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Along with other canonical systems, the renin-angiotensin system (RAS) has shown essential roles in stress. This system is a complex regulatory proteolytic cascade composed of various enzymes, peptides, and receptors. Besides the classical (ACE/Ang II/AT 1 receptor) and the counter-regulatory (ACE2/Ang-(1-7)/Mas receptor) RAS axes, evidence indicates that non-classical components, including Ang III, Ang IV, AT 2, and AT 4, can also be involved in stress. Objective and methods: This comprehensive review summarizes the current knowledge on the participation of RAS components in different adverse environmental stimuli stressors, including air-jet stress, cage switch stress, restraint stress, chronic unpredictable stress, neonatal isolation stress, and post-traumatic stress disorder. Results and conclusion: In general, activating the classical RAS axis potentiates stress-related cardiovascular, endocrine, and behavioral responses, while the stimulation of the counter-regulatory axis attenuates these effects. Pharmacological modulation in both axes is optimistic, offering promising perspectives for stress-related disorders treatment. In this regard, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are potential candidates already available because they block the classical axis, activate the counter-regulatory axis, and are safe and efficient drugs.

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To investigate the association between cytokine peripheral levels and the risk of cardiovascular disease in patients with schizophrenia and controls.A sample of 40 patients and 40 control subjects participated in the study. Psychiatric diagnosis was established following structured clinical assessment. The Framingham Score was used to assess cardiovascular risk (CVR). Serum levels of the cytokines IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were determined by cytometric bead array (CBA) technique, and the serum levels of IL-33, sST2, sTNFR1, sTNFR2, Leptin and Adiponectin by Enzyme-Linked Immunosorbent assay (ELISA).Patients with schizophrenia showed greater frequency of moderate CVR when compared with controls (p = 0.14). In addition, patients showed higher levels of sTNFR2 and Adiponectin compared to controls (p = 0.007 and p 0.001, respectively). Adiponectin and sTNFR2 were associated with CVR only in patients (p = 0.0002 and p = 0.033, respectively). In multivariate analysis controlling for socio-demographic and clinical confounders, illness duration (r = 0.492; p 0.002) and sTNFR2 (r = 0.665; p 0.004) were independent predictors of CVR.Our results reinforce the concept that patients with schizophrenia are at greater risk to develop cardiovascular diseases, and suggest that the associated chronic low-grade inflammation might play a role in this process.

In recent years, deep learning methods have been introduced for segmentation and classification of leaf lesions caused by pests and pathogens. Among the commonly used approaches, convolutional neural networks have provided results with high accuracy. The purpose of this work is to present an effective and practical system capable of segmenting and classifying different types of leaf lesions and estimating the severity of stress caused by biotic agents in coffee leaves using convolutional neural networks. The proposed approach consists of two stages: a semantic segmentation stage with severity calculation and a symptom lesion classification stage. Each stage was tested separately, highlighting the positive and negative points of each one. We obtained very good results for the severity estimation, suggesting that the model can estimate severity values very close to the real values. For the biotic stress classification, the accuracy rates were greater than 97%. Due to the promising results obtained, an App for Android platform was developed and implemented, consisting of semantic segmentation and severity calculation, as well as symptom classification to assist both specialists and farmers to identify and quantify biotic stresses using images of coffee leaves acquired by smartphone.

Background The prediction of in-hospital mortality for ICU patients with COVID-19 is fundamental to treatment and resource allocation. The main purpose was to develop an easily implemented score for such prediction. Methods This was an observational, multicenter, development, and validation study on a national critical care dataset of COVID-19 patients. A systematic literature review was performed to determine variables possibly important for COVID-19 mortality prediction. Using a logistic multivariable model with a LASSO penalty, we developed the Rapid Evaluation of Coronavirus Illness Severity (RECOILS) score and compared its performance against published scores. Results Our development (validation) cohort consisted of 1480 (937) adult patients from 14 (11) Dutch ICUs admitted between March 2020 and April 2021. Median age was 65 (65) years, 31% (26%) died in hospital, 74% (72%) were males, average length of ICU stay was 7.83 (10.25) days and average length of hospital stay was 15.90 (19.92) days. Age, platelets, PaO2/FiO2 ratio, pH, blood urea nitrogen, temperature, PaCO2, Glasgow Coma Scale (GCS) score measured within +/−24 h of ICU admission were used to develop the score. The AUROC of RECOILS score was 0.75 (CI 0.71–0.78) which was higher than that of any previously reported predictive scores (0.68 [CI 0.64–0.71], 0.61 [CI 0.58–0.66], 0.67 [CI 0.63–0.70], 0.70 [CI 0.67–0.74] for ISARIC 4C Mortality Score, SOFA, SAPS-III, and age, respectively). Conclusions Using a large dataset from multiple Dutch ICUs, we developed a predictive score for mortality of COVID-19 patients admitted to ICU, which outperformed other predictive scores reported so far., Acta Anaesthesiologica Scandinavica, 66 (1), ISSN:0001-5172, ISSN:1399-6576

PURPOSE: We describe the large-scale self-initiated recruitment of patients to a self-monitoring initiative for macular pathologic features during the coronavirus disease 2019 (COVID-19) pandemic. DESIGN: Observational study with retrospective analysis. PARTICIPANTS: A total of 2272 patients from the Singapore National Eye Centre (SNEC) whose visits were rescheduled over lockdown (April 13-June 1, 2020) were offered participation in a self-monitoring initiative administered by SNEC with the Alleye application (Switzerland) as the testing instrument. METHODS: This was an observational study with retrospective analysis. Demographics and characteristics were compared between those who signed up and those who did not. Similar comparisons were made between patients who complied with the initiative versus those who did not. Outcomes were tracked for 6 months starting from the commencement of lockdown. MAIN OUTCOME MEASURES: Participation and compliance rates and characteristics of patients who were more likely to participate and comply with the initiative. RESULTS: Seven hundred thirty-two patients (32%) participated in this self-monitoring initiative. Those who participated were younger (62 years of age vs. 68 years of age; P < 0.001), men, and living with family. Patients not receiving treatment and those with poorer vision in the worse-seeing eye were more likely to participate. When grouped according to diagnosis, the proportion who participated was highest for diabetic macular edema (52%), nonneovascular age-related macular degeneration (AMD; 42%), diabetic retinopathy (35%), retinal vein occlusions (18%), and neovascular AMD (15%; P < 0.001). Testing compliance rate was 43% (315/732). Patients who complied with the initiative were older, were receiving treatment, and had poorer vision in the worse-seeing eye. Trigger events occurred in 33 patients, with 5 patients having clinically verified disease progression (1.6%). CONCLUSIONS: We provide clinical data on characteristics of patients with stable retinal diseases who were offered, participated in, and complied with a self-monitoring program. The lower participation rate compared with standardized clinical studies reflects the difficulties in implementation for such initiatives in clinical settings. Despite this, self-monitoring continues to show promise in relieving clinic resources, suggesting the feasibility of scaling such programs beyond the COVID-19 pandemic.

Purpose To evaluate the predictive usefulness of quantitative imaging biomarkers, acquired automatically from OCT scans, of cross-sectional and future visual outcomes of patients with neovascular age-related macular degeneration (AMD) starting anti–vascular endothelial growth factor (VEGF) therapy. Design Retrospective cohort study. Participants Treatment-naive, first-treated eyes of patients with neovascular AMD between 2007 and 2017 at Moorfields Eye Hospital (a large, United Kingdom single center) undergoing anti-VEGF therapy. Methods Automatic segmentation was carried out by applying a deep learning segmentation algorithm to 137 379 OCT scans from 6467 eyes of 3261 patients with neovascular AMD. After applying selection criteria, 926 eyes of 926 patients were analyzed. Main Outcome Measures Correlation coefficients (R2 values) and mean absolute error (MAE) between quantitative OCT (qOCT) parameters and cross-sectional visual function, as well as the predictive value of these parameters for short-term visual change, that is, incremental visual acuity (VA) resulting from an individual injection, as well as VA at distant time points (up to 12 months after baseline). Results Visual acuity at distant time points could be predicted: R2 = 0.80 (MAE, 5.0 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and R2 = 0.7 (MAE, 7.2 ETDRS letters) after injection at 3 and at 12 months after baseline (P Conclusions Automatic segmentation enables rapid acquisition of quantitative and reproducible OCT biomarkers with potential to inform treatment decisions in the care of neovascular AMD. This furthers development of point-of-care decision-aid systems for personalized medicine.

