bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risks of use and non-use of antibiotics in primary care: qualitative study of prescribers’ views
Authors: Boiko Olga , Burgess Caroline , Fox Robin , Ashworth Mark , Gulliford Martin C 
Published: October 2020

PurposeThe emergence of antimicrobial resistance has led to increasing efforts to reduce unnecessary use of antibiotics in primary care, but potential hazards from bacterial infection continue to cause concern. This study investigated how primary care prescribers perceive risk and safety concerns associated with reduced antibiotic prescribing.MethodsQualitative study using semistructured interviews conducted with primary care prescribers from 10 general practices in an urban area and a shire town in England. A thematic analysis was conducted.ResultsThirty participants were recruited, including twenty-three general practitioners, five nurses and two pharmacists. Three main themes were identified: risk assessment, balancing treatment risks and negotiating decisions and risks. Respondents indicated that their decisions were grounded in clinical risk assessment, but this was informed by different approaches to antibiotic use, with most leaning towards reduced prescribing. Prescribers’ perceptions of risk included the consequences of both inappropriate prescribing and inappropriate withholding of antibiotics. Sepsis was viewed as the most concerning potential outcome of non-prescribing, leading to possible patient harm and potential litigation. Risks of antibiotic prescribing included antibiotic resistant and Clostridium difficile infections, as well as side effects, such as rashes, that might lead to possible mislabelling as antibiotic allergy. Prescribers elicited patient preferences for use or avoidance of antibiotics to inform management strategies, which included educational advice, advice on self-management including warning signs, use of delayed prescriptions and safety netting.ConclusionsAttitudes towards antibiotic prescribing are evolving, with reduced antibiotic prescribing now being approached more systematically. The safety trade-offs associated with either use or non-use of antibiotics present difficulties especially when prescribing decisions are inconsistent with patients’ expectations.
Clinical advantage of targeted sequencing for unbiased tumor mutational burden estimation in samples with low tumor purity
Authors: Hong Tae Hee , Cha Hongui , Shim Joon Ho , Lee Boram , Chung Jongsuk , Lee Chung , Kim Nayoung K D , Choi Yoon-La , Hwang Soohyun , Lee Yoomi , Park Sehhoon , Jung Hyun Ae , Kim Ji-Yeon , Park Yeon Hee , Sun Jong-Mu , Ahn Jin Seok , Ahn Myung-Ju , Park Keunchil , Lee Se-Hoon , Park Woong-Yang 
Published: October 2020

BackgroundTumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored.MethodsWe comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker’s predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156).ResultsLow tumor purity was common (range 30%–45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (p<0.001). We found that wTMB was significantly underestimated in low purity samples with a large proportion of clonal variants undetected by whole-exome sequencing. Interestingly, pTMB more accurately predicted progression-free survival (PFS) after immunotherapy than wTMB owing to its superior performance in the low tumor purity subgroup (p=0.054 vs p=0.358). Multivariate analysis revealed pTMB (p=0.016), but not wTMB (p=0.32), as an independent predictor of PFS even in low-purity samples. The net reclassification index using pTMB was 21.7% in the low-purity subgroup (p=0.016).ConclusionsOur data suggest that TMB characterization with targeted deep sequencing might have potential strength in predicting ICI responsiveness due to its enhanced sensitivity for hard-to-detect variants at low-allele fraction. Therefore, pTMB could act as an invaluable biomarker in the setting of both clinical trials and practice outside of trials based on its reliable performance in mitigating the purity-related bias.
Prediction of death after endovascular thrombectomy in the extended window: a secondary analysis of DEFUSE 3 "
Authors: Taussky Philipp , Agnoletto Guilherme , Grandhi Ramesh , Alexander Matthew D , Wong Ka-Ho , Albers Gregory W , de Havenon Adam 
Published: October 2020

