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The primary defect in Kartagener's syndrome is at the ciliary level and so the normal ciliary activity is compromised causing impaired respiratory tract clearance, infertility and defective organ(s) orientation and left-right laterality predisposition during organogenesis. The authors came across the case of a 20-year-old female that was later diagnosed with Kartagener's syndrome. This case may be of particular interest to general physicians and pulmonologists.

Background: Yogic practices may aid in the prevention and management of diabetes mellitus (DM) and reduce cardiovascular complications in the population. The present study has been undertaken to evaluate the effect of yoga therapy on reaction time, biochemical parameters and wellness score of peri and post-menopausal diabetic patients. Materials and Methods: 15 peri and post-menopausal patients receiving standard medical treatment for type 2 DM were recruited and reaction time and biochemical investigations were done before and after a comprehensive yoga therapy program comprising of three times a week sessions for six weeks. A post-intervention, retrospective wellness questionnaire compiled by ACYTER was used to evaluate the comparative feelings of the patients after the therapy program. Results: Yoga training reduced auditory reaction time (ART) from right as well as left hand, the decrease being statistically significant (P

Abstract The current approach to fetal anomaly screening is based on biometric measurements derived from individually selected ultrasound images. In this paper, we introduce a paradigm shift that attains human-level performance in biometric measurement by aggregating automatically extracted biometrics from every frame across an entire scan, with no need for operator intervention. We use a neural network to classify each frame of an ultrasound video recording. We then measure fetal biometrics in every frame where appropriate anatomy is visible. We use a Bayesian method to estimate the true value of each biometric from a large number of measurements and probabilistically reject outliers. We performed a retrospective experiment on 1457 recordings (comprising 48 million frames) of 20-week ultrasound scans, estimated fetal biometrics in those scans and compared our estimates to real-time manual measurements. Our method achieves human-level performance in estimating fetal biometrics and estimates well-calibrated credible intervals for the true biometric value.

OBJECTIVES:. Respiratory failure secondary to COVID-19 is associated with morbidity and mortality. Current anti-inflammatory therapies are effective but are given systemically and have significant side effects. Furosemide has anti-inflammatory properties, can be administered by inhalation, and is inexpensive. We investigated the efficacy of nebulized furosemide as an adjunctive therapy for COVID-19 respiratory failure. DESIGN:. A double-blind, randomized, placebo-controlled trial. SETTING:. Multicenter ICU study. PATIENTS:. Adults requiring invasive mechanical ventilation secondary to COVID-19. INTERVENTION:. Patients were randomized within 48 hours of intubation to receive inhaled furosemide or placebo until day 28, death, or liberation from mechanical ventilation. MEASUREMENTS AND MAIN RESULTS:. The study was stopped early due to waning incidence of COVID-19; 39 patients were available for analysis with mean ± sd age of 70.5 (10.8) years, Acute Physiology and Chronic Health Evaluation II 26.1 (7.8) and Fio2 60.0% (21.9). Baseline characteristics were similar between the groups. For the primary outcome of change in Pao2/Fio2 ratio between day 1 and day 6, it was +31.4 (83.5) in the furosemide arm versus +20.1 (92.8) in the control (p = 0.58). For secondary outcomes, furosemide versus control: 60-day mortality was 48% versus 71% (p = 0.20), hospital stay was 25.6 (21.9) versus 27.4 (25.0) days, p = 0.94 and VFD was 6.0 (9.1) versus 3.1 (7.1), p value of equals to 0.28. A post hoc analysis of the hierarchical composite outcome, alive and ventilator-free favored furosemide. There were no adverse events. CONCLUSIONS:. In this trial of inhaled furosemide for COVID-19 respiratory failure, differences in Pao2/Fio2 ratio to day 6 and other clinical outcomes were not significantly different, although the trial was underpowered due to early termination. Given the favorable profile of inhaled furosemide, further study is warranted in disease states where acute pulmonary inflammation contributes to the underlying pathophysiology.

Abstract Purpose Endoscopic transsphenoidal surgery (ETSS) is an increasingly utilized approach for resection of pituitary tumors. Prior studies have evaluated preoperative tumor size, location, and extent as prognostic factors for surgical resection. There is little data on the relationship between preoperative pituitary tumor radiographic morphology and surgical outcomes. Study Design Retrospective longitudinal study. Setting Single tertiary care institution. Subjects and Methods Preoperative magnetic resonance imaging and computed tomography scans from patients undergoing ETSS for pituitary tumor resections from 2007 to 2017 were retrospectively evaluated. A neuroradiologist classified these pituitary tumors into six morphologic groups, each defined by volume, dimensions, extension, and shape. Surgical difficulty, rates of incomplete resection, and postoperative complications were then stratified in relation to the morphologic groups. Results Pituitary tumors from 131 patients were classified from preoperative imaging into six characteristic morphologies: (1) microtumor, (2) round, (3) transverse oblong, (4) superior‐inferior oblong, (5) bilobed, and (6) large lobulated. Tumors that were characterized with the large lobulated, bilobed, and transverse oblong morphologies correlated with higher rates of postoperative evidence of residual tumor (70%, 36%, and 47%, respectively, all P

Background: Acute kidney injury (AKI) resulting in kidney replacement therapy is rising among critically ill adults. Long-term kidney replacement therapy and critical illness are independently linked to acute and prolonged cognitive impairment, and structural brain pathology. Poor regional cerebral oxygenation (rSO 2 ) may be a contributing factor. Objective: To assess the feasibility of testing the association between intradialytic rSO 2 and acute and long-term neurological outcomes. Design: Longitudinal observational study. Setting and Participants: We enrolled patients initiating continuous kidney replacement therapy or intermittent hemodialysis in the Kingston Health Sciences Centre (KHSC) Intensive Care Unit (ICU). Measurements and Methods: rSO 2 was monitored during the first 72 hours of continuous kidney replacement therapy or throughout each intermittent hemodialysis session. We measured acute neurological impairment by daily delirium screening and long-term neurocognitive outcomes using the Kinarm robot, Repeatable Battery for the Assessment of Neuropsychological Status, and brain magnetic resonance imaging. Results: Of 484 ICU patients, 26 met the screening criteria. Two declined, and 13 met at least one exclusion criteria. Eleven patients were enrolled. Eight died in ICU, one died 2 months after discharge, and one declined follow-up. Data capture rates were high: rSO 2 /vitals (91.3%), and delirium screening and demographics (100%). Longitudinal testing was completed in 50% (1 of 2) of survivors. Limitations: Enrollment was low due to a variety of factors, limiting our ability to evaluate long-term outcomes. Conclusion: rSO 2 and delirium data collection is feasible in critically ill patients undergoing kidney replacement therapy; high mortality limits follow-up.

