Surgical Enlargement of the Aortic Root Does Not Increase the Operative Risk of Aortic Valve Replacement.

BACKGROUND: Surgical aortic root enlargement (ARE) during aortic valve replacement (AVR) allows for larger prosthesis implantation and may be an important adjunct to surgical AVR in the transcatheter valve-in-valve era. The incremental operative risk of adding ARE to AVR has not been established. We aimed to evaluate the early outcomes of patients undergoing AVR with or without ARE. METHODS: From January 1990 to August 2014, 7039 patients underwent AVR (AVR+ARE, n=1854; AVR, n=5185) at a single institution. Patients with aortic dissection and active endocarditis were excluded. Mean age was 65±14 years and 63% were male. Logistic regression and propensity score matching were used to adjust for unbalanced variables in group comparisons. RESULTS: Patients undergoing AVR+ARE were more likely to be female (46% versus 34%, P<0.001) and had higher rates of previous cardiac surgery (18% versus 12%, P<0.001), chronic obstructive pulmonary disease (5% versus 3%, P=0.004), urgent/emergent status (6% versus 4%, P=0.01), and worse New York Heart Association status (P<0.001). Most patients received bioprosthetic valves (AVR+ARE: 73.4% versus AVR: 73.3%, P=0.98) and also underwent concomitant cardiac procedures (AVR+ARE: 68% versus AVR: 67%, P=0.31). Mean prosthesis size implanted was slightly smaller in patients requiring AVR+ARE versus AVR (23.4±2.1 versus 24.1±2.3, P<0.001). In-hospital mortality was higher after AVR+ARE (4.3% versus 3.0%, P=0.008), although when the cohort was restricted to patients undergoing isolated aortic valve replacement with or without root enlargement, mortality was not statistically different (AVR+ARE: 1.7% versus AVR: 1.1%, P=0.29). After adjustment for baseline characteristics, AVR+ARE was not associated with an increased risk of in-hospital mortality when compared with AVR (odds ratio, 1.03; 95% confidence interval, 0.75-1.41; P=0.85). Furthermore, AVR+ARE was not associated with an increased risk of postoperative adverse events. Results were similar if propensity matching was used instead of multivariable adjustments for baseline characteristics. CONCLUSIONS: In the largest analysis to date, ARE was not associated with increased risk of mortality or adverse events. Surgical ARE is a safe adjunct to AVR in the modern era.

The effect of pre-heart transplant body mass index on posttransplant outcomes: An analysis of the ISHLT Registry Data.

We evaluated the effect of pre-heart transplant body mass index (BMI) on posttransplant outcomes using the International Society for Heart and Lung Transplantation Registry. Kaplan-Meier analysis and a multivariable Cox proportional hazard regression model were used for all-cause mortality, and cause-specific hazard regression for cause-specific mortality and morbidity. We assessed 38 498 recipients from 2000 to 2014 stratified by pretransplant BMI. Ten-year survival was 56% in underweight, 59% in normal weight, 57% in overweight, 52% in obese class I, 54% in class II, and 47% in class III patients (P < 0.001). Mortality was increased in underweight (HR 1.29, 95% CI 1.24-1.35), obese class I (HR 1.19, 95% CI 1.13-1.26), class II (HR 1.20, 95% CI 1.08-1.32), and class III patients (HR 1.45, 95% CI 1.15-1.83). Obesity was independently associated with increased death from myocardial infarction, chronic rejection, infection, and renal dysfunction. An underweight BMI lead to increased death from infection, acute and chronic rejection, malignancy, and bleeding. Obese patients had a higher incidence of renal dysfunction, diabetes, stroke, acute rejection, cardiac allograft vasculopathy, and malignancy, and underweight recipients had increased acute rejection. We have shown that pretransplant obese and underweight patients have increased post-heart transplant mortality and morbidity. This has implications for candidate selection and posttransplant management.

Recent decline in the global land evapotranspiration trend due to limited moisture supply.

