bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of covariate adjustment approaches under model misspecification in individually randomized trials
Authors: Tackney Mia S. , Morris Tim , White Ian , Leyrat Clemence , Diaz-Ordaz Karla , Williamson Elizabeth 
Published: January 2023

AbstractAdjustment for baseline covariates in randomized trials has been shown to lead to gains in power and can protect against chance imbalances in covariates. For continuous covariates, there is a risk that the the form of the relationship between the covariate and outcome is misspecified when taking an adjusted approach. Using a simulation study focusing on individually randomized trials with small sample sizes, we explore whether a range of adjustment methods are robust to misspecification, either in the covariate–outcome relationship or through an omitted covariate–treatment interaction. Specifically, we aim to identify potential settings where G-computation, inverse probability of treatment weighting (IPTW), augmented inverse probability of treatment weighting (AIPTW) and targeted maximum likelihood estimation (TMLE) offer improvement over the commonly used analysis of covariance (ANCOVA). Our simulations show that all adjustment methods are generally robust to model misspecification if adjusting for a few covariates, sample size is 100 or larger, and there are no covariate–treatment interactions. When there is a non-linear interaction of treatment with a skewed covariate and sample size is small, all adjustment methods can suffer from bias; however, methods that allow for interactions (such as G-computation with interaction and IPTW) show improved results compared to ANCOVA. When there are a high number of covariates to adjust for, ANCOVA retains good properties while other methods suffer from under- or over-coverage. An outstanding issue for G-computation, IPTW and AIPTW in small samples is that standard errors are underestimated; they should be used with caution without the availability of small-sample corrections, development of which is needed. These findings are relevant for covariate adjustment in interim analyses of larger trials.
Pragmatic cluster randomized trial to evaluate effectiveness and implementation of EHR-facilitated collaborative symptom control in cancer (E2C2): addendum
Authors: Herrin Jeph , Finney Rutten Lila J. , Ruddy Kathryn J. , Kroenke Kurt , Cheville Andrea L. 
Published: January 2023

AbstractWe previously described the hypotheses, outcomes, design, and analysis for E2C2, a pragmatic stepped-wedge trial to assess an intervention to improve symptom control in patients with cancer. Subsequent consideration of the design and cohort led to the addition of a second primary hypothesis. This article describes and presents the rationale for this second hypothesis. This addendum also details a revised analytic approach, necessitated by inconsistencies in the original analytic plan. The design, outcomes, and other aspects of the protocol remain unchanged.
Phenotypic variability in traits related to flight dispersal in the wing dimorphic species Triatoma guasayana
Authors: Gigena Gisel V. , Rodríguez Claudia S. , Fiad Federico G. , Hernández María Laura , Carbajal-de-la-Fuente Ana Laura , Piccinali Romina V. , Sánchez Casaccia Paz , Rojas de Arias Antonieta , Lobbia Patricia , Abrahan Luciana , Bustamante Gomez Marinely , Espinoza Jorge , Cano Florencia , Nattero Julieta 
Published: January 2023

Abstract
Background
Triatoma guasayana is considered an emerging vector of Chagas disease in the Southern Cone of South America. The presence of a triatomine population with brachypterous individuals, in which both wings are reduced, has recently been reported for this species. The aim of the present study was to determine if flight-related traits varied across populations, if these traits could explain differences in flight capacity across populations and if flight-related traits are associated with geographic and/or climatic variation.

Methods
The study involved 66 male T. guasayana specimens from 10 triatomine populations. Digital images of wing, head and pronotum were used to estimate linear and geometric morphometric variables. Variations in size and shape were analysed using one-way analysis of variance and canonical variate analysis (CVA), respectively. Mantel tests were applied to analyse the relationship between morphometric and geographic distances, and the association between size measurements was analysed using Pearson’s correlation. We explored covariation between size and shape variables using partial least square analyses (PLS). The association of geographic and climatic variables with size measurements was tested using linear regression analyses. We performed PLS analyses for shape measurements.

Results
Wing size differed significantly across triatomine populations. The CVA showed that wing shape of the brachypterous population is well discriminated from that of the other populations. The Mantel test showed a positive and significant association between wing shape and geographic distances. The heads of the brachypterous population were significantly larger than those of the other populations. Similar to wing shape, the head shape of the brachypterous population was well discriminated from those of the other populations. Pronotum width did not show significant differences across populations. Geographic and climatic factors were associated with size and shape of both the wing and head, but not with pronotum width.

