Preserved particulate organic carbon is likely derived from the subsurface sulfidic photic zone of the Proterozoic Ocean: evidence from a modern, oxygen-deficient lake.

Biological processes in the Proterozoic Ocean are often inferred from modern oxygen-deficient environments (MODEs) or from stable isotopes in preserved sediment. To date, few MODE studies have simultaneously quantified carbon fixation genes and attendant stable isotopic signatures. Consequently, how carbon isotope patterns reflect these pathways has not been thoroughly vetted. Addressing this, we profiled planktonic productivity and quantified carbon fixation pathway genes and associated organic carbon isotope values (δ13 CPOC ) of size-fractionated (0.2-2.7 and >2.7 µm) particulate matter from meromictic Fayetteville Green Lake, NY, USA. The high-O2 Calvin-Benson-Bassham (CBB) gene (cbbL) was most abundant in the <2.7 µm size fraction in shallow oxic and deep hypoxic waters, corresponding with cyanobacterial and eukaryote algal populations. The low-O2 CBB gene (cbbM) was most abundant near the lower oxycline boundary in the larger size fraction, coincident with purple sulfur bacteria populations. The reverse citric acid cycle gene (aclB) was equally abundant in both size fractions in the deepest photic zone, coinciding with green sulfur bacteria populations. Methane coenzyme reductase A (mcrA), of anaerobic methane cyclers, was most abundant at the lower oxycline boundary in both size fractions, coinciding with Methanoregula populations. δ13 CPOC values overlapped with the high-O2 CBB fixation range except for two negative excursions near the lower oxycline boundary, likely reflecting assimilation of isotopically-depleted groundwater-derived carbon by autotrophs and sulfate-reducers. Throughout aphotic waters, δ13 CPOC values of the large size fraction became 13 C-enriched, likely reflecting abundant purple sulfur bacterial aggregates. Eukaryote algae- or cyanobacteria-like isotopic signatures corresponded with increases in cbbL, cbbM, and aclB, and enrichment of exopolymer-rich prokaryotic photoautotrophs aggregates. Results suggest that δ13 CPOC values of preserved sediments from areas of the Proterozoic Ocean with sulfidic photic zones may reflect a mixture of alternate carbon-fixing populations exported from the deep photic zone, challenging the paradigm that sedimentary stable carbon isotope values predominantly reflect oxygenic photosynthesis from surface waters.

Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes.

The gene KCNJ11 encodes Kir6.2 a major subunit of the ATP-sensitive potassium channel (KATP) expressed in both the pancreas and brain. Heterozygous gain of function mutations in KCNJ11 can cause neonatal diabetes mellitus (NDM). In addition, many patients exhibit neurological defects ranging from modest learning disorders to severe cognitive dysfunction and seizures. However, it remains unclear to what extent these neurological deficits are due to direct brain-specific activity of mutant KATP. We have generated cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) possessing the KCNJ11 mutation p.Val59Met (V59M) and from non-pathogenic/normal hiPSCs (i.e., control/WT). Control cerebral organoids developed neural networks that could generate stable synchronized bursting neuronal activity whereas those derived from V59M cerebral organoids showed reduced synchronization. Histocytochemical studies revealed a marked reduction in neurons localized to upper cortical layer-like structures in V59M cerebral organoids suggesting dysfunction in the development of cortical neuronal network. Examination of temporal transcriptional profiles of neural stem cell markers revealed an extended window of SOX2 expression in V59M cerebral organoids. Continuous treatment of V59M cerebral organoids with the KATP blocker tolbutamide partially rescued the neurodevelopmental differences. Our study demonstrates the utility of human cerebral organoids as an investigative platform for studying the effects of KCNJ11 mutations on neurophysiological outcome.

Adult Bado type I Monteggia fracture dislocation: A case report.

INTRODUCTION: Fractures of the proximal ulnar shaft accompanied by dislocation of the radial head have been described as "Monteggia fracture-dislocations," since the early nineteenth century. In 1967 Bado further classified these Monteggia fractures into four subtypes, based largely on the direction of the radial head dislocation (Bado, 1967). Despite being frequently discussed in the literature, Monteggia fracture dislocations are rare and represent only 0.7% of elbow fracture-dislocations in adults (Papaioannou et al., 2018). In adults, Bado type I lesions, where the radial head is displaced anteriorly are rarer still, and few cases have been reported in the literature (Papaioannou et al., 2018; Suarez et al., 2016; Egol et al., 2005; Saidi et al., 2018; Wong et al., 2015). CASE PRESENTATION: We present here the case of a 55-year-old male presenting with a Bado type I Monteggia fracture dislocation, resulting from direct trauma to the posterior ulnar surface of his arm. He was treated with ORIF five days after the injury, and by hospital discharge had had 75% active range of motion of his elbow to flexion and extension. CONCLUSION: We present this case of a rare adult fracture subtype with a unique mechanism to add to a paucity of existing literature on such cases and the approach to their care. These fracture-dislocations can be easy to miss because the radial dislocation can be subtle and overshadowed by the more obvious ulnar fracture. This case report hopes to contribute to the expedient recognition of this fracture dislocation syndrome, which is crucial to the preservation of range of motion and arm function for these patients.