BackgroundThe Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE 3) clinical trial assessed the use of endovascular thrombectomy (EVT) during the period 6–16 hours after last normal in selected patients. This is a secondary cohort analysis of the DEFUSE 3 data assessing potential predictive variables for mortality in the EVT-treated patients.MethodsThe primary outcome was death within 90 days. Patients who died and those who did not were compared statistically. We developed a predictive score using preprocedural variables that were statistically predictive of death in univariate regression analysis (P<0.1).ResultsOf the 182 patients in the DEFUSE 3 study, 92 (mean age 69 years; 50% male) met our inclusion criteria, and 15.2% of these patients met the primary outcome. Patient age, baseline National Institutes of Health Stroke Scale (NIHSS) score, wake-up stroke, statin use, and history of diabetes were statistically associated with death. Statin use did not improve the prediction score so was excluded. Thus, our model included four predictors, with one point each given for age >75 years, NIHSS ≥20, wake-up stroke, and diabetes, yielding low (0–1), moderate (2), and high (3–4) risk of death. In the low-risk, moderate-risk, and high-risk categories, 2/52 (3.9%), 3/23 (13.0%), and 9/17 (52.9%) of patients died, respectively (P<0.001).ConclusionsDespite selective inclusion criteria and overwhelming benefit for EVT, a substantial number of EVT patients in DEFUSE 3 died. The preprocedural variables age, NIHSS, wake-up stroke, and diabetes may predict this risk. Our predictive score provides a basis for future research to determine which factors influence lethal outcome after EVT.
Impact of insurance type on national variation in cost of endovascular treatment for unruptured cerebral aneurysms
Authors: Lan Matthews , Liles Campbell , Patel Pious D , Gannon Stephen R , Chitale Rohan V 
Published: October 2020

BackgroundIdentifying drivers of nationwide variation in healthcare costs could help reduce overall cost. Endovascular treatment for unruptured cerebral aneurysms (ETUCR) is an elective neurointerventional procedure that allows for detailed analysis of cost variation. This study aimed to investigate the role of insurance type in cost variation of ETUCR.MethodsA retrospective analysis of patients undergoing ETUCR was done. Demographic and hospital data were obtained from the National Inpatient Sample 2012–2015. Multivariate analysis was done using a generalized linear model. Oaxaca–Blinder decomposition was performed to identify factors driving cost variation.ResultsThere was a significant difference in median cost ($25 331.82 vs $25 825.25, respectively, P<0.001) as well as length of stay (P<0.001) and complications (P<0.001) between patients with private insurance and Medicare. In multivariate analysis, insurance type was not predictive of increased cost. Among patients aged 65–75 years there was a higher median cost with private insurance compared to Medicare ($28 373.85 vs $25 558.25, respectively, P<0.001) but no difference in complications or length of stay. Oaxaca–Blinder decomposition showed higher marginal costs associated with private insurance patients at hospitals with greater endovascular operative volume (P=0.015).ConclusionsIn patients aged 65–75 years, private insurance is associated with higher costs compared to Medicare; however, insurance type is not predictive of increased cost in multivariate analysis. Differential treatment of private insurance and Medicare patients at hospitals with greater operative volume seems to influence this difference, likely due to differential reimbursement schemes that lead to weaker cost controls.
Rescue carotid puncture for ischemic stroke treated by endovascular therapy: a multicentric analysis and systematic review
Authors: Allard Julien , Ghazanfari Sam , Mahmoudi Mehdi , Labreuche Julien , Escalard Simon , Delvoye François , Ciccio Gabriele , Smajda Stanislas , Redjem Hocine , Hebert Solène , Consoli Arturo , Costalat Vincent , Desilles Jean-Philippe , Mazighi Mikael , Piotin Michel , Dargazanli Cyril , Lapergue Bertrand , Blanc Raphaël , Maïer Benjamin 
Published: October 2020