Background Neighborhood-level socioeconomic status (SES) is associated with health outcomes, including cardiovascular disease and diabetes, but these associations are rarely studied across large, diverse populations. Methods We used Ward’s Hierarchical clustering to define eight neighborhood clusters across North Carolina using 11 census-based indicators of SES, race, housing, and urbanicity and assigned 6992 cardiac catheterization patients at Duke University Hospital from 2001 to 2010 to clusters. We examined associations between clusters and coronary artery disease index > 23 (CAD), history of myocardial infarction, hypertension, and diabetes using logistic regression adjusted for age, race, sex, body mass index, region of North Carolina, distance to Duke University Hospital, and smoking status. Results Four clusters were urban, three rural, and one suburban higher-middle-SES (referent). We observed greater odds of myocardial infarction in all six clusters with lower or middle-SES. Odds of CAD were elevated in the rural cluster that was low-SES and plurality Black (OR 1.16, 95% CI 0.94-1.43) and in the rural cluster that was majority American Indian (OR 1.31, 95% CI 0.91-1.90). Odds of diabetes and hypertension were elevated in two urban and one rural low- and lower-middle SES clusters with large Black populations. Conclusions We observed higher prevalence of cardiovascular disease and diabetes in neighborhoods that were predominantly rural, low-SES, and non-White, highlighting the importance of public health and healthcare system outreach into these communities to promote cardiometabolic health and prevent and manage hypertension, diabetes and coronary artery disease.

To evaluate the association of various gene expression assays with pathologic complete response (pCR) in the setting of neoadjuvant chemotherapy among patients with breast cancer The National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with stage I-III breast cancer who underwent neoadjuvant chemotherapy and either 21-gene recurrence score (RS) or 70-gene signature (GS). Logistic multivariable analysis (MVA) was performed to identify variables associated with pCR. A total of 3009 patients met our inclusion criteria. The median follow up was 48.0 months (interquartile range 32.2–66.7 months). On logistic MVA for all patients, those with a high risk from GS (adjusted odds ratio [aOR] 3.23, 95% confidence interval [CI] 1.49–8.13, p = 0.006) or with RS ≥ 31 (aOR 1.99, 95% CI 1.41–2.82, p

Purpose To assess the preoperative objective angle alpha and angle kappa measurements of patients deciding to undergo multifocal refractive lens surgery based on a subjective positive multifocal contact lens test (MCLT). Methods Retrospective, consecutive case series. Alpha and kappa angles were measured using the iTrace aberrometer. All patients also performed a 1-week MCLT. Only patients with a positive MCLT underwent surgery. Visual outcome (UCVA) was obtained in the 1-year follow-up. We assessed the preoperative distribution of angle values within MCLT positive and negative patient groups. Results Two hundred seventeen eyes (111 patients) were included. Mean age was 56.4 years (SD 5.6) and 46.9% were female. In 71 eyes (38 patients), MCLT was positive. Of them, 12 eyes (17%) had an angle alpha and angle kappa ≥ 0.5mm. Of 146 eyes (73 patients) who refrained from surgery due to a negative MCLT, 71 eyes (48.6%) had both angles small (pn=24) with high alpha but low kappa sizes improved less (−0.31 logMAR (SD 0.13; p=0.019)). Conclusion Four out of five patients with a positive MCLT also had correspondingly small angle values. One-half of patients with low preoperative angle values refrained from surgery due to a negative MCLT result. One-year visual acuity improvement was substantial and independent from angle sizes.

Wireless communication systems play an essential role in everyday life situations and enable a wide range of location-based services to their users. The imminent adoption of 5G networks worldwide and the future establishment of next-generation wireless networks will allow various applications, such as autonomous vehicles, connected robotics, and most recently, crowd monitoring for fighting infectious diseases, such as COVID-19. In this context, radio localization techniques have become an essential tool to provide solid performance for mobile positioning systems, through increased accuracy or less computational time. With this in mind, we propose a trilateration-based approach using machine learning (ML) and sequential least-square programming (SLSQP) optimization to estimate the outdoor position of mobile terminals in cellular networks. The ML technique employed is the k -nearest neighbors ( k -NN). The optimization methods analyzed are Nelder–Mead (NM), genetic algorithms (GA), and SLSQP. Different environments (noise-free and noisy) and network scenarios (different numbers of base stations) are considered to evaluate the approaches. Numerical results indicate that the k -NN/SLSQP technique has similar accuracy compared to the k -NN/GA with eight generations. Both perform better than k -NN/NM in all scenarios and environments. When comparing computational times, our proposal is considerably more time-efficient. Aside from that, SLSQP computational time is less affected by network scenarios with more base stations in comparison with GA. That feature is significant considering the ultra-dense base station deployment forecasted for the next-generation cellular networks.

Introduction Every year drowning is responsible for 7% of injury-related deaths worldwide, making it the third leading cause of unintentional injury-related death. However, in the United States, little is known regarding the prehospital presentation and management of these patients. The purpose of this study was to describe the drowning population in the United States, with a focus on prehospital time intervals, transport, and cardiac arrest frequency. Methods A retrospective cross-sectional study was performed querying records from emergency medical services encounters across the United States over 30 mo (January 2016 to July 2018) using the ESO (Austin, TX) national emergency medical services data registry. Patients with a dispatch or chief complaint of drowning were included. Descriptive statistics, binomial proportion tests, and general linear and logistic regression models were used. Results There were 1859 encounters that met the study criteria. Median age was 18 y (n=1855, LQ-UQ 4–46). Pediatric patients accounted for 50% (n=919, 95% CI 47–52). Cardiac arrest occurred in 29% (n=537, 95% CI 27–31), and return of spontaneous circulation occurred in 37% (n=186, 95% CI 32–41). Times were 8±5, 19±17, and 15±10 min (mean±SD) for arrival, on-scene, and transport times, respectively. Conclusions This national prehospital drowning study demonstrated that despite an 18% fatality rate in drowning encounters, patients were more likely to have return of spontaneous circulation when compared to the overall prehospital national average, with rates higher in pediatric patients. Future studies with outcomes data should focus on identifying factors that improve cardiopulmonary resuscitation success rates.

Background: Histopathologic studies have demonstrated differential amyloid-β (Aβ) burden between cortical sulci and gyri in Alzheimer’s disease (AD), with sulci having a greater Aβ burden. Objective: To characterize Aβ deposition in the sulci and gyri of the cerebral cortex in vivo among subjects with normal cognition (NC), mild cognitive impairment (MCI), and AD, and to evaluate if these differences could improve discrimination between diagnostic groups. Methods: T1-weighted 3T MR and florbetapir (amyloid) positron emission tomography (PET) data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). T1 images were segmented and the cortex was separated into sulci/gyri based on pial surface curvature measurements. T1 images were registered to PET images and regional standardized uptake value ratios (SUVr) were calculated. A linear mixed effects model was used to analyze the relationship between clinical variables and amyloid PET SUVr measurements in the sulci/gyri. Receiver operating characteristic (ROC) analysis was performed to define amyloid positivity. Logistic models were used to evaluate predictive performance of clinical diagnosis using amyloid PET SUVr measurements in sulci/gyri. Results: 719 subjects were included: 272 NC, 315 MCI, and 132 AD. Gyral and sulcal Aβ increased with worsening cognition, however there was a greater increase in gyral Aβ. Females had a greater gyral and sulcal Aβ burden. Focusing on sulcal and gyral Aβ did not improve predictive power for diagnostic groups. Conclusion: While there were significant differences in Aβ deposition in cerebral sulci and gyri across the AD spectrum, these differences did not translate into improved prediction of diagnosis. Females were found to have greater gyral and sulcal Aβ burden.