Metagenomic Insights Into the Microbial Iron Cycle of Subseafloor Habitats.

Microbial iron cycling influences the flux of major nutrients in the environment (e.g., through the adsorptive capacity of iron oxides) and includes biotically induced iron oxidation and reduction processes. The ecological extent of microbial iron cycling is not well understood, even with increased sequencing efforts, in part due to limitations in gene annotation pipelines and limitations in experimental studies linking phenotype to genotype. This is particularly true for the marine subseafloor, which remains undersampled, but represents the largest contiguous habitat on Earth. To address this limitation, we used FeGenie, a database and bioinformatics tool that identifies microbial iron cycling genes and enables the development of testable hypotheses on the biogeochemical cycling of iron. Herein, we survey the microbial iron cycle in diverse subseafloor habitats, including sediment-buried crustal aquifers, as well as surficial and deep sediments. We inferred the genetic potential for iron redox cycling in 32 of the 46 metagenomes included in our analysis, demonstrating the prevalence of these activities across underexplored subseafloor ecosystems. We show that while some processes (e.g., iron uptake and storage, siderophore transport potential, and iron gene regulation) are near-universal, others (e.g., iron reduction/oxidation, siderophore synthesis, and magnetosome formation) are dependent on local redox and nutrient status. Additionally, we detected niche-specific differences in strategies used for dissimilatory iron reduction, suggesting that geochemical constraints likely play an important role in dictating the dominant mechanisms for iron cycling. Overall, our survey advances the known distribution, magnitude, and potential ecological impact of microbe-mediated iron cycling and utilization in sub-benthic ecosystems.

Reactivation of Pulmonary Tuberculosis During Treatment of Chronic Myelomonocytic Leukemia.

A 76-year-old woman from a tuberculosis (TB) endemic region with chronic myelomonocytic leukemia (CMML) on Azacitidine presented with a non-productive cough. A CT scan of the chest revealed a lobulated opacity in the right upper lobe and antibiotic therapy was initiated for a potential bacterial pneumonia. However, a high suspicion for pulmonary TB remained given her nation of origin, immunosuppression, and imaging findings. Three sputum and bronchoalveolar lavage (BAL) acid-fast bacilli (AFB) smears with PCR testing for Mycobacterium tuberculosis were negative, as were examinations for other potential fungal or bacterial etiologies of the patient's symptoms and imaging findings. While awaiting final TB culture results from BAL, her CMML underwent a transformation to acute myeloid leukemia (AML). Given the urgent need for initiation of chemotherapy, empiric treatment for TB was commenced while awaiting the final TB culture. Within 48-hours of initiating therapy for TB, the patient's fevers subsided. One week after discharge our team was notified of a positive M. tuberculosis culture from BAL. We suspect that our patient had a latent TB infection which reactivated due to her CMML. This case highlights the importance of maintaining a high clinical suspicion for TB in high-risk patients, even in the case of initially negative laboratory examinations. Further, it demonstrates the importance of screening and treating latent TB in patients with leukemias.

Comparison of accelerated CXL alone, accelerated CXL-ICRS, and accelerated CXL-TG-PRK in progressive keratoconus and other corneal ectasias.

PURPOSE: To compare accelerated corneal crosslinking (CXL) alone, CXL with simultaneous intrastromal corneal ring segments (CXL-ICRS), and CXL with simultaneous topography-guided photorefractive keratectomy (CXL-TG-PRK) in progressive keratoconus, pellucid marginal degeneration (PMD), or laser in situ keratomileusis (LASIK)-induced ectasia. SETTING: The Kensington Eye Institute and Bochner Eye Institute, Toronto, Canada. DESIGN: Prospective nonrandomized interventional study. METHODS: Visual and topographical outcomes using a comparative analysis adjusting for preoperative maximum keratometry (Kmax) were evaluated 1 year postoperatively. RESULTS: Four hundred fifty-two eyes from 375 patients with progressive keratoconus, PMD, or LASIK-induced ectasia that underwent accelerated (9 mW/cm, 10 minutes) CXL alone (n = 204), CXL-ICRS (n = 126), or CXL-TG-PRK (n = 122) were included. Change in logarithm of the minimum angle of resolution uncorrected distance visual acuity was significant with CXL-ICRS (-0.31; 95% CI, -0.38 to -0.24) and CXL-TG-PRK (-0.16; 95% CI, -0.24 to -0.09), but not with CXL alone. No significant differences in change were found between the 3 groups. Change in corrected distance visual acuity (CDVA) was significant in all 3 groups: -0.12 (95% CI, -0.15 to -0.10) with CXL alone, -0.23 (95% CI, -0.27 to -0.20) with CXL-ICRS, and -0.17 (95% CI, -0.21 to -0.13) with CXL-TG-PRK. Improvement in CDVA was greater with CXL-ICRS than with CXL alone (-0.08 ± 0.02; P < .0001) and CXL-TG-PRK (-0.05 ± 0.02; P = .005). Change in Kmax was significant with CXL-ICRS [-3.21 diopters (D); 95% CI, -3.98 to -2.45] and CXL-TG-PRK (-3.69 D; 95% CI, -4.49 to -2.90), but not with CXL alone (-0.05 D; 95% CI, -0.66 to 0.55). CONCLUSIONS: CXL alone might be best for keratoconic patients who meet the inclusion criteria. CXL-ICRS might be more effective for eyes with more irregular astigmatism and worse CDVA and CXL-TG-PRK for eyes requiring improvements in irregular astigmatism but still have good CDVA.