BackgroundEndovascular therapy (EVT) for acute ischemic stroke (AIS) can be challenging in older patients with supra-aortic tortuosity. Rescue carotid puncture (RCP) can be an alternative in case of supra-aortic catheterization failure by femoral access, but data regarding RCP are scarce. We sought to investigate the feasibility, effectiveness and safety of RCP for AIS treated by EVT.MethodsPatients treated by EVT with RCP were included from January 2012 to December 2019 in the Endovascular Treatment in Ischemic Stroke (ETIS) multicentric registry. Main outcomes included reperfusion rates ( ≥ TICI2B), 3 month functional outcome (modified Rankin Scale) and 3 month mortality. We also performed an additional systematic review of the literature according to the PRISMA checklist to summarize previous studies on RCP.Results25 patients treated by EVT with RCP were included from the ETIS registry. RCP mainly concerned elderly patients (median age 85 years, range 73–92) with supra-aortic tortuosity (n=16 (64%)). Intravenous thrombolysis (IVT) was used for nine patients (36%). Successful reperfusion was achieved in 64%, 87.5% of patients were dependent at 3 months, and 3 month mortality was 45.8%. The systematic review yielded comparable results. In pooled individual data, there was a shift toward better functional outcome in patients with successful reperfusion (median (IQR) 4 (2–6) vs 6 (4–6), p=0.011).ConclusionRCP mainly concerned elderly patients admitted for AIS with anterior LVO with supra-aortic tortuosity. The procedure seemed feasible, notably for patients treated with IVT, and led to significant reperfusion rates at the end of procedure, but with pronounced unfavorable outcomes at 3 months. RCP should be performed under general anesthesia to avoid life-threatening complications and ensure airways safety. Finally, RCP led to low rates of closure complications, emphasizing that this concern should not withhold RCP, if indicated.
Postcastration adhesions: clinical signs, diagnosis, treatment and prognosis in 20 horses
Authors: Robert Mickael Patrice , Couturier Fleur , McGeown Poppy , Geffroy Olivier , Tessier Caroline 
Published: October 2020

The main goal of this short communication is to report the clinical signs, diagnostic modalities, surgical treatment and prognosis associated with postcastration adhesions. Twenty horses, castrated on average 30 months prior, presented for back pain, hindlimb lameness, jumping problems, behavioural issues or persistent preputial oedema. Cases displayed a tight fibrous band between the scrotal scar and the superficial inguinal ring. After a complete lameness examination was performed, all horses were operated under general anaesthesia in dorsal recumbency to resect the adhesions using two different techniques. Particular attention was given to haemostasis and to minimise tissue trauma. Five horses were lost to follow‐up. Subjective improvement occurred between one week and six months after surgery in 10 out of 12 of the horses according to owners’ evaluation. Horses with competition records available (n=15) had their first start 180±155 days after surgery. Overall client satisfaction with the technique was good (83 per cent).
Comprehensive Metabolic Phenotyping Refines Cardiovascular Risk in Young Adults
Authors: Murthy Venkatesh L. , Reis Jared P. , Pico Alexander R. , Kitchen Robert , Lima Joao A.C. , Lloyd-Jones Donald , Allen Norrina B. , Carnethon Mercedes , Lewis Gregory D. , Nayor Matthew , Vasan Ramachandran S. , Freedman Jane E. , Clish Clary B. , Shah Ravi V. 
Published: October 2020

Background:
Whereas cardiovascular disease (CVD) metrics define risk in individuals >40 years of age, the earliest lesions of CVD appear well before this age. Despite the role of metabolism in CVD antecedents, studies in younger, biracial populations to define precise metabolic risk phenotypes are lacking.

Methods:
We studied 2330 White and Black young adults (mean age, 32 years; 45% Black) in the CARDIA study (Coronary Artery Risk Development in Young Adults) to identify metabolite profiles associated with an adverse CVD phenome (myocardial structure/function, fitness, vascular calcification), mechanisms, and outcomes over 2 decades. Statistical learning methods (elastic nets/principal components analysis) and Cox regression generated parsimonious, metabolite-based risk scores validated in >1800 individuals in the Framingham Heart Study.