Conclusions
Most of the traits related to flight dispersal varied across populations. Wing shape and head shape were found to be better markers for differentiated morphological variation across populations. Head measurements also varied in accordance with this condition. Geographic and climatic variables were associated with most of the flight-related traits.

Graphical Abstract
Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort
Authors: Saleh Rasha N. M. , Hornberger Michael , Ritchie Craig W. , Minihane Anne Marie 
Published: January 2023

Abstract
Background
The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.

Methods
The analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.

Results
APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers.

Conclusion
HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.
Transient central hypoxemia due to intermittent high-degree atrioventricular block in a heart-transplanted patient diagnosed during routine electroencephalography: a case report
Authors: Raboud Matthieu , Humm Andrea M. , Vivekanantham Hari , Suter Philipp 
Published: January 2023

Abstract
Background
Bradycardia frequently occurs in heart-transplanted patients, mainly as a temporally restricted manifestation early after transplantation and often without symptoms. A high-degree atrioventricular block is mostly symptomatic through cerebral hypoxia induced through cerebral hypoperfusion. Only a few published cases show this specific electroencephalography result in this context. The purpose of this case is to bring attention to atypical manifestations of typical cardiac complications after heart transplantation and the importance of perseverance in the diagnostic.

Case presentation
A Central European man in his 50s with history of heart transplantation 31 years previously was admitted to the internal medicine ward for short-lived recurrent episodes of generalized weakness with multiple falls but without loss of consciousness. During routine electroencephalography, the patient perceived this recurrent sensation. This episode coincided with a transient third-degree atrioventricular block followed 8–10 seconds later by a generalized slowing of the electroencephalography, reflecting cerebral hypoxia due to cerebral hypoperfusion. Holter monitoring confirmed the diagnosis. A pacemaker was implanted, consequently resolving the episodes.

Conclusion
This case report illustrates the pathophysiological central hypoxemic origin of episodes of generalized weakness caused by a high-degree atrioventricular block in a patient surviving 29 years after heart transplant. It highlights the benefit of electroencephalography as a diagnostic tool in well-selected patients.
The role of etoposide in the treatment of adult patients with hemophagocytic lymphohistiocytosis
Authors: Zondag Timo C. E. , Lika Aglina , van Laar Jan A. M. 
Published: January 2023

AbstractHemophagocytic lymphohistiocytosis (HLH) is a potentially fatal inflammatory clinical condition, in which an exaggerated immune response is ineffectively regulated. Although etoposide-containing regimens are generally recommended for children with HLH, the exact role of etoposide in the adult setting remains unclear. We performed a systematic review of the literature on the use of etoposide in adults with HLH. All articles written in English on the use of etoposide in adults with HLH available from seven databases and published on or before July 2021 were analyzed. Thirteen studies were found to be relevant to the search results. Ten of these studies report a statistical analysis on the effect of etoposide, of which five found etoposide-containing regimens superior to non-etoposide-containing regimens. Seven studies provided sufficient data to be included in the meta-analysis. For these data, the estimated logit relative risk of etoposide on survival was 1.06 (95% confidence interval: 0.92–1.21, standard error: 2.06). The pooled data of the meta-analysis did thus not support a beneficial effect of etoposide. It should be taken into account that the presented results are highly susceptible to bias and that the effect of etoposide differs between HLH-triggers. Although the meta-analysis does not support the effect of etoposide, we do not recommend abandoning etoposide as treatment modality. The limitations of the meta-analysis, together with several individual articles confirming the benefit of etoposide, justify etoposide for select cases in adults with HLH such as refractory or severe disease with (threatening) multiorgan failure.
A review of Janus kinase inhibitors for the treatment of Covid-19 pneumonia
Authors: Tanaka Yoshiya 
Published: January 2023

Abstract
Background
In inflamed tissue, immune cells are accumulated, and various intercellular signals are involved in the pathogenesis. Janus kinases (JAKs) are typical tyrosine kinases involved in mediating the signaling of multiple cytokines and growth factors and induce the transcription of molecules related to inflammation or immunity via the transcription factor signal transducers and activators of transcription (STAT). Hence, they have garnered significant interest as a therapeutic target. JAK inhibitors have been evaluated as a major drug for remission induction in the treatment of autoimmune diseases such as rheumatoid arthritis.

