Propofol sedation does not improve measures of colonoscopy quality but increase cost - findings from a large population-based cohort study.

Background: Propofol is often used for sedation during colonoscopy. We assessed the impact of propofol sedation on colonoscopy related quality metrics and cost in a population-based cohort study. Methods: All colonoscopies performed at 21 hospitals in the province of Ontario, Canada, during an 18-month period, from April 1, 2017 to October 31, 2018, using either propofol or conscious sedation were evaluated. The primary outcome was adenoma detection rate (ADR) and secondary outcomes were sessile serrated polyp detection rate (ssPDR), polyp detection rate (PDR), cecal intubation rate (CIR), and perforation rate. Binary outcomes were assessed using a modified Poisson regression model adjusted for clustering and potential confounders based on patient, procedure, and physician characteristics. Findings: A total of 46,634 colonoscopies were performed, of which 16,408 (35.2%) received propofol and 30,226 (64.8%) received conscious sedation. Compared to conscious sedation, the use of propofol was associated with a lower ADR (24.6% vs. 27.0%, p < 0.0001) but not ssPDR (5.0% vs. 4.7%, p = 0.26), PDR (40.5% vs 40.4%, p = 0.79), CIR (97.1% vs. 96.8%, p = 0.15) or perforation rate (0.04% vs. 0.06%, p = 0.45). On multi-variable analysis, propofol sedation was not associated with any differences in ADR (RR = 0.90, 95% CI 0.74-1.10, p = 0.30), ssPDR (RR = 1.20, 95% CI 0.90-1.60, p = 0.22), PDR (RR = 1.00, 95% CI 0.90-1.11, p = 0.99), or CIR (RR = 1.00, 95% CI 0.80-1.26, p = 0.99). The additional cost associated with propofol sedation was $12,730,496 for every 100,000 cases. Interpretation: The use of propofol sedation was not associated with improved colonoscopy related quality metrics but increased costs. The routine use of propofol for colonoscopy should be reevaluated. Funding: None.

Cost-Effectiveness Analysis of Pharmacogenomics (PGx)-Based Warfarin, Apixaban, and Rivaroxaban Versus Standard Warfarin for the Management of Atrial Fibrillation in Ontario, Canada.

OBJECTIVE: To assess the cost-effectiveness of pharmacogenomics (PGx)-based warfarin (i.e., warfarin dosing following genetic testing), apixaban, and rivaroxaban oral anticoagulation versus standard warfarin for the treatment of newly diagnosed patients with nonvalvular atrial fibrillation (AF) aged ≥ 65 years. METHODS: We developed a Markov decision-analytic model to compare costs [2017 Canadian dollars (C$)] and quality-adjusted life years (QALYs) from the Ontario health care payer perspective over a life-time horizon. The parameters used in the model were derived from the published literature, the Ontario health care administrative database, and expert opinion. To account for the uncertainty of model parameters, we conducted extensive deterministic and probabilistic sensitivity analyses. The results were summarized using incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves. RESULTS: We found that PGx-based warfarin had an ICER of C$17,584/QALY compared with standard warfarin, and apixaban had an ICER of C$64,590/QALY compared with PGx-based warfarin in our base-case analysis. Rivaroxaban was extendedly dominated by PGx-based warfarin and apixaban. The probabilistic sensitivity analysis showed that apixaban, rivaroxaban, PGx-based warfarin, and standard warfarin were cost-effective at some willingness-to-pay (WTP) thresholds. PGx-based warfarin had a higher probability of being cost-effective than apixaban (51.3% versus 14.3%) at a WTP threshold of C$50,000/QALY. At a WTP threshold of C$100,000/QALY, apixaban had a higher probability of being cost-effective than PGx-based warfarin (54.6% versus 22.6%). CONCLUSION: We found that PGx-based warfarin for patients with AF is cost-effective at a WTP threshold of C$50,000/QALY. Apixaban had a higher probability of being cost-effective (> 50%) at a WTP threshold of C$93,000/QALY.