Abstract Introduction Real-world evidence on the timing and efficacy of enteral nutrition (EN) practices in intensive care unit (ICU) patients with circulatory shock is limited. We hypothesized early EN (EEN), as compared to delayed EN (DEN), is associated with improved clinical outcomes in mechanically ventilated (MV) patients with circulatory shock. Methods We analyzed a dataset from an international, multicenter, pragmatic randomized clinical trial (RCT) evaluating protein dose in ICU patients. Data were collected from ICU admission, and EEN was defined as initiating 48 h. We identified MV patients in circulatory shock to evaluate the association between the timing of EN initiation and clinical outcomes. The regression analysis model controlled for age, mNUTRIC score, APACHE II score, sepsis, and Site. Results We included 626 patients, from 52 ICUs in 14 countries. Median age was 60 years [18–93], 55% had septic shock, 99% received norepinephrine alone, 91% received EN alone, and 50.3% were randomized to a usual protein dose. Forty-two percent of EEN patients had persistent organ dysfunction syndrome plus death at day 28, compared to 53% in the DEN group (p = 0.04). EEN was associated with more ICU-free days (9.3 ± 9.2 vs. 5.7 ± 7.9, p = 0.0002), more days alive and free of vasopressors (7.1 ± 3.1 vs. 6.3 ± 3.2, p = 0.007), and shorter duration of MV among survivors (9.8 ± 10.9 vs. 13.8 ± 14.5, p = 0.0002). This trend was no longer observed in the adjusted analysis. There were no differences in ICU/60-day mortality or feeding intolerance rates between groups. Conclusion In MV patients with circulatory shock, EEN, as compared to DEN, was associated with improved clinical outcomes, but no longer when adjusting for illness severity. RCTs comparing the efficacy of EEN to DEN in MV patients with circulatory shock are warranted.

Abstract Background L-carnitine (L-C), a ubiquitous nutritional supplement, has been investigated as a potential therapy for cardiovascular disease, but its effects on human atherosclerosis are unknown. Clinical studies suggest improvement of some cardiovascular risk factors, whereas others show increased plasma levels of pro-atherogenic trimethylamine N-oxide. The primary aim was to determine whether L-C therapy led to progression or regression of carotid total plaque volume (TPV) in participants with metabolic syndrome (MetS). Methods This was a phase 2, prospective, double blinded, randomized, placebo-controlled, two-center trial. MetS was defined as ≥ 3/5 cardiac risk factors: elevated waist circumference; elevated triglycerides; reduced HDL-cholesterol; elevated blood pressure; elevated glucose or HbA1c; or on treatment. Participants with a baseline TPV ≥ 50 mm3 were randomized to placebo or 2 g L-C daily for 6 months. Results The primary outcome was the percent change in TPV over 6 months. In 157 participants (L-C N = 76, placebo N = 81), no difference in TPV change between arms was found. The L-C group had a greater increase in carotid atherosclerotic stenosis of 9.3% (p = 0.02) than the placebo group. There was a greater increase in total cholesterol and LDL-C levels in the L-C arm. Conclusions Though total carotid plaque volume did not change in MetS participants taking L-C over 6-months, there was a concerning progression of carotid plaque stenosis. The potential harm of L-C in MetS and its association with pro-atherogenic metabolites raises concerns for its further use as a potential therapy and its widespread availability as a nutritional supplement. Trial registration: ClinicalTrials.gov, NCT02117661, Registered April 21, 2014, https://clinicaltrials.gov/ct2/show/NCT02117661 .

Abstract Background Proteins are an essential part of medical nutrition therapy in critically ill patients. Guidelines almost universally recommend a high protein intake without robust evidence supporting its use. Methods Using a large international database, we modelled associations between the hazard rate of in-hospital death and live hospital discharge (competing risks) and three categories of protein intake (low: 1.2 g/kg per day) during the first 11 days after ICU admission (acute phase). Time-varying cause-specific hazard ratios (HR) were calculated from piece-wise exponential additive mixed models. We used the estimated model to compare five different hypothetical protein diets (an exclusively low protein diet, a standard protein diet administered early (day 1 to 4) or late (day 5 to 11) after ICU admission, and an early or late high protein diet). Results Of 21,100 critically ill patients in the database, 16,489 fulfilled inclusion criteria for the analysis. By day 60, 11,360 (68.9%) patients had been discharged from hospital, 4,192 patients (25.4%) had died in hospital, and 937 patients (5.7%) were still hospitalized. Median daily low protein intake was 0.49 g/kg [IQR 0.27–0.66], standard intake 0.99 g/kg [IQR 0.89– 1.09], and high intake 1.41 g/kg [IQR 1.29–1.60]. In comparison with an exclusively low protein diet, a late standard protein diet was associated with a lower hazard of in-hospital death: minimum 0.75 (95% CI 0.64, 0.87), and a higher hazard of live hospital discharge: maximum HR 1.98 (95% CI 1.72, 2.28). Results on hospital discharge, however, were qualitatively changed by a sensitivity analysis. There was no evidence that an early standard or a high protein intake during the acute phase was associated with a further improvement of outcome. Conclusions Provision of a standard protein intake during the late acute phase may improve outcome compared to an exclusively low protein diet. In unselected critically ill patients, clinical outcome may not be improved by a high protein intake during the acute phase. Study registration ID number ISRCTN17829198