Results:

In the CARDIA study, metabolite profiles quantified in early adulthood were associated with subclinical CVD development over 20 years, specifying known and novel pathways of CVD (eg, transcriptional regulation, brain-derived neurotrophic factor, nitric oxide, renin–angiotensin). We found 2 multiparametric, metabolite-based scores linked independently to vascular and myocardial health, with metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, nitric oxide modulation, and collagen metabolism. The metabolite-based vascular scores were lower in men, and myocardial scores were lower in Black participants. Over a nearly 25-year median follow-up in CARDIA, the metabolite-based vascular score (hazard ratio, 0.68 per SD [95% CI, 0.50–0.92];
P
=0.01) and myocardial score (hazard ratio, 0.60 per SD [95% CI, 0.45–0.80];
P
=0.0005) in the third and fourth decades of life were associated with clinical CVD with a synergistic association with outcome (
P
interaction
=0.009). We replicated these findings in 1898 individuals in the Framingham Heart Study over 2 decades, with a similar association with outcome (including interaction), reclassification, and discrimination. In the Framingham Heart Study, the metabolite scores exhibited an age interaction (
P
=0.0004 for a combined myocardial–vascular score with incident CVD), such that young adults with poorer metabolite-based health scores had highest hazard of future CVD.

Conclusions:
Metabolic signatures of myocardial and vascular health in young adulthood specify known/novel pathways of metabolic dysfunction relevant to CVD, associated with outcome in 2 independent cohorts. Efforts to include precision measures of metabolic health in risk stratification to interrupt CVD at its earliest stage are warranted.
Graph-Guided Regularized Regression of Pacific Ocean Climate Variables to Increase Predictive Skill of Southwestern U.S. Winter Precipitation
Authors: Stevens Abby , Willett Rebecca , Mamalakis Antonios , Foufoula-Georgiou Efi , Tejedor Alejandro , Randerson James T. , Smyth Padhraic , Wright Stephen 
Published: October 2020

AbstractUnderstanding the physical drivers of seasonal hydroclimatic variability and improving predictive skill remains a challenge with important socioeconomic and environmental implications for many regions around the world. Physics-based deterministic models show limited ability to predict precipitation as the lead time increases, due to imperfect representation of physical processes and incomplete knowledge of initial conditions. Similarly, statistical methods drawing upon established climate teleconnections have low prediction skill due to the complex nature of the climate system. Recently, promising data-driven approaches have been proposed, but they often suffer from overparameterization and overfitting due to the short observational record, and they often do not account for spatiotemporal dependencies among covariates (i.e., predictors such as sea surface temperatures). This study addresses these challenges via a predictive model based on a graph-guided regularizer that simultaneously promotes similarity of predictive weights for highly correlated covariates and enforces sparsity in the covariate domain. This approach both decreases the effective dimensionality of the problem and identifies the most predictive features without specifying them a priori. We use large ensemble simulations from a climate model to construct this regularizer, reducing the structural uncertainty in the estimation. We apply the learned model to predict winter precipitation in the southwestern United States using sea surface temperatures over the entire Pacific basin, and demonstrate its superiority compared to other regularization approaches and statistical models informed by known teleconnections. Our results highlight the potential to combine optimally the space–time structure of predictor variables learned from climate models with new graph-based regularizers to improve seasonal prediction.
Managing renal forniceal rupture secondary to ureteric calculi in line with the NICE 2019 Renal and Ureteric Stone Guidelines
Authors: Harvey NJ , Rudman HA , Gall ZJ 
Published: October 2020

Objective: To synthesise all available data to determine the best management for urolithiasis-related renal forniceal rupture (RFR), with particular reference to the National Institute for Health and Care Excellence (NICE) 2019 Renal and Ureteric Stone Guidelines. Methods: PubMed search to March 2020 using permutations of renal, forniceal, fornix, calyceal, calyx and rupture. Non-English abstracts, editorial comments, letters to the editor and abstracts of conference proceedings were excluded. Results: An initial PubMed search retrieved 126 titles which were screened for relevance and five further titles were added from associated references. 64 abstracts were subsequently assessed, with 25 articles proceeding to full paper review. Conclusions: In cases of RFR secondary to ureteric calculi, management options, including conservative management, for the stone should be considered without the decision being influenced by the presence of the rupture. Perirenal abscesses secondary to RFR are rare, occurring in less than 0.25% of cases. Evidence supports restricting antibiotic prophylaxis to patients with a history of recurrent urinary tract infections or a positive urine culture, in line with the European Association of Urology’s antibiotic stewardship general management principle. RFR is not inherently a contraindication to primary ureteroscopy, which has particularly relevance with the drive to meet the 2019 NICE recommendations. Level of evidence: Not applicable to this literature review.
Inhaled dry powder alginate oligosaccharide in cystic fibrosis: a randomised, double-blind, placebo-controlled, crossover phase 2b study
Authors: van Koningsbruggen-Rietschel Silke , Davies Jane C. , Pressler Tacjana , Fischer Rainald , MacGregor Gordon , Donaldson Scott H. , Smerud Knut , Meland Nils , Mortensen Jann , Fosbøl Marie Ø. , Downey Damian G. , Myrset Astrid H. , Flaten Hugo , Rye Philip D. 
Published: October 2020

