Transient receptor potential melastatin 7 (TRPM7), a calcium-permeable, ubiquitously expressed ion channel, is critical for axonal development, and mediates hypoxic and ischemic neuronal cell death ...in vitro and in vivo. However, the downstream mechanisms underlying the TRPM7-mediated processes in physiology and pathophysiology remain unclear. In this study, we employed a mouse model of hypoxic-ischemic brain cell death which mimics the pathophysiology of hypoxic-ischemic encephalopathy (HIE). HIE is a major public health issue and an important cause of neonatal deaths worldwide; however, the available treatments for HIE remain limited. Its survivors face life-long neurological challenges including mental retardation, cerebral palsy, epilepsy and seizure disorders, motor impairments, and visual and auditory impairments. Through a proteomic analysis, we identified calcium/calmodulin-dependent protein kinase II (CaMKII) and phosphatase calcineurin as potential mediators of cell death downstream from TRPM7 activation. Further analysis revealed that TRPM7 mediates cell death through CaMKII, calmodulin, calcineurin, p38, and cofilin cascade. In vivo, we found a significant reduction of brain injury and improvement of short- and long-term functional outcomes after HI after administration of specific TRPM7 blocker waixenicin A. Our data demonstrate a molecular mechanism of TRPM7-mediated cell death and identifies TRPM7 as a promising therapeutic and drug development target for HIE.
When multiple living donor candidates come forward to donate a kidney to the same recipient, some living donor programs evaluate one candidate at a time to avoid unnecessary evaluations. Evaluating ...multiple candidates concurrently rather than sequentially may be cost-effective from a societal perspective if it reduces the time recipients spend on dialysis. We used a simple decision tree to estimate the cost-effectiveness of evaluating two to four candidates simultaneously rather than sequentially as potential kidney donors for the same intended recipient. Evaluating two donor candidates simultaneously cost $1,266 (CAD) more than if they were evaluated sequentially, but living donation occurred one month earlier. This translated into $6,931 in averted dialysis costs and a total cost-savings of $5,665 per intended recipient. Simultaneous evaluations also resulted in one percent more living donor transplants and overall gains in quality-of-life as recipients spent less time on dialysis. If recipients were free from dialysis at the start of donor candidate evaluations, simultaneous evaluations also reduced the rate of dialysis initiation by two percent. Benefits were also observed in the three- and four-candidate scenarios. Thus, living donor programs should consider evaluating up to four living donor candidates simultaneously when they come forward for the same recipient as health care system costs incurred are more than offset by avoided dialysis costs.
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Phosphate binders are used to treat hyperphosphatemia among patients with chronic kidney disease (CKD).
To conduct an economic evaluation comparing calcium-free binders sevelamer and lanthanum with ...calcium-based binders for patients with CKD.
Effectiveness data were obtained from a recent meta-analysis of randomized trials. Effectiveness was measured as life-years gained and translated to quality-adjusted life-years (QALYs) using utility weights from the literature. A Markov model consisting of non–dialysis-dependent (NDD)-CKD, dialysis-dependent (DD)-CKD, and death was developed to estimate the incremental costs and effects of sevelamer and lanthanum versus those of calcium-based binders. A lifetime horizon was used and both costs and effects were discounted at 1.5%. All costs are presented in 2015 Canadian dollars from the Canadian public payer perspective. Results of probabilistic sensitivity analysis were presented using cost-effectiveness acceptability curves. Sensitivity analyses were conducted for risk pooling methods, omission of dialysis costs, and persistence of drug effects on mortality.
Sevelamer resulted in an incremental cost-effectiveness ratio of $106,522/QALY for NDD-CKD and $133,847/QALY for DD-CKD cohorts. Excluding dialysis costs, sevelamer was cost-effective in the NDD-CKD cohort ($5,847/QALY) and the DD-CKD cohort ($11,178/QALY). Lanthanum was dominated regardless of whether dialysis costs were included.
Existing evidence does not clearly support the cost-effectiveness of non–calcium-containing phosphate binders (sevelamer and lanthanum) relative to calcium-containing phosphate binders in DD-CKD patients. Our study suggests that sevelamer may be cost-effective before dialysis onset. Because of the remaining uncertainty in several clinically relevant outcomes over time in DD-CKD and NDD-CKD patients, further research is encouraged.