Body
Covid-19 infection due to SARS-CoV-2 has caused a pandemic, with approximately 660 million infections and 6.7 million deaths worldwide (January, 2023). The prognosis is poor and the major causes of death are respiratory failure attributed to rapid pneumonia, thromboembolism due to a cytokine storm, and multi-organ failure. As a treatment modality, molecular targeted therapy, such as cytokine-targeting therapy, is attracting attention, in addition to antiviral drugs. Baricitinib, a JAK inhibitor, is used for the treatment of severe pneumonia, in addition to antiviral drugs and glucocorticoids. The mechanism of action of baricitinib includes inhibition of viral receptor-mediated endocytosis, which involves the NF-κB activating kinase (NAK) family, and mediating the anti-cytokine effects via JAK 1/2 inhibition. It improves severe pneumonia and reduces mortality.

Conclusion
Thus, the development of molecular targeted drugs with elucidated pathological mechanisms may aid in controlling Covid-19 infection.
Causal impact of fire on a globally rare wetland plant: a 40-year Bayesian time series analysis
Authors: Landau Deborah , Cahalan Gabriel Devin , Natesan Batley Prathiba 
Published: January 2023

Abstract
Background
Canby’s dropwort (Oxypolis canbyi (J.M. Coult. & Rose) Fernald) was listed as federally endangered in 1986, yet the species has continued to decline and is no longer found in 11 counties throughout its former range. The seasonal wetlands in which this forb occurs are disappearing from the landscape, often closing in and transitioning to wet forest or are drained and converted to agriculture. We document the effects of reintroducing fire to the only population of O. canbyi in Maryland and examine the resulting population increase using Bayesian interrupted time series analysis with a counterfactual.

Results
After cutting woody vegetation, 3.74 times more stems of dropwort per year were produced over the baseline of no intervention. Subsequently, after fire was reintroduced, 10.80 times more dropwort stems per year were produced in comparison to the time period after cutting woody vegetation. The counterfactual prediction showed that in the absence of intervention with fire, dropwort stem production would likely have declined.

Conclusions
Cutting woody vegetation set the stage for the growth of fine fuels by increasing sun exposure on wetland grasses. It was only after fire was reintroduced that the population of plants expanded significantly in extent and flower production. A process for model selection with a directed acyclic graph followed by Bayesian interrupted time series analysis and a counterfactual was useful for causal inference. Application of fire is an important step in the recovery of the federally endangered dropwort.
Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants inATM,BRCA1,BRCA2,CHEK2, andPALB2
Authors: Yadav Siddhartha , Boddicker Nicholas J. , Na Jie , Polley Eric C. , Hu Chunling , Hart Steven N. , Gnanaolivu Rohan D. , Larson Nicole , Holtegaard Susan , Huang Huaizhi , Dunn Carolyn A. , Teras Lauren R. , Patel Alpa V. , Lacey James V. , Neuhausen Susan L. , Martinez Elena , Haiman Christopher , Chen Fei , Ruddy Kathryn J. , Olson Janet E. , John Esther M. , Kurian Allison W. , Sandler Dale P. , O'Brien Katie M. , Taylor Jack A. , Weinberg Clarice R. , Anton-Culver Hoda , Ziogas Argyrios , Zirpoli Gary , Goldgar David E. , Palmer Julie R. , Domchek Susan M. , Weitzel Jeffrey N. , Nathanson Katherine L. , Kraft Peter , Couch Fergus J. 
Published: January 2023

PURPOSETo estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2.METHODSThe study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status.RESULTSGermline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2.CONCLUSIONWomen diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.
High-Dose Once-Daily Thoracic Radiotherapy in Limited-Stage Small-Cell Lung Cancer: CALGB 30610 (Alliance)/RTOG 0538
Authors: Bogart Jeffrey , Wang Xiaofei , Masters Gregory , Gao Junheng , Komaki Ritsuko , Gaspar Laurie E. , Heymach John , Bonner James , Kuzma Charles , Waqar Saiama , Petty William , Stinchcombe Thomas E. , Bradley Jeffrey D. , Vokes Everett 
Published: January 2023