More than half of the solar energy absorbed by land surfaces is currently used to evaporate water. Climate change is expected to intensify the hydrological cycle and to alter evapotranspiration, with implications for ecosystem services and feedback to regional and global climate. Evapotranspiration changes may already be under way, but direct observational constraints are lacking at the global scale. Until such evidence is available, changes in the water cycle on land−a key diagnostic criterion of the effects of climate change and variability−remain uncertain. Here we provide a data-driven estimate of global land evapotranspiration from 1982 to 2008, compiled using a global monitoring network, meteorological and remote-sensing observations, and a machine-learning algorithm. In addition, we have assessed evapotranspiration variations over the same time period using an ensemble of process-based land-surface models. Our results suggest that global annual evapotranspiration increased on average by 7.1 ± 1.0 millimetres per year per decade from 1982 to 1997. After that, coincident with the last major El Niño event in 1998, the global evapotranspiration increase seems to have ceased until 2008. This change was driven primarily by moisture limitation in the Southern Hemisphere, particularly Africa and Australia. In these regions, microwave satellite observations indicate that soil moisture decreased from 1998 to 2008. Hence, increasing soil-moisture limitations on evapotranspiration largely explain the recent decline of the global land-evapotranspiration trend. Whether the changing behaviour of evapotranspiration is representative of natural climate variability or reflects a more permanent reorganization of the land water cycle is a key question for earth system science.

Hot days induced by precipitation deficits at the global scale.

Global warming increases the occurrence probability of hot extremes, and improving the predictability of such events is thus becoming of critical importance. Hot extremes have been shown to be induced by surface moisture deficits in some regions. In this study, we assess whether such a relationship holds at the global scale. We find that wide areas of the world display a strong relationship between the number of hot days in the regions' hottest month and preceding precipitation deficits. The occurrence probability of an above-average number of hot days is over 70% after precipitation deficits in most parts of South America as well as the Iberian Peninsula and Eastern Australia, and over 60% in most of North America and Eastern Europe, while it is below 30-40% after wet conditions in these regions. Using quantile regression analyses, we show that the impact of precipitation deficits on the number of hot days is asymmetric, i.e. extreme high numbers of hot days are most strongly influenced. This relationship also applies to the 2011 extreme event in Texas. These findings suggest that effects of soil moisture-temperature coupling are geographically more widespread than commonly assumed.

A modified intraventricular balloon method for functional assessment of hearts from donation after circulatory death.

Objective: Functional assessment of hearts during ex-vivo heart perfusion is not well-established. Conventional intraventricular balloon methods for large animals sacrifice the mitral valve. This study assessed the effectiveness of the modified intraventricular balloon method in comparison with other modalities used during working mode in juvenile pigs. Methods: Following asphyxia circulatory arrest, hearts were ischemic for 15 minutes and then reperfused on an ex-vivo device for 2 hours before switching to working mode. Left ventricular pressure was continuously measured during reperfusion by a saline-filled balloon fixated in the left atrium. Spearman Correlation Coefficients with linear regression lines with confidence intervals were analyzed. Results: Maximum dp/dt at 90 minutes of reperfusion and minimum dp/dt at 60 minutes of reperfusion showed a moderate positive correlation to that in working mode, respectively (Rs = 0.61, P = .04 and Rs = 0.60, P = .04). At 60 minutes of reperfusion, minimum dp/dt showed moderate positive correlation to tau (Rs = 0.52, P = .08). Myocardial oxygen consumption during reperfusion consistently decreased at least 30% compared to working mode (at 90 minutes as the highest during reperfusion, 3.3 ± 0.8; in working mode, 5.6 ± 1.4, mLO2/min/100 g, P < .001). Conclusions: Functional parameters of contractility and relaxation measured during reperfusion by the modified balloon method showed significant correlations to respective parameters in working mode. This mitral valve sparing technique can be used to predict viability and ventricular function in the early phase of ex-vivo heart perfusion without loading the heart during working mode.

The Effect of Using a Remote Patient Management Platform in Optimizing Guideline-Directed Medical Therapy in Heart Failure Patients: A Randomized Controlled Trial.

