Membrane binding and pore forming insertion of PEX5 into horizontal lipid bilayer.

The assembly of the peroxisomal translocon involves the transition of a soluble form of the peroxisomal targeting receptor PEX5 into a membrane-bound form, which becomes an integral membrane component of the import pore for peroxisomal matrix proteins. How this transition occurs is still a mystery. We addressed this question using a artificial horizontal bilayer in combination with fluorescence time-correlated single photon counting (TCSPC) and electrophysiological channel recording. Purified human isoform PEX5L and truncated PEX5L(1-335) lacking the cargo binding domain were selectively labeled with thiol-reactive Atto-dyes. Diffusion coefficients of labeled protein in solution show that PEX5L is monomeric with a rather compact spherical conformation, while the truncated protein appeared in a more extended conformation. Labeled PEX5L and the truncated PEX5L(1-335) bind stably to horizontal bilayer thereby accumulating around 100-fold. The diffusion coefficients of the membrane-bound PEX5L forms are 3-4 times lower than in solution, indicating the formation of larger complexes. Electrophysiological single channel recording shows that membrane-bound labeled and non-labeled PEX5L, but not the truncated PEX5L(1-335), can form ion conducting membrane channels. The data suggest that PEX5L is the pore-forming component of the oligomeric peroxisomal translocon and that spontaneous PEX5L membrane surface binding might be an important step in its assembly.

Epitopes as characterized by antibody-verified eplet mismatches determine risk of kidney transplant loss.

To optimize strategies that mitigate the risk of graft loss associated with HLA incompatibility, we evaluated whether sequence defined HLA targets (eplets) that result in donor-specific antibodies are associated with transplant outcomes. To define this, we fit multivariable Cox proportional hazard models in a cohort of 118 382 United States first kidney transplant recipients to assess risk of death-censored graft failure by increments of ten antibody-verified eplet mismatches. To verify robustness of our findings, we conducted sensitivity analysis in this United States cohort and assessed the role of antibody-verified eplet mismatches as autonomous predictors of transplant glomerulopathy in an independent Canadian cohort. Antibody-verified eplet mismatches were found to be independent predictors of death-censored graft failure with hazard ratios of 1.231 [95% confidence interval 1.195, 1. 268], 1.268 [1.231, 1.305] and 1.411 [1.331, 1.495] for Class I (HLA-A, B, and C), -DRB1 and -DQB1 loci, respectively. To address linkage disequilibrium between HLA-DRB1 and -DQB1, we fit models in a subcohort without HLA-DQB1 eplet mismatches and found hazard ratios for death-censored graft failure of 1.384 [1.293, 1.480] for each additional antibody-verified HLA-DRB1 eplet mismatch. In a subcohort without HLA-DRB1 mismatches, the hazard ratio was 1.384 [1.072, 1.791] for each additional HLA-DQB1 mismatch. In the Canadian cohort, antibody-verified eplet mismatches were independent predictors of transplant glomerulopathy with hazard ratios of 5.511 [1.442, 21.080] for HLA-DRB1 and 3.640 [1.574, 8.416] for -DRB1/3/4/5. Thus, donor-recipient matching for specific HLA eplets appears to be a feasible and clinically justifiable strategy to mitigate risk of graft loss.

The Frequency of Routine Blood Sampling and Patient Outcomes Among Maintenance Hemodialysis Recipients.

RATIONALE & OBJECTIVE: Surveillance blood work is routinely performed in maintenance hemodialysis (HD) recipients. Although more frequent blood testing may confer better outcomes, there is little evidence to support any particular monitoring interval. STUDY DESIGN: Retrospective population-based cohort study. SETTING & PARTICIPANTS: All prevalent HD recipients in Ontario, Canada, as of April 1, 2011, and a cohort of incident patients commencing maintenance HD in Ontario, Canada, between April 1, 2011, and March 31, 2016. EXPOSURE: Frequency of surveillance blood work, monthly versus every 6 weeks. OUTCOMES: The primary outcome was all-cause mortality. Secondary outcomes were major adverse cardiovascular events, all-cause hospitalization, and episodes of hyperkalemia. ANALYTICAL APPROACH: Cox proportional hazards with adjustment for demographic and clinical characteristics was used to evaluate the association between blood testing frequency and all-cause mortality. Secondary outcomes were evaluated using the Andersen-Gill extension of the Cox model to allow for potential recurrent events. RESULTS: 7,454 prevalent patients received care at 17 HD programs with monthly blood sampling protocols (n=5,335 patients) and at 8 programs with blood sampling every 6 weeks (n=2,119 patients). More frequent monitoring was not associated with a lower risk for all-cause mortality compared to blood sampling every 6 weeks (adjusted HR, 1.16; 95% CI, 0.99-1.38). Monthly monitoring was not associated with a lower risk for any of the secondary outcomes. Results were consistent among incident HD recipients. LIMITATIONS: Unmeasured confounding; limited data for center practices unrelated to blood sampling frequency; no information on frequency of unscheduled blood work performed outside the prescribed sampling interval. CONCLUSIONS: Monthly routine blood testing in HD recipients was not associated with a lower risk for death, cardiovascular events, or hospitalizations as compared with testing every 6 weeks. Given the health resource implications, the frequency of routine blood sampling in HD recipients deserves careful reassessment.