Background Providing accurate 3-dimensional virtual bone surface models is a prerequisite for virtual surgical planning and additive manufacturing in craniomaxillofacial surgery. For this purpose, magnetic resonance imaging (MRI) may be a radiation-free alternative to computed tomography (CT) and cone beam computed tomography (CBCT). Purpose The aim of this study was to assess the geometric accuracy of 3-dimensional T1-weighted MRI-derived virtual bone surface models of the mandible in comparison to CT and CBCT. Materials and methods Specimens of the mandible from porcine cadavers were scanned with (1) a 3-dimensional T1-weighted MRI sequence (0.6 mm isotropic voxel) optimized for bone imaging, (2) CT, and (3) CBCT. Cortical mandibular structures (n = 10) were segmented using semiautomated and manual techniques. Imaging-based virtual 3-dimensional models were aligned with a high-resolution optical 3-dimensional surface scan of the dissected bone (=ground truth) and global geometric deviations were calculated (mean surface distance [MSD]/root-mean-square distance [RMSD]). Agreement between the imaging modalities was assessed by equivalence testing and Bland-Altman analysis. Results Intra- and inter-rater agreement was on a high level for all modalities. Global geometric deviations (MSD/RMSD) between optical scans and imaging modalities were 0.225 ± 0.020 mm/0.345 ± 0.074 mm for CT, 0.280 ± 0.067 mm/0.371 ± 0.074 mm for MRI, and 0.352 ± 0.076 mm/0.454 ± 0.071 mm for CBCT. All imaging modalities were statistically equivalent within an equivalence margin of ±0.3 mm, and Bland-Altman analysis indicated high agreement as well. Conclusions The results of this study indicate that the accuracy and reliability of MRI-derived virtual 3-dimensional bone surface models is equal to CT and CBCT. MRI may be considered as a reliable alternative to CT and CBCT in computer-assisted craniomaxillofacial surgery.

This study presents information on the water footprint profile associated with lemon production and its derivatives in the province of Tucuman (Argentina). It follows a life cycle approach considering both water consumption and pollution. Our motivation is the prominent role of this activity in the economy of the region and in the world. The scope of the study covers the agricultural and industrial stages through a “from cradle to gate” approach (from lemon cultivation until production of finished products). The system boundaries include both foreground and background processes involving production and transportation of all material and energy inputs. The functional unit is 1 t of each product considered in the study: fresh fruit, essential oil, concentrated juice, and dehydrated peel. The general system is divided into Agriculture, Preselection, Packing, and Industry. Most of the data used stems from local sources to ensure representativeness. For the impact assessment, water scarcity, ecotoxicity, eutrophication, acidification, and human toxicity midpoint indicators are calculated. The analysis shows that the annual production and processing of lemons have an impact on water scarcity of 1·108 m3 world eq. The results for freshwater ecotoxicity, freshwater eutrophication, freshwater acidification, and human toxicity (non-cancer) are 3.60·106 CTUe, 4.87·t P eq, 5.92·10−1 kg SO2 eq, and 2.05·10−3 CTUh, respectively. For all lemon-based products, the indicator of water scarcity strongly depends on the irrigation water in the orchards. For water degradation, the most influential processes are the use and production of agrochemicals. In all cases, the agricultural stage is crucial in the water footprint profile of the finished products. The processes identified as hotspots through the water footprint profile of the products are as follows: irrigation, use, and production of N fertilizers and pesticides (copper compounds, abamectin and glyphosate), manufacturing of packaging material for fresh fruit, and consumption of natural gas. These should be addressed by lemon growers and manufacturers with preferential attention. Being the first local water footprint profile of Argentine lemons, this work is expected to serve as a baseline to provide diagnostic and improvement opportunities in the citrus sector for public and private stakeholders.

Objectives Systemic lupus erythematosus (SLE) is a systemic autoimmune disease associated with neuro-psychiatric (NP) manifestations. Frequency and patterns of neuro-psychiatric systemic lupus erythematosus (NPSLE) vary substantially between patients. We conducted a systematic review (SR) of the literature and examined prevalence and characteristics of NPSLE in the Swiss SLE cohort study (SSCS). Methods The SR search was performed between January 1999 and January 2020. We included prospective/cross-sectional studies focusing on NPSLE. We secured study characteristics, cohort compositions and frequencies of NP manifestations, assessed heterogeneity across reports and investigated sources of variation using meta-regression models. Regarding the SSCS, we reviewed all patients included and classified NP manifestations. Results The SR searches identified 530 studies. We included 22 studies in our meta-analysis, the mean frequency of NPSLE ranged from 10.6% to 96.4%. The frequency of NPSLE in the SSCS was 28.1%. Severe events including cerebrovascular insults, seizures and psychosis appeared in 7.1%, 5.3% and 6.5% respectively. There was a linear relationship between duration of SLE and cumulative incidence of NPSLE. Conclusions The spectrum of NPSLE is very broad. The diagnostic work-up and rates of reported manifestations varied substantially across studies. We call for concerted efforts and consensus regarding definitions of NPSLE that will facilitate accurate diagnosis and attribution to SLE, particularly with a view to timely intervention and patient outcomes.

Aim:Induction chemotherapy (iC) followed by concurrent chemoradiation has been shown to improve overall survival (OS) for locally advanced pancreatic cancer (LAPC). However, the survival benefit of stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy (CFRT) following iC remains unclear.Materials and methods:The National Cancer Database (NCDB) was queried for primary stage III, cT4N0-1M0 LAPC (2004–15). Kaplan–Meier analysis, Cox proportional hazards method and propensity score matching were used.Results:Among 872 patients, 738 patients underwent CFRT and 134 patients received SBRT. Median follow-up was 24·3 and 22·9 months for the CFRT and SBRT cohorts, respectively. The use of SBRT showed improved survival in both the multivariate analysis (hazards ratio 0·78, p = 0·025) and 120 propensity-matched pairs (median OS 18·1 versus 15·9 months, p = 0·004) compared to the CFRT.Findings:This NCDB analysis suggests survival benefit with the use of SBRT versus CFRT following iC for the LAPC.

Background The objective of this study was to evaluate the diagnostic value of intraoperative frozen section analysis (IFSA) of tumor bed margins in patients with oral squamous cell carcinoma (OSCC). Methods This retrospective study includes 194 primary OSCC cases. The impact of intraoperative information by IFSA on final margin status, local recurrence, and disease-specific survival were analyzed. Results IFSA revealed a 50% sensitivity and a 100% specificity, with a positive and negative predictive value of 100% and 89.1%, respectively. In 19 cases, margins were rated positive by IFSA and remained positive in eight cases (42.1%), despite immediate re-resection. This constellation led to higher recurrence and lower survival rates than in cases with consecutive R0 status (each p = 0.046). Positive margins in IFSA were associated with closer final margins (p = 0.022) and early recurrences (p = 0.050). Conclusions Achieving instant R0 status has a crucial impact on disease recurrence and patient survival. IFSA falls short to ensure secure definite surgical margins. Thus, improved intraoperative diagnostic information on the location and extent of OSCC could support patient treatment. Clinical relevance Considering that patient survival has not improved despite progress in surgical and adjuvant therapy, the process and outcome of IFSA was scrutinized as one part of the treatment concept.

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Summary This article examines how chemists, pharmacologists and anaesthetists developed the anaesthetic drug halothane and assessed the clinical use of the drug in the UK in the 1950s. I argue that halothane became seen as a superior drug not because of properties inherent in the new molecule CF3-CHClBr, but because anaesthetists used it to build a professional identity during a period of significant change in British medicine. The recently established National Health Service called for increasing the number of anaesthetists and other specialist hospital consultants. In this context, the specialist knowledge, novel technologies and new practices necessary for the safe usage of halothane enabled anaesthetists to forge a profession. The history of this process shows how professionalisation, pharmaceutical change and healthcare reform have interacted to shape knowledge transfer between laboratory and hospital with consequences for experimental ethics and patient safety.