Accelerated Corneal Cross-Linking: Efficacy, Risk of Progression, and Characteristics Affecting Outcomes. A Large, Single-Center Prospective Study.

PURPOSE: We examined the efficacy and preoperative characteristics that affect outcomes of accelerated (9 mW/cm2 for 10 minutes) corneal cross-linking (CXL). DESIGN: Prospective single-center observational cohort study. METHODS: We enrolled 612 eyes of 391 subjects with progressive keratoconus (n = 589), pellucid marginal degeneration (n = 11), and laser in situ keratomileusis-induced ectasia (n = 12). We evaluated best spectacle-corrected visual acuity (BSCVA), topography, refraction, endothelial cell density, corneal thickness, haze, intraocular pressure, and visual function before and 12 months after the CXL procedure. We tabulated the proportion of those with progression of maximum keratometry (Kmax). We included participant's race, age, sex, and the presence of preoperative apical scarring and environmental allergies in a multivariable linear regression model to determine the effect of these characteristics on outcomes. RESULTS: At 1 year there was no significant change in mean Kmax (n = 569). Progression of Kmax was higher in subgroups with a baseline Kmax >58 diopters (n = 191) and those 14-18 years of age (n = 53). Preoperative BSCVA, Kmax, refraction, corneal cylinder, coma, central corneal thickness, and vision function were statistically and clinically significant predictors of outcomes (P < .001). Preoperative apical scarring led to worsening haze (P = .0001), more astigmatism (P = .002), more central corneal thinning (P = .002), and was protective to the endothelium (P = .008). Race, age, and sex affected some outcomes. CONCLUSION: Mean Kmax was stable at 1 year after accelerated CXL. Younger patients and those with a higher preoperative Kmax need to be monitored closely for progression. Preoperative BSCVA, topography, refraction, CCT, and apical scarring were significant predictors of outcomes.

Choosing appropriate tools and referral criteria for vision screening of children aged 4-5 years in Canada: a quantitative analysis.

OBJECTIVES: To assess the diagnostic accuracy of five vision screening tools used in a school setting using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). DESIGN: We compared the results of the five best evidence-based screening tools available in 2014 to the results of a comprehensive eye exam with cycloplegic refraction by a licenced optometrist. Screening included Cambridge Crowded Acuity Cards, Plusoptix S12 and Spot photoscreeners, Preschool Randot Stereoacuity Test and the Pediatric Vision Scanner (PVS). Referral criteria followed AAPOS (2013) guidelines and published norms. SETTING: A large school in Toronto, Canada, with 25 split classrooms of junior kindergarten (JK: 4 year olds) and senior kindergarten (SK: 5 year olds) children. PARTICIPANTS: Over 2 years, 1132 eligible children were enrolled at the school. After obtaining parental consent, 832 children were screened. Subsequently, 709 children had complete screening and optometry exam data. MAIN OUTCOME MEASURES: The presence/absence of a visual problem based on optometrist's assessment: amblyopia, amblyopia risk factors (reduced stereoacuity, strabismus and clinically significant refractive errors) and any other ocular problem (eg, nystagmus). RESULTS: Overall, 26.5% of the screened children had a visual problem, including 5.9% with amblyopia. Using all five tools, screening sensitivity=84% (95% CI 78 to 89), specificity=49% (95% CI 44 to 53), PPV=37% (95% CI 33 to 42), and NPV=90% (95% CI 86 to 93). The odds of having a correct screening result in SK (mean age=68.2 months) was 1.5 times those in JK (mean age=55.6 months; 95% CI 1.1 to 2.1), with sensitivity improved to 89% (95% CI 80 to 96) and specificity improved to 57% (95% CI 50 to 64) among SK children. CONCLUSIONS: A school-based screening programme correctly identified 84% of those kindergarten children who were found to have a visual problem by a cyclopleged optometry exam. Additional analyses revealed how accuracy varies with different combinations of screening tools and referral criteria.