Drip irrigation uptake in traditional irrigated fields: The edaphological impact.

Historical and traditional flood-irrigated (FI) schemes are progressively being upgraded by means of drip irrigation (DI) to tackle current water and demographic challenges. This modernization process is likely to foster several changes of environmental relevance at the system level. In this paper we assess the effects derived from DI uptake on soil health and structure in ancient FI systems through the case study of Ricote, SE Spain, first established in the 10-13th centuries CE. We approach the topic by means of physico-chemical analyses (pH, electrical conductivity, available P, carbon analyses, bulk density, soil water content and particle size distribution), Electrical Resistivity Measurements (ERT) and robust statistics. We reach a power of 1-ß = 77 aiming at detecting a large effect size (f ≥ 0.4). Results indicate that, compared to FI, DI soils present significantly higher water content, a higher proportion of coarse particles relative to fines due to clay translocation, and less dispersion in salt contents. The soils away from the emitters, which were formerly FI and comparatively account for larger extensions, appear significantly depleted in organic matter, available P and N. These results are not affected by departures from statistical model assumptions and suggest that DI uptake in formerly FI systems might have relevant implications in terms of soil degradation and emission of greenhouse gases. A proper assessment of the edaphological trade-offs derived from this modernization process is mandatory in order to tackle undesired environmental consequences.

Adverse effects of health anxiety on management of a patient with benign paroxysmal positional vertigo, vestibular migraine and chronic subjective dizziness.

INTRODUCTION: Care of patients with vestibular symptoms focuses primarily on physical otoneurologic disorders; however, psychological factors can sustain symptoms, confound assessment, and adversely affect treatment. Health anxiety is a particularly pernicious process that simultaneously magnifies physical symptoms and inhibits medical care. OBJECTIVE: To demonstrate the excess morbidity caused by vestibular health anxiety and its successful management in a patient with otoneurologic disease. METHOD: Report of a 41-year-old woman with recurrent benign paroxysmal positional vertigo, vestibular migraine, and chronic subjective dizziness, who expressed grave concerns about her health, repeatedly questioned her otoneurologic diagnoses, and failed physical therapy and medication treatment until her health anxiety and otoneurologic illnesses were addressed simultaneously. CONCLUSION: Health anxiety is an empirically validated concept that explains troublesome health-related beliefs and behaviors. It is frustrating for patients and health care teams, but can be treated successfully in otoneurology practice, thereby reducing physical symptoms, emotional distress, functional impairment, and health care overutilization.

Early time-restricted eating advances sleep in late sleepers: a pilot randomized controlled trial.

STUDY OBJECTIVES: This study evaluated the effects of early time-restricted eating (eTRE) on shifting the timing of sleep among late sleepers. Primary outcomes included actigraphy- and sleep diary-derived sleep onset, midsleep phase, and wake time with total sleep time as a secondary outcome. METHODS: Fifteen healthy adults with habitual late sleep timing were randomized to receive either eTRE or sleep and nutrition hygiene (control) via a single 30-minute synchronous video session. Participants completed an initial 1-week baseline phase followed by a 2-week intervention phase. Measures included continuous sleep monitoring and sleep and nutrition diaries. RESULTS: Linear mixed-effects modeling demonstrated that eTRE significantly advanced sleep timing compared with controls. Self-reported sleep onset (56.1 [95% confidence interval: 20.5, 91.7] minutes), midpoint (19.5 [7.2, 31.9] minutes), and offset (42.2 [2.9, 81.5] minutes) each moved earlier in eTRE as compared with controls. Similarly, objectively determined sleep onset (66.5 [29.6, 103.4] minutes), midpoint (21.9 [9.1, 34.7] minutes), and offset (39.3 [1.3, 77.3] minutes) each moved earlier in eTRE as compared with controls. Total sleep time showed a nonsignificant increase in the eTRE group as compared with controls. CONCLUSIONS: Late sleepers who were instructed in a single session about eTRE significantly advanced their sleep timing, especially sleep onset. eTRE shows potential as a clinical strategy for advancing sleep timing in late sleepers. CLINICAL TRIAL REGISTRATION: Registry: Chinese Clinical Trial Registry; Name: FAST Asleep: It's All About Timing; URL: https://www.chictr.org.cn/showproj.html?proj=122504; Identifier: ChiCTR2100043691. CITATION: Blum DJ, Hernandez B, Zeitzer JM. Early time-restricted eating advances sleep in late sleepers: a pilot randomized controlled trial. J Clin Sleep Med. 2023;19(12):2097-2106.