BACKGROUND: Guideline-directed medical therapy (GDMT) remains underutilized in patients with heart failure with reduced ejection fraction, leading to morbidity and mortality. OBJECTIVES: The Medly Titrate (Use of Telemonitoring to Facilitate Heart Failure Mediation Titration) study was an open-label, randomized controlled trial to determine whether remote medication titration for patients with heart failure with reduced ejection fraction was more effective than usual care (UC). METHODS: In this study, 108 patients were randomized to remote GDMT titration through the Medly heart failure program (n = 56) vs UC (n = 52). The primary outcome was the proportion of patients completing GDMT titration at 6 months. Secondary outcomes included the number of clinic visits and time required to achieve titration, patient health outcomes, and health care utilization, including urgent clinic/emergency department visits and hospitalization. RESULTS: At 6 months, GDMT titration was completed in 82.1% (95% CI: 71.2%-90.8%) of patients in the intervention arm vs 53.8% in UC (95% CI: 41.1%-67.7%; P = 0.001). Remote titration required fewer in-person (1.62 ± 1.09 vs 2.42 ± 1.65; P = 0.004) and virtual clinic visits (0.50 ± 1.08 vs 1.29 ± 1.86; P = 0.009) to complete titration. Median time to optimization was shorter with remote titration (3.42 months [Q1-Q3: 2.99-4.04 months] vs 5.47 months [Q1-Q3: 4.14-7.33 months]; P < 0.001). The number of urgent clinic/emergency department visits (incidence rate ratio of remote vs control groups: 0.90 [95% CI: 0.53-1.56]; P = 0.70) were similar between groups, with a reduction in all-cause hospitalization with remote titration (incidence rate ratio: 0.55 [95% CI: 0.31-0.97]; P = 0.042). CONCLUSIONS: Remote titration of GDMT in heart failure with reduced ejection fraction was effective, safe, feasible, and increased the proportion of patients achieving target doses, in a shorter period of time with no excess adverse events compared with UC. (Use of Telemonitoring to Facilitate Heart Failure Mediation Titration [Medly Titrate]; NCT04205513).

Impact of a quality improvement initiative with a dedicated anesthesia team on outcomes after surgery for adult congenital heart disease.

Objectives: A quality improvement initiative was introduced to the adult congenital cardiac surgery program at Toronto General Hospital in January 2016. A dedicated Adult Congenital Anesthesia and intensive care unit team was introduced within the cardiac group. The use of factor concentrates was introduced. The study compares perioperative mortality, adverse events, and transfusion burden before and after this process change. Methods: We performed a retrospective analysis of all adult congenital cardiac surgeries from January 2004 to July 2019. Two groups were analyzed: patients undergoing operation before and after 2016. The primary outcome was in-hospital mortality. One-year mortality and prevalence of key morbidities were analyzed as secondary outcomes. A separate analysis looked at patients who had and had not attended an anesthesia-led preassessment clinic. Results: In-hospital mortality was significantly reduced in patients undergoing operation after 2016 (1.1% vs 4.3%, P = .003) despite a higher risk profile. One-year mortality (1.3% vs 5.8%, P = .003) and ventilation times (5.5 hours [3.4-13.0] vs 6.3 hours [4.2-16.2], P = .001) were also reduced. The incidence of stroke and renal failure was similar between groups. Blood product exposure was comparable, but the incidence of chest reopening decreased (1.8% vs 4.8%, P = .022), despite more patients with multiple previous chest wall incisions, on anticoagulation, and with more complex cardiac anatomy. There were no significant outcome differences between those who did or did not attend the preassessment clinic. Conclusions: Both in-hospital and 1-year mortality were significantly reduced after the introduction of a quality improvement program, despite a higher risk profile. Blood product exposure remained unchanged, but there were less chest reopenings.

Association Between the Incidence of Hospitalizations for Acute Cardiovascular Events, Weather, and Air Pollution.

