judith , Ritchie Christine , Czajkowski Kristen , Khodyakov Dmitry , Merlin Jessica 
Published: May 2021

IntroductionManagement of opioid misuse and opioid use disorder (OUD) among individuals with serious illness is an important yet understudied issue. Palliative care clinicians caring for individuals with serious illness, many of whom may live for months or years, describe a complex tension between weighing the benefits of opioids, which are considered a cornerstone of pain management in serious illness, and serious opioid-related harms like opioid misuse and OUD. And yet, little literature exists to inform the management of opioid misuse and OUDs among individuals with serious illness. Our objective is to provide evidence-based management guidance to clinicians caring for individuals with serious illness who develop opioid misuse or OUD.Methods and analysisWe chose a modified Delphi approach, which is appropriate when empirical evidence is lacking and expert input must be used to shape clinical guidance. We sought to recruit 60 clinicians with expertise in palliative care, addiction or both to participate in this study. We created seven patient cases that capture important management challenges in individuals with serious illness prescribed opioid therapy. We used ExpertLens, an online platform for conducting modified Delphi panels. Participants completed three rounds of data collection. In round 1, they rated and commented on the appropriateness of management choices for cases. In round 2, participants reviewed and discussed their own and other participants’ round 1 numerical responses and comments. In round 3 (currently ongoing), participants again reviewed rounds 1 and 2, and are allowed to change their final numerical responses. We used ExpertLens to automatically identify whether there is consensus, or disagreement, among responses in panels. Only round 3 responses will be used to assess final consensus and disagreement.Ethics and disseminationThis project received ethical approval from the University of Pittsburgh’s Institutional Review Board (study 19110301) and the RAND Institutional Research Board (study 2020-0142). Guidance from this work will be disseminated through national stakeholder networks to gain buy-in and endorsement. This study will also form the basis of an implementation toolkit for clinicians caring for individuals with serious illness who are at risk of opioid misuse or OUD.
From screen time to the digital level of analysis: a scoping review of measures for digital media use in children and adolescents
Authors: Browne Dillon Thomas , May Shealyn S , Colucci Laura , Hurst-Della Pietra Pamela , Christakis Dimitri , Asamoah Tracy , Hale Lauren , Delrahim-Howlett Katia , Emond Jennifer A , Fiks Alexander G , Madigan Sheri , Perlman Greg , Rumpf Hans-Jürgen , Thompson Darcy , Uzzo Stephen , Stapleton Jackie , Neville Ross , Prime Heather 
Published: May 2021

ObjectivesThis scoping review aims to facilitate psychometric developments in the field of digital media usage and well-being in young people by (1) identifying core concepts in the area of “screen time” and digital media use in children, adolescents, and young adults, (2) synthesising existing research paradigms and measurement tools that quantify these dimensions, and (3) highlighting important areas of need to guide future measure development.DesignA scoping review of 140 sources (126 database, 14 grey literature) published between 2014 and 2019 yielded 162 measurement tools across a range of domains, users, and cultures. Database sources from Ovid MEDLINE, PsycINFO and Scopus were extracted, in addition to grey literature obtained from knowledge experts and organisations relevant to digital media use in children. To be included, the source had to: (1) be an empirical investigation or present original research, (2) investigate a sample/target population that included children or young persons between the ages of 0 and 25 years of age, and (3) include at least one assessment method for measuring digital media use. Reviews, editorials, letters, comments and animal model studies were all excluded.MeasuresBasic information, level of risk of bias, study setting, paradigm, data type, digital media type, device, usage characteristics, applications or websites, sample characteristics, recruitment methods, measurement tool information, reliability and validity.ResultsSignificant variability in nomenclature surrounding problematic use and criteria for identifying clinical impairment was discovered. Moreover, there was a paucity of measures in key domains, including tools for young children, whole families, disadvantaged groups, and for certain patterns and types of usage.ConclusionThis knowledge synthesis exercise highlights the need for the widespread development and implementation of comprehensive, multi-method, multilevel, and multi-informant measurement suites.
Genomic profiling of advanced cervical cancer to predict response to programmed death-1 inhibitor combination therapy: a secondary analysis of the CLAP trial
Authors: Huang Xin , He Minjun , Peng Hongyu , Tong Chongjie , Liu Zhimin , Zhang Xiaolong , Shao Yang , Zhu Dongqin , Zhang Junli , Yin Jiani C , Yang Fan , Lan Chunyan 
Published: May 2021

