bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surrogate endpoint evaluation using data from one large global randomized controlled trial
Authors: Geybels Milan , Wolthers Benjamin Ole , Kreiner Frederik Flindt , Rasmussen Søren , Bauer Robert 
Published: May 2021

Abstract
Background
Robust identification of surrogate endpoints can help accelerate the development of pharmacotherapies for diseases traditionally evaluated using true endpoints associated with prolonged follow-up. The meta-analysis-based surrogate endpoint evaluation (SEE) integrates data from multiple, usually smaller, trials to statistically confirm a surrogate endpoint as a robust proxy for the true endpoint. To test the applicability of SEE when only a single, larger trial is available, we analysed the cardiovascular (CV) survival endpoint from the large multinational trial LEADER (9340 subjects) that confirmed the CV safety of a diabetes drug (liraglutide). We evaluated if using country as a trial unit adequately facilitated the meta-analysis and calculation of R2 by country group.

Methods
Data were grouped by country, ensuring at least 30 CV deaths (497 in total) in each of the nine resulting by-country groups. In a two-step SEE on the grouped dataset, we first fitted the group-specific Cox proportional hazard models; next, on the trial-level, we regressed the estimated hazard ratio (HR; liraglutide vs placebo) of the true endpoints (CV death: 497 events, or all-cause death: 828 events) on the HR of the surrogate endpoint (major CV adverse event [MACE]: 1302 events) and derived the group-specific R2 and its 95% confidence interval (CI).

Results
Group-level surrogacy of MACE was supported for CV death but not for all-cause death, with $${\text{R}}_{{{\text{group}}}}^{2}$$

R

group

2

values of 0.85 [0.63;1.00]95% CI and 0.23 [0.00;0.67]95% CI, respectively. Sensitivity analyses using different grouping approaches (e.g. grouping by region) corroborated the robustness of the conclusions as well as the appropriateness of the data-grouping approaches.

Conclusions
We derived a specific grouping approach to successfully apply SEE on data from a single trial. This may allow for the statistically robust identification and validation of surrogate endpoints based on the abundance of large monolithic outcome trials conducted as part of drug development programmes in, for example, diabetes.
Development and user-testing of a brief decision aid for aspirin as a preventive approach alongside colorectal cancer screening
Authors: Semedo Lenira , Lifford Kate J. , Edwards Adrian , Seddon Kathy , Brain Kate , Smits Stephanie , Dolwani Sunil 
Published: May 2021

Abstract
Background
Several epidemiological and cohort studies suggest that regular low-dose aspirin use independently reduces the long-term incidence and risk of colorectal cancer deaths by approximately 20%. However, there are also risks to aspirin use, mainly gastrointestinal bleeding and haemorrhagic stroke. Making informed decisions depends on the ability to understand and weigh up benefits and risks of available options. A decision aid to support people to consider aspirin therapy alongside participation in the NHS bowel cancer screening programme may have an additional impact on colorectal cancer prevention. This study aims to develop and user-test a brief decision aid about aspirin to enable informed decision-making for colorectal screening-eligible members of the public.

Methods
We undertook a qualitative study to develop an aspirin decision aid leaflet to support bowel screening responders in deciding whether to take aspirin to reduce their risk of colorectal cancer. The iterative development process involved two focus groups with public members aged 60–74 years (n = 14) and interviews with clinicians (n = 10). Interviews (n = 11) were used to evaluate its utility for decision-making. Analysis was conducted using a framework approach.

Results
Overall, participants found the decision aid acceptable and useful to facilitate decision-making. They expressed a need for individualised risk information, more detail about the potential risks of aspirin, and preferred risk information presented in pictograms when offered different options. Implementation pathways were discussed, including the possibility of involving different clinicians in the process such as GPs and/or community pharmacists. A range of potentially effective timepoints for sending out the decision aid were identified.

Conclusion
An acceptable and usable decision aid was developed to support decisions about aspirin use to prevent colorectal cancer.
A qualitative approach to identify barriers to multi-professional teamwork among medical professors at Iranian teaching hospitals
Authors: Hazrati Hakimeh , Arabshahi Seyed Kamran Soltani , Bigdeli Shoaleh , Behshid Mozhgan , Sohrabi Zohreh 
Published: May 2021