Rationale: Patients with chronic obstructive pulmonary disease (COPD) and anxiety or depression experience more symptoms and exacerbations than patients without these comorbidities. Failure to provide beneficial COPD therapies to appropriate patients (underuse) and provision of potentially harmful therapies to patients without an appropriate indication (overuse) could contribute to respiratory symptoms and exacerbations. Anxiety and depression are known to affect the provision of health services for other comorbid conditions; therefore, underuse or overuse of therapies may explain the increased risk of severe symptoms among these patients. Objectives: To determine whether diagnosed anxiety and depression, as well as significant anxiety and depression symptoms, are associated with underuse and overuse of appropriate COPD therapies. Methods: We analyzed data from a multicenter prospective cohort study of 2,376 participants (smokers and control subjects) enrolled between 2010 and 2015. We identified two subgroups of participants, one at risk for inhaled corticosteroid (ICS) overuse and one at risk for long-acting bronchodilator (LABD) underuse based on the 2011 Global Initiative for Chronic Obstructive Lung Disease statement. Our primary outcomes were self-reported overuse and underuse. Our primary exposures of interest were self-reported anxiety and depression and significant anxiety and depression symptoms. We adopted a propensity-score method with inverse probability of treatment weighting adjusting for differences in prevalence of confounders and performed inverse probability of treatment weighting logistic regression to evaluate all associations between the exposures and outcomes. Results: Among the 1,783 study participants with COPD confirmed by spirometry, 667 (37.4%) did not have an indication for ICS use, whereas 985 (55.2%) had an indication for LABD use. Twenty-five percent (n = 167) of patients reported ICS use, and 72% (n = 709) denied LABD use in each subgroup, respectively. Neither self-reported anxiety and depression nor significant anxiety and depression symptoms were associated with overuse or underuse. At least 50% of patients in both subgroups with significant symptoms of anxiety or depression did not report a preexisting mental health diagnosis. Conclusions: Underuse of LABDs and overuse of ICSs are common but are not associated with comorbid anxiety or depression diagnosis or symptoms. Approximately one-third of individuals with COPD experience anxiety or depression, and most are undiagnosed. There are significant opportunities to improve disease-specific and patient-centered treatment for individuals with COPD.

Rationale: Hypoxemia associated with acute exacerbations of chronic obstructive pulmonary disease (COPD) often resolves with time. Current guidelines recommend that patients recently discharged with supplemental home oxygen after hospitalization should not have renewal of the prescription without assessment for hypoxemia. Understanding patterns of home oxygen reassessment is an opportunity to improve quality and value in home oxygen prescribing and may provide future targets for deimplementation. Objectives: We sought to measure the frequency of home oxygen reassessment within 90 days of hospitalization for COPD and determine the potential population eligible for deimplementation. Methods: We performed a cohort study of patients ≥40 years hospitalized for COPD at five Veterans Affairs facilities who were prescribed home oxygen at discharge. Our primary outcome was the frequency of reassessment within 90 days by oxygen saturation (Sp(O(2))) measurement. Secondary outcomes included the proportion of patients potentially eligible for discontinuation (Sp(O(2)) > 88%) and patients in whom oxygen was discontinued. Our primary exposures were treatment with long-acting bronchodilators, prior history of COPD exacerbation, smoking status, and pulmonary hypertension. We used a mixed-effects Poisson model to measure the association between patient-level variables and our outcome, clustered by site. We also performed a positive deviant analysis using chart review to uncover system processes associated with high-quality oxygen prescribing. Results: A total of 287 of 659 (43.6%; range 24.8–78.5% by site) patients had complete reassessment within 90 days. None of our patient-level exposures were associated with oxygen reassessment. Nearly half of those with complete reassessment were eligible for discontinuation on the basis of Medicare guidelines (43.2%; n = 124/287). When using the newest evidence available by the Long-Term Oxygen Treatment Trial, most of the cohort did not have resting hypoxemia (84.3%; 393/466) and would be eligible for discontinuation. The highest-performing Veterans Affairs facility had four care processes to support oxygen reassessment and discontinuation, versus zero to one at all other sites. Conclusions: Fewer than half of patients prescribed home oxygen after a COPD exacerbation are reassessed within 90 days. New system processes supporting timely reassessment and discontinuation of unnecessary home oxygen therapy could improve the quality and value of care.

Summary Background Urinary tract infections (UTIs) are among the most prevalent microbial diseases and their financial burden on society is substantial. In the context of increasing antibiotic resistance, finding alternative treatments for UTIs is a top priority. We aimed to determine whether intravesical bacteriophage therapy with a commercial bacteriophage cocktail is effective in treating UTI. Methods We did a randomised, placebo-controlled, clinical trial, at the Alexander Tsulukidze National Centre of Urology, Tbilisi, Georgia. Men older than 18 years of age, who were scheduled for transurethral resection of the prostate (TURP), with complicated UTI or recurrent uncomplicated UTI but no signs of systemic infection, were allocated by block randomisation in a 1:1:1 ratio to receive intravesical Pyo bacteriophage (Pyophage; 20 mL) or intravesical placebo solution (20 mL) in a double-blind manner twice daily for 7 days, or systemically applied antibiotics (according to sensitivities) as an open-label standard-of-care comparator. Urine culture was taken via urinary catheter at the end of treatment (ie, day 7) or at withdrawal from the trial. The primary outcome was microbiological treatment response after 7 days of treatment, measured by urine culture; secondary outcomes included clinical and safety parameters during the treatment period. Analyses were done in a modified intention-to-treat population of patients having received at least one dose of the allocated treatment regimen. This trial is registered with ClinicalTrials.gov , NCT03140085 . Findings Between June 2, 2017, and Dec 14, 2018, 474 patients were screened for eligibility and 113 (24%) patients were randomly assigned to treatment (37 to Pyophage, 38 to placebo, and 38 to antibiotic treatment). 97 patients (28 Pyophage, 32 placebo, 37 antibiotics) received at least one dose of their allocated treatment and were included in the primary analysis. Treatment success rates did not differ between groups. Normalisation of urine culture was achieved in five (18%) of 28 patients in the Pyophage group compared with nine (28%) of 32 patients in the placebo group (odds ratio [OR] 1·60 [95% CI 0·45–5·71]; p=0·47) and 13 (35%) of 37 patients in the antibiotic group (2·66 [0·79–8·82]; p=0·11). Adverse events occurred in six (21%) of 28 patients in the Pyophage group compared with 13 (41%) of 32 patients in the placebo group (OR 0·36 [95% CI 0·11–1·17]; p=0·089) and 11 (30%) of 37 patients in the antibiotic group (0·66 [0·21–2·07]; p=0·47). Interpretation Intravesical bacteriophage therapy was non-inferior to standard-of-care antibiotic treatment, but was not superior to placebo bladder irrigation, in terms of efficacy or safety in treating UTIs in patients undergoing TURP. Moreover, the bacteriophage safety profile seems to be favourable. Although bacteriophages are not yet a recognised or approved treatment option for UTIs, this trial provides new insight to optimise the design of further large-scale clinical studies to define the role of bacteriophages in UTI treatment. Funding Swiss Continence Foundation, the Swiss National Science Foundation, and the Swiss Agency for Development and Cooperation. Translations For the Georgian and German translations of the abstract see Supplementary Materials section.

Objective Due to increased risks of overdose fatalities and injuries associated with coprescription of opioids and benzodiazepines, healthcare systems have prioritized deprescribing this combination. Although prior work has examined providers’ perspectives on deprescribing each medication separately, perspectives on deprescribing patients with combined use is unclear. We examined providers’ perspectives on coprescribed opioids and benzodiazepines and identified barriers and facilitators to deprescribing. Design Qualitative study using semistructured interviews. Setting One multisite Veterans Affairs (VA) healthcare system in the United States of America. Subjects Primary care and mental health prescribers, key clinical leaders, clinical pharmacist specialists (N = 39). Methods Interviews were audio-recorded, transcribed, and analyzed using thematic analysis. Themes were identified iteratively, through a multidisciplinary team-based process. Results Analyses identified four themes related to barriers and facilitators to deprescribing: inertia, prescriber self-efficacy, feasibility of deprescribing/tapering, and promoting deprescribing, as well as a fifth theme, consequences of deprescribing. Results highlighted the complexity of deprescribing when multiple prescribers are involved, a need for additional support and time, and concerns about patients’ reluctance to discontinue these medications. Facilitators included agreement with the goal of deprescribing and fear of negative consequences if medications are continued. Providers spoke to how deprescribing efforts impaired patient-provider relationships and informed their decisions not to start patients on these medications. Conclusions Although providers agree with the goal, prescribers’ belief in a limited deprescribing role, challenges with coordination among prescribers, concerns about insufficient time and patients’ resistance to discontinuing these medications need to be addressed for efforts to be successful.

