Neuronal and behavioral responses to naturalistic texture im-ages in macaque monkeys.

The visual world is richly adorned with texture, which can serve to delineate important elements of natural scenes. In anes-thetized macaque monkeys, selectivity for the statistical features of natural texture is weak in V1, but substantial in V2, sug-gesting that neuronal activity in V2 might directly support texture perception. To test this, we investigated the relation between single cell activity in macaque V1 and V2 and simultaneously measured behavioral judgments of texture. We generated stim-uli along a continuum between naturalistic texture and phase-randomized noise and trained two macaque monkeys to judge whether a sample texture more closely resembled one or the other extreme. Analysis of responses revealed that individual V1 and V2 neurons carried much less information about texture naturalness than behavioral reports. However, the sensitivity of V2 neurons, especially those preferring naturalistic textures, was significantly closer to that of behavior compared with V1. The firing of both V1 and V2 neurons predicted perceptual choices in response to repeated presentations of the same ambiguous stimulus in one monkey, despite low individual neural sensitivity. However, neither population predicted choice in the second monkey. We conclude that neural responses supporting texture perception likely continue to develop downstream of V2. Fur-ther, combined with neural data recorded while the same two monkeys performed an orientation discrimination task, our results demonstrate that choice-correlated neural activity in early sensory cortex is unstable across observers and tasks, untethered from neuronal sensitivity, and thus unlikely to reflect a critical aspect of the formation of perceptual decisions.Significance statement As visual signals propagate along the cortical hierarchy, they encode increasingly complex aspects of the sensory environment and likely have a more direct relationship with perceptual experience. We replicate and extend previous results from anes-thetized monkeys differentiating the selectivity of neurons along the first step in cortical vision from area V1 to V2. However, our results further complicate efforts to establish neural signatures that reveal the relationship between perception and the neu-ronal activity of sensory populations. We find that choice-correlated activity in V1 and V2 is unstable across different observers and tasks, and also untethered from neuronal sensitivity and other features of nonsensory response modulation.

Deceased donor kidney function and branched chain amino acid metabolism during ex vivo normothermic perfusion.

Current kidney perfusion protocols are not optimized for addressing the ex vivo physiological and metabolic needs of the kidney. Ex vivo normothermic perfusion may be utilized to distinguish high-risk kidneys to determine suitability for transplantation. Here, we assessed the association of tissue metabolic changes with changes in a kidney injury biomarker and functional parameters in eight deceased donor kidneys deemed unsuitable for transplantation during a 12-hour ex vivo normothermic perfusion. The kidneys were grouped into good and poor performers based on blood flow and urine output. The mean age of the deceased kidney donors was 43 years with an average cold ischemia time of 37 hours. Urine output and creatinine clearance progressively increased and peaked at six hours post-perfusion among good performers. Poor performers had 71 ng/ml greater (95% confidence interval 1.5, 140) urinary neutrophil gelatinase-associated lipocalin at six hours compared to good performers corresponding to peak functional differences. Organ performance was distinguished by tissue metabolic differences in branched chain amino acid metabolism and that their tissue levels negatively correlated with urine output among all kidneys at six hours. Tissue lipid profiling showed poor performers were highlighted by the accumulation of membrane structure components including glycerolipids and sphingolipids at early perfusion time points. Thus, we showed that six hours is needed for kidney function recovery during ex vivo normothermic perfusion and that branched chain amino acid metabolism may be a major determinant of organ function and resilience.

Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19.

BACKGROUND: REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown. METHODS: We randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-CoV-2 infection (as measured by reverse-transcriptase-quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity). RESULTS: Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P<0.001). In weeks 2 to 4, a total of 2 of 753 participants in the REGEN-COV group (0.3%) and 27 of 752 participants in the placebo group (3.6%) had symptomatic SARS-CoV-2 infection (relative risk reduction, 92.6%). REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%). Among symptomatic infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, respectively), and the duration of a high viral load (>104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted. CONCLUSIONS: Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318.).