Evaluation of a Brief Sleep Intervention Designed to Improve the Sleep, Mood, and Cognitive Performance of Esports Athletes.

This study evaluated a brief sleep intervention designed to improve the sleep, mood, and cognitive performance of professional electronic sports (esports) athletes from three major esports regions (i.e., Asia, North America, and Oceania). Fifty-six esports athletes from South Korea (N = 34), the United States (N = 7), and Australia (N = 15) completed the study. Participants completed an initial 2-week pre-intervention phase to establish a baseline, followed by a 2-week intervention phase that involved a group sleep education class, 1:1 session with a trained clinical psychologist, and daily biofeedback. A wrist activity monitor and daily sleep diary were used to monitor sleep during both phases, while at pre- and post-intervention, participants completed a battery of sleep and mood questionnaires and underwent cognitive performance testing. Sleep knowledge increased from pre- to post-intervention (d = 0.83 [95% CI −1.21, −0.43], p =< 0.001), while there were modest improvements in sleep diary estimates (i.e., sleep onset latency (Mdiff = −2.9 min, p = 0.02), sleep onset time (Mdiff = −12 min, p = 0.03), and sleep efficiency (Mdiff = 1.1%, p = 0.004)) and wrist activity monitor estimates (i.e., sleep onset time (Mdiff = −18 min, p = 0.01)). Insomnia severity scores decreased significantly (d = 0.47 [95% CI 0.08, 0.84], p = 0.001), while sleepiness scores increased but not meaningfully (d = 0.23 [95% CI −0.61, 0.14], p = 0.025). However, there was no significant change in mood (i.e., depression and anxiety) or cognitive performance scores (i.e., mean reaction time or lapses). Sleep interventions for esports athletes require further investigation. Future research should examine whether a stepped-care model, whereby increasing therapeutic input is provided as needed, can optimize sleep, mood, and cognitive performance outcomes.

A New Twist in ABC Transporter Mediated Multidrug Resistance - Pdr5 is a Drug/proton Co-transporter.

The two major efflux pump systems that are involved in multidrug resistance (MDR) are (i) ATP binding cassette (ABC) transporters and (ii) secondary transporters. While the former use binding and hydrolysis of ATP to facilitate export of cytotoxic compounds, the latter utilize electrochemical gradients to expel their substrates. Pdr5 from Saccharomyces cerevisiae is a prominent member of eukaryotic ATP binding cassette (ABC) transporters that are involved in multidrug resistance (MDR) and used as a frequently studied model system. Although investigated for decades, the underlying molecular mechanisms of drug transport and substrate specificity remain elusive. Here, we provide electrophysiological data on the reconstituted Pdr5 demonstrating that this MDR efflux pump does not only actively translocate its substrates across the lipid bilayer, but at the same time generates a proton motif force in the presence of Mg2+-ATP and substrates by acting as a proton/drug co-transporter. Importantly, a strictly substrate dependent co-transport of protons was also observed in in vitro transport studies using Pdr5-enriched plasma membranes. We conclude from these results that the mechanism of MDR conferred by Pdr5 and likely other transporters is more complex than the sole extrusion of cytotoxic compounds and involves secondary coupled processes suitable to increase the effectiveness.

A network analysis investigation of the comorbidity between sleep dysfunction and PTSD symptomatology among Filipino domestic workers in Macao (SAR) China.