BackgroundThe Camrelizumab Plus Apatinib in Patients with Advanced Cervical Cancer trial was a single-arm, phase II study that showed promising activity of the programmed death-1 (PD-1) inhibitor camrelizumab plus the vascular endothelial growth factor receptor-2 inhibitor apatinib in patients with advanced cervical cancer. However, the predictive biomarkers for treatment outcomes are unknown. In this study, we aimed to identify potential predictors of treatment response in PD-1 inhibitor combination therapy.MethodsGenomic profiling was performed on patients with available biopsy or surgical samples by targeted next-generation sequencing of 425 cancer-related genes in this preplanned, secondary analysis. Somatic alterations, including all non-synonymous mutations, and tumor mutational burden (TMB) were assessed for their predictive values in objective response rate, progression-free survival (PFS), and overall survival (OS).ResultsA subset of 32 patients was included in this analysis. Top altered genes includedPIK3CA(43.8%),STK11(25%),FBXW7(15.6%), andPTEN(15.6%). The PI3K/AKT pathway was among the most frequently dysregulated pathways, and its genetic alterations were identified in 68.8% of patients.PIK3CA(PFS HR 0.33, p=0.05; OS HR 0.23, p=0.04) andPTEN(PFS HR 3.71e-09, p=0.05; OS HR 3.64e-09, p=0.08) alterations were associated with improved outcomes. PI3K/AKT pathway genetic alterations showed improved predictive power compared with eitherPIK3CAorPTENalterations alone (PFS HR 0.33, p=0.03; OS HR 0.25, p=0.02), whileERBB3mutations (PFS HR 34.9, p<0.001; OS HR 19.8, p<0.001) correlated with poor survival. TMB-high (≥5 mut/Mb) was associated with prolonged PFS (HR 0.26, p<0.01) and OS (HR 0.31, p=0.05). Multivariate analysis showedERBB3mutations (PFS p=0.01, OS p<0.001), PD-L1 positive (PFS p=0.01, OS p=0.05), and high TMB (PFS p=0.01, OS p=0.05) remained significantly associated with survival.ConclusionsWe uncovered that genetic alterations inPIK3CA,PTEN,ERBB3, and PI3K/AKT pathway, as well as TMB, could be novel predictive biomarkers in patients with cervical cancer treated with PD-1 inhibitor combination therapy.Trial registration numberNCT03816553.
Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors
Authors: Kobayashi Tomoko , Iwama Shintaro , Sugiyama Daisuke , Yasuda Yoshinori , Okuji Takayuki , Ito Masaaki , Ito Sachiko , Sugiyama Mariko , Onoue Takeshi , Takagi Hiroshi , Hagiwara Daisuke , Ito Yoshihiro , Suga Hidetaka , Banno Ryoichi , Nishikawa Hiroyoshi , Arima Hiroshi 
Published: May 2021

BackgroundPituitary dysfunction is a life-threatening immune-related adverse event (irAE) induced by immune checkpoint inhibitors (ICIs). To date, it is not possible to identify patients who may develop pituitary irAEs prior to ICI treatment. The aim of this study was to characterize the predisposition for ICI-induced pituitary irAEs by analyzing anti-pituitary antibodies (APAs) and human leukocyte antigens (HLAs).MethodsIn this case–control study, APAs and HLA alleles were analyzed in 62 patients (17 who developed ICI-induced isolated adrenocorticotropic hormone deficiency (ICI-IAD), 5 who developed ICI-induced hypophysitis (ICI-H) and 40 who did not develop pituitary irAEs) treated with ICIs between November 2, 2015, and March 31, 2020, at Nagoya University Hospital. The main outcome measures in this study were the association between the development of pituitary irAEs with APAs at baseline and after treatment and HLA alleles.ResultsEleven of 17 (64.7%) patients who developed ICI-IAD had APAs at baseline, whereas APAs were positive only in 1 of 40 (2.5%) control patients. Although APAs were negative at baseline in all patients who developed ICI-H, they had become positive before the onset of ICI-H in 3 of 4 patients several weeks after ipilimumab administration. At the onset of ICI-IAD and ICI-H, APAs were positive in 15 of 17 (88.2%) and 4 of 5 (80%) patients, respectively. The prevalence of HLA-Cw12, HLA-DR15, HLA-DQ7, and HLA-DPw9 was significantly higher in patients with ICI-IAD, whereas that of HLA-Cw12 and HLA-DR15 was significantly higher in patients with ICI-H than in controls.ConclusionsThis study showed distinct and overlapped patterns of APAs and HLA alleles between ICI-IAD and ICI-H. Our findings also showed that positive APAs at baseline and after treatment, together with susceptible HLA alleles, could become predictive biomarkers for ICI-IAD and ICI-H, respectively.Trial registration numberUMIN000019024.
Empiric antifungals do not decrease the risk for organ space infection in patients with perforated peptic ulcer
Authors: Barmparas Galinos , Alhaj Saleh Adel , Huang Raymond , Eaton Barbara C , Bruns Brandon R , Raines Alexander , Bryant Cressilee , Crane Christopher E , Scherer Elizabeth P , Schroeppel Thomas J , Moskowitz Eliza , Regner Justin L , Frazee Richard , Campion Eric M , Bartley Matthew , Mortus Jared R , Ward Jeremy , Margulies Daniel R , Dissanaike Sharmila 
Published: May 2021