A Web-Based Mental Health Platform for Individuals Seeking Specialized Mental Health Care Services: Multicenter Pragmatic Randomized Controlled Trial.

BACKGROUND: Web-based self-directed mental health applications are rapidly emerging to address health service gaps and unmet needs for information and support. OBJECTIVE: The aim of this study was to determine if a multicomponent, moderated Web-based mental health application could benefit individuals with mental health symptoms severe enough to warrant specialized mental health care. METHODS: A multicenter, pragmatic randomized controlled trial was conducted across several outpatient mental health programs affiliated with 3 hospital programs in Ontario, Canada. Individuals referred to or receiving treatment, aged 16 years or older, with access to the internet and an email address, and having the ability to navigate a Web-based mental health application were eligible. A total of 812 participants were randomized 2:1 to receive immediate (immediate treatment group, ITG) or delayed (delayed treatment group, DTG) access for 3 months to the Big White Wall (BWW), a multicomponent Web-based mental health intervention based in the United Kingdom and New Zealand. The primary outcome was the total score on the Recovery Assessment Scale, revised (RAS-r) which measures mental health recovery. Secondary outcomes were total scores on the Patient Health Questionnaire-9 item (PHQ-9), the Generalized Anxiety Disorder Questionnaire-7 item (GAD-7), the EuroQOL 5-dimension quality of life questionnaire (EQ-5D-5L), and the Community Integration Questionnaire. An exploratory analysis examined the association between actual BWW use (categorized into quartiles) and outcomes among study completers. RESULTS: Intervention participants achieved small, statistically significant increases in adjusted RAS-r score (4.97 points, 95% CI 2.90 to 7.05), and decreases in PHQ-9 score (-1.83 points, 95% CI -2.85 to -0.82) and GAD-7 score (-1.55 points, 95% CI -2.42 to -0.70). Follow-up was achieved for 55% (446/812) at 3 months, 48% (260/542) of ITG participants and 69% (186/270) of DTG participants. Only 58% (312/542) of ITG participants logged on more than once. Some higher BWW user groups had significantly greater improvements in PHQ-9 and GAD-7 relative to the lowest use group. CONCLUSIONS: The Web-based application may be beneficial; however, many participants did not engage in an ongoing way. This has implications for patient selection and engagement as well as delivery and funding structures for similar Web-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02896894; https://clinicaltrials.gov/ct2/show/NCT02896894 (Archived by WebCite at http://www.webcitation.org/78LIpnuRO).

Frequency of Screening for Weaning From Mechanical Ventilation: Two Contemporaneous Proof-of-Principle Randomized Controlled Trials.

OBJECTIVES: It is unknown whether more frequent screening of invasively ventilated patients, identifies patients earlier for a spontaneous breathing trial, and shortens the duration of ventilation. We assessed the feasibility of conducting a large trial to evaluate screening frequency in critically ill adults in the North American context. DESIGN: We conducted two contemporaneous, multicenter, pilot, randomized controlled trials (the LibeRation from MEchanicaL VEntilAtion and ScrEening Frequency [RELEASE] and Screening Elderly PatieNts For InclusiOn in a Weaning [SENIOR] trials) to address concerns regarding the potential for higher enrollment, fewer adverse events, and better outcomes in younger patients. SETTING: Ten and 11 ICUs in Canada, respectively. PATIENTS: Parallel trials of younger (RELEASE < 65 yr) and older (SENIOR ≥ 65 yr) critically ill adults invasively ventilated for at least 24 hours. INTERVENTIONS: Each trial compared once daily screening to "at least twice daily" screening led by respiratory therapists. MEASUREMENTS AND MAIN RESULTS: In both trials, we evaluated recruitment (aim: 1-2 patients/month/ICU) and consent rates, reasons for trial exclusion, protocol adherence (target: ≥ 80%), crossovers (aim: ≤ 10%), and the effect of the alternative screening frequencies on adverse events and clinical outcomes. We included 155 patients (53 patients [23 once daily, 30 at least twice daily] in RELEASE and 102 patients [54 once daily, 48 at least twice daily] in SENIOR). Between trials, we found similar recruitment rates (1.32 and 1.26 patients/month/ICU) and reasons for trial exclusion, high consent and protocol adherence rates (> 92%), infrequent crossovers, and few adverse events. Although underpowered, at least twice daily screening was associated with a nonsignificantly faster time to successful extubation and more successful extubations but significantly increased use of noninvasive ventilation in both trials combined. CONCLUSIONS: Similar recruitment and consent rates, few adverse events, and comparable outcomes in younger and older patients support conduct of a single large trial in North American ICUs assessing the net clinical benefits associated with more frequent screening.

Sex differences in delayed cerebral ischemia after subarachnoid hemorrhage.