Impact of Warm Ischemia Time on Donation After Circulatory Death Kidney Transplant Outcomes.

BACKGROUND: Efforts to address the shortage of donor organs include increasing the use of renal allografts from donors after circulatory death (DCD). While warm ischemia time (WIT) is thought to be an important factor in DCD kidney evaluation, few studies have compared the relationship between WIT and DCD kidney outcomes, and WIT acceptance practices remain variable. METHODS: We conducted a single-center retrospective review of all adult patients who underwent deceased donor kidney transplantation from 2000 to 2021. We evaluated the impact of varied functional warm ischemia time (fWIT) in controlled DCD donors by comparing donor and recipient characteristics and posttransplant outcomes between high fWIT (>60 min), low fWIT (≤60 min), and kidneys transplanted from donors after brain death (DBD). RESULTS: Two thousand eight hundred eleven patients were identified, 638 received low fWIT DCD, 93 received high fWIT DCD, and 2080 received DBD kidneys. There was no significant difference in 5-year graft survival between the DCD low fWIT, high fWIT, and DBD groups, with 84%, 83%, and 83% of grafts functioning, respectively. Five-year patient survival was 91% in the low fWIT group, 92% in the high fWIT group, and 90% in the DBD group. An increase in kidney donor risk index (KDRI) (HR 3.37, 95% CI = 2.1-5.7) and high CIT compared to low CIT (HR 2.12, 95% CI = 1.4-3.1) have higher hazard ratios for 1-year graft failure. CONCLUSIONS: Increased acceptance of kidneys from selected DCD donors with prolonged fWIT may present an opportunity to increase kidney utilization while preserving outcomes. Our group specifically prioritizes the use of kidneys from younger donors, with lower KDPI, and without acute kidney injury, or risk factors for underlying chronic kidney disease.

Addressing sex-based disparities in solid organ transplantation in the United States - a conference report.

Solid organ transplantation provides the best treatment for end-stage organ failure, but significant sex-based disparities in transplant access exist. On June 25, 2021, a virtual multidisciplinary conference was convened to address sex-based disparities in transplantation. Common themes contributing to sex-based disparities were noted across kidney, liver, heart, and lung transplantation, specifically the existence of barriers to referral and wait listing for women, the pitfalls of using serum creatinine, the issue of donor/recipient size mismatch, approaches to frailty and a higher prevalence of allosensitization among women. In addition, actionable solutions to improve access to transplantation were identified, including alterations to the current allocation system, surgical interventions on donor organs, and the incorporation of objective frailty metrics into the evaluation process. Key knowledge gaps and high-priority areas for future investigation were also discussed.

Rates of health services use among residents of retirement homes in Ontario: a population-based cohort study.

BACKGROUND: Because there are no standardized reporting systems specific to residents of retirement homes in North America, little is known about the health of this distinct population of older adults. We evaluated rates of health services use by residents of retirement homes relative to those of residents of long-term care homes and other populations of older adults. METHODS: We conducted a retrospective cohort study using population health administrative data from 2018 on adults 65 years or older in Ontario. We matched the postal codes of individuals to those of licensed retirement homes to identify residents of retirement homes. Outcomes included rates of hospital-based care and physician visits. RESULTS: We identified 54 733 residents of 757 retirement homes (mean age 86.7 years, 69.0% female) and 2 354 385 residents of other settings. Compared to residents of long-term care homes, residents of retirement homes had significantly higher rates per 1000 person months of emergency department visits (10.62 v. 4.48, adjusted relative rate [RR] 2.61, 95% confidence interval [CI] 2.55 to 2.67), hospital admissions (5.42 v. 2.08, adjusted RR 2.77, 95% CI 2.71 to 2.82), alternate level of care (ALC) days (6.01 v. 2.96, adjusted RR 1.51, 95% CI 1.48 to 1.54), and specialist physician visits (6.27 v. 3.21, adjusted RR 1.64, 95% CI 1.61 to 1.68), but a significantly lower rate of primary care visits (16.71 v. 108.47, adjusted RR 0.13, 95% CI 0.13 to 0.14). INTERPRETATION: Residents of retirement homes are a distinct population with higher rates of hospital-based care. Our findings can help to inform policy debates about the need for more coordinated primary and supportive health care in privately operated congregate care homes.

