bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study protocol for a multicentre, prospective cohort study of the association of angiotensin II type 1 receptor blockers on outcomes of coronavirus infection
Authors: Russell James A. , Marshall John C , Slutsky Arthur , Murthy Srinivas , Sweet Dave , Lee Terry , Singer Joel , Patrick David M , Du Bin , Peng Zhiyong , Cheng Matthew , Burns Kevin D , Harhay Michael O 
Published: December 2020

IntroductionThe COVID-19 epidemic grows and there are clinical trials of antivirals. There is an opportunity to complement these trials with investigation of angiotensin II type 1 receptor blockers (ARBs) because an ARB (losartan) was effective in murine influenza pneumonia.Methods and analysisOur innovative design includes: ARBs; alignment with the WHO Ordinal Scale (primary endpoint) to align with other COVID-19 trials; joint longitudinal analysis; and predictive biomarkers (angiotensins I, 1–7, II and ACE1 and ACE2). Our hypothesis is: ARBs decrease the need for hospitalisation, severity (need for ventilation, vasopressors, extracorporeal membrane oxygenation or renal replacement therapy) or mortality of hospitalised COVID-19 infected adults. Our two-pronged multicentre pragmatic observational cohort study examines safety and effectiveness of ARBs in (1) hospitalised adult patients with COVID-19 and (2) out-patients already on or not on ARBs. The primary outcome will be evaluated by ordinal logistic regression and main secondary outcomes by both joint longitudinal modelling analyses. We will compare rates of hospitalisation of ARB-exposed versus not ARB-exposed patients. We will also determine whether continuing ARBs or not decreases the primary outcome. Based on published COVID-19 cohorts, assuming 15% of patients are ARB-exposed, a total sample size of 497 patients can detect a proportional OR of 0.5 (alpha=0.05, 80% power) comparing WHO scale of ARB-exposed versus non-ARB-exposed patients.Ethics and disseminationThis study has core institution approval (UBC Providence Healthcare Research Ethics Board) and site institution approvals (Health Research Ethics Board, University of Alberta; Comite d’etique de la recerche, CHU Sainte Justine (for McGill University and University of Sherbrook); Conjoint Health Research Ethics Board, University of Calgary; Queen’s University Health Sciences & Affiliated Hospitals Research Ethics Board; Research Ethics Board, Sunnybrook Health Sciences Centre; Veritas Independent Research Board (for Humber River Hospital); Mount Sinai Hospital Research Ethics Board; Unity Health Toronto Research Ethics Board, St. Michael’s Hospital). Results will be disseminated by peer-review publication and social media releases.Trial registration numberNCT04510623
Real-world patterns of pegloticase use for treatment of gout: descriptive multidatabase cohort study
Authors: Chen Sarah K , Liu Jun , Kim Seoyoung C 
Published: December 2020

ObjectivePegloticase is used in severe refractory gout or in cases of intolerance to other urate-lowering therapies. We sought to evaluate the patterns of pegloticase use in the USA and the incidence of safety outcomes.MethodsWe conducted a retrospective descriptive study using data from two US commercial insurance claims databases (2010–2018). We identified new initiators of pegloticase with ≥1 gout diagnosis code in the 365-day baseline period prior to pegloticase initiation. We measured the number and duration of pegloticase infusions. We assessed the risk of anaphylaxis or anaphylactoid reactions, cardiovascular events, including myocardial infarction or stroke, and hospitalisation for heart failure (new onset or exacerbations) while undergoing pegloticase therapy.ResultsAmong 2.9 million patients with ≥1 diagnosis of gout, we identified only 483 (179 in Optum and 304 in MarketScan) pegloticase initiators. The mean age and % female was 55.6 years, 10.9% for MarketScan and 60.6 years and 17.3% for Optum. Hypertension was present in up to 85%, diabetes mellitus in 38%, chronic kidney disease in 46% and heart failure in 21% of the patients. The median number of infusions was four and the duration of therapy was 3 months. During the mean 0.5-year follow-up time on pegloticase, there were 3 (0.6%) anaphylaxis, 7 (1.4%) composite cardiovascular, 31 (6.4%) heart failure hospitalisations and 3 (0.6%) deaths.ConclusionPegloticase is rarely used in gout, and the median duration of pegloticase therapy was 3 months. There were few anaphylaxis events captured in this claims-based study, while heart failure hospitalisations were common.
Clinical and metabolic characteristics of the Diabetes Intervention Accentuating Diet and Enhancing Metabolism (DIADEM-I) randomised clinical trial cohort
Authors: Zaghloul Hadeel , Chagoury Odette , Elhadad Sara , Hayder Ahmed Salma , Suleiman Noor , Al Naama Abdulla , El Nahas Katie , Al Hamaq Abdulla , Charlson Mary , Wells Martin T , Al Abdulla Samya , Abou-Samra Abdul Badi , Taheri Shahrad 
Published: December 2020