Purpose: The UMass Chan Medical School/New England AIDS Education and Training Center Community-Based HIV and Viral Hepatitis Fellowship was launched in 2014 to train physicians and nurse practitioners to become experts in outpatient management of HIV, hepatitis B and C, and latent tuberculosis. The purpose of this study was to identify areas of strength and improvement and understand fellows’ perceptions of the program and its impact on their current positions and career trajectories. Methods: Qualitative study utilizing a semi-structured interview guide with (11) fellowship graduates (8 MDs; 3 NPs). 45 to 60 min interviews were conducted in April and May 2021, recorded and transcribed. Transcripts were analyzed for representative themes and general patterns in the data. Results: Results indicate high satisfaction with the fellowship, which left a positive and indelible impact on their careers and patient care. Fellows highlighted the program’s commitment to health equity, its role in transforming them into leaders and advocates for HIV in primary care, and their ability to balance their work and training demands with their personal lives and needs. The fellowship motivated them to become more involved in public health initiatives, serve marginalized communities and reduce their health disparities. They expressed confidence in their ability to independently manage outpatient HIV, viral hepatitis B and C, and latent tuberculosis, and found areas of overlap with their work in primary care. Conclusion: As the care of people with HIV becomes more commonplace in primary care clinics, it is imperative that primary care providers receive the necessary training and education to meet this need. Our study of 11 former fellows shows that the Community-Based HIV and Viral Hepatitis Fellowship offers such training, spreads it to other institutions, and can be a model for other programs nationwide.

Data clustering plays a significant role in biomedical sciences, particularly in single-cell data analysis. Researchers use clustering algorithms to group individual cells into populations that can be evaluated across different levels of disease progression, drug response, and other clinical statuses. In many cases, multiple sets of clusters must be generated to assess varying levels of cluster specificity. For example, there are many subtypes of leukocytes (e.g. T cells), whose individual preponderance and phenotype must be assessed for statistical/functional significance. In this report, we introduce a novel hierarchical density clustering algorithm (HAL-x) that uses supervised linkage methods to build a cluster hierarchy on raw single-cell data. With this new approach, HAL-x can quickly predict multiple sets of labels for immense datasets, achieving a considerable improvement in computational efficiency on large datasets compared to existing methods. We also show that cell clusters generated by HAL-x yield near-perfect F1-scores when classifying different clinical statuses based on single-cell profiles. Our hierarchical density clustering algorithm achieves high accuracy in single cell classification in a scalable, tunable and rapid manner.

Background: Discussing goals of care with heart failure patients is recommended but is not done systematically, due to factors such as time and personal beliefs. A recent survey showed that one-fifth of clinicians believe that implantable cardioverter defibrillator deactivation (ICDD) is unethical or constitutes physician-assisted suicide. We investigated whether individuals’ characteristics are associated with these beliefs. Methods: The Decision-Making About Goals of Care for Hospitalized Patients With Heart Failure (DECIDE-HF) survey was given to healthcare providers at 9 hospitals to assess their perceived barriers to goals-of-care discussions. The association between respondent characteristics and their beliefs was examined using 2 adjusted logistic regression models. Results: We included 760 clinicians (459 nurses, 94 fellows, and 207 cardiologists). The responses varied among professions, with the belief that ICDD is unethical considered to be important barrier by nurses (24%), fellows (10%), and staff (7%); P < 0.001). After adjusting for site, spirituality being more important in life (odds ratio [OR]: 2.21; 95% confidence interval [CI]:1.37-3.56; P = 0.001, compared to less important), region of training (Asia [OR: 5.88; 95% CI: 2.12-16.31; P = 0.001] and Middle East [OR: 5.55; 95% CI:1.57-19.63; P = 0.008] compared to Canada), and years in practice (OR: 1.32; 95% CI: 1.07-1.63; P = 0.01 per decade) influenced beliefs about ICDD being unethical, with similar results for the belief that ICDD represents physician-assisted suicide. Conclusions: Sociocultural factors, region of training, and profession influence clinicians’ beliefs about ICDD being unethical and representing physician-assisted suicide. These factors and beliefs must be acknowledged when facing the delicate issue of end-of-life discussion. Résumé: Contexte: Une discussion sur les objectifs de soins avec les patients atteints d'insuffisance cardiaque est recommandée, mais elle n'est pas systématiquement menée en raison de facteurs tels que les contraintes de temps et les croyances personnelles. Selon une enquête récente, un cinquième des cliniciens croient qu'une désactivation d'un défibrillateur cardioverteur implantable (DDCI) est contraire à l’éthique ou représente un suicide assisté par le médecin. Nous avons vérifié si des caractéristiques individuelles sont associées à ces croyances. Méthodologie: L'enquête DECIDE-HF (Decision-Making About Goals of Care for Hospitalized Patients With Heart Failure) a été réalisée chez des professionnels de la santé de neuf hôpitaux dans le but d’évaluer les obstacles qu'ils percevaient face à la discussion sur les objectifs de soins. Le lien entre les caractéristiques des répondants et leurs croyances a été analysé à l'aide de deux modèles ajustés de régression logistique. Résultats: Nous avons interrogé 760 cliniciens (459 infirmières, 94 médecins associés et 207 cardiologues). Les réponses ont varié d'une profession à l'autre, la croyance qu'une DDCI est contraire à l’éthique étant considérée comme un obstacle important par 24 % des infirmières, 10 % des médecins associés et 7 % des membres du personnel (p