The incidence of oropharyngeal cancer has risen over the past 2 decades. This rise has been attributed to human papillomavirus (HPV), but information on temporal trends in incidence of HPV-associated ...cancers across Canada is limited.
We collected social, clinical and demographic characteristics and p16 protein status (p16-positive or p16-negative, using this immunohistochemistry variable as a surrogate marker of HPV status) for 3643 patients with oropharyngeal cancer diagnosed between 2000 and 2012 at comprehensive cancer centres in British Columbia (6 centres), Edmonton, Calgary, Toronto and Halifax. We used receiver operating characteristic curves and multiple imputation to estimate the p16 status for missing values. We chose a best-imputation probability cut point on the basis of accuracy in samples with known p16 status and through an independent relation between p16 status and overall survival. We used logistic and Cox proportional hazard regression.
We found no temporal changes in p16-positive status initially, but there was significant selection bias, with p16 testing significantly more likely to be performed in males, lifetime never-smokers, patients with tonsillar or base-of-tongue tumours and those with nodal involvement (
< 0.05 for each variable). We used the following variables associated with p16-positive status for multiple imputation: male sex, tonsillar or base-of-tongue tumours, smaller tumours, nodal involvement, less smoking and lower alcohol consumption (
< 0.05 for each variable). Using sensitivity analyses, we showed that different imputation probability cut points for p16-positive status each identified a rise from 2000 to 2012, with the best-probability cut point identifying an increase from 47.3% in 2000 to 73.7% in 2012 (
< 0.001).
Across multiple centres in Canada, there was a steady rise in the proportion of oropharyngeal cancers attributable to HPV from 2000 to 2012.
In perioperative settings, frailty assessment has been shown to reduce mortality. This study examined the cost effectiveness of frailty assessment among patients aged 65 with coronary artery disease ...under consideration for coronary artery bypass grafting surgery.
A combined decision tree and Markov model was developed to estimate costs and quality-adjusted life years (QALYs) over a 21-year time horizon. Clinical parameters were obtained from published literature. Utilities were derived from the literature and the Canadian Community Health Survey. Costs were obtained from the Ontario fee schedule and published literature. Sensitivity and scenario analyses were conducted to assess the robustness of the results. Expected value of perfect information (EVPI) analysis was conducted to estimate the value of further research.
The frailty assessment initiative had a lower average cost than no frailty assessment ($19,567 compared with $20,062). QALYs with frailty assessment were 0.47 years more than with no frailty assessment. Thus, frailty assessment was dominant compared with no frailty assessment. Results were robust to changes in the input parameters. At a willingness to pay (WTP) threshold of $50,000/QALY, there was 100% probability of frailty assessment being cost-effective, and the EVPI per patient was $0. Scenario and sensitivity analysis showed frailty screening remained cost effective when changing the cohort average age, removing health benefits for nonfrail patients, and using subjective judgement to modify effectiveness parameters.
Frailty assessment may be good value for money. However, limited availability of geriatric consultation services, may hinder implementation. Thus, the estimated benefits of frailty screening may not be achievable in practice.
Il a été déterminé que l’évaluation de la fragilité permettait de réduire la mortalité en contexte périopératoire. Les auteurs du présent article ont examiné le rapport coût-efficacité de l’évaluation de la fragilité des patients âgés de 65 ans atteints d’une coronaropathie chez qui un pontage aortocoronarien était envisagé.
Les coûts et les années de vie ajustées en fonction de la qualité (AVAQ) ont été estimés sur un horizon de 21 ans au moyen d’un arbre décisionnel et d’un modèle de Markov. Les paramètres cliniques sont extraits d’études publiées, et les valeurs d’utilité sont dérivées d’études publiées et de l’Enquête sur la santé dans les collectivités canadiennes. Les coûts sont tirés du barème des frais et honoraires en vigueur en Ontario et d’études publiées. Des analyses de sensibilité et de scénarios ont été réalisées pour évaluer la robustesse des résultats. Enfin, une analyse de la valeur espérée de l’information parfaite (VEIP) a été effectuée pour estimer la valeur de recherches futures.