Direct Oral Anticoagulation Versus Warfarin in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves: a Retrospective, Real-World Cohort Study.

OBJECTIVE: In this retrospective cohort study of consecutive patients with atrial fibrillation and surgical or transcatheter bioprosthetic valve, we compared the efficacy and safety of direct oral anticoagulants with warfarin. METHODS: Using linked health administrative databases housed at the Institute for Clinical Evaluative Sciences, we identified consecutive patients in Ontario (Canada) 65 years of age or older with AF who underwent bioprosthetic valve replacement between 1 April 2012 and 31 March 2017. We created a time-varying Cox model to examine the relationship between the type of anticoagulant and time to thrombotic or bleeding events after adjustment for baseline risk of thrombosis using the CHA2DS2-VASc score and risk of bleeding using the HAS-BLED scores. We conducted prespecified subgroup analyses according to whether valve implantation was surgical or transcatheter. RESULTS: We identified 2245 eligible patients. The mean age was 79 years, 41% were female, and 39% had transcatheter aortic valve replacement. Risk of death or thrombosis was not different between direct oral anticoagulants and warfarin after adjustment for CHA2DS2-VASc score (hazard ratio [HR] 1.02, 95% confidence interval [CI], 0.83-1.25). Risk of death or bleeding was not different between direct oral anticoagulants and warfarin after adjustment for HAS-BLED score (HR 0.89, 95% CI 0.75-1.07). Subgroup analyses of surgical or transcatheter valves were consistent with overall results. CONCLUSIONS: In a real-world population of patients with atrial fibrillation and bioprosthetic valve replacement, we found no difference between direct oral anticoagulants and warfarin with regard to the risk of thrombosis or bleeding.

Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial.

Importance: Easy-to-administer anti-SARS-CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage. Objective: To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported. Interventions: Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156). Main Outcomes and Measures: The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL). Results: Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, -13.3% [95% CI, -26.3% to -0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19. Conclusions and Relevance: Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04452318.

Rates of rebleeding, thrombosis and mortality associated with resumption of anticoagulant therapy after anticoagulant-related bleeding.

BACKGROUND: Data on resuming oral anticoagulants (OACs) after bleeding are primarily from studies involving patients given warfarin, with few data on direct OACs (DOACs). We aimed to characterize prescribing patterns for OACs after OAC-related bleeding and compare the rates of bleeding, thrombosis and mortality in patients who resumed either type of OAC with those who did not. METHODS: We conducted a population-based cohort study of adults aged 66 years or older who were admitted to hospital for bleeding while receiving OACs from Apr. 1, 2012, to Mar. 31, 2017, using linked administrative health databases from Ontario. We used competing risk methods to calculate cause-specific adjusted hazard ratios (HRs) for thrombosis, bleeding and mortality with resumption of OACs adjusted as a time-varying covariate. We determined time to OAC resumption using the Kaplan-Meier method. RESULTS: We included 6793 patients with gastrointestinal (n = 4297, 63.3%), intracranial (n = 805, 11.9%) or other bleeding (n = 1691, 25.0%). At cohort entry, 3874 patients (57.0%) were prescribed warfarin and 2919 patients (43.0%) were prescribed a DOAC. The most common indication for OAC was atrial fibrillation (n = 5557, 81.8%), followed by venous thromboembolism (n = 1367, 20.1%). Oral anticoagulants were resumed in 4792 patients (70.5%) within 365 days of the index bleed. The median time to resumption was 46 (interquartile range 6-550) days. We found that resuming OAC was associated with reduced rates of thrombosis (adjusted HR 0.60, 95% confidence interval [CI] 0.50-0.72) and mortality (adjusted HR 0.54, 95% CI 0.48-0.60), and an increased rate of rebleeding (adjusted HR 1.88, 95% CI 1.64-2.17). INTERPRETATION: We found that resuming OAC is associated with a reduction in thrombosis and mortality but an increase in bleeding. Randomized controlled trials that evaluate the net benefit of strategies for resumption of OAC after a bleeding event are warranted.