AbstractBackgroundIn some cases of diseases, such as infectious, neurological and chronic ones prevention and treatment is complex. Therefore, a single medical specialty alone cannot effectively manage treatment of patients due to health care needs of them and complexities of treatment. Instead, a team composed of different healthcare disciplines with effective, continuous, and organized communication must follow up various aspects of patient care. In this regard, the present qualitative study aimed to shed light on the experiences of clinical teachers of multi-professional teamwork barriers within Iranian teaching hospitals.MethodsIn this qualitative research, the experiences of medical clinical teachers of multi-professional teamwork barriers within teaching hospitals were explained. Sampling was theoretical and the data were collected from experienced clinical teachers and medical students studying at several Universities of Medical Sciences through semi-structured interviews and observation, which were continued until data saturation. Fifteen clinical teachers and five medical students participated in the study. The interviews were analyzed using conventional content analysis.ResultsThree main categories were extracted. The first category was “enhancing the culture of interdisciplinary education” included “paving the way for an interdisciplinary culture”, “enhancing teamwork culture”, and “having a general view of medical sciences instead of specialization”. The second category was “barriers of interdisciplinary education” included “influence of the dominant culture of specialization in society”, “poor interdisciplinary education infrastructure”, and “individualism as a value of society”. And the third category was “consequences of specialization” included “medical sciences education under the shadow of specialization”, “possibility to harming patients”, and “distrust of society in the services provided by the 1st and 2nd level centers”.ConclusionIt seems that attitudinal barriers, teamwork difficulties, and the culture of individualism are evident in Iran; more, roles of the healthcare team and the status of each member is not clear. Designing interactive curriculum and arranging clinical settings to facilitate exchange of ideas among clinical teachers and students of different disciplines, is a step forward to achieving a common value concept, language, and common perception, and establishing cooperation and understanding among disciplines involved, which leads to further understanding of the professional responsibilities of other disciplines.
The work of having a chronic condition: development and psychometric evaluation of the distribution of co-care activities (DoCCA) scale
Authors: von Thiele Schwarz Ulrica , Roczniewska Marta , Pukk Härenstam Karin , Karlgren Klas , Hasson Henna , Menczel Sivan , Wannheden Carolina 
Published: May 2021

AbstractBackgroundChronic care involves multiple activities that can be performed by individuals and healthcare staff as well as by other actors and artifacts, such as eHealth services. Thus, chronic care management can be viewed as a system where the individual interacts with people and eHealth services performing activities to maintain or improve health and functioning, calledco-care. Yet, the system perspective is not reflected in concepts such as person-centered care and shared decision making. This limits the understanding of individuals’ global experience of chronic care management and subsequently the ability to optimize chronic care. The aim of this study was threefold: (1) to propose a theory-based operationalization of co-care for chronic care management, (2) to develop a scale to measure co-care as a distributed system of activities, and (3) to evaluate the scale’s psychometric properties. With the theory of distributed cognition as a theoretical underpinning, co-care was operationalized along three dimensions: experience ofactivities,needs support, andgoal orientation.MethodsInformed by the literature on patient experiences and work psychology, a scale denoted Distribution of Co-Care Activities (DoCCA) was developed with the three conceptualized dimensions, the activities dimension consisting of three sub-factors:demands,unnecessary tasks, androle clarity. It was tested with 113 primary care patients with chronic conditions in Sweden at two time points.ResultsA confirmatory factor analysis showed support for a second-order model with the three conceptualized dimensions, with activities further divided into the three sub-factors. Cronbach’s alpha values indicated a good to excellent reliability of the subscales, and correlations across time points with panel data indicated satisfactory test-retest reliability. Convergent, concurrent and predictive validity of the scale were, overall, satisfactory.ConclusionsThe psychometric evaluation supports a model consisting of activities (demands, unnecessary tasks, and role clarity), needs support and goal orientation that can be reliably measured with the DoCCA scale. The scale provides a way to assess chronic care management as a system, considering the perspective of the individuals with the chronic condition and how they perceive the work that must be done, across situations, either by themselves or through healthcare, eHealth, or other means.
Acute exacerbation of fibrotic hypersensitivity pneumonitis: incidence and outcomes
Authors: Kang Jieun , Kim Yeon Joo , Choe Jooae , Chae Eun Jin , Song Jin Woo 
Published: May 2021

Abstract
Background
Patients with fibrotic hypersensitivity pneumonitis (HP) show variable clinical courses, and some experience rapid deterioration (RD), including acute exacerbation (AE). However, little is known about AE in fibrotic HP. Here, we retrospectively examined the incidence, risk factors, and outcomes of AE in fibrotic HP.

Methods
The incidence rates of AE were calculated in 101 patients with biopsy-proven HP. AE was defined as the worsening of dyspnoea within 30 days, with new bilateral lung infiltration and no evidence of infection or other causes of dyspnoea.

Results
During follow-up (median: 30 months), 18 (17.8%) patients experienced AE. The 1, 3, and 5 year incidence rates of AE were 6.0, 13.6, and 22.8%, respectively. Lower diffusing capacity of the lung for carbon monoxide (DLCO) and a radiologic usual interstitial pneumonia (UIP)-like pattern were risk factors for AE. In-hospital mortality after AE was 44.4%. Median survival from diagnosis was significantly shorter in patients with AE (26.0 months) than in those with no-AE RD (55.0 months; p = 0.008) or no RD (not reached; p < 0.001). AE remained a significant predictor of all-cause mortality (hazard ratio, 8.641; 95% confidence interval, 3.388–22.040; p < 0.001) after adjustment for age, body mass index, lung function, lymphocyte levels in bronchoalveolar lavage fluid, and the presence of a UIP-like pattern.