Risk stratification for treating people at ultra-high risk for psychosis: A cost-effectiveness analysis.

People who are at ultra-high risk (UHR) for psychosis receive clinical care with the aim to prevent first-episode psychosis (FEP), regardless of the risk of conversion to psychosis. An economic model from the Canadian health system perspective was developed to evaluate the cost-effectiveness of treating all with UHR compared to risk stratification over a 15-year time horizon, based on conversion probability, expected quality-of-life and costs. The analysis used a decision tree followed by a Markov model. Health states included: Not UHR, UHR with <20 % risk of conversion to FEP (based on the North American Prodrome Longitudinal Study risk calculator), UHR with ≥20 % risk, FEP, Remission, Post-FEP, and Death. The analysis found that: risk stratification (i.e., only treating those with ≥20 % risk) had lower costs ($1398) and quality-adjusted life-years (0.055 QALYs) per person compared to treating all. The incremental cost-effectiveness ratio for 'treat all' was $25,448/QALY, and suggests treating all may be cost-effective. The model was sensitive to changes to the probability of conversion.

Pricing Treatments Cost-Effectively when They Have Multiple Indications: Not Just a Simple Threshold Analysis.

BACKGROUND: Economic evaluations of treatments increasingly employ price-threshold analyses. When a treatment has multiple indications, standard price-threshold analyses can be overly simplistic. We examine how rules governing indication-specific prices and reimbursement decisions affect value-based price analyses. METHODS: We analyze a 2-stage game between 2 players: the therapy's manufacturer and the payer purchasing it for patients. First, the manufacturer selects a price(s) that may be indication specific. Then, the payer decides whether to provide reimbursement at the offered price(s). We assume known indication-specific demand. The manufacturer seeks to maximize profit. The payer seeks to maximize total population incremental net monetary benefit and will not pay more than their willingness-to-pay threshold. We consider game variants defined by constraints on the manufacturer's ability to price and payer's ability to provide reimbursement differentially by indication. RESULTS: When both the manufacturer and payer can make indication-specific decisions, the problem simplifies to multiple single-indication price-threshold analyses, and the manufacturer captures all the consumer surplus. When the manufacturer is restricted to one price and the payer must make an all-or-nothing reimbursement decision, the selected price is a weighted average of indication-specific threshold prices such that reimbursement of more valuable indications subsidizes reimbursement of less valuable indications. With a single price and indication-specific coverage decisions, the manufacturer may select a high price where fewer patients receive treatment because the payer restricts reimbursement to the set of indications providing value commensurate with the high price. However, the manufacturer may select a low price, resulting in reimbursement for more indications and positive consumer surplus. CONCLUSIONS: When treatments have multiple indications, economic evaluations including price-threshold analyses should carefully consider jurisdiction-specific rules regarding pricing and reimbursement decisions. HIGHLIGHTS: With treatment prices rising, economic evaluations increasingly employ price-threshold analyses to identify value-based prices. Standard price-threshold analyses can be overly simplistic when treatments have multiple indications.Jurisdiction-specific rules governing indication-specific prices and reimbursement decisions affect value-based price analyses.When the manufacturer is restricted to one price for all indications and the payer must make an all-or-nothing reimbursement decision, the selected price is a weighted average of indication-specific threshold prices such that reimbursement of the more valuable indications subsidize reimbursement of the less valuable indications.With a single price and indication-specific coverage decisions, the manufacturer may select a high price with fewer patients treated than in the first-best solution. There are also cases in which the manufacturer selects a lower price, resulting in reimbursement for more indications and positive consumer surplus.

Impact of COVID-19-related health care disruptions on pathologic cancer staging during the first pandemic year: a retrospective cohort study from March 2018 to March 2021.