Effect of socio-demographic and health factors on the association between multimorbidity and acute care service use: population-based survey linked to health administrative data.

BACKGROUND: This study explores how socio-demographic and health factors shape the relationship between multimorbidity and one-year acute care service use (i.e., hospital, emergency department visits) in older adults in Ontario, Canada. METHODS: We linked multiple cycles (2005-2006, 2007-2008, 2009-2010, 2011-2012) of the Canadian Community Health Survey (CCHS) to health administrative data to create a cohort of adults aged 65 and older. Administrative data were used to estimate one-year service use and to identify 12 chronic conditions used to measure multimorbidity. We examined the relationship between multimorbidity and service use stratified by a range of socio-demographic and health variables available from the CCHS. Logistic and Poisson regressions were used to explore the association between multimorbidity and service use and the role of socio-demographic factors in this relationship. RESULTS: Of the 28,361 members of the study sample, 60% were between the ages of 65 and 74 years, 57% were female, 72% were non-immigrant, and over 75% lived in an urban area. Emergency department visits and hospitalizations consistently increased with the level of multimorbidity. This study did not find strong evidence of moderator or interaction effects across a range of socio-demographic factors. Stratified analyses revealed further patterns, with many being similar for both services - e.g., the odds ratios were higher at all levels of multimorbidity for men, older age groups, and those with lower household income. Rurality and immigrant status influenced emergency department use (higher in rural residents and non-immigrants) but not hospitalizations. Multimorbidity and the range of socio-demographic variables remained significant predictors of service use in the regressions. CONCLUSIONS: Strong evidence links multimorbidity with increased acute care service use. This study showed that a range of factors did not modify this relationship. Nevertheless, the factors were independently associated with acute care service use, pointing to modifiable risk factors that can be the focus of resource allocation and intervention design to reduce service use in those with multimorbidity. The study's results suggest that optimizing acute care service use in older adults requires attention to both multimorbidity and social determinants, with programs that are multifactorial and integrated across the health and social service sectors.

The impact of multimorbidity level and functional limitations on the accuracy of using self-reported survey data compared to administrative data to measure general practitioner and specialist visits in community-living adults.

BACKGROUND: Researchers often use survey data to study the effect of health and social variables on physician use, but how self-reported physician use compares to administrative data, the gold standard, in particular within the context of multimorbidity and functional limitations remains unclear. We examine whether multimorbidity and functional limitations are related to agreement between self-reported and administrative data for physician use. METHODS: Cross-sectional data from 52,854 Ontario participants of the Canadian Community Health Survey linked to administrative data were used to assess agreement on physician use. The number of general practitioner (GP) and specialist visits in the previous year was assessed using both data sources; multimorbidity and functional limitation were from self-report. RESULTS: Fewer participants self-reported GP visits (84.8%) compared to administrative data (89.1%), but more self-reported specialist visits (69.2% vs. 64.9%). Sensitivity was higher for GP visits (≥90% for all multimorbidity levels) compared to specialist visits (approximately 75% for 0 to 90% for 4+ chronic conditions). Specificity started higher for GP than specialist visits but decreased more swiftly with multimorbidity level; in both cases, specificity levels fell below 50%. Functional limitations, age and sex did not impact the patterns of sensitivity and specificity seen across level of multimorbidity. CONCLUSIONS: Countries around the world collect health surveys to inform health policy and planning, but the extent to which these are linked with administrative, or similar, data are limited. Our study illustrates the potential for misclassification of physician use in self-report data and the need for sensitivity analyses or other corrections.