OBJECTIVE In this study the authors sought to investigate the sex differences in the risk of delayed cerebral ischemia (DCI), delayed cerebral infarction, and the role of hormonal status. METHODS Ten studies included in the SAHIT (SAH International Trialists) repository were analyzed using a fitting logistic regression model. Heterogeneity between the studies was tested using I2 statistics, and the results were pooled using a random-effects model. Multivariable analysis was adjusted for the effects of neurological status and fixed effect of study. An additional model was examined in which women and men were split into groups according to an age cut point of 55 years, as a surrogate to define hormonal status. RESULTS A pooled cohort of 6713 patients was analyzed. The risk of DCI was statistically significantly higher in women than in men (OR 1.29, 95% CI 1.12-1.48); no difference was found with respect to cerebral infarction (OR 1.17, 95% CI 0.98-1.40). No difference was found in the risk of DCI when comparing women ≤ 55 and > 55 years (OR 0.87, 95% CI 0.74-1.02; p = 0.08) or when comparing men ≤ 55 and > 55 years (p = 0.38). Independent predictors of DCI were World Federation of Neurosurgical Societies (WFNS) grade, Fisher grade, age, and sex. Independent predictors of infarction included WFNS grade, Fisher grade, and aneurysm size. CONCLUSIONS Female sex is associated with a higher risk of DCI. Sex differences may play a role in the pathogenesis of DCI but are not associated with menopausal status. The predictors of DCI and cerebral infarction were identified in a very large cohort and reflect experience from multiple institutions.

Interactive media as a tool for reducing waiting anxiety at paediatric rehabilitation hospitals: a randomized controlled trial.

AIM: To investigate the efficacy of waiting room media for reducing anxiety and increasing satisfaction at a paediatric rehabilitation hospital. METHOD: In this clustered, parallel, randomized controlled trial, 310 young people with disabilities (age range 5-19y) and their parents attending outpatient clinics were assigned to interactive media (n=113), a silent nature video (n=97), or media-free comparison (n=100) groups. Young person and parent anxiety was reported using the State-Trait Anxiety Inventory (STAI) on arrival and after 10 minutes in the waiting space. Questionnaires measured young person, parent, and staff satisfaction. RESULTS: Young people exposed to interactive media reported a postexposure state anxiety that was 1.1 raw points (2.7 standardized points) lower on the STAI than the comparison group (95% confidence interval [CI] -1.9 to -0.22). There was no difference in postexposure state anxiety between the passive media and comparison groups (95% CI -0.64 to 1.1). Parents' state anxiety did not differ between conditions, but interactive media were associated with greater satisfaction (p=0.009). Of 120 staff, 119 reported that interactive media improved the clinic experience for families. INTERPRETATION: Interactive media designed for accessible, hands-free play mitigate waiting anxiety and increases satisfaction. This paper provides evidence to guide design and decision-making around the use of interactive media in health care spaces. WHAT THIS PAPER ADDS: Interactive media reduced preclinic waiting anxiety for young people with disabilities. Interactive media were accessible to young people with a range of mobility. Interactive media increased parental and staff satisfaction in the clinic. Guidelines for the design of hands-free, inclusive interactive media for health care facilities are presented.

Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery.

BACKGROUND: The effect of a restrictive versus liberal red-cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. METHODS: In this multicenter, open-label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red-cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red-cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red-cell transfusion and other clinical outcomes. RESULTS: The primary outcome occurred in 11.4% of the patients in the restrictive-threshold group, as compared with 12.5% of those in the liberal-threshold group (absolute risk difference, -1.11 percentage points; 95% confidence interval [CI], -2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive-threshold group and 3.6% in the liberal-threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red-cell transfusion occurred in 52.3% of the patients in the restrictive-threshold group, as compared with 72.6% of those in the liberal-threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between-group differences with regard to the other secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy regarding red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).

The effect of brief case management on emergency department use of frequent users in mental health: Findings of a randomized controlled trial.

Frequent users of hospital emergency departments (EDs) are a medically and socially vulnerable population. The Coordinated Access to Care from Hospital EDs (CATCH-ED) study examined the effectiveness of a brief case management intervention in reducing ED use and improving health outcomes among frequent ED users with mental health or addiction challenges in a large urban centre. Adults (≥18 years of age) who had five or more ED visits in the past 12-months, with at least one visit for mental health or addictions problems were randomized to either brief case management (N = 83) or usual care (N = 83) and followed for 12 months. The primary outcome of effectiveness was the frequency of ED visits during 12 months after study enrolment. Secondary outcomes included days in hospital, mental health and addiction symptom severity and health-related quality of life, measured by the SF-12. Compared to usual care, CATCH-ED participants saw a 14% reduction in frequency of ED visits during the 12-month post-randomization period [rate ratio (RR) = 0.86, 95% CI 0.64-1.15)], however, this finding did not reach statistical significance. There were also no statistically significant differences between the groups at 12 months in the number of days spent in hospital (RR = 1.16, 95% CI 0.59-2.29), physical (1.50, 95% CI -2.15-5.15) or mental (-3.97, 95% CI -8.13-0.19) component scores of the SF-12, severity of psychiatric symptoms (-0.41, 95% CI -2.30-1.49), alcohol (0.053 95% -0.017-0.12) or drug (-0.0027, 95% CI -0.0028-0.023) use. Compared to usual care, a brief case management intervention did not result in significantly reduced ED use or improved health outcomes among frequent ED users with mental health or addictions challenges in a large urban centre in Canada. Future studies need to evaluate the availability and accessibility of community-based resources for individuals with frequent ED use.