Posttraumatic stress disorder (PTSD) is highly comorbid with sleep dysfunction. This association was previously explained based on cognitive and emotional dysfunction. The current study extends this literature by investigating the symptom level comorbidity of sleep dysfunction and DSM-5 PTSD utilizing a network approach. Participants were trauma-exposed female Filipino domestic workers (N = 1241). Network analysis was applied to 23 items: 18 items from PCL-5 measuring PTSD (Community 1) and 5 items from PSQI assessing sleep dysfunction (Community 2). The results showed that the symptoms within each community had the strongest correlations. Bridge connections were identified between the sleep dysfunction and PTSD symptom communities. Symptoms with the highest bridge strength were concentration difficulties, recklessness, irritability, and sleep disturbance. This is among the first studies investigating the comorbidity between PTSD and sleep dysfunction from the network approach. Future interventions may be developed that emphasize the bridge symptoms to address comorbidity among trauma exposed migrants.

Molecular architecture of black widow spider neurotoxins.

Latrotoxins (LaTXs) are presynaptic pore-forming neurotoxins found in the venom of Latrodectus spiders. The venom contains a toxic cocktail of seven LaTXs, with one of them targeting vertebrates (α-latrotoxin (α-LTX)), five specialized on insects (α, ß, γ, δ, ε- latroinsectotoxins (LITs), and one on crustaceans (α-latrocrustatoxin (α-LCT)). LaTXs bind to specific receptors on the surface of neuronal cells, inducing the release of neurotransmitters either by directly stimulating exocytosis or by forming Ca2+-conductive tetrameric pores in the membrane. Despite extensive studies in the past decades, a high-resolution structure of a LaTX is not yet available and the precise mechanism of LaTX action remains unclear. Here, we report cryoEM structures of the α-LCT monomer and the δ-LIT dimer. The structures reveal that LaTXs are organized in four domains. A C-terminal domain of ankyrin-like repeats shields a central membrane insertion domain of six parallel α-helices. Both domains are flexibly linked via an N-terminal α-helical domain and a small ß-sheet domain. A comparison between the structures suggests that oligomerization involves major conformational changes in LaTXs with longer C-terminal domains. Based on our data we propose a cyclic mechanism of oligomerization, taking place prior membrane insertion. Both recombinant α-LCT and δ-LIT form channels in artificial membrane bilayers, that are stabilized by Ca2+ ions and allow calcium flux at negative membrane potentials. Our comparative analysis between α-LCT and δ-LIT provides first crucial insights towards understanding the molecular mechanism of the LaTX family.

The Prevalence of Acute Kidney Injury in Patients Hospitalized With COVID-19 Infection: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: Coronavirus disease 2019 (COVID-19) may be associated with high rates of acute kidney injury (AKI) and kidney replacement therapy (KRT), potentially overwhelming health care resources. Our objective was to determine the pooled prevalence of AKI and KRT among hospitalized patients with COVID-19. STUDY DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, the Cochrane Library, and a registry of preprinted studies, published up to October 14, 2020. STUDY SELECTION: Eligible studies reported the prevalence of AKI in hospitalized patients with COVID-19 according to the Kidney Disease: Improving Global Outcomes (KDIGO) definition. DATA EXTRACTION & SYNTHESIS: We extracted data on patient characteristics, the proportion of patients developing AKI and commencing KRT, important clinical outcomes (discharge from hospital, ongoing hospitalization, and death), and risk of bias. OUTCOMES & MEASURES: We calculated the pooled prevalence of AKI and receipt of KRT along with 95% CIs using a random-effects model. We performed subgroup analysis based on admission to an intensive care unit (ICU). RESULTS: Of 2,711 records reviewed, we included 53 published and 1 preprint study in the analysis, which comprised 30,657 hospitalized patients with COVID-19. Data for AKI were available for 30,639 patients (n = 54 studies), and receipt of KRT, for 27,525 patients (n = 48 studies). The pooled prevalence of AKI was 28% (95% CI, 22%-34%; I 2 = 99%), and the pooled prevalence of KRT was 9% (95% CI, 7%-11%; I 2 = 97%). The pooled prevalence of AKI among patients admitted to the ICU was 46% (95% CI, 35%-57%; I 2 = 99%), and 19% of all ICU patients with COVID-19 (95% CI, 15%-22%; I 2 = 88%) commenced KRT. LIMITATIONS: There was significant heterogeneity among the included studies, which remained unaccounted for in subgroup analysis. CONCLUSIONS: AKI complicated the course of nearly 1 in 3 patients hospitalized with COVID-19. The risk for AKI was higher in critically ill patients, with a substantial number receiving KRT at rates higher than the general ICU population. Because COVID-19 will be a public health threat for the foreseeable future, these estimates should help guide KRT resource planning.

The Risk of Acute Kidney Injury with Oral Anticoagulants in Elderly Adults with Atrial Fibrillation.