Background The COVID-19 pandemic has a disruptive impact on our society. We therefore conducted a population survey to describe: 1) stress, concerns and quality of life 2) access to healthcare and cancelled/delayed healthcare and 3) productivity during the first 8 weeks of the coronavirus lockdown in the general population. Methods An online cross-sectional survey was conducted in a representative sample after 8 weeks of the coronavirus lockdown in Belgium and the Netherlands. The survey included a series of three validated questionnaires about quality of life delayed/cancelled medical care and productivity loss using validated questionnaires. Results In total, 2099 Belgian and 2058 Dutch respondents completed the survey with a mean age of 46.4 and 42.0 years, respectively. Half of the respondents were female in both countries. A small proportion tested positive for COVID-19, 1.4% vs 4.7%, respectively. The majority of respondents with a medical condition was worried about their current health state due to the pandemic (53%) vs (63%), respectively. Respondents experienced postponed/cancelled care (26%) and were concerned about the availability of medication (32%) for both countries. Productivity losses due to the COVID-19 restrictions were calculated in absenteeism (36%) and presenteeism (30%) for Belgium, and (19%) and (35%) for the Netherlands. Most concerns and productivity losses were reported by respondents with children Conclusions This study describes stress, quality of life, medical resource loss and productivity losses in Belgium and the Netherlands after 8 weeks of coronavirus lockdown. The results underline the burden on society.

One of the significant challenges in the field of drug delivery remains to be insufficient targeting of diseased tissues or cells. While efforts to perform targeted drug delivery by engineered nanoparticles have shown some success, there are underlying targeting, toxicity and immunogenicity challenges. On the other hand, live cells usually have innate targeting mechanisms, and can be used as drug delivery vehicles to increase the efficiency with which a drug accumulates to act on the intended tissue. In some cases, when no native cell types exhibit the desired therapeutic phenotype, preferred outcomes can be achieved by genetically modifying and reprogramming cells with gene circuits. This review highlights recent advances in the use of cells to deliver therapeutics. Specifically, we discuss how red blood cells (RBCs), platelets, neutrophils, mesenchymal stem cells (MSCs), and bacteria have been utilized to advance drug delivery.

Background Accelerated epigenetic age has been proposed as a biomarker of increased aging, which may indicate disruptions in cellular and organ system homeostasis and thus contribute to sensitivity to environmental exposures. Methods Using 497 participants from the CATHGEN cohort, we evaluated whether accelerated epigenetic aging increases cardiovascular sensitivity to traffic-related air pollution (TRAP) exposure. We used residential proximity to major roadways and source apportioned air pollution models as measures of TRAP exposure, and chose peripheral arterial disease (PAD) and blood pressure as outcomes based on previous associations with TRAP. We used Horvath epigenetic age acceleration (AAD) and phenotypic age acceleration (PhenoAAD) as measures of age acceleration, and adjusted all models for chronological age, race, sex, smoking, and socioeconomic status. Results We observed significant interactions between TRAP and both AAD and PhenoAAD. Interactions indicated that increased epigenetic age acceleration elevated associations between proximity to roadways and PAD. Interactions were also observed between AAD and gasoline and diesel source apportioned PM2.5. Conclusion Epigenetic age acceleration may be a biomarker of sensitivity to air pollution, particularly for TRAP in urban cohorts. This presents a novel means by which to understand sensitivity to air pollution and provides a molecular measure of environmental sensitivity.

Acute Kidney Injury (AKI) comprises a rapidly developed renal failure and is associated with high mortality rates. The Renin–Angiotensin System (RAS) plays a pivotal role in AKI, as the over-active RAS axis exerts major deleterious effects in disease progression. In this sense, the conversion of Angiotensin II (Ang II) into Angiotensin-(1-7) (Ang-(1-7)) by the Angiotensin-converting enzyme 2 (ACE2) is of utmost importance to prevent worse clinical outcomes. Previous studies reported the beneficial effects of oral diminazene aceturate (DIZE) administration, an ACE2 activator, in renal diseases models. In the present study, we aimed to evaluate the therapeutic effects of DIZE administration in experimental AKI induced by gentamicin (GM) in rats. Our findings showed that treatment with DIZE improved renal function and tissue damage by increasing Ang-(1-7) and ACE2 activity, and reducing TNF-α. These results corroborate with a raising potential of ACE2 activation as a strategy for treating AKI.

Made available in DSpace on 2022-04-29T08:33:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-03-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Universidade Estadual Paulista Aim: This study aimed to evaluate the association between serum myostatin levels, hospital mortality, and muscle mass and strength following ST-segment elevation myocardial infarction (STEMI). Methods: This was a prospective observational study. Within 48 hours of admission, bioelectrical impedance and handgrip strength were assessed and blood samples collected for myostatin evaluation. Hospital mortality was recorded. A multiple logistic regression model was also constructed, adjusted by parameters that exhibited significant differences in the univariate analysis, to evaluate the association between myostatin levels and hospital mortality. Results: One hundred and two (102) patients were included: mean age was 60.5±10.6 years, 67.6% were male, and 6.9% died during hospital stay. Univariate analysis showed that patients with lower myostatin levels had higher mortality rates. Serum myostatin levels positively correlated with handgrip strength (r=0.355; p

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned., Author summary The 2009 influenza pandemic was a stark reminder that ongoing vigilance is critical to protect the public from an influenza pandemic. The continual evolution of influenza viruses and emergence from animal reservoirs, leads to the need to quickly identify strains that pose a public health risk. In these studies, members of the National Institutes of Allergy and Infectious Diseases (NIAID) Centers for Excellence in Influenza Research and Surveillance (CEIRS) network worked together to demonstrate that the emerging canine H3 influenza viruses posed a low risk to public health and identified several therapeutic options in the event of an emergence. In addition to providing important new basic research, many lessons were learned that may be important in dealing with any emerging disease outbreak.