Improving the Appropriate Use of Transthoracic Echocardiography: The Echo WISELY Trial.

BACKGROUND: Appropriate use criteria (AUC) have defined transthoracic echocardiogram (TTE) indications for which there is a clear lack of benefit as rarely appropriate (rA). OBJECTIVES: This study sought to investigate the impact of an AUC-based educational intervention on outpatient TTE ordering by cardiologists and primary care providers. METHODS: The authors conducted a prospective, investigator-blinded, multicenter, randomized controlled trial of an AUC-based educational intervention aimed at reducing rA outpatient TTEs. The study was conducted at 8 hospitals across 2 countries. The authors randomized cardiologists and primary care providers to receive either intervention or control (no intervention). The primary outcome measure was the proportion of rA TTEs. RESULTS: One hundred and ninety-six physicians were randomized, and 179 were included in the analysis. From December 2014 to April 2016, the authors assessed 14,697 TTEs for appropriateness, of which 99% were classifiable using the 2011 AUC. The mean proportion of rA TTEs was significantly lower in the intervention versus the control group (8.8% vs. 10.1%; odds ratio [OR]: 0.75; 95% confidence interval [CI]: 0.57 to 0.99; p = 0.039). In physicians who ordered, on average, at least 1 TTE per month, there was a significantly lower proportion of rA TTEs in the intervention versus the control group (8.6% vs. 11.1%; OR: 0.76; 95% CI: 0.57 to 0.99; p = 0.047). There was no difference in the TTE ordering volume between the intervention and control groups (mean 77.7 ± 89.3 vs. 85.4 ± 111.4; p = 0.83). CONCLUSIONS: An educational intervention reduced the number of rA TTEs ordered by attending physicians in a variety of ambulatory care environments. This may prove to be an effective strategy to improve the use of imaging. (A Multi-Centered Feedback and Education Intervention Designed to Reduce Inappropriate Transthoracic Echocardiograms [Echo WISELY]; NCT02038101).

The "DOC" screen: Feasible and valid screening for depression, Obstructive Sleep Apnea (OSA) and cognitive impairment in stroke prevention clinics.

BACKGROUND: Post-stroke Depression, Obstructive sleep apnea (OSA) and Cognitive impairment ("DOC") are associated with greater mortality, worse recovery and poorer quality of life. Best practice recommendations endorse routine screening for each condition; yet, all are under-assessed, diagnosed and treated. We seek to determine the feasibility and validity of an integrated tool ("DOC" screen) to identify stroke clinic patients at high-risk of depression, OSA, and cognitive impairment. METHODS: All consecutive new referrals to a regional Stroke Prevention Clinic who were English-speaking and non-aphasic were eligible to be screened. Time for screen completion was logged. DOC screen results were compared to the neuropsychological battery and polysomnogram assessments using a modified receiver operator characteristic and area under the curve analysis. Data is reported to conform to STARD guidelines. FINDINGS: 1503 people were screened over 2 years. 89% of eligible patients completed the screen in 5 minutes or less (mean 4.2 minutes), less than half the time it takes to complete the Montreal Cognitive Assessment (MoCA). 437 people consented to detailed testing. Of those, 421 completed the Structured Clinical Interview for Depression within 3 months of screening, 387 completed detailed neuropsychological testing within 3 months, and 88 had overnight polysomnograms. Screening scores combined with demographic variables (age, sex, education, body mass index), had excellent validity compared to gold standard diagnoses: DOC-Mood AUC 0.90; DOC-Apnea AUC 0.80; DOC-Cog AUC 0.81. DOC screen scores can reliably categorize patients in to low-, intermediate- or high-risk groups for further action and can do so with comparable accuracy to more time-consuming screens. CONCLUSIONS: Systematic screening of depression, obstructive sleep apnea, and cognitive impairment in 5 minutes or less is feasible and valid in a high volume stroke clinic using the DOC screen. The DOC screen may facilitate improved identification and treatment of these comorbidities to improve function in patients after stroke and in those with other neurological diseases that share these comorbid conditions (e.g. Alzheimer's disease/mild cognitive impairment, Parkinson's disease, Traumatic Brain Injury, multiple sclerosis).