BACKGROUND: The COVID-19 pandemic has created major disruptions in cancer care, with reductions in diagnostic tests and treatments. We evaluated the impact of these health care-related changes on cancer staging by comparing cancers staged before and during the pandemic. METHODS: We performed a retrospective cohort study at London Health Sciences Centre and St. Joseph's Health Care London, London, Ontario, Canada. We evaluated all pathologically staged breast, colorectal, prostate, endometrial and lung cancers (the 5 most common cancers by site, excluding nonmelanoma skin cancer) over a 3-year period (Mar. 15, 2018-Mar. 14, 2021). The pre-COVID-19 group included procedures performed between Mar. 15, 2018, and Mar. 14, 2020, and the COVID-19 group included procedures performed between Mar. 15, 2020, and Mar. 14, 2021. The primary outcome was cancer stage group, based on the pathologic tumour, lymph node, metastasis system. We performed univariate analyses to compare demographic characteristics, pathologic features and cancer stage between the 2 groups. We performed multivariable ordinal regression analyses using the proportional odds model to evaluate the association between stage and timing of staging (before v. during the pandemic). RESULTS: There were 4055 cases across the 5 cancer sites. The average number of breast cancer staging procedures per 30 days increased during the pandemic compared to the yearly average in the pre-COVID-19 period (41.3 v. 39.6), whereas decreases were observed for endometrial cancer (15.9 v. 16.4), colorectal cancer (21.8 v. 24.3), prostate cancer (13.6 v. 18.5) and lung cancer (11.5 v. 15.9). For all cancer sites, there were no statistically significant differences in demographic characteristics, pathologic features or cancer stage between the 2 groups (p > 0.05). In multivariable regression analysis, for all cancer sites, cases staged during the pandemic were not associated with higher stage (breast: odds ratio [OR] 1.071, 95% confidence interval [CI] 0.826-1.388; colorectal: OR 1.201, 95% CI 0.869-1.661; endometrium: OR 0.792, 95% CI 0.495-1.252; prostate: OR 1.171, 95% CI 0.765-1.794; and lung: OR 0.826, 95% CI 0.535-1.262). INTERPRETATION: Cancer cases staged during the first year of the COVID-19 pandemic were not associated with higher stage; this likely reflects the prioritization of cancer procedures during times of reduced capacity. The impact of the pandemic period on staging procedures varied between cancer sites, which may reflect differences in clinical presentation, detection and treatment.

White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: A meta-analysis, systematic review, and recommendations for future study harmonization.

INTRODUCTION: The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps. METHODS: A meta-analysis and systematic review was performed investigating associations between baseline WMHs and longitudinal cognitive outcomes in cognitively normal populations, and populations with mild cognitive impairment (MCI), Alzheimer's disease (AD), and stroke. RESULTS: Baseline WMHs increase the risk of cognitive impairment and dementia across diagnostic categories and most consistently in MCI and post-stroke populations. Apolipoprotein E (APOE) genotype and domain-specific cognitive changes relating to strategic anatomical locations, such as frontal WMH and executive decline, represent important considerations. Meta-analysis reliability was assessed using multiple methods of estimation, and results suggest that heterogeneity in study design and reporting remains a significant barrier. DISCUSSION: Recommendations and future directions for study of WMHs are provided to improve cross-study comparison and translation of research into consistent clinical interpretation.

Impact of non-pharmaceutical interventions and vaccination on COVID-19 outbreaks in Nunavut, Canada: a Canadian Immunization Research Network (CIRN) study.