Conclusions
AE was not uncommon among patients with fibrotic HP and significantly affected prognosis. A lower DLCO value and radiologic UIP-like pattern at diagnosis were associated with the development AE in patients with fibrotic HP.
Alteration of payload in extracellular vesicles by crosstalk with mesenchymal stem cells from different origin
Authors: Park Dong Jun , Park Jeong-Eun , Kong Tae Hoon , Seo Young Joon 
Published: May 2021

Abstract
Background
The application of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) requires customized materials to target disease or cell damage. We hypothesized that EVs exert different inflammatory effects on one recipient cell, although stem cells of different origins in humans have similar payloads.

Results
Here, the payload of EVs released by crosstalk between MSCs and human middle ear epithelial cells (HMEECs) extracted from adipose tissue, bone marrow and tonsils significantly increased the level of anti-inflammatory factors. EVs derived from the co-culture medium decreased TNF-α, COX-2, IL-1β, and IL-6 levels to approximately zero within 3 h in HMEECs. Expression of miR-638 and amyloid-β A4 precursor protein-binding family A member 2 was analyzed using microarrays and gene ontology analysis, respectively.

Conclusions
In conclusion, stem cells of different origins have different payloads through crosstalk with recipient-specific cells. Inducing specific factors in EVs by co-culture with MSCs could be valuable in regenerative medicine.

Graphical abstract
The socio-spatial determinants of COVID-19 diffusion: the impact of globalisation, settlement characteristics and population
Authors: Sigler Thomas , Mahmuda Sirat , Kimpton Anthony , Loginova Julia , Wohland Pia , Charles-Edwards Elin , Corcoran Jonathan 
Published: May 2021

AbstractBackgroundCOVID-19 is an emergent infectious disease that has spread geographically to become a global pandemic. While much research focuses on the epidemiological and virological aspects of COVID-19 transmission, there remains an important gap in knowledge regarding the drivers of geographical diffusion between places, in particular at the global scale. Here, we use quantile regression to model the roles of globalisation, human settlement and population characteristics as socio-spatial determinants of reported COVID-19 diffusion over a six-week period in March and April 2020. Our exploratory analysis is based on reported COVID-19 data published by Johns Hopkins University which, despite its limitations, serves as the best repository of reported COVID-19 cases across nations.ResultsThe quantile regression model suggests that globalisation, settlement, and population characteristics related to high human mobility and interaction predict reported disease diffusion. Human development level (HDI) and total population predict COVID-19 diffusion in countries with a high number of total reported cases (per million) whereas larger household size, older populations, and globalisation tied to human interaction predict COVID-19 diffusion in countries with a low number of total reported cases (per million). Population density, and population characteristics such as total population, older populations, and household size are strong predictors in early weeks but have a muted impact over time on reported COVID-19 diffusion. In contrast, the impacts of interpersonal and trade globalisation are enhanced over time, indicating that human mobility may best explain sustained disease diffusion.ConclusionsModel results confirm that globalisation, settlement and population characteristics, and variables tied to high human mobility lead to greater reported disease diffusion. These outcomes serve to inform suppression strategies, particularly as they are related to anticipated relocation diffusion from more- to less-developed countries and regions, and hierarchical diffusion from countries with higher population and density. It is likely that many of these processes are replicated at smaller geographical scales both within countries and within regions. Epidemiological strategies must therefore be tailored according to human mobility patterns, as well as countries’ settlement and population characteristics. We suggest that limiting human mobility to the greatest extent practical will best restrain COVID-19 diffusion, which in the absence of widespread vaccination may be one of the best lines of epidemiological defense.
Heterogeneity in design and analysis of ICU delirium randomized trials: a systematic review
Authors: Colantuoni Elizabeth , Koneru Mounica , Akhlaghi Narjes , Li Ximin , Hashem Mohamed D. , Dinglas Victor D. , Neufeld Karin J. , Harhay Michael O. , Needham Dale M. 
Published: May 2021

Abstract
Background
There is a growing number of randomized controlled trials (RCTs) evaluating interventions to prevent or treat delirium in the intensive care unit (ICU). Efforts to improve the conduct of delirium RCTs are underway, but none address issues related to statistical analysis. The purpose of this review is to evaluate heterogeneity in the design and analysis of delirium outcomes and advance methodological recommendations for delirium RCTs in the ICU.