Abstract Background The optimal protein dose in critical illness is unknown. We aim to conduct a systematic review of randomized controlled trials (RCTs) to compare the effect of higher versus lower protein delivery (with similar energy delivery between groups) on clinical and patient-centered outcomes in critically ill patients. Methods We searched MEDLINE, EMBASE, CENTRAL and CINAHL from database inception through April 1, 2021.We included RCTs of (1) adult (age ≥ 18) critically ill patients that (2) compared higher vs lower protein with (3) similar energy intake between groups, and (4) reported clinical and/or patient-centered outcomes. We excluded studies on immunonutrition. Two authors screened and conducted quality assessment independently and in duplicate. Random-effect meta-analyses were conducted to estimate the pooled risk ratio (dichotomized outcomes) or mean difference (continuous outcomes). Results Nineteen RCTs were included (n = 1731). Sixteen studies used primarily the enteral route to deliver protein. Intervention was started within 72 h of ICU admission in sixteen studies. The intervention lasted between 3 and 28 days. In 11 studies that reported weight-based nutrition delivery, the pooled mean protein and energy received in higher and lower protein groups were 1.31 ± 0.48 vs 0.90 ± 0.30 g/kg and 19.9 ± 6.9 versus 20.1 ± 7.1 kcal/kg, respectively. Higher vs lower protein did not significantly affect overall mortality [risk ratio 0.91, 95% confidence interval (CI) 0.75–1.10, p = 0.34] or other clinical or patient-centered outcomes. In 5 small studies, higher protein significantly attenuated muscle loss (MD −3.44% per week, 95% CI −4.99 to −1.90; p

Abstract Background People are living longer than ever before. However, with living longer comes increased problems that negatively impact on quality of life and the quality of death. Tools are needed to help individuals assess whether they are practicing the best attitudes and behaviors that are associated with a future long life, high quality of life, high quality of death and a satisfying post-death legacy. The purpose of paper is to describe the process we used to develop a novel questionnaire (“Preparedness for the Future Questionnaire™ or Prep FQ”) and to define its psychometric properties. Methods Using a multi-step development procedure, items were generated, for the new questionnaire after which the psychometric properties were tested with a heterogeneous sample of 502 Canadians. Using an online polling panel, respondents were asked to complete demographic questions as well as the Prep-FQ, Global Rating of Life Satisfaction, the Keyes Psychological Well-Being scale and the Short-Form 12. Results The final version of the questionnaire contains 34 items in 8 distinct domains (“Medico-legal”, “Social”, “Psychological Well-being”, “Planning”, “Enrichment”, “Positive Health Behaviors”, “Negative Health Behaviors”, and “Late-life Planning”). We observed minimum missing data and good usage of all response options. The average overall Prep FQ score is 51.2 (SD = 13.3). The Cronbach alphas assessing internal reliability for the Prep FQ domains ranged from 0.33 to 0.88. The intra-class correlation coefficient (ICC) used to assess the test–retest reliability had an overall score of 0.87. For the purposes of establishing construct validity, all the pre-specified relationships between Prep FQ and the other questionnaires were met. Conclusion Analyses of this novel measure offered support for its face validity, construct validity, test–retest reliability, and internal consistency. With the development of this useful and valid scale, future research can utilize this measure to engage people in the process of comprehensively assessing and improving their state of preparedness for the future, tracking their progress along the way. Ultimately, this program of research aims to improve the quality and quantity of peoples live by helping them ‘think ahead’ and ‘plan ahead’ on the aspects of their daily life that matter to their future.

Background: Multidisciplinary care is recommended for patients with advanced chronic kidney disease (CKD). A formalized, risk-based approach to CKD management is being adopted in some jurisdictions. In Ontario, Canada, the eligibility criteria for multidisciplinary CKD care funding were revised between 2016 and 2018 to a 2 year risk of kidney replacement therapy (KRT) greater than 10% calculated by the 4-variable Kidney Failure Risk Equation (KFRE). Implementation of the risk-based approach has led to the discharge of prevalent CKD patients. Objective: The primary objective of this study was to determine the frequency of occurrence of death and KRT initiation in patients discharged from CKD clinic. Design: Retrospective cohort study Setting: Single center multidisciplinary CKD clinic in Ontario, Canada Patients: Four hundred and twenty five patients seen at least once in 2013 at the multidisciplinary CKD clinic Measurements: Outcomes included discharge status, death, re-referral and KRT initiation. Reasons for discharge were recorded. Methods: Outcomes were extracted from available electronic medical records and the provincial death registry between the patient’s initial clinic visit in 2013 and January 1, 2020. KFRE-2 scores were calculated using the 4-variable KFRE equation. The hazard rates of death and KRT after discharge due to stable eGFR/low KFRE were compared to patients who remained in the clinic. Results: Of the 425 CKD patients, 69 (16%) and 19 (4%) were discharged to primary care and general nephrology, respectively. Of those discharged, 7 (8%) were re-referred to nephrology or CKD clinic, while only 2 (2%) discharged patients required subsequent KRT. The hazard of mortality was reduced after discharge from the clinic due to stable eGFR/low KFRE (adjusted HR = 0.45 [95% CI, 0.25-0.78, P = .005]). Limitations: Single center, observational retrospective study design and unknown kidney function over time post discharge for most patients Conclusions: Discharge of low risk patients from multidisciplinary CKD clinic appears feasible and safe, with fewer than 1 in 40 discharged patients subsequently initiated on KRT over the following 7 years.

BackgroundThe LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor. ObjectiveWe aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. MethodsThe SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses. ResultsThe SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status. ConclusionsWe have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase. International Registered Report Identifier (IRRID)DERR1-10.2196/36261