Background: The incidence of hospitalizations for cardiovascular events has been associated with specific weather conditions and air pollution. A comprehensive model including the interactions between various environmental factors remains to be developed. Objectives: The purpose of this study was to develop a comprehensive model of the association between weather patterns and the incidence of cardiovascular events and use this model to forecast near-term spatiotemporal risk. Methods: We present a spatiotemporal analysis of the association between atmospheric data and the incidence rate of hospital admissions related to heart failure (922,132 episodes), myocardial infarction (521,988 episodes), and ischemic stroke (263,529 episodes) in ∼24 million people in Canada between 2007 and 2017. Our hierarchical Bayesian model captured the spatiotemporal distribution of hospitalizations and identified weather and air pollution-related factors that could partially explain fluctuations in incidence. Results: Models that included weather and air pollution variables outperformed models without those covariates for most event types. Our results suggest that environmental factors may interact in complex ways on human physiology. The impact of environmental factors was magnified with increasing age. The weather and air pollution variables included in our models were predictive of the future incidence of heart failure, myocardial infarction, and ischemic strokes. Conclusions: The increasing importance of environmental factors on cardiovascular events with increasing age raises the need for the development of educational materials for older patients to recognize environmental conditions where exacerbations are more likely. This model could be the basis of a forecasting system used for local, short-term clinical resource planning based on the anticipated incidence of events.

Rethinking Donor and Recipient Risk Matching in Europe and North America: Using Heart Transplant Predictors of Donor and Recipient Risk.

BACKGROUND: In Europe, there is greater acceptance of hearts from higher-risk donors for transplantation, whereas in North America, the donor heart discard rate is significantly higher. A Donor Utilization Score (DUS) was used to compare European and North American donor characteristics for recipients included in the International Society for Heart and Lung Transplantation registry from 2000 to 2018. DUS was further evaluated as an independent predictor for 1-year freedom from graft failure, after adjusting for recipient risk. Lastly, we assessed donor-recipient risk matching with the outcome of 1-year graft failure. METHODS: DUS was applied to the International Society for Heart and Lung Transplantation cohort using meta-modeling. Posttransplant freedom from graft failure was summarized by Kaplan-Meier survival. Multivariable Cox proportional hazard regression was applied to quantify the effects of DUS and Index for Mortality Prediction After Cardiac Transplantation score on the 1-year risk of graft failure. We present 4 donor/recipient risk groups using the Kaplan-Meier method. RESULTS: European centers accept significantly higher-risk donor hearts compared to North America. DUS 0.45 versus 0.54, P<0.005). DUS was an independent predictor for graft failure with an inverse linear relationship when adjusted for covariates (P<0.001). The Index for Mortality Prediction After Cardiac Transplantation score, a validated tool to assess recipient risk, was also independently associated with 1-year graft failure (P<0.001). In North America, 1-year graft failure was significantly associated with donor-recipient risk matching (log-rank P<0.001). One-year graft failure was highest with pairing of high-risk recipients and donors (13.1% [95% CI, 10.7%-13.9%]) and lowest among low-risk recipients and donors (7.4% [95% CI, 6.8%-8.0%]). Matching of low-risk recipients with high-risk donors was associated with significantly less graft failure (9.0% [95% CI, 8.3%-9.7%]) than high-risk recipients with low-risk donors (11.4% [95% CI, 10.7%-12.2%]) Conclusions: European heart transplantation centers are more likely to accept higher-risk donor hearts than North American centers. Acceptance of borderline-quality donor hearts for lower-risk recipients could improve donor heart utilization without compromising recipient survival.

Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles.

Resident macrophages orchestrate homeostatic, inflammatory, and reparative activities. It is appreciated that different tissues instruct specialized macrophage functions. However, individual tissues contain heterogeneous subpopulations, and how these subpopulations are related is unclear. We asked whether common transcriptional and functional elements could reveal an underlying framework across tissues. Using single-cell RNA sequencing and random forest modeling, we observed that four genes could predict three macrophage subsets that were present in murine heart, liver, lung, kidney, and brain. Parabiotic and genetic fate mapping studies revealed that these core markers predicted three unique life cycles across 17 tissues. TLF+ (expressing TIMD4 and/or LYVE1 and/or FOLR2) macrophages were maintained through self-renewal with minimal monocyte input; CCR2+ (TIMD4−LYVE1−FOLR2−) macrophages were almost entirely replaced by monocytes, and MHC-IIhi macrophages (TIMD4−LYVE1−FOLR2−CCR2−), while receiving modest monocyte contribution, were not continually replaced. Rather, monocyte-derived macrophages contributed to the resident macrophage population until they reached a defined upper limit after which they did not outcompete pre-existing resident macrophages. Developmentally, TLF+ macrophages were first to emerge in the yolk sac and early fetal organs. Fate mapping studies in the mouse and human single-cell RNA sequencing indicated that TLF+ macrophages originated from both yolk sac and fetal monocyte precursors. Furthermore, TLF+ macrophages were the most transcriptionally conserved subset across mouse tissues and between mice and humans, despite organ- and species-specific transcriptional differences. Here, we define the existence of three murine macrophage subpopulations based on common life cycle properties and core gene signatures and provide a common starting point to understand tissue macrophage heterogeneity.