Methods
Relevant databases, including PubMed and Embase, were searched with no restrictions on language or publication date; the search was conducted on July 8, 2019. RCTs conducted on adult ICU patients with delirium as the primary outcome were included where trial results were available. Data on frequency and duration of delirium assessments, delirium outcome definitions, and statistical methods were independently extracted in duplicate. The review was registered with PROSPERO (CRD42020141204).

Results
Among 65 eligible RCTs, 44 (68%) targeted the prevention of delirium. The duration of follow-up varied, with 31 (48%) RCTs having ≤7 days of follow-up, and only 24 (37%) conducting delirium assessments after ICU discharge. The incidence of delirium was the most common outcome (50 RCTs, 77%) for which 8 unique statistical methods were applied. The most common method, applied to 51 of 56 (91%) delirium incidence outcomes, was the two-sample test comparing the proportion of patients who ever experienced delirium. In the presence of censoring of patients at ICU discharge or death, this test may be misleading. The impact of censoring was also not considered in most analyses of the duration of delirium, as evaluated in 24 RCTs, with 21 (88%) delirium duration outcomes analyzed using a non-parametric test or two-sample t test. Composite outcomes (e.g., rank-based delirium- and coma-free days), used in 11 (17%) RCTs, seldom explicitly defined how ICU discharge, and death were incorporated into the definition and were analyzed using non-parametric tests (11 of 13 (85%) composite outcomes).

Conclusions
To improve delirium RCTs, outcomes should be explicitly defined. To account for censoring due to ICU discharge or death, survival analysis methods should be considered for delirium incidence and duration outcomes; non-parametric tests are recommended for rank-based delirium composite outcomes.

Trial registration
PROSPERO CRD42020141204. Registration date: 7/3/2019.
The Drinkers’ Intervention to Prevent Tuberculosis (DIPT) trial among heavy drinkers living with HIV in Uganda: study protocol of a 2×2 factorial trial
Authors: Lodi Sara , Emenyonu Nneka I. , Marson Kara , Kwarisiima Dalsone , Fatch Robin , McDonell Michael G. , Cheng Debbie M. , Thirumurthy Harsha , Gandhi Monica , Camlin Carol S. , Muyindike Winnie R. , Hahn Judith A. , Chamie Gabriel 
Published: May 2021

Abstract
Background
The risk of tuberculosis (TB) is high among people with HIV (PWH). Heavy alcohol drinking independently increases TB risk and approximately 25% of PWH globally engage in heavy drinking. While isoniazid (INH) preventive therapy decreases TB incidence and mortality among PWH, heavy drinking during INH is associated with liver toxicity and poor adherence. Interventions are, therefore, urgently needed to decrease alcohol use and improve adherence to INH in this population in settings with high prevalence of HIV and TB like Uganda.

Methods
The Drinkers’ Intervention to Prevent TB (DIPT) study is a 2×2 factorial randomized controlled trial among HIV/TB co-infected adults (≥18 years) who engage in heavy alcohol drinking and live in Uganda. The trial will allocate 680 participants with a 1:1:1:1 individual randomization to receive 6 months of INH and one of the following interventions: (1) no incentives (control), (2) financial incentives contingent on low alcohol use, (3) financial incentives contingent on high adherence to INH, and (4) escalating financial incentives for both decreasing alcohol use and increasing adherence to INH. Incentives will be in the form of escalating lottery-based monetary rewards. Participants will attend monthly visits to refill isoniazid medications, undergo liver toxicity monitoring, and, except for controls, determine eligibility for prizes. We will estimate (a) the effect of incentives contingent on low alcohol use on reduction in heavy drinking, measured via a long-term objective and self-reported metric of alcohol use, at 3- and 6-month study visits, and (b) the effect of incentives contingent on high adherence to INH, measured as >90% pill-taking days by medication event monitoring system cap opening. We will use qualitative methods to explore the mechanisms of any influence of financial incentives on HIV virologic suppression.

Discussion
This study will provide new information on low-cost strategies to both reduce alcohol use and increase INH adherence among people with HIV and TB infection who engage in heavy drinking in low-income countries with high HIV and TB prevalence.

Trial registration
ClinicalTrials.gov NCT03492216. Registered on April 10, 2018
Letter to the Editor in response to the Position statement and best practice recommendations on the imaging use of ultrasound from the European Society of Radiology ultrasound subcommittee
Authors: Kalinka Chris , Dickson Jeanette , Evans Richard , Morris Edward , Parker Pamela , Walton Gill , Ramsden William , Harrison Gill 
Published: May 2021

AbstractThis letter to the editor is in response to the consensus statement from the Ultrasound Subcommittee of the European Society of Radiology, the European Union of Medical Specialists (UEMS) Section of Radiology, and the European Federation of Societies for Ultrasound in Medicine and Biology. It highlights the role of the non-medical sonographer in the UK and the evidence underpinning this safe and effective practice.