Laminar Differences in Responses to Naturalistic Texture in Macaque V1 and V2.

Most single units recorded from macaque secondary visual cortex (V2) respond with higher firing rates to synthetic texture images containing "naturalistic" higher-order statistics than to spectrally matched "noise" images lacking these statistics. In contrast, few single units in V1 show this property. We explored how the strength and dynamics of response vary across the different layers of visual cortex by recording multiunit (defined as high-frequency power in the local field potential) and gamma-band activity evoked by brief presentations of naturalistic and noise images in V1 and V2 of anesthetized macaque monkeys of both sexes. As previously reported, recordings in V2 showed consistently stronger responses to naturalistic texture than to spectrally matched noise. In contrast to single-unit recordings, V1 multiunit activity showed a preference for images with naturalistic statistics, and in gamma-band activity this preference was comparable across V1 and V2. Sensitivity to naturalistic image structure was strongest in the supragranular and infragranular layers of V1, but weak in granular layers, suggesting that it might reflect feedback from V2. Response timing was consistent with this idea. Visual responses appeared first in V1, followed by V2. Sensitivity to naturalistic texture emerged first in V2, followed by the supragranular and infragranular layers of V1, and finally in the granular layers of V1. Our results demonstrate laminar differences in the encoding of higher-order statistics of natural texture, and suggest that this sensitivity first arises in V2 and is fed back to modulate activity in V1.SIGNIFICANCE STATEMENT The circuit mechanisms responsible for visual representations of intermediate complexity are largely unknown. We used a well validated set of synthetic texture stimuli to probe the temporal and laminar profile of sensitivity to the higher-order statistical structure of natural images. We found that this sensitivity emerges first and most strongly in V2 but soon after in V1. However, sensitivity in V1 is higher in the laminae (extragranular) and recording modalities (local field potential) most likely affected by V2 connections, suggesting a feedback origin. Our results show how sensitivity to naturalistic image structure emerges across time and circuitry in the early visual cortex.

Urologic complications after transplantation of 225 en bloc kidneys from small pediatric donors ≤20 kg: Incidence, management, and impact on graft survival.

Pediatric en bloc kidney transplants (EBKs) from small deceased pediatric donors are associated with increased early graft loss and morbidity. Yet, urologic complications post-EBK and their potential impact on graft survival have not been systematically studied. We retrospectively studied urological complications requiring intervention for 225 EBKs performed at our center January 2005 to September 2017 from donors ≤20 kg into recipients ≥18 years. Overall ureteral complication incidence after EBK was 9.8% (n = 22) (12% vs 2% for EBK donors < 10 vs ≥ 10 kg, respectively [P = .031]). The most common post-EBK urologic complication was a stricture (55%), followed by urine leak (41%). In all, 95% of all urologic complications occurred early within 5 months posttransplant (median, 138 days). Urologic complications could be successfully managed nonoperatively in 50% of all cases and had no impact on graft or patient survival. In summary, urologic complications after EBK were common, associated with lower donor weights, occurred early posttransplant, and were often amenable to nonoperative treatment, without adversely affecting survival. We conclude that the higher urologic complication rate after EBK (1) should not prevent increased utilization of small pediatric donor en bloc kidneys for properly selected recipients, and (2) warrants specific discussion with EBK recipients during the preoperative consent process.

Barriers to live and deceased kidney donation by patients with chronic neurological diseases: Implications for donor selection, donation timing, logistics, and regulatory compliance.