BACKGROUND: Nunavut, the northernmost Arctic territory of Canada, experienced three community outbreaks of the coronavirus disease 2019 (COVID-19) from early November 2020 to mid-June 2021. We sought to investigate how non-pharmaceutical interventions (NPIs) and vaccination affected the course of these outbreaks. METHODS: We used an agent-based model of disease transmission to simulate COVID-19 outbreaks in Nunavut. The model encapsulated demographics and household structure of the population, the effect of NPIs, and daily number of vaccine doses administered. We fitted the model to inferred, back-calculated infections from incidence data reported from October 2020 to June 2021. We then compared the fit of the scenario based on case count data with several counterfactual scenarios without the effect of NPIs, without vaccination, and with a hypothetical accelerated vaccination program whereby 98% of the vaccine supply was administered to eligible individuals. RESULTS: We found that, without a territory-wide lockdown during the first COVID-19 outbreak in November 2020, the peak of infections would have been 4.7 times higher with a total of 5,404 (95% CrI: 5,015-5,798) infections before the start of vaccination on January 6, 2021. Without effective NPIs, we estimated a total of 4,290 (95% CrI: 3,880-4,708) infections during the second outbreak under the pace of vaccination administered in Nunavut. In a hypothetical accelerated vaccine rollout, the total infections during the second Nunavut outbreak would have been 58% lower, to 1,812 (95% CrI: 1,593-2,039) infections. Vaccination was estimated to have the largest impact during the outbreak in April 2021, averting 15,196 (95% CrI: 14,798-15,591) infections if the disease had spread through Nunavut communities. Accelerated vaccination would have further reduced the total infections to 243 (95% CrI: 222-265) even in the absence of NPIs. CONCLUSIONS: NPIs have been essential in mitigating pandemic outbreaks in this large, geographically distanced and remote territory. While vaccination has the greatest impact to prevent infection and severe outcomes, public health implementation of NPIs play an essential role in the short term before attaining high levels of immunity in the population.

Intravenous Thrombolysis After First-Ever Ischemic Stroke and Reduced Incident Dementia Rate.

BACKGROUND: The use of intravenous thrombolysis is associated with improved clinical outcomes. Whether thrombolysis is associated with reduced incidence of poststroke dementia remains uncertain. We sought to estimate if the use of thrombolysis following first-ever ischemic stroke was associated with a reduced rate of incident dementia using a pragmatic observational design. METHODS: We included first-ever ischemic stroke patients from the Ontario Stroke Registry who had not previously been diagnosed with dementia. The primary outcome was incident dementia ascertained by a validated diagnostic algorithm. We employed inverse probability of treatment-weighted Cox proportional hazard models to estimate the cause-specific hazard ratio for the association of thrombolysis and incident dementia at 1 and 5 years following stroke. RESULTS: From July 2003 to March 2013, 7072 patients with ischemic stroke were included, 3276 (46.3%) were female and mean age was 71.0 (SD, 12.8) years. Overall, 38.2% of the cohort (n=2705) received thrombolysis, 77.2% (n=2087) of which was administered within 3 hours of stroke onset. In the first year following stroke, thrombolysis administration was associated with a 24% relative reduction in the rate of developing dementia (cause-specific hazard ratio, 0.76 [95% CI, 0.58-0.97]). This association remained significant at 5 years (cause-specific hazard ratio, 0.79 [95% CI, 0.66-0.91]) and at the end of follow-up (median 6.3 years; cause-specific hazard ratio, 0.79 [95% CI, 0.68-0.89]). CONCLUSIONS: Thrombolysis administration following first-ever ischemic stroke was independently associated with a reduced rate of dementia. Incident dementia should be considered as a relevant outcome when evaluating risk/benefit of thrombolysis in ischemic stroke patients.

Impact of university re-opening on total community COVID-19 burden.

BACKGROUND: University students have higher average number of contacts than the general population. Students returning to university campuses may exacerbate COVID-19 dynamics in the surrounding community. METHODS: We developed a dynamic transmission model of COVID-19 in a mid-sized city currently experiencing a low infection rate. We evaluated the impact of 20,000 university students arriving on September 1 in terms of cumulative COVID-19 infections, time to peak infections, and the timing and peak level of critical care occupancy. We also considered how these impacts might be mitigated through screening interventions targeted to students. RESULTS: If arriving students reduce their contacts by 40% compared to pre-COVID levels, the total number of infections in the community increases by 115% (from 3,515 to 7,551), with 70% of the incremental infections occurring in the general population, and an incremental 19 COVID-19 deaths. Screening students every 5 days reduces the number of infections attributable to the student population by 42% and the total COVID-19 deaths by 8. One-time mass screening of students prevents fewer infections than 5-day screening, but is more efficient, requiring 196 tests needed to avert one infection instead of 237. INTERPRETATION: University students are highly inter-connected with the surrounding off-campus community. Screening targeted at this population provides significant public health benefits to the community through averted infections, critical care admissions, and COVID-19 deaths.