Rationale & Objective: The Kidney Failure Risk Equation (KFRE) is widely used to predict the risk of kidney replacement therapy (KRT) initiation in chronic kidney disease (CKD) stages G3-G5. The new Grams calculator developed for advanced CKD (stage G4+) predicts KRT initiation, cardiovascular events, and death by uniquely incorporating the competing risk of death. We aimed to validate this tool in a stage G4+ cohort for death and KRT. Study Design: Retrospective cohort study. Setting & Participants: 442 patients with CKD stage G4+ (mean ± SD age, 73 ± 12 years; mean ± SD estimated glomerular filtration rate, 20 ± 6.2 mL/min/1.73 m2) who visited the multidisciplinary CKD clinic at Kingston Health Sciences Center in Ontario, Canada. Outcomes & Analytical Approach: Discrimination and calibration were examined for the outcome of death using the 2- and 4-year Grams scores. The 2- and 5-year KFRE and 2- and 4-year Grams scores were compared in terms of discrimination and calibration for KRT. Results: There were 91, 161, and 206 death events and 90, 145, and 159 KRT events in our cohort at 2, 4, and 5 years, respectively. The Grams model demonstrated modest discrimination for death at 4 years (area under the curve [AUC] 0.70; 95% CI, 0.65-0.75) and performed worse at 2 years (AUC, 0.63; 95% CI, 0.57-0.70). It only overpredicted death by approximately 10% across most of the predicted range. Both models had similar discrimination for KRT at 2 years (KFRE AUC, 0.83; 95% CI, 0.78-0.88 and Grams AUC, 0.8; 95% CI, 0.76-0.87), 4 years (Grams AUC, 0.82; 95% CI, 0.77-0.86), and 5 years (KFRE AUC, 0.81; 95% CI, 0.76-0.85). There was excellent calibration for KRT using the 2-year KFRE and Grams values for predicted risk thresholds of ≤15% and using the 5-year KFRE and 4-year Grams values for predicted risk thresholds of ≤20%. At higher risk ranges, KFRE overpredicts and Grams underpredicts the KRT risk. Limitations: This is a single-center study with a primarily White cohort limited by smaller sample sizes at the higher ranges of the predicted risks, particularly for the Grams calculator. Conclusions: The Grams model provides moderately accurate death predictions, and consideration should be given to its incorporation into patient education and advanced care planning. Both the Grams and KFRE models remain clinically useful for determining KRT risks in advanced CKD.

Abstract Background Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis. Methods LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned. Discussion This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis. Trial registration clinicaltrials.gov, NCT03680274, first posted 21 September 2018.

Introduction Initiation of acute kidney replacement therapy (KRT) is common in critically ill adults admitted to the intensive care unit (ICU), and associated with increased morbidity and mortality. KRT has been linked to poor neurocognitive outcomes, leading to reduced quality of life and increased utilisation of healthcare resources. Adults on dialysis in the ICU may be particularly at risk of neurocognitive impairment, as survivors of critical illness are already predisposed to developing cerebrovascular disease and cognitive dysfunction long-term relative to healthy controls. Regional cerebral oxygen saturation may provide a critical early marker of long-term neurocognitive impairment in this population. This study aims to understand cerebral oxygenation in patients undergoing KRT (continuous or intermittent) in the ICU. These findings will be correlated with long-term cognitive and functional outcomes, and structural brain pathology.Methods and analysis 108 patients scheduled to undergo treatment for acute kidney injury with KRT in the Kingston Health Sciences Centre ICU will be recruited into this prospective observational study. Enrolled patients will be assessed with intradialytic cerebral oximetry using near infrared spectroscopy. Delirium will be assessed daily with the Confusion Assessment Method-ICU (CAM-ICU) and severity quantified as cumulative CAM-ICU-7 scores. Neurocognitive impairment will be assessed at 3 and 12 months after hospital discharge using the Kinarm and Repeatable Battery for the Assessment of Neuropsychological Status. Structural brain pathology on MRI will also be measured at the same timepoints. Driving safety, adverse events and medication adherence will be assessed at 12 months to evaluate the impact of neurocognitive impairment on functional outcomes.Ethics and dissemination This study is approved by the Queen’s University Health Sciences/Affiliated Teaching Hospitals Research Ethics Board (DMED-2424-20). Results will be presented at critical care conferences, and a lay summary will be provided to patients in their preferred format.Trial registration number NCT04722939

Summary: Large-scale algal oil production requires continuous outputs and a trade-off between growth and oil content. Two unrelated marine algae (Nannochloropsis oceanica [CCAP 849/10] and Chlorella vulgaris [CCAP 211/21A]) that showed high oil production under batch culture were studied under controlled semicontinuous cultivation conditions. Three essential attributes maximized oil productivity: (i) downregulation of cell size to maximize light absorption under N limitation; (ii) low nutrient-depletion thresholds to trigger oil induction; (iii) a means of carbohydrate suppression in favor of oil. N. oceanica responded better to input N/P variations and is more suited to continuous oil production. A low N/P ratio was effective in both suppressing carbohydrate and reducing cell size concomitant with oil production. In C. vulgaris, nutrient starvation thresholds for oil were higher and carbohydrate was preferentially induced, which impeded stress-level optimization for oil. These differences, which impact continuous oil production at scale, are driven by species adaptation to specific marine habitats. Video abstract: Video abstract:

IntroductionThe pathophysiologic differences between methacholine-induced cough but normal airway sensitivity (COUGH) and healthy individuals (CONTROL) are incompletely understood and may be due to differences in the bronchodilating effect of deep inspirations (DIs). The purpose of this study is to compare the bronchodilating effect of DIs in individuals with classic asthma (CA), cough variant asthma (CVA), and COUGH with CONTROL and to assess impulse oscillometry (IOS) measures as predictors of the bronchodilating effect of DIs.MethodsA total of 43 adults [18 female; 44.8 ± 12.3 years (mean ± SD); n = 11 CA, n = 10 CVA, n = 7 COUGH, n = 15 CONTROL] underwent modified high-dose methacholine challenge, with IOS and partial/maximal expiratory flow volume (PEFV/MEFV) maneuvers (used to calculate DI Index) to a maximum change (Δ) in FEV1 of 50% from baseline (MAX). Cough count and dyspnea were measured at each dose. The relation between IOS parameters and DI Index was assessed at baseline and MAX using multivariable linear regression analysis.ResultsCough frequency, dyspnea intensity, and baseline peripheral resistance (R5–R20) were significantly greater in COUGH compared with CONTROL (p = 0.006, p = 0.029, and p = 0.035, respectively). At MAX, the DI Index was significantly lower in COUGH (0.01 ± 0.36) compared with CA (0.67 ± 0.97, p = 0.008), CVA (0.51 ± 0.73, p = 0.012), and CONTROL (0.68 ± 0.45, p = 0.005). Fres and R5–R20 were independent IOS predictors of the DI Index.ConclusionThe bronchodilating effect is impaired in COUGH and preserved in mild CA, CVA, and CONTROL. Increased peripheral airway resistance and decreased resonant frequency are associated with a decreased DI Index. COUGH is a clinical phenotype distinct from healthy normals and asthma.

