bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of drug safety advisories on drug utilisation: an international interrupted time series and meta-analysis
Authors: Morrow Richard L , Mintzes Barbara , Souverein Patrick C , De Bruin Marie L , Roughead Elizabeth Ellen , Lexchin Joel , Kemp-Casey Anna , Puil Lorri , Sketris Ingrid , Mangin Dee , Hallgreen Christine E , Pearson Sallie-Anne , Lopert Ruth , Bero Lisa , Ofori-Asenso Richard , Gnjidic Danijela , Sarpatwari Ameet , Perry Lucy T , Dormuth Colin R 
Published: January 2022

ObjectiveTo evaluate the association between regulatory drug safety advisories and changes in drug utilisation.DesignWe conducted controlled, interrupted times series analyses with administrative prescription claims data to estimate changes in drug utilisation following advisories. We used random-effects meta-analysis with inverse-variance weighting to estimate the average postadvisory change in drug utilisation across advisories.Study populationWe included advisories issued in Canada, Denmark, the UK and the USA during 2009–2015, mainly concerning drugs in common use in primary care. We excluded advisories related to over-the-counter drugs, drug-drug interactions, vaccines, drugs used primarily in hospital and advisories with co-interventions within ±6 months.Main outcome measuresChange in drug utilisation, defined as actual versus predicted percentage change in the number of prescriptions (for advisories without dose-related advice), or in the number of defined daily doses (for dose-related advisories), per 100 000 population.ResultsAmong advisories without dose-related advice (n=20), the average change in drug utilisation was −5.83% (95% CI −10.93 to –0.73; p=0.03). Advisories with dose-related advice (n=4) were not associated with a statistically significant change in drug utilisation (−1.93%; 95% CI −17.10 to 13.23; p=0.80). In a post hoc subgroup analysis of advisories without dose-related advice, we observed no statistically significant difference between the change in drug utilisation following advisories with explicit prescribing advice, such as a recommendation to consider the risk of a drug when prescribing, and the change in drug utilisation following advisories without such advice.ConclusionsAmong safety advisories issued on a wide range of drugs during 2009–2015 in 4 countries (Canada, Denmark, the UK and the USA), the association of advisories with changes in drug utilisation was variable, and the average association was modest.
Risk of infective endocarditis after surgical and transcatheter aortic valve replacement
Authors: Cahill Thomas J , Raby Jonathan , Jewell Paul D , Brennan Paul F , Banning Adrian P , Byrne Jonathan , Kharbanda Rajesh K , MacCarthy Philip A , Thornhill Martin H , Sandoe Jonathan A T , Spence Mark S , Ludman Peter , Hildick-Smith David J R , Redwood Simon R , Prendergast Bernard D 
Published: January 2022

ObjectiveTo define the incidence and risk factors for infective endocarditis (IE) following surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI).MethodsAll patients who underwent first SAVR or TAVI in England between 2007 and 2016 were identified from the NICOR databases. Hospital admissions with a primary diagnosis of IE were identified by linkage with the NHS Hospital Episode Statistics database. Approval was obtained from the NHS Research Ethics Committee.Results2057 of 91 962 patients undergoing SAVR developed IE over a median follow-up of 53.9 months—an overall incidence of 4.81 [95% CI 4.61 to 5.03] per 1000 person-years. Correspondingly, 140 of 14 195 patients undergoing TAVI developed IE over a median follow-up of 24.5 months—an overall incidence of 3.57 [95% CI 3.00 to 4.21] per 1000 person-years. The cumulative incidence of IE at 60 months was higher after SAVR than after TAVI (2.4% [95% CI 2.3 to 2.5] vs 1.5% [95% CI 1.3 to 1.8], HR 1.60, p<0.001). Across the entire cohort, SAVR remained an independent predictor of IE after multivariable adjustment. Risk factors for IE included younger age, male sex, atrial fibrillation, and dialysis.ConclusionsIE is a rare complication of SAVR and TAVI. In our population, the incidence of IE was higher after SAVR than after TAVI.
Targeting CD38 and PD-1 with isatuximab plus cemiplimab in patients with advanced solid malignancies: results from a phase I/II open-label, multicenter study
Authors: Zucali Paolo Andrea , Lin Chia-Chi , Carthon Bradley C , Bauer Todd M , Tucci Marcello , Italiano Antoine , Iacovelli Roberto , Su Wu-Chou , Massard Christophe , Saleh Mansoor , Daniele Gennaro , Greystoke Alastair , Gutierrez Martin , Pant Shubham , Shen Ying-Chun , Perrino Matteo , Meng Robin , Abbadessa Giovanni , Lee Helen , Dong Yingwen , Chiron Marielle , Wang Rui , Loumagne Laure , Lépine Lucie , de Bono Johann 
Published: January 2022