Live and deceased kidney donation by the numerous patients with advanced, progressive systemic neurological diseases, and other chronic neurological conditions (eg, high C-spine injury) remains largely unexplored. In a review of our current clinical practice, we identified multiple regulatory and clinical barriers. For live donation, mandatory reporting of postdonation donor deaths within 2 years constitutes a strong programmatic disincentive. We propose that the United Network for Organ Sharing should provide explicit regulatory guidance and reassurance for programs wishing to offer live donation to patients at higher risk of death during the reporting period. Under the proposal, live donor deaths within 30 days would still be regarded as donation-related, but later deaths would be related to the underlying disease. For deceased donation, donation after circulatory death (DCD) immediately following self-directed withdrawal of life-sustaining treatment ("conscious DCD") is not universally covered by existing DCD agreements with donor hospitals. Organ procurement organizations should thus systematically strive to revise these agreements. Obtaining adequate first-person consent from these communicatively severely impaired patients may be challenging. Optimized preservation and allocation protocols may maximize utilization of these DCD kidneys. Robust public debate and action by all stakeholders is necessary to lower existing barriers and maximize donation opportunities for patients with chronic neurological conditions.

Effect of Patient-Centered Transitional Care Services on Clinical Outcomes in Patients Hospitalized for Heart Failure: The PACT-HF Randomized Clinical Trial.

Importance: Health care services that support the hospital-to-home transition can improve outcomes in patients with heart failure (HF). Objective: To test the effectiveness of the Patient-Centered Care Transitions in HF transitional care model in patients hospitalized for HF. Design, Setting, and Participants: Stepped-wedge cluster randomized trial of 2494 adults hospitalized for HF across 10 hospitals in Ontario, Canada, from February 2015 to March 2016, with follow-up until November 2016. Interventions: Hospitals were randomized to receive the intervention (n = 1104 patients), in which nurse-led self-care education, a structured hospital discharge summary, a family physician follow-up appointment less than 1 week after discharge, and, for high-risk patients, structured nurse homevisits and heart function clinic care were provided to patients, or usual care (n = 1390 patients), in which transitional care was left to the discretion of clinicians. Main Outcomes and Measures: Primary outcomes were hierarchically ordered as composite all-cause readmission, emergency department (ED) visit, or death at 3 months; and composite all-cause readmission or ED visit at 30 days. Secondary outcomes were B-PREPARED score for discharge preparedness (range: 0 [most prepared] to 22 [least prepared]); the 3-Item Care Transitions Measure (CTM-3) for quality of transition (range: 0 [worst transition] to 100 [best transition]); the 5-level EQ-5D version (EQ-5D-5L) for quality of life (range: 0 [dead] to 1 [full health]); and quality-adjusted life-years (QALY; range: 0 [dead] to 0.5 [full health at 6 months]). Results: Among eligible patients, all 2494 (mean age, 77.7 years; 1258 [50.4%] women) completed the trial. There was no significant difference between the intervention and usual care groups in the first primary composite outcome (545 [49.4%] vs 698 [50.2%] events, respectively; hazard ratio [HR], 0.99 [95% CI, 0.83-1.19]) or in the second primary composite outcome (304 [27.5%] vs 408 [29.3%] events, respectively; HR, 0.93 [95% CI, 0.73-1.18]). There were significant differences between the intervention and usual care groups in the secondary outcomes of mean B-PREPARED score at 6 weeks (16.6 vs 13.9; difference, 2.65 [95% CI, 1.37-3.92]; P < .001); mean CTM-3 score at 6 weeks (76.5 vs 70.3; difference, 6.16 [95% CI, 0.90-11.43]; P = .02); and mean EQ-5D-5L score at 6 weeks (0.7 vs 0.7; difference, 0.06 [95% CI, 0.01 to 0.11]; P = .02) and 6 months (0.7 vs 0.6; difference, 0.06 [95% CI, 0.01-0.12]; P = .02). There was no significant difference in mean QALY between groups at 6 months (0.3 vs 0.3; difference, 0.00 [95% CI, -0.02 to 0.02]; P = .98). Conclusions and Relevance: Among patients with HF in Ontario, Canada, implementation of a patient-centered transitional care model compared with usual care did not improve a composite of clinical outcomes. Whether this type of intervention could be effective in other health care systems or locations would require further research. Trial Registration: ClinicalTrials.gov Identifier: NCT02112227.