Le coût moyen de l’exécution d’une évaluation de la fragilité était inférieur à celui de la non-exécution d’une telle évaluation (19 567 $ comparativement à 20 062 $). Les AVAQ associées à l’évaluation de la fragilité s’établissaient à 0,47 année de plus que les AVAQ en l’absence d’évaluation. L’évaluation de la fragilité était donc dominante par rapport à l’absence d’évaluation. Les résultats se sont révélés robustes aux changements des paramètres d’entrée. À un seuil de volonté de payer de 50 000 $ par AVAQ, la probabilité que l’évaluation de la fragilité soit rentable était de 100 % et la VEIP par patient s’établissait à 0 $. Les analyses de scénarios et de sensibilité ont montré que l’évaluation de la fragilité demeure rentable même lorsqu’on change l’âge moyen de la cohorte, qu’on ne tient pas compte des bienfaits pour la santé des patients qui ne sont pas considérés comme étant fragiles et qu’on modifie de manière subjective les paramètres relatifs à l’efficacité.
L’évaluation de la fragilité pourrait permettre d’optimiser les ressources. Toutefois, l’offre restreinte de services de consultation en gériatrie pourrait faire obstacle à la mise en œuvre d’une telle initiative. Les avantages estimés d’une évaluation de la fragilité ne sont donc peut-être pas réalisables dans la pratique.
Globally, lung cancer is the leading cause of cancer death. Previous trials demonstrated that low-dose computed tomography lung cancer screening of high-risk individuals can reduce lung cancer ...mortality by 20% or more. Lung cancer screening has been approved by major guidelines in the United States, and over 4,000 sites offer screening. Adoption of lung screening outside the United States has, until recently, been slow. Between June 2017 and May 2019, the Ontario Lung Cancer Screening Pilot successfully recruited 7,768 individuals at high risk identified by using the PLCOm2012noRace lung cancer risk prediction model. In total, 4,451 participants were successfully screened, retained and provided with high-quality follow-up, including appropriate treatment. In the Ontario Lung Cancer Screening Pilot, the lung cancer detection rate and the proportion of early-stage cancers were 2.4% and 79.2%, respectively; serious harms were infrequent; and sensitivity to detect lung cancers was 95.3% or more. With abnormal scans defined as ones leading to diagnostic investigation, specificity was 95.5% (positive predictive value, 35.1%), and adherence to annual recall and early surveillance scans and clinical investigations were high (>85%). The Ontario Lung Cancer Screening Pilot provides insights into how a risk-based organized lung screening program can be implemented in a large, diverse, populous geographic area within a universal healthcare system.
Living donor kidney transplantation is the most promising way to avoid or minimize the amount of time a recipient spends on dialysis before transplantation. We studied 887 living kidney donors at 5 ...transplant centers in Ontario, Canada, who started their evaluation and donated between April 2006 and March 2014. Using a series of hypothetical scenarios, we estimated the impact of an earlier living donor evaluation completion and donation on the number pre‐emptive transplants, the time spent on dialysis, healthcare cost savings from averted dialysis costs (CAD $2016), and the number of additional transplants. During the study period, if the donor transplants occurred 3 months earlier, the healthcare system would save on average $12 055 (standard deviation SD $13 594) per recipient; 21 recipients could have avoided dialysis altogether, and 57 additional transplants (a 26% increase) could have occurred each year. For the 220 living kidney donor transplants performed in Ontario, Canada, each year, this translates to a total annual cost savings of $2.7M. In conclusion, a more timely evaluation of living donor candidates and their intended recipients may increase the supply of kidneys for transplantation. Improved evaluation efficiency may also yield more pre‐emptive transplants and substantial healthcare cost savings through averted dialysis costs.
An earlier and more efficient living donor candidate evaluation may enable more living donor transplants, improve recipient outcomes, and reduce healthcare costs.
A prolonged living kidney donor evaluation may result in worse outcomes for transplant recipients. Better knowledge of the duration of this process may help inform future donors and identify ...opportunities for improvement.
1 prospective and 1 retrospective cohort study.
At 16 Canadian and Australian transplantation centers (prospective cohort) and 5 Ontario transplantation centers (retrospective cohort), we assessed the duration of living kidney donor evaluation and explored donor, recipient, and transplantation factors associated with longer evaluation times. Data were obtained from 2 sources: donor medical records using chart abstraction and health care administrative databases.