The European Medicines Agency Review of Luspatercept for the Treatment of Adult Patients With Transfusion-dependent Anemia Caused by Low-risk Myelodysplastic Syndromes With Ring Sideroblasts or Beta-thalassemia.

Luspatercept is a recombinant fusion protein that selectively binds to ligands belonging to the transforming growth factor-beta superfamily, resulting in erythroid maturation and differentiation. On June 25, 2020, a marketing authorization valid through the European Union (EU) was issued for luspatercept for the treatment of adult patients with transfusion-dependent anemia caused by very low-, low-, and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, or those with transfusion-dependent beta thalassemia (BT). Luspatercept was evaluated in 2 separate phase 3, double-blind, placebo-controlled multicentre trials. The primary endpoints of these trials were the percentage of patients achieving transfusion independence over ≥8 weeks or longer for patients with MDS, and the percentage of patients achieving a ≥33% reduction in transfusion burden from baseline to week 13-24 for patients with BT. In the MDS trial, the percentage of responders was 37.91% versus 13.16%, P < 0.0001, for patients receiving luspatercept versus placebo, respectively. In the BT trial, the percentage of responders was 21.4% versus 4.5% (P < 0.0001) for luspatercept versus placebo, respectively. Treatment with luspatercept led to similar incidences of adverse events (AEs), but higher incidences of grade ≥3 AEs and serious AEs compared to placebo. The most frequently reported treatment-emergent AEs (≥15%) in the pooled luspatercept group were headache; back pain, bone pain, and arthralgia; diarrhea; fatigue; pyrexia; and cough. The aim of this article is to summarize the scientific review of the application, which led to the regulatory approval in the EU.

Associations between the spatiotemporal distribution of Kawasaki disease and environmental factors: evidence supporting a multifactorial etiologic model.

The etiology of Kawasaki Disease (KD), the most common cause of acquired heart disease in children in developed countries, remains elusive, but could be multifactorial in nature as suggested by the numerous environmental and infectious exposures that have previously been linked to its epidemiology. There is still a lack of a comprehensive model describing these complex associations. We present a Bayesian disease model that provides insight in the spatiotemporal distribution of KD in Canada from 2004 to 2017. The disease model including environmental factors had improved Watanabe-Akaike information criterion (WAIC) compared to the base model which included only spatiotemporal and demographic effects and had excellent performance in recapitulating the spatiotemporal distribution of KD in Canada (98% and 86% spatial and temporal correlations, respectively). The model suggests an association between the distribution of KD and population composition, weather-related factors, aeroallergen exposure, pollution, atmospheric concentration of spores and algae, and the incidence of healthcare encounters for bacterial pneumonia or viral intestinal infections. This model could be the basis of a hypothetical data-driven framework for the spatiotemporal distribution of KD. It also generates novel hypotheses about the etiology of KD, and provides a basis for the future development of a predictive and surveillance model.

Findings from a Rapid Assessment of Avoidable Blindness (RAAB) in the Southwest Region of Kyrgyzstan.