BACKGROUND AND OBJECTIVES: Anticoagulation with either a vitamin K antagonist or a direct oral anticoagulant may be associated with AKI. Our objective was to assess the risk of AKI among elderly individuals with atrial fibrillation newly prescribed a direct oral anticoagulant (dabigatran, rivaroxaban, or apixaban) versus warfarin. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our population-based cohort study included 20,683 outpatients in Ontario, Canada, ≥66 years with atrial fibrillation who were prescribed warfarin, dabigatran, rivaroxaban, or apixaban between 2009 and 2017. Inverse probability of treatment weighting on the basis of derived propensity scores for the treatment with each direct oral anticoagulant was used to balance baseline characteristics among patients receiving each of the three direct oral anticoagulants compared with warfarin. Cox proportional hazards regression was performed in the weighted population to compare the association between the prescribed anticoagulant and the outcomes of interest. The exposure was an outpatient prescription of warfarin or one of the direct oral anticoagulants. The primary outcome was a hospital encounter with AKI, defined using Kidney Disease Improving Global Outcomes thresholds. Prespecified subgroup analyses were conducted by eGFR category and by the percentage of international normalized ratio measurements in range, a validated marker of anticoagulation control. RESULTS: Each direct oral anticoagulant was associated with a significantly lower risk of AKI compared with warfarin (weighted hazard ratio, 0.65; 95% confidence interval, 0.53 to 0.80 for dabigatran; weighted hazard ratio, 0.85; 95% confidence interval, 0.73 to 0.98 for rivaroxaban; and weighted hazard ratio, 0.81; 95% confidence interval, 0.72 to 0.93 for apixaban). In the subgroup analysis, the lower risk of AKI associated with each direct oral anticoagulant was consistent across each eGFR strata. The risk of AKI was significantly lower among users of each of the direct oral anticoagulants compared with warfarin users who had a percentage of international normalized ratio measurements ≤56%. CONCLUSIONS: Direct oral anticoagulants were associated with a lower risk of AKI compared with warfarin.

Experiences of Transgender Participants in Emergency Departments: Findings from the OutLook Study.

Purpose: Even in cases of medical emergency, mistreatment and negative experiences in life or in medical settings can deter trans patients from seeking necessary care. The purpose of this study was to identify factors associated with trans persons' emergency department (ED) avoidance in the mixed urban-rural Region of Waterloo, Ontario, Canada. Methods: The OutLook Study was a community-based partnership that created an online, cross-sectional questionnaire for lesbian, gay, bisexual, transgender, and other sexual and gender minority community members. Participants in this analysis were 16 years of age or older, lived, worked, or attended school in Waterloo Region, and identified as trans (n=112). Binary logistic regression was used to test associations between sociodemographic, resilience, and risk variables, and ED avoidance. Sociodemographic variables statistically significant at p<0.05 at the bivariate level were included as controls to explore different combinations of resilience and risk factor in multivariable models. Results: Participants reporting complete or partially complete medical transitions were more likely to report ED avoidance, compared to those who had not initiated medical transition. Elevated transphobia was associated with greater likelihood of avoidance. However, increasing levels of social support decreased the likelihood of avoidance. In multivariable models, social support, support from a special person, and transphobia were always significant, regardless of controlled variables. Conclusion: Transphobia-enacted in the contexts of everyday life and health care-can deter patients from seeking care. Patient-centered care requires careful attention to trans identity and health needs, especially in emergency settings. In the absence of structural changes, providers can take steps to mitigate the erasure and discrimination trans patients experience and anticipate when accessing EDs.

An Environmental Scan of Canadian Quality Metrics for Patients on In-Center Hemodialysis.