IntroductionInfection control in patients with perforated peptic ulcers (PPU) commonly includes empiric antifungals (AF). We investigated the variation in the use of empiric AF and explored the association between their use and the subsequent development of organ space infection (OSI).MethodsThis was a secondary analysis of a multicenter, case–control study of patients treated for PPU at nine institutions between 2011 and 2018. Microbiology and utilization of empiric AF, defined as AF administered within 24 hours from the index surgery, were recorded. Patients who received empiric AF were compared with those who did not. The primary outcome was OSI and secondary outcome was OSI with growth ofCandidaspp. A logistic regression was used to adjust for differences between the two cohorts.ResultsA total of 554 patients underwent a surgical procedure for PPU and had available timing of AF administration. The median age was 57 years and 61% were male. Laparoscopy was used in 24% and omental patch was the most common procedure performed (78%). Overall, 239 (43%) received empiric AF. There was a large variation in the use of empiric AF among participating centers, ranging from 25% to 68%. The overall incidence of OSI was 14% (77/554) and was similar for patients who did or did not receive empiric AF. The adjusted OR for development of OSI for patients who received empiric AF was 1.04 (95% CI 0.64 to 1.70), adjusted p=0.86. The overall incidence of OSI with growth ofCandidaspp was 5% and was similar for both groups (adjusted OR 1.29, 95% CI 0.59 to 2.84, adjusted p=0.53).ConclusionFor patients undergoing surgery for PPU, the use of empiric AF did not yield any significant clinical advantage in preventing OSI, even those due toCandidaspp. Use of empiric AF in this setting is unnecessary.Study typeOriginal article, case series.Level of evidenceIII.
Maximum Likelihood Estimation of Power-law Degree Distributions via Friendship Paradox-based Sampling
Authors: Nettasinghe Buddhika , Krishnamurthy Vikram 
Published: May 2021

This article considers the problem of estimating a power-law degree distribution of an undirected network using sampled data. Although power-law degree distributions are ubiquitous in nature, the widely used parametric methods for estimating them (e.g., linear regression on double-logarithmic axes and maximum likelihood estimation with uniformly sampled nodes) suffer from the large variance introduced by the lack of data-points from the tail portion of the power-law degree distribution. As a solution, we present a novel maximum likelihood estimation approach that exploits the
friendship paradox
to sample more efficiently from the tail of the degree distribution. We analytically show that the proposed method results in a smaller bias, variance and a Cramèr–Rao lower bound compared to the vanilla maximum likelihood estimate obtained with uniformly sampled nodes (which is the most commonly used method in literature). Detailed numerical and empirical results are presented to illustrate the performance of the proposed method under different conditions and how it compares with alternative methods. We also show that the proposed method and its desirable properties (i.e., smaller bias, variance, and Cramèr–Rao lower bound compared to vanilla method based on uniform samples) extend to parametric degree distributions other than the power-law such as exponential degree distributions as well. All the numerical and empirical results are reproducible and the code is publicly available on Github.
Combination Model of Thyrotrophin Receptor Antibody and Volumetric Orbital Apex Crowding Index as an Indicator of Dysthyroid Optic Neuropathy
Authors: Deng Zhihong , Chen Lu , Tan Jia , Wang Sha , Liu Dan , Wang Jinwei , Jiang Chengzhi , Yang Jie , Xu Bei 
Published: May 2021