Purpose: Reliable data on eye care needs in Kyrgyzstan are not readily available. The purpose of this study was to determine the prevalence and causes of blindness and visual impairment in persons aged 50 and above in the southwest of Kyrgyzstan and to support the Ministry of Health (MoH) in the planning of eye care in the region.Methods: A population-based survey was conducted in three states (Oblast) in the southwest region of Kyrgyzstan. Sixty clusters of 50 people aged 50 years and older were selected by probability proportionate to size sampling. Ethical approval was obtained from the MoH, consent was obtained from each participant.Results: A total number of 3,000 persons aged 50 and older were sampled. Among these 2,897 (95.9%) were examined. The prevalence of bilateral blindness was 1.7% [95%CI: 1.1-2.4]. Cataract (43.3%) was the main cause of blindness, followed by glaucoma (30%), age-related macular degeneration (ARMD) (8.3%), other posterior segment diseases (6.7%) and non-trachomatous corneal opacities (5%). The prevalence of blindness and visual impairment increased strongly with age. The cataract surgical coverage in blind persons was 59%.Conclusion: Cataract and glaucoma were the major causes of blindness and visual impairment in persons 50 and above. The majority of the causes (85%) were avoidable, with 45% (cataract and uncorrected aphakia) treatable, 6.7% (corneal opacity and phthisis) preventable by primary health care/eye care services and 33.3% (cataract surgical complications, glaucoma) preventable by specialized ophthalmic services. The data suggest that an expansion of eye care services to reduce avoidable blindness is needed, as ageing will lead to an increase in older people at risk and a higher demand for eye care in the future.

Noncardiac determinants of death and intensive care morbidity in adult congenital heart disease surgery.

OBJECTIVES: Predicting perioperative morbidity and mortality in cardiac surgery for adult congenital heart disease is challenging because it encompasses a wide spectrum of disease. There is a paucity of published outcome data, and there are no perioperative risk score calculators for this population group. We set out to identify robust determinants of morbidity and mortality in this patient population under going cardiac surgery. METHODS: We collected data on 20 socioeconomic and pathophysiologic variables in 784 consecutive adults with congenital heart disease who underwent cardiac surgery between 2004 and 2015 at a single center. Using logistic regression, we sought to identify which of these factors were associated with the primary composite adverse outcome of in-hospital mortality, prolonged ventilation exceeding 7 days, and severe acute renal failure requiring dialysis. Secondary outcome analysis identified variables that were significant predictors for 1-year mortality. RESULTS: Composite adverse outcome occurred in 54 of 784 patients (6.9%). Significant predictors of the composite adverse outcome by multivariate regression include Mayo End-Stage Liver Disease modified score, cognitive impairment, number of chest wall incisions from previous cardiac surgery, body mass index, and cardiac anatomic category. Two survivors of the composite adverse outcome died within a few weeks postdischarge. Only 657 of 784 patients had 1-year follow-up data; 40 of 657 patients died at 1 year. One-year mortality was predicted by anticoagulation, Mayo End-Stage Liver Disease modified score, and anatomic category. CONCLUSIONS: Recognition and quantification of noncardiac comorbidities preoperatively predict the risk of adverse events and mortality in addition to cardiac anatomic factors.

Improving Prenatal Diagnosis of Coarctation of the Aorta.

BACKGROUND: The purpose of the study was to evaluate the association between fetal echocardiographic measurements and the need for intervention (primary coarctation repair, staged coarctation repair, or catheter intervention) in prenatally diagnosed coarctation of the aorta. METHODS: A single-centre retrospective cohort study (2005-2015) of 107 fetuses diagnosed with suspected coarctation of the aorta in the setting of an apex-forming left ventricle and antegrade flow across the mitral and aortic valves. RESULTS: Median gestational age at diagnosis was 32 weeks (interquartile range, 23-35 weeks). Fifty-six (52%) did not require any neonatal intervention, 51 patients (48%) underwent a biventricular repair. In univariable analysis, an increase in ascending aorta (AAo) peak Doppler flow velocity (odds ratio [OR], 1.40 [95% confidence interval [CI], 1.05-1.91] per 20 cm/s; P = 0.03) was associated with intervention. No intervention was associated with larger isthmus size (OR, 0.23; P < 0.001), transverse arch diameter (OR, 0.23; P < 0.001), and aortic (OR, 0.72; P = 0.02), mitral (OR, 0.58; P = 0.001), and AAo (OR, 0.53; P < 0.001) z-scores. In multivariable analysis, higher peak AAo Doppler (OR, 2.51 [95% CI, 1.54-4.58] per 20 cm/s; P = 0.001) and younger gestational age at diagnosis (OR, 0.81 [95% CI, 0.70-0.93] per week; P = 0.005) were associated with intervention, whereas a higher AAo z-score (OR, 0.65 [95% CI, 0.43-0.94] per z; P = 0.029) and transverse arch dimension (OR, 0.44 [95% CI, 0.18-0.97]; P = 0.05) decreased the risk of intervention. CONCLUSIONS: In prenatally suspected coarctation, the variables associated with intervention comprised smaller AAo and transverse arch size, earlier gestational age at diagnosis, and the additional finding of a higher peak AAo Doppler.