BackgroundOligoG is a low molecular-weight alginate oligosaccharide that improves the viscoelastic properties of cystic fibrosis (CF) mucus and disrupts biofilms, thereby potentiating the activity of antimicrobial agents. The efficacy of inhaled OligoG was evaluated in adult patients with CF.MethodsA randomised, double-blind, placebo-controlled multicentre crossover study was used to demonstrate safety and efficacy of inhaled dry powder OligoG. Subjects were randomly allocated to receive OligoG 1050 mg per day (10 capsules three times daily) or matching placebo for 28 days, with 28-day washout periods following each treatment period. The primary end-point was absolute change in percentage predicted forced expiratory volume in 1 s (FEV1) at the end of 28-day treatment. The intention-to-treat (ITT) population (n=65) was defined as randomised to treatment with at least one administration of study medication and post-dosing evaluation.ResultsIn this study, 90 adult subjects were screened and 65 were randomised. Statistically significant improvement in FEV1was not observed in the ITT population. Adverse events included nasopharyngitis, cough and pulmonary exacerbation. The number and proportions of patients with adverse events and serious adverse events were similar between OligoG and placebo group.ConclusionsInhalation of OligoG-dry powder over 28 days was safe in adult CF subjects. Statistically significant improvement of FEV1was not reached. The planned analyses did not indicate a significant treatment benefit with OligoG compared to placebo.Post hocexploratory analyses showed subgroup results that indicate that further studies of OligoG in this patient population are justified.
Impact of season and geography on CompEx Asthma: a composite end-point for exacerbations
Authors: Jauhiainen Alexandra , Scheepers Lieke E.J.M. , Fuhlbrigge Anne L. , Harrison Tim , Zangrilli James , Garcia Gil Esther , Gustafson Per , Fagerås Malin , Da Silva Carla A. 
Published: October 2020

BackgroundCompEx Asthma, a novel composite end-point combining severe exacerbations (SevEx) with asthma-worsening events, was recently developed. Further characterisation of CompEx Asthma is needed to illustrate the applicability of this end-point. The objective was to evaluate CompEx Asthma as a rate end-point to determine how seasonal and geographical factors impact this novel outcome.MethodsSeven 24–56-week randomised controlled trials of budesonide/formoterol (BUD/FORM) and benralizumab were analysed. Annualised event rates (AERs) and treatment effects (hazard ratio (HR)) were analysed with Poisson and Andersen–Gill models, respectively. Seasonality was analysed by month and five geographical regions were evaluated.ResultsThe studies included 10 815 patients (63% female, mean age 42–49 years). CompEx Asthma AER mirrored seasonal variations in SevEx AER. CompEx Asthma AERs were higherversusSevEx in BUD/FORM and benralizumab trials (range 2.7–4.5-fold and 1.3–2.0-fold increase, respectively) and were less variableversusSevEx between regions (ratios of greatest:smallest AERs: 1.36 for CompExversus2.28 for SevEx (BUD/FORM); 1.81 for CompExversus2.22 for SevEx (benralizumab)). Treatment effects for CompEx Asthma and SevEx were generally similar across regions and months. However, in Eastern Europe, where SevEx rates were lowest, treatment effect was greater with CompEx AsthmaversusSevEx, reaching statistical significance in the benralizumab studies (HR (95% CI): 0.67 (0.53–0.85)versus0.87 (0.65–1.15)).ConclusionThis study confirmed the reliability of CompEx Asthma as a rate end-point and allowed detection of variations in seasonal SevEx rates, reduction of variation in rates across regions and potential greater sensitivity to treatment effects.