PURPOSE Although level 1 evidence supports 45-Gy twice-daily radiotherapy as standard for limited-stage small-cell lung cancer, most patients receive higher-dose once-daily regimens in clinical practice. Whether increasing radiotherapy dose improves outcomes remains to be prospectively demonstrated. METHODS This phase III trial, CALGB 30610/RTOG 0538 (ClinicalTrials.gov identifier: NCT00632853 ), was conducted in two stages. In the first stage, patients with limited-stage disease were randomly assigned to receive 45-Gy twice-daily, 70-Gy once-daily, or 61.2-Gy concomitant-boost radiotherapy, starting with either the first or second (of four total) chemotherapy cycles. In the second stage, allocation to the 61.2-Gy arm was discontinued following planned interim toxicity analysis, and the study continued with two remaining arms. The primary end point was overall survival (OS) in the intention-to-treat population. RESULTS Trial accrual opened on March 15, 2008, and closed on December 1, 2019. All patients randomly assigned to 45-Gy twice-daily (n = 313) or 70-Gy once-daily radiotherapy (n = 325) are included in this analysis. After a median follow-up of 4.7 years, OS was not improved on the once-daily arm (hazard ratio for death, 0.94; 95% CI, 0.76 to 1.17; P = .594). Median survival is 28.5 months for twice-daily treatment, and 30.1 months for once-daily treatment, with 5-year OS of 29% and 32%, respectively. Treatment was tolerable, and the frequency of severe adverse events, including esophageal and pulmonary toxicity, was similar on both arms. CONCLUSION Although 45-Gy twice-daily radiotherapy remains the standard of care, this study provides the most robust information available to help guide the choice of thoracic radiotherapy regimen for patients with limited-stage small-cell lung cancer.
Medical Oncologists' Knowledge and Perspectives on the Use of Biosimilars in the United States
Authors: Peipert John Devin , Kaiser Karen , Kircher Sheetal , Greene George J. , Shaunfield Sara , Hauner Katherina , Cella David , Mroczek Daniel K. 
Published: January 2023

PURPOSE: Despite increasing availability of biosimilar cancer treatments, little is known about oncologists' knowledge and concerns regarding biosimilar use in the United States. We surveyed medical oncologists to examine their knowledge, attitudes, and experience with biosimilars. METHODS: Oncologists recruited via the ASCO Research Survey Pool completed a 29-question survey in 2020 designed with input from clinical and health care system experts and literature review. RESULTS: Of the 269 respondents, most treated patients with biosimilars (n = 236, 88%) and reported that biosimilars were required at their institution (n = 168, 63%). Approximately half (n = 140, 52%) of oncologists correctly responded that biosimilars were not the same as generic medicines. Commonly reported barriers to use of biosimilars included concerns regarding a perceived lack of relevant research (n = 85, 33% reporting quite a bit/very much), the potential for extrapolation (n = 83, 33%), and efficacy limitations (n = 77, 30%). More oncologists from university hospitals (n = 36, 22%) than from community/private hospitals (n = 28, 38%) or private practices (n = 13, 38%) were concerned about biosimilar efficacy. A high proportion of oncologists reported that information on safety (n = 259, 99%) and efficacy (n = 255, 99%) is important when considering whether to use biosimilars. Less than half reported that their institution provided education about biosimilars (n = 108, 40%). CONCLUSION: In this sample of medical oncologists, knowledge about basic features of biosimilars was limited and access to information about biosimilars was insufficient. The present study determined that educational programs on biosimilars for oncologists are needed and identified priorities for such efforts.
Trends in Educational Assortative Marriage in China Over the Past Century
Authors: Dong Hao , Xie Yu 
Published: January 2023

Abstract
In the past century, China has undergone rapid and dramatic social and economic changes. This article describes trends in educational assortative marriages of cohorts born in 1906–1995 in China. We measure educational attainment relatively as an individual's percentile position in the education distribution of a 10-year birth cohort and study trends using comparable, easy-to-interpret couple rank-rank correlations. We analyze microdata samples from the 1982, 1990, 2000, and 2010 China censuses and the 2015 1% intercensus survey and nationally representative surveys between 1996 and 2018. We find a large and steady increase in educational assortative marriage over the past century, except among those born in 1946–1965, whose schooling and marriage were impacted by the Cultural Revolution. Our study highlights the critical roles of social, political, and economic contexts in shaping trends in educational assortative marriage.