BACKGROUND The anterior inferior iliac spine (AIIS) prominence is increasingly recognized in the setting of femoroacetabular impingement (FAI). The AIIS prominence may contribute to decreased hip flexion after acetabular reorientation in patients with acetabular dysplasia. AIIS morphologies have been characterized in numerous populations including asymptomatic, FAI, and athletic populations, but the morphology of the AIIS in patients with symptomatic acetabular dysplasia undergoing periacetabular osteotomy (PAO) has not been studied. In acetabular dysplasia, deficiency of the anterosuperior acetabular rim is commonly present and may result in the AIIS being positioned closer to the acetabular rim. Understanding morphological variation of the AIIS in patients with symptomatic dysplasia, and its relationship to dysplasia subtype and severity may aid preoperative planning, surgical technique, and evaluation of postoperative issues after PAO. QUESTIONS/PURPOSES In this study, we sought to determine: (1) the variability of AIIS morphology types in hips with symptomatic acetabular dysplasia and (2) whether the differences in the proportion of AIIS morphologies are present between dysplasia pattern and severity subtypes. METHODS Using our hip preservation database, we identified 153 hips (148 patients) who underwent PAO from October 2013 to July 2015. Inclusion criteria for the current study were (lateral center-edge angle [LCEA] < 20°), Tonnis Grade of 0 or 1 on plain AP radiographs of the pelvis, preoperative low-dose CT scan, and no prior surgery, trauma, neuromuscular, ischemic necrosis, or Perthes-like deformity. A total of 50 patients (50 hips) with symptomatic acetabular dysplasia undergoing evaluation for surgical planning of PAO remained for retrospective evaluation; we used these patients' low-dose CT scans for analysis. The median (range) age of patients in the study was 24 years (13 to 49). Ninety percent (45 of 50) of the hips were in female patients, whereas 10% (5 of 50) were in male patients. The morphology of the AIIS was classified on three-dimensional CT reconstructions according to a previously published classification to define the relationship between the AIIS and the acetabular rim. The morphology of the AIIS was classified as Type I (AIIS well proximal to acetabular rim), Type II (AIIS extending to level of acetabular rim), or Type III (AIIS extending distal to acetabular rim). Acetabular dysplasia subtype was characterized according to a prior protocol as either predominantly an anterosuperior acetabular deficiency, a posterosuperior acetabular deficiency, or a global acetabular deficiency. Acetabular dysplasia severity was distinguished as mild (LCEA 15° to 20°) or moderate/severe (LCEA < 15°). To answer our first question, regarding the proportions of each AIIS morphology in the dysplasia population, we calculated proportions and 95% CI estimates. To answer our second question, regarding the proposition of AIIS type between subtypes of dysplasia type and severity, we used a chi-square test or Fisher's exact test to compare categorical variables. A p value of < 0.05 was considered significant. RESULTS Seventy-two percent (36 of 50; 95% CI 58% to 83%) of patients had a Type II or III AIIS morphology. Type I AIIS morphology was found in 28% of patients (14 of 50; 95% CI 18% to 42%), Type II AIIS morphology in 62% (31 of 50; 95% CI 48% to 74%), and Type III AIIS/morphology in 10% (5 of 50; 95% CI 4% to 21%). A Type I AIIS was seen in seven of 15 of patients with anterosuperior acetabular deficiency, three of 18 of patients with global deficiency, and four of 17 patients with posterosuperior deficiency (p = 0.08). There was no difference in the variability of AIIS morphologies between the different subtypes of acetabular dysplasia pattern and no difference in AIIS morphology variability between patients with mild versus moderate/severe dysplasia. CONCLUSIONS The morphology of the AIIS in patients with acetabular dysplasia is commonly prominent, with 72% of hips having Type II or Type III morphologies. CLINICAL RELEVANCE The AIIS is often prominent in patients with acetabular dysplasia undergoing PAO, regardless of dysplasia pattern or severity. Prominent AIIS morphologies may affect hip flexion ROM after acetabular reorientation. AIIS morphology is a variable that should be considered during preoperative planning for PAO. Future studies are needed to assess the clinical significance of a prominent AIIS on intraoperative findings and postoperative status after PAO.

BACKGROUND Periacetabular osteotomy (PAO) increases acetabular coverage of the femoral head and medializes the hip's center, restoring normal joint biomechanics. Past studies have reported data regarding the degree of medialization achieved by PAO, but measurement of medialization has never been validated through a comparison of imaging modalities or measurement techniques. The ilioischial line appears to be altered by PAO and may be better visualized at the level of the inferior one-third of the femoral head, thus, an alternative method of measuring medialization that begins at the inferior one-third of the femoral head may be beneficial. QUESTIONS/PURPOSES (1) What is the true amount and variability of medialization of the hip's center that is achieved with PAO? (2) Which radiographic factors (such as lateral center-edge angle [LCEA] and acetabular inclination [AI]) correlate with the degree of medialization achieved? (3) Does measurement of medialization on plain radiographs at the center of the femoral head (traditional method) or inferior one-third of the femoral head (alternative method) better correlate with true medialization? (4) Are intraoperative fluoroscopy images different than postoperative radiographs for measuring hip medialization? METHODS We performed a retrospective study using a previously established cohort of patients who underwent low-dose CT after PAO. Inclusion criteria for this study included PAO as indicated for symptomatic acetabular dysplasia, preoperative CT scan, and follow-up between 9 months and 5 years. A total of 333 patients who underwent PAO from February 2009 to July 2018 met these criteria. Additionally, only patients who were between 16 and 50 years old at the time of surgery were included. Exclusion criteria included prior ipsilateral surgery, femoroacetabular impingement (FAI), pregnancy, neuromuscular disorder, Perthes-like deformity, inadequate preoperative CT, and inability to participate. Thirty-nine hips in 39 patients were included in the final study group; 87% (34 of 39) were in female patients and 13% (5 of 39 hips) were in male patients. The median (range) age at the time of surgery was 27 years (16 to 49). Low-dose CT images were obtained preoperatively and at the time of enrollment postoperatively; we also obtained preoperative and postoperative radiographs and intraoperative fluoroscopic images. The LCEA and AI were assessed on plain radiographs. Hip medialization was assessed on all imaging modalities by an independent, blinded assessor. On plain radiographs, the traditional and alternative methods of measuring hip medialization were used. Subgroups of good and fair radiographs, which were determined by the amount of pelvic rotation that was visible, were used for subgroup analyses. To answer our first question, medialization of all hips was assessed via measurements made on three-dimensional (3-D) CT hip reconstruction models. For our second question, Pearson correlation coefficients, one-way ANOVA, and the Student t-test were calculated to assess the correlation between radiographic parameters (such as LCEA and AI) and the amount of medialization achieved. For our third question, statistical analyses were performed that included a linear regression analysis to determine the correlation between the two radiographic methods of measuring medialization and the true medialization on CT using Pearson correlation coefficients, as well as 95% confidence intervals and standard error of the estimate. For our fourth question, Pearson correlation coefficients were calculated to determine whether using intraoperative fluoroscopy to make medialization measurements differs from measurements made on radiographs. RESULTS The true amount of medialization of the hip center achieved by PAO in our study as assessed by reference-standard CT measurements was 4 ± 3 mm; 46% (18 of 39 hips) were medialized 0 to 5 mm, 36% (14 hips) were medialized 5 to 10 mm, and 5% (2 hips) were medialized greater than 10 mm. Thirteen percent (5 hips) were lateralized (medialized < 0 mm). There were small differences in medialization between LCEA subgroups (6 ± 3 mm for an LCEA of ≤ 15°, 4 ± 4 mm for an LCEA between 15° and 20°, and 2 ± 3 mm for an LCEA of 20° to 25° [p = 0.04]). Hips with AI ≥ 15° (6 ± 3 mm) achieved greater amounts of medialization than did hips with AI of < 15° (2 ± 3 mm; p < 0.001). Measurement of medialization on plain radiographs at the center of the femoral head (traditional method) had a weaker correlation than using the inferior one-third of the femoral head (alternative method) when compared with CT scan measurements, which were used as the reference standard. The traditional method was not correlated across all radiographs or only good radiographs (r = 0.16 [95% CI -0.17 to 0.45]; p = 0.34 and r = 0.26 [95% CI -0.06 to 0.53]; p = 0.30), whereas the alternative method had strong and very strong correlations when assessed across all radiographs and only good radiographs, respectively (r = 0.71 [95% CI 0.51 to 0.84]; p < 0.001 and r = 0.80 [95% CI 0.64 to 0.89]; p < 0.001). Measurements of hip medialization made on intraoperative fluoroscopic images were not found to be different than measurements made on postoperative radiographs (r = 0.85; p < 0.001 across all hips and r = 0.90; p < 0.001 across only good radiographs). CONCLUSION Using measurements made on preoperative and postoperative CT, the current study demonstrates a mean true medialization achieved by PAO of 4 mm but with substantial variability. The traditional method of measuring medialization at the center of the femoral head may not be accurate; the alternate method of measuring medialization at the lower one-third of the femoral head is a superior way of assessing the hip center's location. We suggest transitioning to using this alternative method to obtain the best clinical and research data, with the realization that both methods using plain radiography appear to underestimate the true amount of medialization achieved with PAO. Lastly, this study provides evidence that the hip center's location and medialization can be accurately assessed intraoperatively using fluoroscopy. LEVEL OF EVIDENCE Level III, diagnostic study.