BackgroundPreclinical data suggest that concurrent treatment of anti-CD38 and antiprogrammed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies substantially reduce primary tumor growth by reversing T-cell exhaustion and thus enhancing anti-PD-1/PD-L1 efficacy.MethodsThis phase I/II study enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of phase I were to investigate the safety and tolerability of isatuximab (anti-CD38 monoclonal antibody)+cemiplimab (anti-PD-1 monoclonal antibody, Isa+Cemi) in patients with mCRPC (naïve to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase II used Simon’s two-stage design with response rate as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) patients receiving Isa+Cemi were enrolled in phase II. Safety, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, and tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping.ResultsIsa+Cemi demonstrated a manageable safety profile with no new safety signals. All patients experienced ≥1 treatment-emergent adverse event. Grade≥3 events occurred in 13 (54.2%) patients with mCRPC and 12 (60.0%) patients with NSCLC. Based on PCWG3 criteria, assessment of best overall response with Isa+Cemi in mCRPC revealed no complete responses (CRs), one (4.2%) unconfirmed partial response (PR), and five (20.8%) patients with stable disease (SD). Per RECIST V.1.1, patients with NSCLC receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. In post-therapy biopsies obtained from patients with mCRPC or NSCLC, Isa+Cemi treatment resulted in a reduction in median CD38+ tumor-infiltrating immune cells from 40% to 3%, with no consistent modulation of PD-L1 on tumor cells or T regulatory cells in the TME. The combination triggered a significant increase in peripheral activated and cytolytic T cells but, interestingly, decreased natural killer cells.ConclusionsThe present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, such CD38 inhibition was not associated with significant antitumor activity. A lack of efficacy was observed in these small cohorts of patients with mCRPC or NSCLC.Trial registration numbersNCT03367819.
Association of antibiotic treatment with immune-related adverse events in patients with cancer receiving immunotherapy
Authors: Jing Ying , Chen Xue , Li Kunyan , Liu Yaoming , Zhang Zhao , Chen Yiqing , Liu Yuan , Wang Yushu , Lin Steven H , Diao Lixia , Wang Jing , Lou Yanyan , Johnson Douglas B , Chen Xiang , Liu Hong , Han Leng 
Published: January 2022

BackgroundTo determine whether antibiotic treatment is a risk factor for immune-related adverse events (irAEs) across different patients with cancer receiving anti-PD-1/PD-L1 therapies.MethodsThe retrospective analysis includes clinical information from 767 patients with cancer treated at Hunan Cancer Hospital from 2017 to 2020. The pharmacovigilance data analysis includes individual cases of 38,705 safety reports from the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2014 to 2020, and 25,122 cases of safety reports from the World Health Organization database VigiBase from 2014 to 2019. All cases that received anti-PD-1/PD-L1 treatment were included. Multiomics data from patients across 25 cancer types were download from The Cancer Genome Atlas. Logistic regression and propensity score algorithm was employed to calculate OR of irAEs.ResultsRetrospective analysis of in-house patients showed that irAE potential risks are higher in all cancer (OR 2.12, 95% CI 1.38 to 3.22, false discovery rate (FDR) adjusted-p=1.93×10−3) and patients with lung cancer (OR 3.16, 95% CI 1.67 to 5.95, FDR adjusted-p=1.93×10−3) when using antibiotics. Potential risk of irAEs in patients with lung cancer with antibiotic treatment is significantly higher in FAERS (OR 1.39, 95% CI 1.21 to 1.59; FDR adjusted-p=1.62×10−5) and VigiBase (OR 1.32, 95% CI 1.09 to 1.59, FDR adjusted-p=0.05). Mechanistically, decreased microbial diversity caused by antibiotics use may increase the irAE risk through mediating the irAE-related factors.ConclusionsOur study is the first to comprehensively demonstrate the associations of irAEs and antibiotic during anti-PD-1/PD-L1 therapy across a wide spectrum of cancers by analyzing multisource data. Administration of antibiotics should be carefully evaluated in patients with cancer treated by anti-PD-1/PD-L1 to avoid potentially increasing irAE risk.
Sex-specific muscle activation and oxygenation kinetics during a repetitive forward pointing task
Authors: Yoon SangHoon , Bailey Christopher A. , Côté Julie N. 
Published: January 2022