BACKGROUND: Quality metrics or indicators help guide quality improvement work by reporting on measurable aspects of health care upon which improvement efforts can focus. For recipients of in-center hemodialysis (ICHD) in Canada, it is unclear what ICHD quality indicators exist and whether they adequately cover different domains of health care quality. OBJECTIVES: To identify and evaluate current Canadian ICHD quality metrics to document a starting point for future collaborations and standardization of quality improvement in Canada. DESIGN: Environmental scan of quality metrics in ICHD, and subsequent indicator evaluation using a modified Delphi approach. SETTING: Canadian ICHD units. PARTICIPANTS: Sixteen-member pan-Canadian working group with expertise in ICHD and quality improvement. MEASUREMENTS: We classified the existing indicators based on the Institute of Medicine (IOM) and Donabedian frameworks. METHODS: Each metric was rated by a 5-person subcommittee using a modified Delphi approach based on the American College of Physicians/Agency for Healthcare Research and Quality criteria. We shared these consensus ratings with the entire 16-member panel for additional comments. RESULTS: We identified 27 metrics that are tracked across 8 provinces, with only 9 (33%) tracked by multiple provinces (ie, more than 1 province). We rated 9 metrics (33%) as "necessary" to distinguish high-quality from low-quality care, of which only 2 were tracked by multiple provinces (proportion of patients by primary access and rate of vascular access-related bloodstream infections). Most (16/27, 59%) indicators assessed the IOM domains of safe or effective care, and none of the "necessary" indicators measured the IOM domains of timely, patient-centered, or equitable care. LIMITATIONS: The environmental scan is a nonexhaustive list of quality indicators in Canada. The panel also lacked representation from patients, administrators, and allied health professionals, with more representation from academic sites. CONCLUSIONS: Quality indicators in Canada mainly focus on safe and effective care, with little provincial overlap. These results highlight current gaps in quality of care measurement for ICHD, and this initial work should provide programs with a starting point to combine highly rated indicators with newly developed indicators into a concise balanced scorecard that supports quality improvement initiatives across all aspects of ICHD care. TRIAL REGISTRATION: not applicable.

CONTEXTE: Les mesures ou indicateurs de la qualité contribuent à guider les travaux d'amélioration de la qualité des soins de santé en indiquant les aspects mesurables sur lesquels les efforts peuvent se concentrer. On connait peu les indicateurs de la qualité existant au Canada pour les bénéficiaires de l'hémodialyse en centre (HDC). On ignore également si ces indicateurs couvrent adéquatement les différents domaines de la qualité des soins de santé. OBJECTIFS: Définir et évaluer les mesures actuelles de la qualité des soins d'HDC au Canada. Ces travaux serviront à documenter le point de départ de futures collaborations et la normalisation de l'amélioration de la qualité au Canada. TYPE D'ÉTUDE: Analyse contextuelle des mesures de la qualité en HDC, suivie de leur évaluation par une méthode Delphi modifiée. CADRE: Des unités d'HDC au Canada. SUJETS: Un groupe de travail pancanadien constitué de 16 membres ayant une expertise en HDC et en amélioration de la qualité. MESURES: Les indicateurs existants ont été évalués à l'aide des modèles de l'IOM (Institute of Medicine) et de Donabedian. MÉTHODOLOGIE: Chaque indicateur a été évalué par un sous-comité de cinq personnes à l'aide d'une méthode Delphi modifiée basée sur les critères de l'American College of Physicians/Agency for Healthcare Research and Quality. Les évaluations consensuelles ont été partagées avec l'ensemble des 16 membres pour recueillir des commentaires supplémentaires. RÉSULTATS: Nous avons répertorié 27 indicateurs suivis dans 8 provinces, dont 9 (33 %) sont suivis dans plus d'une province. Neuf indicateurs (33 %) ont été classés comme « nécessaires ¼ pour départager les soins de haute qualité des soins de faible qualité, dont seulement deux (la proportion de patients selon l'accès primaire et le taux de bactériémies liées à l'accès vasculaire) sont suivis par plusieurs provinces. La majorité des indicateurs (16/27; 59 %) a évalué les domaines de l'IOM relatifs aux soins sûrs ou efficaces; aucun des indicateurs « nécessaires ¼ n'a mesuré les domaines de l'IOM relatifs aux soins opportuns, centrés sur le patient ou équitables. LIMITES: Au Canada, l'analyse contextuelle consiste en une liste non exhaustive d'indicateurs de la qualité. Le groupe de travail manquait de représentants des patients, des administrateurs et des professionnels paramédicaux, les sites universitaires étant mieux représentés. CONCLUSION: Au Canada, les indicateurs de la qualité se concentrent principalement sur la prestation de soins sûrs et efficaces, et les chevauchements entre les provinces sont rares. Ces résultats mettent en évidence les lacunes actuelles dans l'évaluation de la qualité des soins d'HDC. Ces travaux préliminaires devraient fournir aux programmes un point de départ pour combiner des indicateurs bien cotés à d'autres nouvellement développés dans une fiche d'évaluation concise destinée à soutenir les initiatives d'amélioration de la qualité dans tous les aspects des soins entourant l'HDC. ENREGISTREMENT DE L'ESSAI: Sans objet.

Quality Improvement Program Improves Time in Therapeutic Range for Hemodialysis Recipients Taking Warfarin.