Study Design Simulations using data from a prospective cohort study. Objectives To illustrate how prospective cohort data can be employed in randomized controlled trial (RCT) planning to assess feasibility and operational challenges, using TASCI (Transcutaneous tibial nerve stimulation in patients with Acute Spinal Cord Injury to prevent neurogenic detrusor overactivity: a nationwide randomized, sham-controlled, double-blind clinical trial) as a case study. Setting Spinal cord injury rehabilitation centers in Switzerland. Methods TASCI is nested in the multicenter Swiss Spinal Cord Injury Cohort Study (SwiSCI), which prospectively includes patients with acute spinal cord injury. In simulations, data from 640 patients, collected by SwiSCI, were used to investigate different scenarios of patient eligibility and study consent, as well as the performance of the randomization list. Descriptive analysis was used to describe the population of interest and the simulation results; multivariable logistic regression analysis was performed to identify predictors of discharge within the TASCI intervention time period. Results The recruitment target of 114 patients is obtainable within the originally envisioned three-year time period under the most favorable recruitment scenario examined. The distribution of the primary prognostic factor produced imbalance in the randomization lists and informed further discussion of the cut-off values used in stratification. Influxes of patients resulted in overlapping intervention periods for multiple participants, which guided resource allocation. Early discharge was related to the primary prognostic factor and study center, but is only anticipated in about 8% of participants. Conclusions Prospective cohort data are a very valuable resource for planning RCTs.

To design effective national policies for action against climate change is one of the great challenges of our time. In federal and decentralized countries, there is an additional complexity: such policies must be accepted, adopted, and implemented by the provinces, which are sovereign over their natural resources. From the comparative study of two key national environmental laws in Argentina, the National Law of Native Forests (LNBN) and the National Law of Glaciers (LNG), we ask: what are the necessary conditions for a national environmental policy to be adopted and implemented by provincial jurisdictions? We argue that the LNBN, unlike the LNG, was adopted and implemented by the provinces because it follows a vision of sustainable development, establishes mechanisms for the distribution of competences between the national and provincial states and proposes concrete incentives that encourage provincial involvement.

Background Understanding student motivational factors such as test anxiety and science confidence is important for increasing retention in science, technology, engineering, and math (STEM), especially for underrepresented students, such as women. We investigated motivational metrics in over 400 introductory biology students in Norway, a country lauded for its gender equality. Specifically, we measured test anxiety and science confidence and combined students’ survey responses with their performance in the class. Results We found that female students expressed more test anxiety than did their male counterparts, and the anxiety they experienced negatively predicted their performance in class. By contrast, the anxiety male students experienced did not predict their performance. Conversely, men had higher confidence than women, and confidence interacted with gender, so that the difference between its impact on men’s and women’s performance was marginally significant. Conclusions Our findings have implications for STEM instructors, in Norway and beyond: specifically, to counter gender-based performance gaps in STEM courses, minimize the effects of test anxiety.

Introduction The Internet Gaming Disorder Scale – Short Form (IGDS9-SF) assesses the severity, harmful effects and/or consequences of excessive online and offline gaming. Its conciseness and theoretical foundations on current diagnostic criteria of gaming disorders make it a useful resource for clinical and screening settings. Objective To describe the process of cross-cultural adaptation of the IGDS9-SF to the Brazilian context. Methods The cross-cultural adaptation involved the steps of independent translation of the instrument, synthesis version, back-translation, pre-test and elaboration of the final version. Content validity assessment was conducted by a multidisciplinary committee of experts and consisted of both a quantitative analysis (calculation of content validity coefficients – CVC) and a qualitative analysis (assessment of the experts’ comments and suggestions). The pre-test sample consisted of 30 gamers with variable sociodemographic characteristics. Results The cross-cultural adaptation of the scale followed the proposed protocol, and the CVC was satisfactory (≥ 0.83) for all the structures and equivalences assessed. Most of the suggestions made by the experts were accepted (mainly adjustments and language standardization). The gamers who participated in the pre-test judged the scale easy to understand and did not suggest changes. Discussion The Brazilian version of the IGDS9-SF showed adequate content validity and is available for researchers and clinicians, as well as for the investigation of additional psychometric characteristics.

Bone volume changes following vascularized bone flaps and possible confounding factors over time are described in the literature with some controversy. The purpose of this study was to evaluate the bone volume behavior of two frequently used free flaps.Computed tomography (CT) scans were examined with regard to bone volume using the software program ITK-SNAP for all patients who required mandibular reconstruction with a free fibula flap (FFF, conventionally vs assisted by computer-aided design/computer-aided manufacturing (CAD/CAM)) or iliac crest flap (DCIA) following mandibular resection because of benign or malign processes, between August 2010 and August 2015. Clinical data, complication rates, and CT scans were analyzed retrospectively. Additionally, complication rates (microvascular revision, flap loss, postoperative fistula or dehiscence, and postoperative bone exposure) were compared within early (≤30 days), late (31st-100th day), and overall (≤100th day) postoperative time intervals.113 cases, comprizing 89 FFF and 24 DCIA cases, were included. FFF showed superior bone volume behavior over the DCIA flap. Multivariable regression models assessed the relationships between the following and bone volume behavior: interval between operation and CT scan (p 0.683), age (p = 0.004), gender (p = 0.006), BMI (p = 0.400), adjuvant radiation therapy (p = 0.334), reconstruction with DCIA flap (p 0.0001), number of segments (p = 0.02), and incidence of dental implant insertion (p = 0.45).The bone volume of FFFs remains stable. DCIA flaps show a higher bone volume reduction, but the postoperative course might be associated with fewer complications. Time interval between operation and CT scan, age, gender, reconstruction with DCIA flap, and number of fibula segments contributed significantly to bone volume behavior.

Background Urodynamic investigations have a pivotal role in the diagnosis of lower urinary tract symptoms. Despite expert statements and guidelines supporting their usefulness for clinical decision making in various clinical domains, the academic debate remains controversial. Objective To provide a metaepidemiological inventory of studies assessing the diagnostic properties of urodynamic investigations. Design, setting, and participants Systematic searches without language restrictions were performed in (Pre-)Medline, EMBASE, and the Cochrane Library from inception until August 31, 2018. Checking of reference lists of included studies and reviews complemented searches. Records were compiled and screened for possible inclusion by reading title and abstracts by two teams of two research fellows. Inclusion criteria were as follows: prospective data collection and urodynamic investigations performed either as a diagnostic test or using a therapy monitoring instrument. No a priori selection on clinical domain was done. Double reading was performed on records marked “included.” Extraction into a developed and piloted matrix was performed in duplicate and checked by a third research fellow. Outcome measurements and statistical analysis Of each included article, study specifics, objective, study design, type of data collection, clinical domain, type and description of test used, and type of outcome were extracted and attributed to a framework. Results and limitations Electronic searches retrieved 20 841 records. After screening, 299 abstracts were considered relevant. The main reasons for exclusion were as follows: animal studies, no primary data, editorial/opinion based on published data or reviews, primary objective of the study being not the assessment of urodynamic investigations, and post hoc (opportunistic) correlation studies. Conclusions To our knowledge, this is the first comprehensive collection of studies assessing the clinical usefulness of urodynamic investigations. The collection is the starting point for a series of systematic reviews assessing the diagnostic properties of urodynamic investigations. Patient summary The usefulness of urodynamic investigations for clinical decision making is under debate. We established an inventory of diagnostic studies on urodynamics to assess the value of urodynamics in various clinical applications.

Management of head and neck defects in a radiated field can be quite challenging owing to the dearth of vasculature and significant degree of post-radiation fibrosis. In this setting, arteriovenous (AV) loop vascular grafts can bypass nonviable local vessels to provide viable and reliable inflow and outflow vessels for free tissue transfer in an otherwise hostile environment. Prior reports of the Corlett loop utilizing a cephalic vein transposition has been described however a common carotid-to-internal jugular AV loop has not been recently reported. Three patients underwent carotid artery to internal jugular vein AV loop creation to facilitate free-flap reconstruction secondary to radiation-induced vessel depletion. The specific technique described utilizes the saphenous vein as a donor and spares the cephalic vein for the possibility of flap complication. All three cases resulted in successful reconstruction, maintaining healthy tissue, vascular flow, and flap viability at all follow-up intervals. In our experience, vascular augmentation via AV loop formation provides reliable vascular inflow and outflow in the vessel-depleted neck to facilitate microvascular reconstruction. Sparing the cephalic vein yields an additional salvage mechanism in the event of venous congestion.