ObjectivesDiabetes Intervention Accentuating Diet and Enhancing Metabolism-I (DIADEM-I) is the first randomised controlled trial (RCT) in the Middle East and North Africa (MENA) region testing the effectiveness of an intensive lifestyle intervention (ILI) for weight loss and diabetes remission. We report on the recruitment process and baseline characteristics of the DIADEM-I cohort based on origin (Middle East vs North Africa), and waist circumference.DesignDIADEM-I is an open-label randomised, controlled, parallel group RCT recruiting young individuals (18–50 years) with early type 2 diabetes (≤3 years since diagnosis) originating from MENA. Individuals from primary care were randomised to usual medical care or ILI (total dietary replacement phase using meal replacement products, followed by staged food reintroduction and physical activity support). The primary outcome is weight loss at 12 months. Other outcomes are glycaemic control and diabetes remission.SettingPrimary care, Qatar.Participants147 (73% men) randomised within DIADEM-I who were included in the final trial data analysis.Outcome measuresRecruitment metrics, and baseline clinical and metabolic characteristics.ResultsOf 1498 people prescreened, 267 (18%) were invited for screening and 209 (78%) consented. 173 (83%) were eligible. 15 (7%) withdrew before randomisation and the remaining 158 were randomised. Mean age was 42.1 (SD 5.6) years and mean body mass index was: 36.3 (5.5) kg/m2 (women) and 34.4 (5.4) kg/m2 (men). Mean diabetes duration was 1.8 (1.0) years and mean glycosylated haemoglobin (HbA1c) was 7.0% (1.30) (52.5 mmol/mol (SD 14.3)). Participants originated from 13 countries. Those from North Africa reported greater physical activity and had lower family history of diabetes. 90% of subjects were taking diabetes medications and 31% antihypertensives. Those with greater waist circumference had significantly higher insulin resistance and lower quality of life.ConclusionRecruitment of participants originating from the MENA region into the RCT was successful, and study participation was readily accepted. While DIADEM-I participants originated from 13 countries, there were few baseline differences amongst participants from Middle East versus North Africa, supporting generalisability of RCT results.Trial registration numberISRCTN20754766; NCT03225339
Trends in acid suppressant drug prescriptions in primary care in the UK: a population-based cross-sectional study
Authors: Abrahami Devin , McDonald Emily Gibson , Schnitzer Mireille , Azoulay Laurent 
Published: December 2020

ObjectiveTo examine proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) prescribing patterns over a 29-year period by quantifying annual prevalence and prescribing intensity over time.DesignPopulation-based cross-sectional study.SettingMore than 700 general practices contributing data to the UK Clinical Practice Research Datalink (CPRD).ParticipantsWithin a cohort of 14 242 329 patients registered in the CPRD, 3 027 383 patients were prescribed at least one PPI or H2RA from 1 January 1990 to 31 December 2018.Primary and secondary outcome measuresAnnual prescription rates were estimated by dividing the number of patients prescribed a PPI or H2RA by the total CPRD population. Change in prescribing intensity (number of prescriptions per year divided by person-years of follow-up) was calculated using negative binomial regression.ResultsFrom 1990 to 2018, 21.3% of the CPRD population was exposed to at least one acid suppressant drug. During that period, PPI prevalence increased from 0.2% to 14.2%, while H2RA prevalence remained low (range: 1.2%–3.4%). Yearly prescribing intensity to PPIs increased during the first 15 years of the study period but remained relatively constant for the remainder of the study period. In contrast, yearly prescribing intensity of H2RAs decreased from 1990 to 2009 but has begun to slightly increase over the past 5 years.ConclusionsWhile PPI prevalence has been increasing over time, its prescribing intensity has recently plateaued. Notwithstanding their efficacy, PPIs are associated with a number of adverse effects not attributed to H2RAs, whose prescribing intensity has begun to increase. Thus, H2RAs remain a valuable treatment option for individuals with gastric conditions.
What is known about the health service use and follow-up of immediate family members bereaved by suicide? Scoping review protocol
Authors: Petersen Sindre Hoff , Kalseth Jorid , Kaspersen Silje L 
Published: December 2020