Impact of organ prioritization for immunologic sensitization and waiting times for heart transplantation.

BACKGROUND: The Canadian status 4S category prioritizes highly sensitized patients with a calculated panel reactive antibody (CPRA) > 80% awaiting heart transplantation. We examined the effect of sensitization and status 4S and developed a predictive model to estimate waiting time in Canada. METHODS: A retrospective review was performed of patients listed for heart transplant at the Ottawa Heart Institute and Toronto General Hospital (Ontario, Canada). We evaluated the association of CPRA and priority listing status on waiting time and post-transplant outcomes. Waiting time risk factor analysis was performed using a multivariable parametric accelerated failure time model with a Weibull distribution. RESULTS: Of 394 patients listed (75% male, 51 ± 12 years), 291 (74%) received a transplant and 33 (8%) died waiting. The cumulative incidence of transplant decreased across higher CPRA groups but was similar for moderately and highly sensitized groups: 67%, 70%, 50%, and 40% at 12 months for CPRA 0%, 1% to 50%, 51% to 80%, and > 80%, respectively (p = 0.020). Status 4S patients experienced longer waiting times compared with other high priority status 3.5 and 4 and had increased risk of death on the waiting list (p = 0.014). Over a median follow-up of 2.4 years (interquartile range, 1.2-4.1), rejection occurred in 64 sensitized patients (24%) compared with 24 non-sensitized patients (9%; p = 0.019), but there was no difference in survival, allograft dysfunction, or cardiac allograft vasculopathy. A model predicting transplant waiting time, including CPRA, blood group, priority listing status, age, and weight, was developed and showed adequate discrimination and calibration. CONCLUSIONS: Waiting time to heart transplant is increased for highly and moderately sensitized patients, suggesting the need to reevaluate the CPRA > 80% threshold for status 4S prioritization in Canada. Extended waiting times, despite 4S prioritization, supports consideration of additional factors to CPRA in ensuring equitable organ access for sensitized patients.

Spatiotemporal clustering of cases of Kawasaki disease and associated coronary artery aneurysms in Canada.

Detailed epidemiologic examination of the distribution of Kawasaki disease (KD) cases could help elucidate the etiology and pathogenesis of this puzzling condition. Location of residence at KD admission was obtained for patients diagnosed in Canada (excluding Quebec) between March 2004 and March 2015. We identified 4,839 patients, 164 of whom (3.4%) developed a coronary artery aneurysm (CAA). A spatiotemporal clustering analysis was performed to determine whether non-random clusters emerged in the distributions of KD and CAA cases. A high-incidence KD cluster occurred in Toronto, ON, between October 2004 and May 2005 (116 cases; relative risk (RR) = 3.43; p < 0.001). A cluster of increased CAA frequency emerged in Mississauga, ON, between April 2004 and September 2005 (17% of KD cases; RR = 4.86). High-incidence clusters also arose in British Columbia (November 2010 to March 2011) and Alberta (January 2010 to November 2012) for KD and CAA, respectively. In an exploratory comparison between the primary KD cluster and reference groups of varying spatial and temporal origin, the main cluster demonstrated higher frequencies of conjunctivitis, oral mucosa changes and treatment with antibiotics, suggesting a possible coincident infectious process. Further spatiotemporal evaluation of KD cases might help understand the probable multifactorial etiology.

Neural Networks for Prognostication of Patients With Heart Failure.