Abstract Background Limited understanding of the cancer biology of metastatic sites is a major factor contributing to poor outcomes in cancer patients. The regional lymph nodes are the most common site of metastasis in most solid cancers and their involvement is a strong predictor of relapse in breast cancer (BC). We have previously shown that ezrin, a cytoskeletal–membrane linker protein, is associated with lymphovascular invasion and promotes metastatic progression in BC. However, the efficacy of pharmacological inhibition of ezrin in blocking cancer cell migration and metastasis remains unexplored in BC. Methods We quantified ezrin expression in a BC tissue microarray (n = 347) to assess its correlation with risk of relapse. Next, we developed a quantitative intravital microscopy (qIVM) approach, using a syngeneic lymphatic reporter mouse tumor model, to investigate the effect of systemic ezrin inhibition on cancer cell migration and metastasis. Results We show that ezrin is expressed at significantly higher levels in lymph node metastases compared to matched primary tumors, and that a high tumor ezrin level is associated with increased risk of relapse in BC patients with regional disease. Using qIVM, we observe a subset of cancer cells that retain their invasive and migratory phenotype at the tumor-draining lymph node. We further show that systemic inhibition of ezrin, using a small molecule compound (NSC668394), impedes the migration of cancer cells in vivo. Furthermore, systemic ezrin inhibition leads to reductions in metastatic burden at the distal axillary lymph node and lungs. Conclusions Our findings demonstrate that the tumor ezrin level act as an independent biomarker in predicting relapse and provide a rationale for therapeutic targeting of ezrin to reduce the metastatic capacity of cancer cells in high-risk BC patients with elevated ezrin expression.

Testing the association between genetic variants and a range of phenotypes can assist drug development. Here, in a phenome-wide association study in up to 697,815 individuals, Diogo et al. identify genotype–phenotype associations predicting efficacy, alternative indications or adverse drug effects.

Abstract Functional characterization of the noncoding genome is essential for biological understanding of gene regulation and disease. Here, we introduce the computational framework PINES (Phenotype-Informed Noncoding Element Scoring), which predicts the functional impact of noncoding variants by integrating epigenetic annotations in a phenotype-dependent manner. PINES enables analyses to be customized towards genomic annotations from cell types of the highest relevance given the phenotype of interest. We illustrate that PINES identifies functional noncoding variation more accurately than methods that do not use phenotype-weighted knowledge, while at the same time being flexible and easy to use via a dedicated web portal.

Neuromyelitis optica (NMO) is a rare autoimmune condition characterized by inflammation and demyelination of the optic nerve and the spinal cord. Here, Estrada et al. identify NMO susceptibility variants in the MHC region and find that autoantibody-positive NMO genetically overlaps with lupus.

Abstract Background Over the last decade, health care delivery has shifted to partnering with patients and their families to improve health and quality of care, and to lower costs. Partnering with family members (FMs) of critically ill patients who lack capacity is particularly important for improving experiences and outcomes for both patients and FMs. How best to apply such partnering strategies, however, is yet unknown. The IMPACT trial will evaluate two interventions that enable partnerships with families of critically ill patients, each in a distinct content area, but similar in that they empower and support FMs. Methods This multi-center, open-label, randomized, phase II clinical trial aims to randomize 150 older, long-stay ICU patients and their families into one of three groups (50 in each group): (1) The OPTimal nutrition by Informing and Capacitating FMs of best practices (OPTICs) group, a multi-faceted intervention to engage and empower FMs to advocate for, and audit, best nutritional practices for their critically ill FMs, (2) A web-based decision-support intervention called the ICU Workbook (The Canadian Researchers at the End of Life Network (CARENET) ICU Workbook; https://www.myicuguide.ca/ . Accessed 3 Feb 2017.) to support families in shared decision-making process regarding goals of medical treatments, and (3) Usual care. The main outcomes for this trial include nutritional adequacy in hospital and hand-grip strength prior to hospital discharge; satisfaction with decision-making; decision conflict; and degree of shared decision-making. Discussion With the goal of improving the functional recovery of nutritionally high-risk older patients and the quality of care at the end of life for these patients and their FMs in the ICU, we have proposed two novel family capacitation strategies. We hope that the nutrition and decision-support interventions implemented and evaluated in our study will contribute to the evidentiary basis for best family partnered care pathways focused on optimizing the quality of ICU care for patients with life-threatening illness and their families. Trial registration Clinical trials.gov, ID: NCT02920086 . Registered on 30 September 2016. Protocol version dated 11 October 2016.

Abstract Background The standard definition for protocol adherence is the proportion of all scheduled doses that are delivered. In clinical research, this definition has several limitations when evaluating protocol adherence in trials that study interventions requiring continuous titration. Discussion Building upon a specific case study, we analyzed a recent trial of a continuously titrated intervention to assess the impact of different definitions of protocol deviations on the interpretation of protocol adherence. The OVATION pilot trial was an open-label randomized controlled trial of higher (75–80 mmHg) versus lower (60–65 mmHg) mean arterial pressure (MAP) targets for vasopressor therapy in shock. In this trial, potential protocol deviations were defined as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. An adjudication committee reviewed each potential deviation to determine if it was clinically-justified or not. There are four reasons for this contextual measurement and reporting of protocol adherence. First, between-arm separation is a robust measure of adherence to complex protocols. Second, adherence assessed by protocol deviations varies in function of the definition of deviations and the frequency of measurements. Third, distinguishing clinically-justified vs. not clinically-justified protocol deviations acknowledges clinically sensible bedside decision-making and offers a clear terminology before the trial begins. Finally, multiple metrics exist to report protocol deviations, which provides different information but complementary information on protocol adherence. Conclusions In trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence. Definitions for protocol deviations should be prespecified and correlated with between-arm separation, if it can be measured.