Background Tocilizumab (TCZ) has been used in the management of COVID‐19‐related cytokine release syndrome (CRS). Concerns exist regarding the risk of infections and drug‐related toxicities. We sought to evaluate the incidence of these TCZ complications among COVID‐19 patients. Methods All adult inpatients with COVID‐19 between March 1st and April 25th, 2020 that received TCZ were included. We compared the rate of late‐onset infections (>48 hours following admission) to a control group matched according to intensive care unit admission and mechanical ventilation requirement. Post‐TCZ toxicities evaluated included: elevated liver function tests (LFTs), GI perforation, diverticulitis, neutropenia, hypertension, allergic reactions, and infusion‐related reactions. Results Seventy‐four patients were included in each group. Seven‐teen infections in the TCZ group (23%) and 6 (8%) infections in the control group occurred >48 hours after admission (p=0.013). Most infections were bacterial with pneumonia being the most common manifestation. Among patients receiving TCZ, LFT elevations were observed in 51%, neutropenia in 1.4%, and hypertension in 8%. The mortality rate among those that received TCZ was greater than the control (39% versus 23%, p=0.03). Conclusion Late onset infections were significantly more common among those receiving TCZ. Combining infections and TCZ‐related toxicities, 61% of patients had a possible post‐TCZ complication. While awaiting clinical trial results to establish the efficacy of TCZ for COVID‐19 related CRS, the potential for infections and TCZ related toxicities should be carefully weighed when considering use. This article is protected by copyright. All rights reserved.

Background Although inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear. Research Question Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes? Study Design and Methods We conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site. Results The trial enrolled 738 patients (73.4% men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95% CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (incidence rate ratio, 1.64; 95% CI, 1.01-2.66). Interpretation Among patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies.

Only a fraction of species found so far has been described, particularly cryptic species uncovered by molecular data. The latter might require the use of molecular data for its diagnosis, but it is important to make use of the diagnostic content of the molecular data itself. The molecular character‐based model provides discrete molecular diagnostic characters within DNA sequences that can be used in species descriptions fulfilling the requirement of most codes of nomenclature for a character‐based description of species. Here, we introduce fastachar, a software developed to extract molecular diagnostic characters from one or several taxonomically informative DNA markers of a selected taxon compared with those of other taxa in a single step. The input data consist of a single file with aligned sequences in the fasta format, which can be created using alignment software such as mega or geneious. fastachar is an easy‐to‐use software with a graphical interface. Thus, the software does not require the user to have any knowledge of the underlying programming environment (Python). We hope this software, based on the method proposed by Jörger and Schrödl (Frontiers in Zoology, 10, 59, 2013) to describe cryptic species, will encourage researchers to take the final step in taxonomy: the formal description of species. We propose the use of this method and fastachar also for the inclusion of molecular data in the description of any species. fastachar is released as open‐source software under GNU General Public License V3 and is freely available for all major operating systems from https://github.com/smerckel/FastaChar.

Body mass index (BMI) has long been the proxy for patient selection in obese patients presenting for abdominally based breast reconstruction. BMI, however, fails to accurately reflect the distribution of abdominal adipose tissue. This study aims to quantify the effect of abdominal wall thickness on the incidence of post-operative complications and contrast abdominal wall thickness and BMI as predictors of post-operative morbidity.We performed a retrospective review of 106 consecutive patients who underwent abdominally based breast reconstruction. Abdominal wall thickness was quantified using preoperative CT angiograms. Primary outcomes included delayed wound healing (abdomen and/or breast), flap fat necrosis, return to OR in 30 days, infection, and flap loss.Patients experiencing delayed abdominal wound healing (n=38), delayed breast wound healing (n=27), and flap fat necrosis (n=24) had significantly thicker abdominal wall measurements (p0.0015). Of the 24 patients with palpable fat necrosis, 11 required excision. Increasing abdominal wall thickness significantly increased the odds of delayed abdominal wound healing (p=0.0005), delayed breast wound healing (p=0.0009), flap fat necrosis (p=0.0028), and infection (p=0.0198). Compared to BMI, abdominal wall thickness proved to be a more accurate predictor of delayed breast wound healing, any delayed wound healing, flap fat necrosis, and infection.Our data indicate that as abdominal wall thickness increases, so does the risk of postoperative morbidity. Abdominal wall thickness outperformed BMI as a predictor of postoperative morbidity in several areas. This suggests that objective data obtained from preoperative CT scans may allow more accurate, individualized perioperative risk assessment.

The purpose of this study was to evaluate a magnetic resonance imaging (MRI) protocol for direct visualization of the inferior alveolar nerve in the setting of mandibular fractures. Fifteen patients suffering from unilateral mandible fractures involving the inferior alveolar nerve (15 affected IAN and 15 unaffected IAN from contralateral side) were examined on a 3 T scanner (Elition, Philips Healthcare, Best, the Netherlands) and compared with 15 healthy volunteers (30 IAN in total). The sequence protocol consisted of a 3D STIR, 3D DESS and 3D T1 FFE sequence. Apparent nerve-muscle contrast-to-noise ratio (aNMCNR), apparent signal-to-noise ratio (aSNR), nerve diameter and fracture dislocation were evaluated by two radiologists and correlated with nerve impairment. Furthermore, dislocation as depicted by MRI was compared to computed tomography (CT) images. Patients with clinically evident nerve impairment showed a significant increase of aNMCNR, aSNR and nerve diameter compared to healthy controls and to the contralateral side (p

Huntington’s Disease (HD) is an autosomal dominant, progressive neurodegenerative disorder characterized by severe symptoms, including motor impairment, cognitive decline, and psychiatric alterations. Several systems, molecules, and mediators have been associated with the pathophysiology of HD. Among these, there is the Renin-Angiotensin System (RAS), a peptide hormone system that has been associated with the pathology of neuropsychiatric and neurodegenerative disorders. Important alterations in this system have been demonstrated in HD. However, the role of RAS components in HD is still unclear and needs further investigation. Nonetheless, modulation of the RAS components may represent a potential therapeutic strategy for the treatment of HD.

Cerebrovascular Diseases (CVD) comprise a wide spectrum of disorders, all sharing an acquired or inherited alteration of the cerebral vasculature. CVD have been associated with important changes in systemic and tissue Renin-Angiotensin System (RAS). The aim of this review was to summarize and to discuss recent findings related to the modulation of RAS components in CVD. The role of RAS axes is more extensively studied in experimentally induced stroke. By means of AT1 receptors in the brain, Ang II hampers cerebral blood flow and causes tissue ischemia, inflammation, oxidative stress, cell damage and apoptosis. On the other hand, Ang-(1-7) by stimulating Mas receptor promotes angiogenesis in brain tissue, decreases oxidative stress, neuroinflammation, and improves cognition, cerebral blood flow, neuronal survival, learning and memory. In regard to clinical studies, treatment with Angiotensin Converting Enzyme (ACE) inhibitors and AT1 receptor antagonists exerts preventive and therapeutic effects on stroke. Besides stroke, studies support a similar role of RAS molecules also in traumatic brain injury and cerebral aneurysm. The literature supports a beneficial role for the alternative RAS axis in CVD. Further studies are necessary to investigate the therapeutic potential of ACE2 activators and/or Mas receptor agonists in patients with CVD.

BackgroundFollowing several years of qualitative research, we have developed evidence-based guidance on setting up and conducting remote video consultations. Drawing on emerging evidence, we have also adapted the guidance to ensure accessibility and relevance for those using video calling during and beyond the COVID-19 pandemic.FindingsThis article describes the research underpinning this guidance material, with a focus on three key areas: (1) IT infrastructure, (2) organisational routines and workflows, and (3) interactional work of a video consultation. Our research highlights that such change is not merely about installing and using new technology. It involves introducing and sustaining major changes to a complex system with multiple interacting components.ConclusionIf remote video consultations are to be adopted at scale, implementation will need to follow a socio-technical approach, continually adjusting the technology and work processes to become better aligned.