A Randomized Control Trial Using a Validated Prediction Model for Diagnosing Acute Heart Failure in Undifferentiated Dyspneic Emergency Department Patients-Results of the GASP4Ar Study.

BACKGROUND: Diagnosing acute heart failure (AHF) in undifferentiated dyspneic emergency department (ED) patients can be challenging. We prospectively studied a validated diagnostic prediction model for AHF that uses patient age, clinician pretest probability for AHF, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a continuous value to determine its utility and performance. METHODS AND RESULTS: This was a multicenter randomized controlled trial of undifferentiated dyspneic patients with an indeterminate pretest probability of AHF as assessed by the treating emergency physician (EP). After recording its components, the calculated model results with validated treatment threshold guidelines were provided to EPs for patients randomized to the intervention arm. Final diagnoses with the use of 60-day follow-up information were adjudicated by 2 independent cardiologists. The primary outcomes were accuracy of the model and of physician diagnosis comparing intervention and standard care arms. A total of 197 patients were randomized and had outcome data recorded; 41% were determined to have had heart failure. Final EP diagnostic accuracy was 76% (sensitivity 68.2%, specificity 83.9%) with no significant difference between exposed versus blinded arms (accuracy 77% vs 74%; P = .77). Area under the model receiver operating characteristic curve was 0.93. Using the model treatment thresholds would have redirected 48% of patients with 95% accuracy. CONCLUSIONS: This study prospectively validated the diagnostic accuracy of our AHF model in a significant proportion of indeterminate dyspneic ED patients, but provision of this information did not improveEP diagnostic accuracy. Future studies should determine how such a clinical prediction tool could be effectively integrated into routine practice and improve early management of suspected AHF patients in the ED.

A pragmatic randomized control trial and realist evaluation on the implementation and effectiveness of an internet application to support self-management among individuals seeking specialized mental health care: a study protocol.

BACKGROUND: Mental illness is a substantial and rising contributor to the global burden of disease. Access to and utilization of mental health care, however, is limited by structural barriers such as specialist availability, time, out-of-pocket costs, and attitudinal barriers including stigma. Innovative solutions like virtual care are rapidly entering the health care domain. The advancement and adoption of virtual care for mental health, however, often occurs in the absence of rigorous evaluation and adequate planning for sustainability and spread. METHODS: A pragmatic randomized controlled trial with a nested comparative effectiveness arm, and concurrent realist process evaluation to examine acceptability, effectiveness, and cost-effectiveness of the Big White Wall (BWW) online platform for mental health self-management and peer support among individuals aged 16 and older who are accessing mental health services in Ontario, Canada. Participants will be randomized to 3 months of BWW or treatment as usual. At the end of the 3 months, participants in the intervention group will have the opportunity to opt-in to an intervention extension arm. Those who opt-in will be randomized to receive an additional 3 months of BWW or no additional intervention. The primary outcome is recovery at 3 months as measured by the Recovery Assessment Scale-revised (RAS-r). Secondary outcomes include symptoms of depression and anxiety measured with the Personal Health Questionnaire-9 item (PHQ-9) and the Generalized Anxiety Disorder Questionnaire-7 item (GAD-7) respectively, quality of life measured with the EQ-5D-5L, and community integration assessed with the Community Integration Questionnaire. Cost-effectiveness evaluations will account for the cost of the intervention and direct health care costs. Qualitative interviews with participants and stakeholders will be conducted throughout. DISCUSSION: Understanding the impact of virtual strategies, such as BWW, on patient outcomes and experience, and health system costs is essential for informing whether and how health system decision-makers can support these strategies system-wide. This requires clear evidence of effectiveness and an understanding of how the intervention works, for whom, and under what circumstances. This study will produce such effectiveness data for BWW, while simultaneously exploring the characteristics and experiences of users for whom this and similar online interventions could be helpful. TRIAL REGISTRATION: Clinicaltrials.gov NCT02896894 . Registered on 31 August 2016 (retrospectively registered).

Efficacy and safety of non-immersive virtual reality exercising in stroke rehabilitation (EVREST): a randomised, multicentre, single-blind, controlled trial.