Abstract Background Nutrition guidelines recommendations differ on the use of parenteral nutrition (PN), and existing clinical trial data are inconclusive. Our recent observational data show that amounts of energy/protein received early in the intensive care unit (ICU) affect patient mortality, particularly for inadequate nutrition intake in patients with body mass indices (BMIs) of 35. Thus, we hypothesized increased nutrition delivery via supplemental PN (SPN) + enteral nutrition (EN) to underweight and obese ICU patients would improve 60-day survival and quality of life (QoL) versus usual care (EN alone). Methods In this multicenter, randomized, controlled pilot trial completed in 11 centers across four countries, adult ICU patients with acute respiratory failure expected to require mechanical ventilation for >72 hours and with a BMI of

Despite considerable evidence demonstrating that waist circumference (WC) is independently associated with cardiovascular disease (CVD) and/or all-cause mortality, whether the addition of WC improves risk prediction models is unclear. The objective was to evaluate the improvement in risk prediction with the addition of WC, alone or in combination with BMI, to the Framingham Risk Score (FRS) and a population specific model. 34,377 men and 9,477 women aged 20 to 79 years who completed a baseline examination at the Cooper Clinic (Dallas, TX) during 1977–2003 and enrolled in the Aerobics Center Longitudinal Study (ACLS). WC was measured at the level of the umbilicus and expressed as a continuous variable. Deaths among participants were identified using the National Center for Health Statistics National Death Index. A total of 728 fatal cardiovascular disease (CVD) events occurred over a mean follow-up period of 13.1 ± 7.5 years. WC was significantly higher in CVD decedents (P = .002). The FRS C-statistic for fatal CVD in men was 0.836 (0.816–0.855) and 0.883 (0.851–0.915) in women. The addition of WC did not improve the C-statistic in men (0.831 (0.809–0.853)) or women (0.883 (0.850–0.916)). Similar findings were observed for non-fatal CVD and all-cause mortality, and when WC was added to a population specific model. Upon adding WC, the net-reclassification index was 0.024 with an integrated discrimination improvement of -0.0004. The addition of WC, alone or in combination with BMI, did not substantively improve risk prediction for CVD or all-cause mortality compared to the Framingham Risk Score or a population specific model.

Despite considerable evidence demonstrating that waist circumference (WC) is independently associated with cardiovascular disease (CVD) and/or all-cause mortality, whether the addition of WC improves risk prediction models is unclear. The objective was to evaluate the improvement in risk prediction with the addition of WC, alone or in combination with BMI, to the Framingham Risk Score (FRS) and a population specific model. 34,377 men and 9,477 women aged 20 to 79 years who completed a baseline examination at the Cooper Clinic (Dallas, TX) during 1977-2003 and enrolled in the Aerobics Center Longitudinal Study (ACLS). WC was measured at the level of the umbilicus and expressed as a continuous variable. Deaths among participants were identified using the National Center for Health Statistics National Death Index. A total of 728 fatal cardiovascular disease (CVD) events occurred over a mean follow-up period of 13.1 ± 7.5 years. WC was significantly higher in CVD decedents (P = .002). The FRS C-statistic for fatal CVD in men was 0.836 (0.816-0.855) and 0.883 (0.851-0.915) in women. The addition of WC did not improve the C-statistic in men (0.831 (0.809-0.853)) or women (0.883 (0.850-0.916)). Similar findings were observed for non-fatal CVD and all-cause mortality, and when WC was added to a population specific model. Upon adding WC, the net-reclassification index was 0.024 with an integrated discrimination improvement of -0.0004. The addition of WC, alone or in combination with BMI, did not substantively improve risk prediction for CVD or all-cause mortality compared to the Framingham Risk Score or a population specific model.

Background: Burn injury represents a significant public health problem worldwide. More than in any other injury, the inflammation and catabolism associated with severe burns can exacerbate nutrient deficiencies resulting in impaired immune function and increased risk of developing infection, organ dysfunction and death. Consequently, over the last few decades numerous trials have evaluated the impact of different nutritional strategies in severe burn injury. Glutamine is of particular interest, as it appears vital for a number of key stress-response pathways in serious illness. The purpose of the current manuscript is to provide the rationale and protocol for a large clinical trial of supplemental enteral glutamine in 2700 severe burn-injured patients. Methods: We propose a multicentre, double-blind, pragmatic, randomized, clinical trial involving 80 tertiary intensive care unit (ICU) burn centres worldwide. We aim to enrol patients with deep second- and/or third-degree burns at moderate or high risk for death. We will exclude patients admitted > 72 h before screening and patients with advanced liver and kidney disease. The study intervention consists of enteral glutamine 0.5 g/kg/day vs. isocaloric maltodextran control delivered enterally. Primary outcome will be six-month mortality. Key secondary outcomes include time to discharge alive from hospital, ICU and hospital mortality, length of stay and health-related quality of life at six months. Significance: This study will be the first large international multicentre trial examining the effects of glutamine in burn patients. Negative or positive, the results of this trial will inform the clinical practice of burns care worldwide. Clinicaltrials.gov ID #NCT00985205