Pediatric en bloc kidney transplantation from very small (≤10 kg) donation after circulatory death (versus brain death) donors: Single-center matched-pair analysis of 130 transplants.

En bloc kidney transplants (EBK) from very small pediatric donation after circulatory death (DCD) donors are infrequent because of the perception that DCD adversely impacts outcomes. We retrospectively studied 130 EBKs from donors ≤10 kg (65 consecutive DCD vs 65 donation after brain death [DBD] transplants; pair-matched for donor weight and terminal creatinine, and for preservation time). For DCD vs DBD, median donor weight was 5.0 vs 5.0 kg; median recipient age was 57 vs 48 years (P = .006). Graft losses from thrombosis (DCD, 5%; DBD, 7%) or primary nonfunction (DCD, 3%; DBD, 0%) were similar in both groups (P = .7). Delayed graft function rate was higher for DCD (25%) vs DBD (14%) (P = .2). Graft survival (death-censored) for DCD vs DBD at 5 years was 87% vs 91% (P = .3). Median estimated GFR (mL/min per 1.73 m2 ) was significantly lower for DCD recipients at 1 and 3 months; at 6 years it remained stable at 100 (DCD) and 99 (DBD). DCD impacted early posttransplant graft function, but did not appear to impart added risk for graft loss and long-term function. Very small (≤10 kg) DCD EBK donors should be considered as an option to augment the deceased kidney donor pool; larger studies with longer follow-up must confirm these findings.

Knowledge to action: Rationale and design of the Patient-Centered Care Transitions in Heart Failure (PACT-HF) stepped wedge cluster randomized trial.

INTRODUCTION: Heart Failure (HF) is a common cause of hospitalization in older adults. The transition from hospital to home is high-risk, and gaps in transitional care can increase the risk of re-hospitalization and death. Combining health care services supported by meta-analyses, we designed the PACT-HF transitional care model. METHODS: Adopting an integrated Knowledge Translation (iKT) approach in which decision-makers and clinicians are partners in research, we implement and test the effectiveness of PACT-HF among patients hospitalized for HF. We use a pragmatic stepped wedge cluster randomized trial design to introduce the complex health service intervention to 10 large hospitals in a randomized sequence until all hospitals initiate the intervention. The goal is for all patients hospitalized with HF to receive self-care education, multidisciplinary care, and early follow-up with their health care providers; and in addition, for high-risk patients to receive post-discharge nurse-led home visits and outpatient care in Heart Function clinics. This requires integration of care across hospitals, home care agencies, and outpatient clinics in our publicly funded health care system. While hospitals are the unit of recruitment and analysis, patients (estimated sample size of 3200) are the unit of analysis. Primary outcomes are hierarchically ordered as time to composite all-cause readmissions / emergency department (ED) visits / death at 3 months and time to composite all-cause readmissions / ED visits at 30 days. In a nested study of 8 hospitals, we measure the patient-centered outcomes of Discharge Preparedness, Care Transitions Quality, and Quality Adjusted Life Years (QALY); and the 6-month health care resource use and costs. We obtain all clinical and cost outcomes via linkages to provincial administrative databases. CONCLUSIONS: This protocol describes the implementation and testing of a transitional care model comprising health care services informed by high-level evidence. The study adopts an iKT and pragmatic approach, uses a robust study design, links clinical trial data with outcomes held in administrative databases, and includes patient-reported outcomes. Findings will have implications on clinical practice, health care policy, and Knowledge Translation (KT) research methodology.

Development and validation of a cardiovascular disease risk-prediction model using population health surveys: the Cardiovascular Disease Population Risk Tool (CVDPoRT).