INTRODUCTION: Studies have shown that achieving a time in therapeutic range (TTR) for warfarin of greater than 60% is associated with a lower risk of bleeding. However, many patients on hemodialysis (HD) do not achieve this target. METHODS: We audited TTR achievement at the in-center HD unit of our hospital in 2017 and found that only 40% of patients had achieved a TTR >60%. We aimed to improve the percentage of HD patients achieving target TTR within 2 years. We reported each patient's individualized trend in quarterly TTR to their primary warfarin prescriber as an audit-feedback report. These reports were generated, disseminated, and subsequently improved following a series of plan-do-study-act cycles. We then used statistical process control to assess for changes in the percentage of HD patients achieving target TTR over time. RESULTS: In the primary analysis, 28 patients were included in the baseline period, and 46 were included in the intervention period. At baseline, the percentage of patients achieving a TTR >60% varied between 33% and 45% (mean ± SD, 40% ± 5%); post-intervention, this metric improved and varied between 52% and 71% (mean ± SD, 61% ± 8%). In time-series analysis, there was evidence of statistically significant variation between the 2 periods and evidence of sustained improvement. CONCLUSIONS: A quality improvement program consisting of an audit-feedback report that raises awareness of the quality gap in TTR achievement can result in substantial improvement in the safe and efficacious administration of warfarin to patients receiving maintenance hemodialysis.

Predicting mortality among critically ill patients with acute kidney injury treated with renal replacement therapy: Development and validation of new prediction models.

PURPOSE: Severe acute kidney injury (AKI) is associated with a significant risk of mortality and persistent renal replacement therapy (RRT) dependence. The objective of this study was to develop prediction models for mortality at 90-day and 1-year following RRT initiation in critically ill patients with AKI. METHODS: All patients who commenced RRT in the intensive care unit for AKI at a tertiary care hospital between 2007 and 2014 constituted the development cohort. We evaluated the external validity of our mortality models using data from the multicentre OPTIMAL-AKI study. RESULTS: The development cohort consisted of 594 patients, of whom 320(54%) died and 40 (15% of surviving patients) remained RRT-dependent at 90-day Eleven variables were included in the model to predict 90-day mortality (AUC:0.79, 95%CI:0.76-0.82). The performance of the 90-day mortality model declined upon validation in the OPTIMAL-AKI cohort (AUC:0.61, 95%CI:0.54-0.69) and showed modest calibration. Similar results were obtained for mortality model at 1-year. CONCLUSIONS: Routinely collected variables at the time of RRT initiation have limited ability to predict mortality in critically ill patients with AKI who commence RRT.

The metabolic modulators, Etomoxir and NVP-LAB121, fail to reverse pressure overload induced heart failure in vivo.

Shifting substrate oxidation in heart muscle from fatty acids to glucose (substrate-switch) may improve contractile function in heart failure. We tested whether application of two agents (etomoxir and NVP-LAB121) capable of inducing a substrate-switch reverts the onset of heart failure in rats with chronic pressure-overload. Hypertrophy was induced by aortic banding in rats for 1 or 15 weeks. Rats were treated for 10 days with the CPT-1-inhibitor etomoxir [29.5 micromol/(kg day)] or with NVP-LAB121 [60 micromol/(kg day)], a pyruvate-dehydrogenase-kinase-inhibitor, before assessment by echocardiography and perfusion as isolated working hearts. We also analyzed PDH- and CPT1-activity and expression of alpha- and beta-MHC by RT-PCR. Aortic banding increased heart-to-body-weight-ratio (g/kg) from 3.44 +/- 0.26 to 4.14 +/- 0.48 after 1 week and from 2.80 +/- 0.21 to 6.54 +/- 0.26 after 15 weeks. Ejection fraction was impaired after 15 weeks (57 +/- 11 vs. 73 +/- 8%, P < 0.05) and rats exhibited signs of heart failure. Total PDH activity was the same in all groups. CPT-1 activity was unchanged after 1 week but decreased after 15 weeks (P < 0.01). Neither etomoxir nor NVP-LAB121 affected cardiac function in vivo, but etomoxir improved function of the isolated heart. The drugs did not affect total PDH and CPT-1 activity, but increased PDH-activity status, prevented a decrease in PDK4 expression in heart failure, increased alpha and beta-MHC expression and shifted substrate oxidation toward glucose in the isolated working rat heart. In conclusion, pharmacologic induction of substrate-switching is associated with changes in myofibrillar isoform expression but does not reverse heart failure in vivo. The improvement of function in vitro deserves further investigation.

Thinking Volume First: Developing a Multifaceted Systematic Approach to Volume Management in Hemodialysis.