Background. Dysthyroid optic neuropathy (DON) is one of the most serious vision-threatening complications of thyroid eye disease (TED); however, accurate and established diagnostic tools for DON are yet lacking. The present study was aimed at identifying new diagnostic factors for the accurate diagnosis of DON. Methods. This retrospective cross-sectional study included 25 TED patients (50 eyes) with enlarged extraocular muscles, no previous anti-inflammatory therapy, and the absence of other vision-affecting diseases between May 2017 and August 2019. Baseline data, such as gender, age, ophthalmological history, thyroid disease and management, TED history including clinical features, management, and long-term results, ophthalmological examinations, serology examinations, and single-photon emission computed tomography/computed tomography (SPECT/CT) results, were extracted. The diagnostic criteria were as follows: (1) best-corrected visual acuity (BCVA) loss coexisting with either of the following—increased latency or reduction of amplitude on visual evoked potential (VEP), impaired color vision, visual field defects, contrast sensitivity impairment, and optic disk swelling—and (2)

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in CT. Univariate and multivariate logistic regression analyses assessed the differences in age, gender, eyes, medical history, clinical activity, thyroid hormone and antibodies, uptake ratio (UR) of extraocular muscles in SPECT/CT, and volumetric orbital apex crowding index (VACI) using the generalized estimation equation. Consequently, the receiver operating characteristic curve (ROC) of the significant factors was constructed. Results. Univariate analysis revealed significant differences in the clinical activity, free triiodothyronine (FT3), free thyroxine (FT4), thyrotrophin receptor antibody (TRAb) levels, the UR of superior and medial rectus, and VACI between DON and TED (without DON) groups. Multivariate regression analysis revealed that TRAb and VACI were significantly different. ROC analysis showed that the univariate models of TRAb or VACI and the multivariate model were effective indicators of DON, while the multivariate model had the highest area under the ROC curve. Conclusion. A combination of TRAb and VACI is an effective indicator for DON.
Flightless I Homolog Reverses Enzalutamide Resistance through PD-L1–Mediated Immune Evasion in Prostate Cancer
Authors: Ruan Hailong , Bao Lin , Tao Zhen , Chen Ke 
Published: May 2021

AbstractTumor cells can evade immune surveillance and immune killing during the emergence of endocrine therapy resistance in prostate cancer, but the mechanisms underlying this phenomenon are still unclear. Flightless I homolog (FLII) is a coregulator for transcription factors in several malignancies. Here, we have demonstrated that endocrine therapy resistance can induce an immunosuppressive prostate tumor microenvironment and immune evasion through FLII downregulation, which leads to activation of the YBX1/PD-L1 signaling pathway. FLII expression negatively correlated with expression of PD-L1 in tumors. Mechanism studies demonstrated that FLII physically interacted with YBX1 to inhibit nuclear localization of YBX1 and thereby suppress transcription of PDL1 in enzalutamide-resistant tumors. Restoration of FLII expression reversed enzalutamide resistance through activation of T-cell responses in the tumor microenvironment through inhibition of the YBX1/PD-L1 pathway. We also found that reversal of endocrine therapy resistance and immune evasion was mediated by proliferation of effector CD8+ T cells and inhibition of tumor infiltration by regulatory T cells and myeloid-derived suppressor cells. Taken together, our results demonstrate a functional and biological interaction between endocrine therapy resistance and immune evasion mediated through the FLII/YBX1/PD-L1 cascade. Combination therapy with FLII expression and endocrine therapy may benefit patients with prostate cancer by preventing tumor immune evasion.
Patterns of orthopaedic injury among hospitalised personal mobility device users and bicycle riders: a comparative study
Authors: Koh Don Thong Siang , Woo Yew Lok , Wong Ting Hway , Tan Mann Hong 
Published: May 2021

Abstract

Introduction:
Personal mobility devices (PMDs), such as electronic scooters or motorised bicycles, are efficient modes of transportation. Their recent popularity has also resulted in an increase in PMD-related injuries. We aimed to characterise and compare the nature of injuries sustained by PMD users and bicycle riders.