BACKGROUND: Routinely collected data from large population health surveys linked to chronic disease outcomes create an opportunity to develop more complex risk-prediction algorithms. We developed a predictive algorithm to estimate 5-year risk of incident cardiovascular disease in the community setting. METHODS: We derived the Cardiovascular Disease Population Risk Tool (CVDPoRT) using prospectively collected data from Ontario respondents of the Canadian Community Health Surveys, representing 98% of the Ontario population (survey years 2001 to 2007; follow-up from 2001 to 2012) linked to hospital admission and vital statistics databases. Predictors included body mass index, hypertension, diabetes, and multiple behavioural, demographic and general health risk factors. The primary outcome was the first major cardiovascular event resulting in hospital admission or death. Death from a noncardiovascular cause was considered a competing risk. RESULTS: We included 104 219 respondents aged 20 to 105 years. There were 3709 cardiovascular events and 818 478 person-years follow-up in the combined derivation and validation cohorts (5-year cumulative incidence function, men: 0.026, 95% confidence interval [CI] 0.025-0.028; women: 0.018, 95% 0.017-0.019). The final CVDPoRT algorithm contained 12 variables, was discriminating (men: C statistic 0.82, 95% CI 0.81-0.83; women: 0.86, 95% CI 0.85-0.87) and was well-calibrated in the overall population (5-year observed cumulative incidence function v. predicted risk, men: 0.28%; women: 0.38%) and in nearly all predefined policy-relevant subgroups (206 of 208 groups). INTERPRETATION: The CVDPoRT algorithm can accurately discriminate cardiovascular disease risk for a wide range of health profiles without the aid of clinical measures. Such algorithms hold potential to support precision medicine for individual or population uses. Study registration: ClinicalTrials.gov, no. NCT02267447.

Measuring Burden of Unhealthy Behaviours Using a Multivariable Predictive Approach: Life Expectancy Lost in Canada Attributable to Smoking, Alcohol, Physical Inactivity, and Diet.

BACKGROUND: Behaviours such as smoking, poor diet, physical inactivity, and unhealthy alcohol consumption are leading risk factors for death. We assessed the Canadian burden attributable to these behaviours by developing, validating, and applying a multivariable predictive model for risk of all-cause death. METHODS: A predictive algorithm for 5 y risk of death-the Mortality Population Risk Tool (MPoRT)-was developed and validated using the 2001 to 2008 Canadian Community Health Surveys. There were approximately 1 million person-years of follow-up and 9,900 deaths in the development and validation datasets. After validation, MPoRT was used to predict future mortality and estimate the burden of smoking, alcohol, physical inactivity, and poor diet in the presence of sociodemographic and other risk factors using the 2010 national survey (approximately 90,000 respondents). Canadian period life tables were generated using predicted risk of death from MPoRT. The burden of behavioural risk factors attributable to life expectancy was estimated using hazard ratios from the MPoRT risk model. FINDINGS: The MPoRT 5 y mortality risk algorithms were discriminating (C-statistic: males 0.874 [95% CI: 0.867-0.881]; females 0.875 [0.868-0.882]) and well calibrated in all 58 predefined subgroups. Discrimination was maintained or improved in the validation cohorts. For the 2010 Canadian population, unhealthy behaviour attributable life expectancy lost was 6.0 years for both men and women (for men 95% CI: 5.8 to 6.3 for women 5.8 to 6.2). The Canadian life expectancy associated with health behaviour recommendations was 17.9 years (95% CI: 17.7 to 18.1) greater for people with the most favourable risk profile compared to those with the least favourable risk profile (88.2 years versus 70.3 years). Smoking, by itself, was associated with 32% to 39% of the difference in life expectancy across social groups (by education achieved or neighbourhood deprivation). CONCLUSIONS: Multivariable predictive algorithms such as MPoRT can be used to assess health burdens for sociodemographic groups or for small changes in population exposure to risks, thereby addressing some limitations of more commonly used measurement approaches. Unhealthy behaviours have a substantial collective burden on the life expectancy of the Canadian population.