BACKGROUND: Non-immersive virtual reality is an emerging strategy to enhance motor performance for stroke rehabilitation. There has been rapid adoption of non-immersive virtual reality as a rehabilitation strategy despite the limited evidence about its safety and effectiveness. Our aim was to compare the safety and efficacy of virtual reality with recreational therapy on motor recovery in patients after an acute ischaemic stroke. METHODS: In this randomised, controlled, single-blind, parallel-group trial we enrolled adults (aged 18-85 years) who had a first-ever ischaemic stroke and a motor deficit of the upper extremity score of 3 or more (measured with the Chedoke-McMaster scale) within 3 months of randomisation from 14 in-patient stroke rehabilitation units from four countries (Canada [11], Argentina [1], Peru [1], and Thailand [1]). Participants were randomly allocated (1:1) by a computer-generated assignment at enrolment to receive a programme of structured, task-oriented, upper extremity sessions (ten sessions, 60 min each) of either non-immersive virtual reality using the Nintendo Wii gaming system (VRWii) or simple recreational activities (playing cards, bingo, Jenga, or ball game) as add-on therapies to conventional rehabilitation over a 2 week period. All investigators assessing outcomes were masked to treatment assignment. The primary outcome was upper extremity motor performance measured by total time to complete the Wolf Motor Function Test (WMFT) at the end of the 2 week intervention period, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NTC01406912. FINDINGS: The study was done between May 12, 2012, and Oct 1, 2015. We randomly assigned 141 patients: 71 received VRWii therapy and 70 received recreational activity. 121 (86%) patients (59 in the VRWii group and 62 in the recreational activity group) completed the final assessment and were included in the primary analysis. Each group improved WMFT performance time relative to baseline (decrease in median time from 43·7 s [IQR 26·1-68·0] to 29·7 s [21·4-45·2], 32·0% reduction for VRWii vs 38·0 s [IQR 28·0-64·1] to 27·1 s [21·2-45·5], 28·7% reduction for recreational activity). Mean time of conventional rehabilitation during the trial was similar between groups (VRWii, 373 min [SD 322] vs recreational activity, 397 min [345]; p=0·70) as was the total duration of study intervention (VRWii, 528 min [SD 155] vs recreational activity, 541 min [142]; p=0·60). Multivariable analysis adjusted for baseline WMFT score, age, sex, baseline Chedoke-McMaster, and stroke severity revealed no significant difference between groups in the primary outcome (adjusted mean estimate of difference in WMFT: 4·1 s, 95% CI -14·4 to 22·6). There were three serious adverse events during the trial, all deemed to be unrelated to the interventions (seizure after discharge and intracerebral haemorrhage in the recreational activity group and heart attack in the VRWii group). Overall incidences of adverse events and serious adverse events were similar between treatment groups. INTERPRETATION: In patients who had a stroke within the 3 months before enrolment and had mild-to-moderate upper extremity motor impairment, non-immersive virtual reality as an add-on therapy to conventional rehabilitation was not superior to a recreational activity intervention in improving motor function, as measured by WMFT. Our study suggests that the type of task used in motor rehabilitation post-stroke might be less relevant, as long as it is intensive enough and task-specific. Simple, low-cost, and widely available recreational activities might be as effective as innovative non-immersive virtual reality technologies. FUNDING: Heart and Stroke Foundation of Canada and Ontario Ministry of Health.

Validating a Pragmatic Approach to Cognitive Screening in Stroke Prevention Clinics Using the Montreal Cognitive Assessment.

BACKGROUND AND PURPOSE: The Montreal Cognitive Assessment (MoCA) is used commonly to identify cognitive impairment (CI), but there are multiple published cut points for normal and abnormal. We seek to validate a pragmatic approach to screening for moderate-severe CI, by classifying patients into high-, intermediate-, and low-risk categories. METHODS: A total of 390 participants attending an academic Stroke Prevention Clinic completed the MoCA and more detailed neuropsychological testing. Between April 23, 2012 and April 30, 2014, all consecutive new referrals to the regional Stroke Prevention Clinic who were English-speaking, not severely aphasic, and could see and write well enough to complete neuropsychological testing were assessed for inclusion, and consenting patients were enrolled. CI was defined as ≥2 SDs below normal for age and education on at least 2 cognitive subtests. A single cut point for CI was compared with 2 cut points (high sensitivity and high specificity) generated using receiver operator characteristic and area under the curve analyses. The intermediate-risk group contained those scoring between the 2 cut points. RESULTS: Thirty-four percent of participants had a symptomatic or silent stroke, 34% were seen for possible or probable transient ischemic attack, and 32% were diagnosed with other vascular or nonvascular conditions. Using a single cut point, sensitivity and specificity were optimal with MoCA ≤22, (sensitivity=60.4%, specificity=89.9%, area under the curve=0.801, positive predictive value=48.5%, negative predictive value=93.5%, positive likelihood ratio=6, and negative likelihood ratio=0.4). Using 2 cut points, sensitivity was optimal with MoCA ≥28 (sensitivity=96.2%, negative predictive value =97.6%, and negative likelihood ratio=1.27), and specificity was optimal with MoCA ≤22 (specificity=89.9%, positive predictive value=48.5%, and positive likelihood ratio=6). CONCLUSIONS: Stratifying participants into 3 categories facilitates the identification of a homogenous group at low risk for CI, as well as 2 other groups with intermediate and higher risk. This approach could facilitate clinical care pathways and patient selection for research.