Background Prognostication of heart failure patients from cardiopulmonary exercise test (CPET) currently involves simplification of complex time-series data into summary indices. We hypothesized that prognostication could be improved by considering the totality of the data generated during a CPET, instead of using summary indices alone. Methods and Results Complete data from 1156 CPETs were used to predict clinical deterioration (characterized by initiation of mechanical circulatory support, listing for heart transplantation or mortality) 1 year post-CPET. We compared the prognostic value (area under the receiver operating characteristic curve) of (1) the most predictive summary indices, (2) staged data collected at discrete intervals using multivariable regression models, and (3) breath-by-breath data using a feedforward neural network. The top-performing models were compared with the commonly used CPET risk score, using absolute net reclassification index. All models were trained and assessed using a 100-iteration Monte Carlo cross-validation. A total of 190 (16.4%) patients experienced clinical deterioration. The summary indices demonstrated subpar discriminative value (area under the receiver operating characteristic curve ≤0.800). Each multivariable model outperformed the summary indices, with the neural network incorporating breath-by-breath data achieving the best performance (area under the receiver operating characteristic curve =0.842). When compared with the CPET risk score (area under the receiver operating characteristic curve =0.759), the top-performing model obtained a net reclassification index of 4.9%. Conclusions The current practice of considering summary indices in isolation fails to realize the full value of CPET data. This may lead to less accurate prognostication of patients and in consequence, inaccurate selection of patients for advanced therapy. Clinical practices, like CPET prognostication, must be continuously reevaluated to ensure optimal usage of valuable (and oft-underutilized) data sources.

Environmental epidemiology of Kawasaki disease: Linking disease etiology, pathogenesis and global distribution.

BACKGROUND: The pathogenesis of Kawasaki disease (KD) is commonly ascribed to an exaggerated immunologic response to an unidentified environmental or infectious trigger in susceptible children. A comprehensive framework linking epidemiological data and global distribution of KD has not yet been proposed. METHODS AND FINDINGS: Patients with KD (n = 81) were enrolled within 6 weeks of diagnosis along with control subjects (n = 87). All completed an extensive epidemiological questionnaire. Geographic localization software characterized the subjects' neighborhood. KD incidence was compared to atmospheric biological particles counts and winds patterns. These data were used to create a comprehensive risk framework for KD, which we tested against published data on the global distribution. Compared to controls, patients with KD were more likely to be of Asian ancestry and were more likely to live in an environment with low exposure to environmental allergens. Higher atmospheric counts of biological particles other than fungus/spores were associated with a temporal reduction in incidence of KD. Finally, westerly winds were associated with increased fungal particles in the atmosphere and increased incidence of KD over the Greater Toronto Area. Our proposed framework was able to explain approximately 80% of the variation in the global distribution of KD. The main limitations of the study are that the majority of data used in this study are limited to the Canadian context and our proposed disease framework is theoretical and circumstantial rather than the result of a single simulation. CONCLUSIONS: Our proposed etiologic framework incorporates the 1) proportion of population that are genetically susceptible; 2) modulation of risk, determined by habitual exposure to environmental allergens, seasonal variations of atmospheric biological particles and contact with infectious diseases; and 3) exposure to the putative trigger. Future modelling of individual risk and global distribution will be strengthened by taking into consideration all of these non-traditional elements.

Consensus statement on physical rehabilitation in children and adolescents with osteogenesis imperfecta.

On the occasion of the 13th International Conference on Osteogenesis imperfecta in August 2017 an expert panel was convened to develop an international consensus paper regarding physical rehabilitation in children and adolescents with Osteogenesis imperfecta. The experts were chosen based on their clinical experience with children with osteogenesis imperfecta and were identified by sending out questionnaires to specialized centers and patient organizations in 26 different countries. The final expert-group included 16 representatives (12 physiotherapists, two occupational therapists and two medical doctors) from 14 countries. Within the framework of a collation of personal experiences and the results of a literature search, the participating physiotherapists, occupational therapists and medical doctors formulated 17 expert-statements on physical rehabilitation in patients aged 0-18 years with osteogenesis imperfecta.