BACKGROUNDThe optimal approach to titrate vasopressor therapy is unclear. Recent sepsis guidelines recommend a mean arterial pressure (MAP) target of 65 mmHg and higher for chronic hypertensive patients. As data emerge from clinical trials comparing blood pressure targets for vasopressor therapy, an accurate description of usual care is required to interpret study results. Our aim was to measure MAP values during vasopressor therapy in Canadian intensive care units (ICUs) and to compare these with stated practices and guidelines.METHODIn a multicenter prospective cohort study of critically ill adults with severe hypotension, we recorded MAP and vasopressor doses hourly. We investigated variability across patients and centres using multivariable regression models and Analysis of variance (ANOVA), respectively.RESULTSWe included data from 56 patients treated in 6 centers. The mean (standard deviation [SD]) age and Acute Physiology and Chronic Health Evaluation (APACHE) II score were 64 (14) and 25 (8). Half (28 of 56) of the patients were at least 65 years old, and half had chronic hypertension. The patient-averaged MAP while receiving vasopressors was 75 mm Hg (6) and the median (1st quartile, 3rd quartile) duration of vasopressor therapy was 43 hours (23, 84). MAP achieved was not associated with history of underlying hypertension (p = 0.46) but did vary by center (pCONCLUSIONSIn this multicenter, prospective observational study, the patient-level average MAP while receiving vasopressors for severe hypotension was 75 mmHg, approximately 10 mmHg above current recommendations and stated practices. Moreover, our results do not support the notion that clinicians tailor vasopressor therapy to individual patient characteristics such as underlying chronic hypertension but MAP achieved while receiving vasopressors varied by site.

OBJECTIVES:Vasopressors are not recommended by current trauma guidelines, but recent reports indicate that they are commonly used. We aimed to describe the early hemodynamic management of trauma patients outside densely populated urban centers. METHODS:We conducted a single-center retrospective cohort study in a Canadian regional trauma center. All adult patients treated for traumatic injury in 2013 who died within 24 hours of admission or were transferred to the intensive care unit were included. A systolic blood pressure

BACKGROUND: Loud snoring is a common symptom in the general population. The evidence-based literature indicates that snoring may be associated with sleep fragmentation and sleep apnea, which may affect cognitive function and predispose to occupational injury. High rates of occupational injury occur on farms and may be related to personal and health factors. Thus, loud snoring may not be a trivial symptom and should be considered as important in medical assessments.

BACKGROUND: The significance of Candida species in respiratory tract (RT) secretions in critically ill patients is unclear.

BACKGROUND AND STUDY AIMS: Surveillance for mucosal dysplasia in patients with chronic ulcerative colitis requires numerous biopsies (often over 40). The aim of the present study was to determine if two biopsies could be obtained with jumbo forceps before removing them from the instrument (double biopsy technique), as opposed to one biopsy per pass, without sacrificing the histological quality of the biopsy material.

Background: Cardiovascular disease, which is due in part to progressive vascular calcification, is the leading cause of death among patients with end stage kidney disease (ESKD) on dialysis. A role for vitamin K in the prevention of vascular calcification is plausible based on the presence of vitamin K dependent proteins in vascular tissue, including matrix gla protein (MGP). Evidence from animal models and observational studies support a role for vitamin K in the prevention of vascular calcification. A large-scale study is needed to investigate the effect of vitamin K supplementation on the progression of vascular calcification in patients with ESKD, a group at risk for sub-clinical vitamin K deficiency. Methods/Design: We plan a prospective, randomized, double-blind, multicenter controlled trial of incident ESKD patients on hemodialysis in centers within North America. Eligible subjects with a baseline coronary artery calcium score of greater than or equal to 30 Agatston Units, will be randomly assigned to either the treatment group (10 mg of phylloquinone three times per week) or to the control group (placebo administration three times per week). The primary endpoint is the progression of coronary artery calcification defined as a greater than 15% increase in CAC score over baseline after 12 months. Discussion: Vitamin K supplementation is a simple, safe and cost-effective nutritional strategy that can easily be integrated into patient care. If vitamin K reduces the progression of coronary artery calcification it may lead to decreased morbidity and mortality in men and women with ESKD. Trial registration: NCT 01528800.

Astaxanthin from Haematococcus pluvialis is commercially produced in a two-stage process, involving green vegetative (macrozooid) and red aplanospore stages. This approach has been scaled up to an industrial process but constraints limit its commercial success and profitability, including: contamination issues, high pigment extraction costs, requirements for high light levels and photo-bleaching in the red stage. However, in addition to the aplanospore stage, this alga can produce astaxanthin in vegetative palmelloid and motile macrozooid cells. In this study, a two-stage process utilising different media in the green stage, with subsequent re-suspension in medium without nitrate was employed to optimise the formation of red motile macrozooids. Optimal growth in the green phase was obtained on cultivation under mixotrophic conditions in EG:JM media followed by re-suspension in medium without nitrate resulting in red motile macrozooids with an astaxanthin content of 2.74% (78.4% of total carotenoids) and a lipid content of 35.3% (rich in unsaturated fatty acids. It is envisaged that the red motile macrozooids could be harvested and fed as a whole-cell product directly in the animal feed and aquaculture sectors, or used as a blend of carotenoids and polyunsaturated fatty acids (PUFAs) in nutraceutical products.

Studies have questioned whether renal dysfunction in sickle cell disease is linked to hemolysis-associated vasculopathy. We have investigated renal function and markers of hemolysis in a cohort of 424 adult African-British patients with sickle cell disease. While significant associations were found in HbSS and HbSβ0 (sickle cell anemia) patients with and without controlling for covariates between hemolytic markers and albuminuria, the associations were not significant in patients with HbSC. Estimated glomerular filtration rate, a marker of renal function, correlated significantly with reticulocyte count and bilirubin. Alpha thalassemia, present in 34% of the sickle cell anaemia patients, had a protective effect against albuminuria in this group. Altogether, the incidence of hyperfiltration was 71% and microalbuminuria 37%, making nephropathy a common complication of sickle cell anemia.

Pooled sequencing can be a cost-effective approach to disease variant discovery, but its applicability in association studies remains unclear. We compare sequence enrichment methods coupled to next-generation sequencing in non-indexed pools of 1, 2, 10, 20 and 50 individuals and assess their ability to discover variants and to estimate their allele frequencies. We find that pooled resequencing is most usefully applied as a variant discovery tool due to limitations in estimating allele frequency with high enough accuracy for association studies, and that in-solution hybrid-capture performs best among the enrichment methods examined regardless of pool size.