Donor and recipient demographics, direct versus paired donation, center-level variables.
Duration of living donor evaluation.
The median total duration of transplantation evaluation (time from when the candidate started the evaluation until donation) was 10.3 (IQR, 6.5-16.7) months. The median duration from evaluation start until approval to donate was 7.9 (IQR, 4.6-14.1) months, and from approval until donation was 0.7 (IQR, 0.3-2.4) months, respectively. The median time between the first and last consultation among donors who completed a nephrology, surgery, and psychosocial assessment in the prospective cohort was 3.0 (IQR, 1.0-6.3) months, and between computed tomography angiography and donation was 4.8 (IQR, 2.6-9.2) months. After adjustment, the total duration of transplantation evaluation was longer if the donor participated in paired donation (6.6 95% CI, 1.6-9.7 months) and if the recipient was referred later relative to the donor’s evaluation start date (0.9 95% CI, 0.8-1.0 months per month of delayed referral). Results depended on whether the recipient was receiving dialysis.
Living donor candidates who did not donate were not included and proxy measures were used for some dates in the donor evaluation process.
The duration of kidney transplant donor evaluation is variable and can be lengthy. Better understanding of the reasons for a prolonged evaluation may inform quality improvement initiatives to reduce unnecessary delays.
Consider a theoretical situation in which 2 patients with similar baseline characteristics receive a kidney transplant on the same day: 1 from a standard criteria deceased donor, the other from a ...living donor. Which kidney transplant will last longer?
We conducted a population-based cohort study using linked administrative healthcare databases from Ontario, Canada, from January 1, 2005, to March 31, 2014, to evaluate several posttransplant outcomes in individuals who received a kidney transplant from a standard criteria deceased donor (n = 1523) or from a living donor (n = 1373). We used PS weighting using overlap weights, a novel weighting method that emphasizes the population of recipients with the most overlap in baseline characteristics.
Compared with recipients of a living donor, the rate of all-cause graft failure was not statistically higher for recipients of a standard criteria deceased donor (hazard ratio, 1.1; 95% confidence interval CI, 0.8-1.6). Recipients of a standard criteria deceased donor, compared with recipients of a living donor had a higher rate of delayed graft function (23.6% versus 18.7%; odds ratio, 1.3; 95% CI, 1.0-1.6) and a longer length of stay for the kidney transplant surgery (mean difference, 1.7 d; 95% CI, 0.5-3.0).
After accounting for many important donor and recipient factors, we failed to observe a large difference in the risk of all-cause graft failure for recipients of a standard criteria deceased versus living donor. Some estimates were imprecise, which meant we could not rule out the presence of smaller clinically important effects.
The healthcare costs to evaluate, perform surgery, and follow a living kidney donor for the year after donation are poorly described.
We obtained information on the healthcare costs of 1099 living ...kidney donors between April 1, 2004, and March 31, 2014, from Ontario, Canada, using comprehensive healthcare administrative databases. We estimated the cost of 3 periods of the living donation process: the predonation evaluation period (start of evaluation until the day before donation), perioperative period (day of donation until 30-days postdonation), and 1 year of follow-up period (after perioperative period until 1 year postdonation). We analyzed data for donors and healthy matched nondonor controls using regression-based methods to estimate the incremental cost of living donation. Costs are presented from the perspective of the Canadian healthcare payer (2017 CAD $).
The incremental healthcare costs (compared with controls) for the evaluation, perioperative, and follow-up periods were CAD $3596 (95% confidence interval CI, CAD $3350-$3842), CAD $11 694 (95% CI, CAD $11 415-CAD $11 973), and $1011 (95% CI, CAD $793-CAD $1230), respectively, totalling CAD $16 290 (95% CI, CAD $15 814-CAD $16 767). The evaluation cost was higher if the intended recipient started dialysis partway through the donor evaluation (CAD $886; 95% CI, CAD $19, CAD $1752). The perioperative cost varied across transplant centers (P < 0.0001).
Although substantial costs of living donor care are related to the nephrectomy procedure, comprehensive assessment of costs must also include the evaluation and follow-up periods. These estimates are informative for planning future work to support and expand living donation and transplantation, and directing efforts to improve the cost efficiency of living donor care.
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