We compared the minute-by-minute muscle activity and oxygenation responses to a repetitive arm motion-induced fatiguing task between the sexes in order to address the literature gap on these time-dependent fatigue responses. Twenty-six (13 females) healthy adults performed a repetitive pointing task (RPT) with the arm moving forward/backward at shoulder height until reaching 8/10 (Borg CR10) for neck/shoulder perceived exertion (RPE). Neck/shoulder RPE, oxygenation and electromyography were recorded every minute and compared between first and second half of the task and between the sexes. Greater changes in oxygen supply and activation amplitude occurred during the second half of the task. Despite similar time to fatigue-terminal (p > 0.05), females showed greater anterior deltoid activation amplitude at all time points than males, and only the males showed increases in anterior and posterior deltoid activation amplitudes. In females, middle (ρ = –0.34, p = 0.04) and posterior (ρ = –0.44, p = 0.01) deltoid amplitudes were negatively correlated with perceived exertion during the first half of the task. Results suggest that reduced modulation of anterior deltoid activation amplitude in females may reflect a sub-optimal fatigue-mitigation mechanism compared with males and may help explain their greater susceptibility to neck/shoulder musculoskeletal disorders. Novelty: Despite similar fatigability and trapezius oxygenation, females showed greater deltoid activation throughout the task. Deltoid activation increased in males but not in females. The results support the important role of the deltoid in sex-specific neck/shoulder injury mechanisms.
Harnessing Whole Genome Polygenic Risk Scores to Stratify Individuals Based on Cardiometabolic Risk Factors and Biomarkers at Age 10 in the Lifecourse—Brief Report
Authors: Richardson Tom G. , O’Nunain Katie , Relton Caroline L. , Davey Smith George 
Published: January 2022

Background:
In this study, we investigated the capability of polygenic risk scores to stratify a cohort of young individuals into risk deciles based on 10 different cardiovascular traits and circulating biomarkers.

Methods:
We first conducted large-scale genome-wide association studies using data on adults (mean age 56.5 years) enrolled in the UK Biobank study (n=393 193 to n=461 460). Traits and biomarkers analyzed were body mass index, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, apolipoprotein A-I, C-reactive protein and vitamin D. Findings were then leveraged to build whole genome polygenic risk scores in participants from the Avon Longitudinal Study of Parents and Children (mean age, 9.9 years) which were used to stratify this cohort into deciles in turn and analyzed against their respective traits.

Results:

For each of the 10 different traits assessed, we found strong evidence of an incremental trend across deciles (all
P
<0.0001). Large differences were identified when comparing top and bottom deciles; for example, using the apolipoprotein B polygenic risk scores there was a mean difference of 13.2 mg/dL for this established risk factor of coronary heart disease in later life.

Conclusions:
Although the use of polygenic prediction in a clinical setting may currently be premature, our findings suggest they are becoming increasingly powerful as a means of predicting complex trait variation at an early stage in the lifecourse.
Comparison of Different Dosages of Alteplase in Atrial Fibrillation–Related Acute Ischemic Stroke After Intravenous Thrombolysis: A Nationwide, Multicenter, Prospective Cohort Study in Taiwan
Authors: Lin Sheng‐Feng , Chen Chien‐Fu , Hu Han‐Hwa , Ho Bo‐Lin , Chen Chih‐Hung , Chan Lung , Lin Huey‐Juan , Sun Yu , Lin Yung‐Yang , Chen Po‐Lin , Lin Shinn‐Kuang , Wei Cheng‐Yu , Lin Yu‐Te , Lee Jiunn‐Tay , Chao A‐Ching , Lin Sheng‐Feng , Chen Chien‐Fu , Hu Han‐Hwa , Ho Bo‐Lin , Chen Chih‐Hung , Chan Lung , Lin Huey‐Juan , Sun Yu , Lin Yung‐Yang , Chen Po‐Lin , Lin Shinn‐Kuang , Wei Cheng‐Yu , Lin Yu‐Te , Lee Jiunn‐Tay , Chao A‐Ching 
Published: January 2022

Background
Insufficient evidence is available for patients with acute ischemic stroke with atrial fibrillation (AF) to determine the efficacy and safety of different dosages of intravenous thrombolysis treatment. This study examined clinical outcomes in Chinese patients with stroke with and without AF after intravenous thrombolysis treatment with different intravenous thrombolysis doses.