Methods:
This retrospective study compared injury patterns among PMD and bicycle users. 140 patients were admitted between November 2013 and September 2018. Parameters studied included patients’ demographics (e.g. age, gender and body mass index), type of PMD, nature of injury, surgical intervention required, duration of hospitalisation and time off work.

Results:
Of 140 patients, 46 (32.9%) patients required treatment at the department of orthopaedic surgery. 19 patients were PMD users while 27 were bicycle riders. 16 (84.2%) patients with PMD-related injuries were men. PMD users were significantly younger (mean age 45 ± 15 years) when compared to bicycle riders (mean age 56 ± 17 years; P <0.05). A quarter (n = 5, 26.3%) of PMD users sustained open fractures and over half (n = 10, 52.6%) required surgical intervention. Among 27 bicycle users, 7.4% (n = 2) of patients sustained open fractures and 70.4% (n = 19) required surgical intervention. Both groups had comparable inpatient stay duration and time off work.

Conclusion:
PMD-related orthopaedic traumas are high-energy injuries, with higher rates of open fractures, when compared to bicycle injuries. In addition, PMD users are significantly younger and of economically viable age. Prolonged hospitalisation and time off work have socioeconomic implications. Caution should be exercised when using PMDs.
Thermal strain and fluid balance during a 72-km military route march in a field setting
Authors: Poon Beng Hoong , Prakaash Suriya , Teo Ya Shi , Fan Priscilla Weiping , Lee Jason Kai Wei 
Published: May 2021

Introduction:
A physiological profiling study was conducted to evaluate thermal strain as well as fluid and electrolyte balances on heat-acclimatised men performing a 72-km route march in a field setting.

Methods:
38 male soldiers (age range 18–23 years) participated in the study, as part of a cohort that marched for 72 km, with loads for about 26 hours. Core temperature and heart rate sensors were used for the duration of the march. Fluid and food intake and output were monitored for the duration of the march. Blood samples were taken one day before the march (pre-march), immediately after the march (Post 1) and on the 15th day after the march to ascertain recovery (Post 2) to assess fluid and electrolyte profiles.

Results:
Mean core temperature was within safe limits, ranging from 37.1 to 38.1°C throughout the march. There was an overall decrease in serum sodium levels, a decline in serum sodium concentration in 28 participants and three instances of hyponatraemia (serum sodium concentration <135 mmol/L).

Conclusion:
Our study found low thermal strain heat-acclimatised individuals during a 72-km route march. However, there was an overall decrease in serum sodium levels, even when the participants were allowed to drink ad libitum. Challenges of exercise-associated hyponatraemia during prolonged activities remain to be addressed.
Towards a More Precise Understanding of Pseudo-Jonathan’s Origins
Authors: Gottlieb Leeor 
Published: May 2021

Abstract
Many have assumed that Targum Pseudo-Jonathan (TgPsJ) is the product of first millennium Palestine. This study presents evidence suggesting that TgPsJ is neither from the first millennium, nor from Palestine. TgPsJ displays an unawareness of some basic facts with regard to the geography of the land of Israel, which makes the argument for its author being a native of Palestine unpersuasive. Excerpts from Even Bochan, a twelfth-century Hebrew lexicon written by Menachem ben Shelomo, the author of Sekhel Tov, exhibit textual similarities to statements found elsewhere only in TgPsJ. The nature of these statements lead to the conclusion that Even Bochan precedes TgPsJ and not vice versa. This suggests that the origins of TgPsJ are to be found in twelfth-century Italy.
Legal Exclusions: Émigré Lawyers, Admissions to Legal Practice and the Cultural Transformation of the Australian Legal Profession
Authors: Dehm Sara 
Published: May 2021

AbstractLegal histories of Australia have largely overlooked the exclusion of European émigré lawyers from legal practice in Australia. This article recovers part of this forgotten history by tracing the drawn-out legal admission bids of two Jewish émigré lawyers in the mid-20th century: German-born Rudolf Kahn and Austrian-born Edward Korten. In examining their legal lives and doctrinal legacies, this article demonstrates the changing role and requirement of British subjecthood in the historical constitution and slow cultural transformation of the Australian legal profession. This article suggests that contemporary efforts to promoting cultural diversity in the Australian legal profession are enriched by paying attention to this long and difficult history of legal exclusions.