IntroductionSuicide remains a major public health issue around the world. People bereaved by suicide are a vulnerable group who are at considerable risk of developing mental and physical health problems, such as complicated grief, post-traumatic stress disorder or cardiovascular disease. Many unanswered questions remain, in particular, in terms of their use of healthcare services. This protocol describes how we aim to systematically scope the existing literature on the professional follow-up and health service use by families bereaved by suicide. The scoping review will help to identify research gaps in the literature and aid in the planning and commission of future research. We will provide a summary of research findings.Methods and analysisWe will use the scoping review framework provided by the Joanna Briggs Institute. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews will be used as a guide for reporting our results. We plan to conduct an extensive literature search using relevant health-related databases (MEDLINE, Embase, PsycINFO and CINAHL) and Web of Science. Two independent reviewers will screen the articles in a two-stage process: (1) titles and abstracts and (2) full-text documents.Ethics and disseminationThis scoping review will identify and consider only previously published research. Hence, no ethical approval is considered necessary. We will disseminate the results in a scientific journal and at conferences, as well as through user organisations for people bereaved by suicide and social media.
How primary healthcare in Iceland swiftly changed its strategy in response to the COVID-19 pandemic
Authors: Sigurdsson Emil Larus , Blondal Anna Bryndis , Jonsson Jon Steinar , Tomasdottir Margret Olafia , Hrafnkelsson Hannes , Linnet Kristjan , Sigurdsson Johann Agust 
Published: December 2020

ObjectiveTo describe how the primary healthcare (PHC) in Iceland changed its strategy to handle the COVID-19 pandemic.DesignDescriptive observational study.SettingReykjavik, the capital of Iceland.PopulationThe Reykjavik area has a total of 233 000 inhabitants.Main outcome measuresThe number and the mode of consultations carried out. Drug prescriptions and changes in the 10 most common diagnoses made in PHC. Laboratory tests including COVID-19 tests. Average numbers in March and April 2020 compared with the same months in 2018 and 2019.ResultsPragmatic strategies and new tasks were rapidly applied to the clinical work to meet the foreseen healthcare needs caused by the pandemic. The number of daytime consultations increased by 35% or from 780 to 1051/1000 inhabitants (p<0.001) during the study period. Telephone and web-based consultations increased by 127% (p<0.001). The same tendency was observed in out-of-hours services. The number of consultations in maternity and well-child care decreased only by 4% (p=0.003). Changes were seen in the 10 most common diagnoses. Most noteworthy, apart from a high number of COVID-19 suspected disease, was that immunisation, depression, hypothyroidism and lumbago were not among the top 10 diagnoses during the epidemic period. The number of drug prescriptions increased by 10.3% (from 494 to 545 per 1000 inhabitants, p<0.001). The number of prescriptions from telephone and web-based consultations rose by 55.6%. No changes were observed in antibiotics prescriptions.ConclusionsAs the first point of contact in the COVID-19 pandemic, the PHC in Iceland managed to change its strategy swiftly while preserving traditional maternity and well-child care, indicating a very solid PHC with substantial flexibility in its organisation.
Adenoviral vaccines promote protective tissue-resident memory T cell populations against cancer
Authors: van der Gracht Esmé TI , Schoonderwoerd Mark JA , van Duikeren Suzanne , Yilmaz Ayse N , Behr Felix M , Colston Julia M , Lee Lian N , Yagita Hideo , van Gisbergen Klaas PJM , Hawinkels Lukas JAC , Koning Frits , Klenerman Paul , Arens Ramon 
Published: December 2020

BackgroundAdenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8+T cells elicited upon immunization with adenoviral vectors.MethodsAdenoviral vaccine vectors encoding the full-length E7 protein from human papilloma virus (HPV) or the immunodominant epitope from E7 were generated, and mice were immunized intravenously with different quantities (107, 108or 109infectious units). The magnitude, kinetics and tumor protection capacity of the induced vaccine-specific T cell responses were evaluated.ResultsThe adenoviral vaccines elicited inflationary E7-specific memory CD8+T cell responses in a dose-dependent manner. The magnitude of these vaccine-specific CD8+T cells in the circulation related to the development of E7-specific CD8+tissue-resident memory T (TRM) cells, which were maintained for months in multiple tissues after vaccination. The vaccine-specific CD8+T cell responses conferred long-term protection against HPV-induced carcinomas in the skin and liver, and this protection required the induction and accumulation of CD8+TRMcells. Moreover, the formation of CD8+TRMcells could be enhanced by temporal targeting CD80/CD86 costimulatory interactions via CTLA-4 blockade early after immunization.ConclusionsTogether, these data show that adenoviral vector-induced CD8+T cell inflation promotes protective TRMcell populations, and this can be enhanced by targeting CTLA-4.
Olivine chemistry of the Quaternary Datong basalts of the Trans-North China Orogen: insights into mantle source lithology and redox–hydration state
Authors: Hong Lubing , Zhang Yinhui , Zhang Le , Xu Yi-Gang , Liu Zhe , He Pengli 
Published: December 2020

Abstract

Cenozoic intraplate basalts are widespread above the Big Mantle Wedge (BMW) and its front in East Asia. While the mantle source lithology and redox-hydration state have been demonstrated to be crucial in the generation of basalts above the BMW, their nature and role in the basalts above the front of the BMW is poorly constrained. To address this, we report olivine compositions of the Quaternary Datong basalts. Datong basalts exhibit ocean island basalt-like trace-element compositions and depleted Sr–Nd isotopes with slightly enriched signatures (enriched mantle I, EMI) for tholeiitic basalts. Olivines of the Datong basalts show high Ni and Fe/Mn, and low Ca, Mn and Mn/Zn values, pointing to a pyroxenite source. Applying V and Ca partition coefficients between olivine and whole rock, respectively, the Datong basalts lie −0.44 to 0.64 log units above the fayalite–magnetite–quartz buffer for
f
O
2
, and contain 2.1–3.4 wt% H
2
O but highly variable H
2
O/Ce values (265–1498). Both
f
O
2
and H
2
O/Ce in the basalts vary with whole-rock and olivine compositions, indicating that the source was the main control. Thus, there is a heterogeneous redox–hydration state in the source, the EMI component being relatively reduced but extremely wet and recycled oceanic crust being relatively oxidized but dry. The extremely wet EMI component was probably derived from the mantle transition zone. In the light of our findings, we propose a model in which mantle upwelling carried the recycled oceanic crust and EMI component from the mantle transitional zone to shallow mantle, owing to the Pacific slab stagnating in the mantle transitional zone, to form pyroxenite, which subsequently melted to generate Datong basalts.
Clinical Validation of a Machine-learning–derived Signature Predictive of Outcomes from First-line Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer
Authors: Abraham Jim P. , Magee Daniel , Cremolini Chiara , Antoniotti Carlotta , Halbert David D. , Xiu Joanne , Stafford Phillip , Berry Donald A. , Oberley Matthew J. , Shields Anthony F. , Marshall John L. , Salem Mohamed E. , Falcone Alfredo , Grothey Axel , Hall Michael J. , Venook Alan P. , Lenz Heinz-Josef , Helmstetter Anthony , Korn W. Michael , Spetzler David B. 
Published: December 2020

Abstract

Purpose:
FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab is considered standard first-line treatment option for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with bevacizumab in patients with mCRC.

Experimental Design:
A machine-learning approach was applied and tested on clinical and next-generation sequencing data from a real-world evidence (RWE) dataset and samples from the prospective TRIBE2 study resulting in identification of a molecular signature, FOLFOXai. Algorithm training considered time-to-next treatment (TTNT). Validation studies used TTNT, progression-free survival, and overall survival (OS) as the primary endpoints.

Results:
A 67-gene signature was cross-validated in a training cohort (N = 105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit. The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR, 0.629; P = 0.04 and FOLFOXIRI HR, 0.483; P = 0.02). FOLFOXai was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers, as well as pancreatic ductal adenocarcinoma.