Methods and Results
This multicenter, prospective cohort study recruited 2351 patients with acute ischemic stroke (1371 with AF and 980 without AF) treated with intravenous thrombolysis using alteplase. The Totaled Health Risks in Vascular Events score is a validated risk‐scoring tool used for assessing patients with acute ischemic stroke with and without AF. We evaluated favorable functional outcome at day 90 and symptomatic intracranial hemorrhage within 24 to 36 hours and outcomes of the patients receiving different doses of alteplase. Compared with the non‐AF group, the AF group exhibited a 2‐ to 3‐fold increased risk of symptomatic intracranial hemorrhage according to the National Institute of Neurological Disorders and Stroke standard (relative risk [RR], 2.10 [95% CI, 1.35–3.26]). Favorable functional outcome at 90 days and symptomatic intracranial hemorrhage rates according to the European Cooperative Acute Stroke Study II and the Safe Implementation of Thrombolysis in Stroke‐Monitoring Study standards did not significantly differ between the AF and non‐AF groups. In addition, the low‐dose alteplase subgroup exhibited an increased risk of symptomatic intracranial hemorrhage according to the National Institute of Neurological Disorders and Stroke standard (RR, 2.84 [95% CI, 1.63–4.96]). A validation study confirmed these findings after adjustment for scores determined using different stroke risk‐scoring tools.

Conclusions
Different alteplase dosages did not affect functional status at 90 days in the AF and non‐AF groups. Thus, the adoption of low‐dose alteplase simply because of AF is not recommended.
Doing Drag in Blackface
Authors: Colvin Sarah 
Published: January 2022

Abstract
This article acknowledges racism and sexism as ethical problems in Grimmelshausen’s novel Courasche. Its charismatic protagonist is not only old and a woman (and therefore arguably a witch), but adds racialised exclusion to her portfolio when she narrates her autobiography in blackface. Here the author interrogates Grimmelshausen’s narratorial masks using Medina’s conception of the infelicitous subject, who has a paradoxical double function: infelicitous subjects simultaneously demonstrate how things should not be done and sow seeds of doubt about the practices and beliefs of the normative economy. Recognising the problem racism and sexism represent in Courasche raises the question whether Grimmelshausen’s engagement with knowledge is conventional or innovative; whether Courasche merely reproduces, or also destabilises, epistemic injustice. Courasche as a protagonist is an exemplar of transgression. But is her transgressive infelicity epistemically constitutive – does it contribute to the creation of new discursive contexts?
Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis
Authors: Burgos Miguel , Cavero-Redondo Iván , Álvarez-Bueno Celia , Galán-Moya Eva María , Pandiella Atanasio , Amir Eitan , Ocaña Alberto 
Published: January 2022

Background: Identification of membrane proteins differentially expressed on tumor cells is a key step in drug development. The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a cell adhesion protein belonging to the immunoglobulin superfamily. Here, we explore the prognostic role CEACAM6 expression on patient outcome in cancer. Methods: A systematic search for studies evaluating the association between tumor expression of CEACAM6 and overall survival (OS) and disease-free survival (DFS) was performed. Hazard ratios (HR) were pooled in a meta-analysis using generic inverse variance and random effect modeling. Subgroup analyses were conducted based on tumor type and method of HR extraction. Results: Sixteen studies met the inclusion criteria. CEACAM6 expression was associated with worse OS [HR = 1.96, 95% confidence interval (CI) = 1.51–2.53], and DFS (HR = 2.49, 95% CI = 2.01–3.07) with subgroup analysis showing no significant differences between disease site subgroups. Conclusions: High expression of CEACAM6 is associated with worse OS and DFS in different malignancies. CEACAM6 is a target for the future development of novel therapeutics.
Risk-standardized sepsis mortality map of the United States
Authors: Hu Jiun-Ruey , Yo Chia-Hung , Lee Hsin-Ying , Su Chin-Hua , Su Ming-Yang , Huang Amy Huaishiuan , Liu Ye , Hsu Wan-Ting , Lee Matthew , Chen Yee-Chun , Lee Chien-Chang 
Published: January 2022