PURPOSE OF REVIEW: Volume overload and hypovolemia-induced symptoms are common in the hemodialysis (HD) population and frequently result in emergency department visits and hospitalization. A structured strategy for the reporting, evaluation, and management of disordered volume status may improve clinical outcomes and the patient experience. We developed a new strategy that systematically addresses volume issues by leveraging the electronic medical record, technological adjuncts, and multidisciplinary expertise to institute new processes of care in our HD unit. SOURCES OF INFORMATION: This initiative was implemented in a unit located in an urban academic hospital where 250 patients receive maintenance HD. This initiative involved a multidisciplinary team of health professionals including physicians, nurse practitioners, social workers, and dieticians. METHODS: We generated volume metrics for HD recipients based on routinely collected data from the unit's electronic medical record. We then engaged stakeholders in a root cause analysis to identify the major causes of abnormal volume metrics locally. We subsequently developed interventions that were designed to address each of the major causes in a pragmatic and sustainable program. KEY FINDINGS: The final product was a local volume management program with 3 components. First, we integrated volume metric reporting into the routine surveillance bloodwork reports across our unit. This enabled the clinical teams to more easily target patients at risk for volume-related adverse events and provide them with closer surveillance. Those identified with abnormal volume metrics were then evaluated with the use of technologic adjuncts such as lung ultrasound and bioimpedance spectroscopy to complement traditional assessments of volume status. Finally, those with abnormal volume metrics underwent rigorous interdisciplinary review for potential nutritional/social interventions. LIMITATIONS: While we report the successful initial implementation of the program within a single center, it remains unclear whether this initiative will lead to meaningful benefits for HD recipients, be readily applicable in other centers, or be sustainable in the long term. IMPLICATIONS: This volume management program will need further evaluation linked to outcome assessment and feasibility in other centers before wider adoption is advocated.

CONTEXTE MOTIVANT LA REVUE: La surcharge volémique et les symptômes induits par l'hypovolémie sont fréquents chez les patients hémodialysés (HD) et entraînent souvent des visites aux urgences et des hospitalisations. Une stratégie structurée de notification, d'évaluation et de gestion des déséquilibres hydriques peut améliorer les résultats cliniques et l'expérience du patient. Nous avons développé une nouvelle stratégie qui aborde systématiquement les problèmes de volémie en exploitant les dossiers médicaux électroniques, les auxiliaires technologiques et une expertise multidisciplinaire pour instaurer de nouvelles procédures de soins dans notre unité d'hémodialyse. SOURCES: Cette initiative a été mise en œuvre dans l'unité de dialyse d'un centre hospitalier universitaire en milieu urbain, dans lequel 250 patients reçoivent des traitements d'HD périodiques. Une équipe multidisciplinaire constituée de médecins, d'infirmières-praticiennes, de travailleurs sociaux et de nutritionnistes a participé à l'initiative. MÉTHODOLOGIE: Nous avons généré des données de volémie pour les patients hémodialysés à partir des données recueillies sur une base régulière dans le dossier médical informatisé de l'unité. Nous avons ensuite fait participer les différents intervenants à l'analyse des causes profondes afin de déterminer les principales causes des anomalies volémiques observées dans notre unité. Enfin, nous avons développé des interventions pour traiter chacune des principales causes à l'aide d'un programme viable et pragmatique. PRINCIPAUX RÉSULTATS: Le résultat est un programme local de prise en charge de la volémie à trois composants. Premièrement, nous avons intégré la mesure de la volémie dans les rapports d'analyses sanguines de surveillance de routine dans toute l'unité. Cela a permis aux équipes soignantes de cibler plus facilement les patients susceptibles de subir des manifestations indésirables liées à la volémie et de les surveiller de plus près. Les patients présentant une mesure de volémie anormale ont ensuite été évalués à l'aide d'auxiliaires technologiques tels que l'ultrasonographie pulmonaire et la spectroscopie de bioimpédance, en complément de l'évaluation traditionnelle du statut volémique. Enfin, les patients présentant des anomalies volémiques ont fait l'objet d'un examen interdisciplinaire rigoureux en vue de potentielles interventions nutritionnelles/sociales. LIMITES: Bien que nous rapportions le succès de la mise en œuvre initiale du programme dans un centre, nous ignorons si cette initiative apportera des bienfaits significatifs aux patients hémodialysés, si elle s'appliquera facilement à d'autres centres ou si elle est viable à long terme. CONCLUSION: Ce programme de gestion de la volémie devra faire l'objet d'une évaluation plus poussée quant à l'examen des résultats cliniques et à sa faisabilité dans d'autres centres avant que son adoption à d'autres centres ne soit préconisée.