Conclusions:
Application of FOLFOXai could lead to improvements of treatment outcomes for patients with mCRC and other cancers because patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens.
Ventilation With Argon Improves Survival With Good Neurological Recovery After Prolonged Untreated Cardiac Arrest in Pigs
Authors: Fumagalli Francesca , Olivari Davide , Boccardo Antonio , De Giorgio Daria , Affatato Roberta , Ceriani Sabina , Bariselli Simone , Sala Giulia , Cucino Alberto , Zani Davide , Novelli Deborah , Babini Giovanni , Magliocca Aurora , Russo Ilaria , Staszewsky Lidia , Salio Monica , Lucchetti Jacopo , Maisano Antonio Marco , Fiordaliso Fabio , Furlan Roberto , Gobbi Marco , Luini Mario Vittorio , Pravettoni Davide , Scanziani Eugenio , Belloli Angelo , Latini Roberto , Ristagno Giuseppe 
Published: December 2020

Background
Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest.

Methods and Results

Cardiac arrest was ischemically induced in 36 pigs and left untreated for 12 minutes before starting cardiopulmonary resuscitation. Animals were randomized to 4‐hour post‐resuscitation ventilation with: 70% nitrogen–30% oxygen (control); 50% Ar–20% nitrogen–30% oxygen (Ar 50%); and 70% Ar–30% oxygen (Ar 70%). Hemodynamic parameters and myocardial function were monitored and serial blood samples taken. Pigs were observed up to 96 hours for survival and neurological recovery. Heart and brain were harvested for histopathology. Ten animals in each group were successfully resuscitated. Ninety‐six‐hour survival was 60%, 70%, and 90%, for the control, Ar 50%, and Ar 70% groups, respectively. In the Ar 50% and Ar 70% groups, 60% and 80%, respectively, achieved good neurological recovery, in contrast to only 30% in the control group (
P
<0.0001). Histology showed less neuronal degeneration in the cortex (
P
<0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus (
P
=0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation (
P
<0.05), were present in Ar‐treated animals compared with controls. Ar 70% pigs also had complete left ventricular function recovery and smaller infarct and cardiac troponin release (
P
<0.01).

Conclusions
Post‐resuscitation ventilation with Ar significantly improves neurologic recovery and ameliorates brain injury after cardiac arrest with long no‐flow duration. Benefits are greater after Ar 70% than Ar 50%.
Risk Factor Burden and Long‐Term Prognosis of Patients With Premature Coronary Artery Disease
Authors: Zeitouni Michel , Clare Robert M. , Chiswell Karen , Abdulrahim Jawan , Shah Nishant , Pagidipati Neha P. , Shah Svati H. , Roe Matthew T. , Patel Manesh R. , Jones W. Schuyler 
Published: December 2020

Background
Coronary artery disease (CAD) is increasing among young adults. We aimed to describe the cardiovascular risk factors and long‐term prognosis of premature CAD.

Methods and Results
Using the Duke Databank for Cardiovascular Disease, we evaluated 3655 patients admitted between 1995 and 2013 with a first diagnosis of obstructive CAD before the age of 50 years. Major adverse cardiovascular events (MACEs), defined as the composite of death, myocardial infarction, stroke, or revascularization, were ascertained for up to 10 years. Cox proportional hazard regression models were used to assess associations with the rate of first recurrent event, and negative binomial log‐linear regression was used for rate of multiple event recurrences. Past or current smoking was the most frequent cardiovascular factor (60.8%), followed by hypertension (52.8%) and family history of CAD (39.8%). Within a 10‐year follow‐up, 52.9% of patients had at least 1 MACE, 18.6% had at least 2 recurrent MACEs, and 7.9% had at least 3 recurrent MACEs, with death occurring in 20.9% of patients. Across follow‐up, 31.7% to 37.2% of patients continued smoking, 81.7% to 89.3% had low‐density lipoprotein cholesterol levels beyond the goal of 70 mg/dL, and 16% had new‐onset diabetes mellitus. Female sex, diabetes mellitus, chronic kidney disease, multivessel disease, and chronic inflammatory disease were factors associated with recurrent MACEs.

Conclusions
Premature CAD is an aggressive disease with frequent ischemic recurrences and premature death. Individuals with premature CAD have a high proportion of modifiable cardiovascular risk factors, but failure to control them is frequently observed.