Objective Sepsis is the leading cause of in-hospital mortality in the United States (US). Quality improvement initiatives for improving sepsis care depend on accurate estimates of sepsis mortality. While hospital 30-day risk-standardized mortality rates have been published for patients hospitalized with acute myocardial infarction, heart failure, and pneumonia, risk-standardized mortality rates for sepsis have not been well characterized. We aimed to construct a sepsis risk-standardized mortality rate map for the United States, to illustrate disparities in sepsis care across the country. Methods This cross-sectional study included adults from the US Nationwide Inpatient Sample who were hospitalized with sepsis between 1 January 2010 and 30 December 2011. Hospital-level risk-standardized mortality rates were calculated using hierarchical logistic modelling, and were risk-adjusted with predicted mortality derived from (1) the Sepsis Risk Prediction Score, a logistic regression model, and (2) gradient-boosted decision trees, a supervised machine learning (ML) algorithm. Results Among 1,739,033 adults hospitalized with sepsis, 50% were female, and the median age was 71 years (interquartile range: 58–81). The national median risk-standardized mortality rate for sepsis was 18.4% (interquartile range: 17.0, 21.0) by the boosted tree model, which had better discrimination than the Sepsis Risk Prediction Score model (C-statistic 0.87 and 0.78, respectively). The highest risk-standardized mortality rates were found in Wyoming, North Dakota, and Mississippi, while the lowest were found in Arizona, Colorado, and Michigan. Conclusions Wide variation exists in sepsis risk-standardized mortality rates across states, representing opportunities for improvement in sepsis care. This represents the first map of state-level variation of risk-standardized mortality rates in sepsis.
Eculizumab for refractory thrombosis in antiphospholipid syndrome
Authors: Hussain Habiba , Tarantino Michael D. , Chaturvedi Shruti , McCrae Keith R. , Roberts Jonathan C. 
Published: January 2022

Abstract
Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis with antiphospholipid antibodies. Dysregulation of the complement pathway has been implicated in APS pathophysiology. We report the successful use of eculizumab, an anti-C5 monoclonal antibody, in controlling and preventing recurrent thrombosis in a refractory case of APS. An 18-year-old female was diagnosed with APS after developing extensive, unprovoked deep vein thrombosis (DVT) of axillary, inferior vena cava, and brachiocephalic veins. Thrombophilia evaluation revealed triple-positive lupus anticoagulant, β-2 glycoprotein IgM, IgA, and anticardiolipin antibodies (each &gt;40 U/mL) with persistently positive titers after 12 weeks. She was refractory to multiple anticoagulants alone (enoxaparin, fondaparinux, apixaban, rivaroxaban, and warfarin) with antiplatelet (aspirin and clopidogrel) and adjunctive therapies (hydroxychloroquine, immunosuppression with steroids and rituximab, and plasmapheresis). Despite these, she continued to develop recurrent thrombosis and additionally developed hepatic infarction and pulmonary embolism with failure to decrease titers after 6 weeks of plasma exchange. Following this event, eculizumab (600 mg weekly × 4 weeks followed by 900 mg every 2 weeks) was initiated in combination with fondaparinux, aspirin, clopidogrel, and hydroxychloroquine. She has remained on this regimen without recurrence of thrombosis. Our case suggests that eculizumab may have a role as a therapeutic option in refractory thrombosis in APS.
Practical recommendations for implementing a Bayesian adaptive phase I design during a pandemic
Authors: Ewings Sean , Saunders Geoff , Jaki Thomas , Mozgunov Pavel 
Published: January 2022

Abstract
Background
Modern designs for dose-finding studies (e.g., model-based designs such as continual reassessment method) have been shown to substantially improve the ability to determine a suitable dose for efficacy testing when compared to traditional designs such as the 3 + 3 design. However, implementing such designs requires time and specialist knowledge.

Methods
We present a practical approach to developing a model-based design to help support uptake of these methods; in particular, we lay out how to derive the necessary parameters and who should input, and when, to these decisions. Designing a model-based, dose-finding trial is demonstrated using a treatment within the AGILE platform trial, a phase I/II adaptive design for novel COVID-19 treatments.

Results
We present discussion of the practical delivery of AGILE, covering what information was found to support principled decision making by the Safety Review Committee, and what could be contained within a statistical analysis plan. We also discuss additional challenges we encountered in the study and discuss more generally what (unplanned) adaptations may be acceptable (or not) in studies using model-based designs.

Conclusions
This example demonstrates both how to design and deliver an adaptive dose-finding trial in order to support uptake of these methods.