Association of lewy bodies, hippocampal sclerosis and amyloid angiopathy with dementia in community-dwelling elderly: A systematic review and meta-analysis.

INTRODUCTION: We measured the proportion of Lewy body pathology (LB), hippocampal sclerosis (HS), and cerebral amyloid angiopathy (CAA) among community-dwelling people with and without dementia. METHODS: We searched for community-based cohorts with postmortem brain autopsy until 1 January 2020. We calculated the summary risk difference and 95% confidence interval (95% CI) using a random-effects model in R. RESULTS: We found 12 articles, comprising 2197 demented and 2104 non-demented participants. LB, HS, CAA were prevalent lesions among community-dwelling elderly (15%, 10%, and 24%, respectively). These significantly increased the risk of dementia (LB: risk difference 38%, 95% CI 20-56%, HS: 34%, 24-44%, CAA: 19%, 3-34%). 20% of cases with neocortical LB, 17% with bilateral HS, and 42% with moderate/severe CAA pathology remained non-demented by death. DISCUSSION: LB or HS or CAA are common neuropathologies among community-dwelling elderly. Although these lesions independently are associated with dementia, many remain non-demented, by death.

Multifaceted strategies for the control of COVID-19 outbreaks in long-term care facilities in Ontario, Canada.

The novel coronavirus disease 2019 (COVID-19) has caused severe outbreaks in Canadian long-term care facilities (LTCFs). In Canada, over 80% of COVID-19 deaths during the first pandemic wave occurred in LTCFs. We sought to evaluate the effect of mitigation measures in LTCFs including frequent testing of staff, and vaccination of staff and residents. We developed an agent-based transmission model and parameterized it with disease-specific estimates, temporal sensitivity of nasopharyngeal and saliva testing, results of vaccine efficacy trials, and data from initial COVID-19 outbreaks in LTCFs in Ontario, Canada. Characteristics of staff and residents, including contact patterns, were integrated into the model with age-dependent risk of hospitalization and death. Estimates of infection and outcomes were obtained and 95% credible intervals were generated using a bias-corrected and accelerated bootstrap method. Weekly routine testing of staff with 2-day turnaround time reduced infections among residents by at least 25.9% (95% CrI: 23.3%-28.3%), compared to baseline measures of mask-wearing, symptom screening, and staff cohorting alone. A similar reduction of hospitalizations and deaths was achieved in residents. Vaccination averted 2-4 times more infections in both staff and residents as compared to routine testing, and markedly reduced hospitalizations and deaths among residents by 95.9% (95% CrI: 95.4%-96.3%) and 95.8% (95% CrI: 95.5%-96.1%), respectively, over 200 days from the start of vaccination. Vaccination could have a substantial impact on mitigating disease burden among residents, but may not eliminate the need for other measures before population-level control of COVID-19 is achieved.

A comparison of COVID-19 epidemiological indicators in Sweden, Norway, Denmark, and Finland.

Aims: To compare the early impact of COVID-19 infections and mortality from February to July 2020 across the Nordic nations of Sweden, Norway, Denmark, and Finland through available public data sources and conduct a descriptive analysis of the potential factors that drove different epidemiological outcomes, with a focus on Sweden's response. Methods: COVID-19 cases, deaths, tests, case age distribution, and the difference between 2020 all-cause mortality and the average mortality of the previous 5 years were compared across nations. Patterns in cell phone mobility data, testing strategies, and seniors' care home deaths were also compared. Data for each nation were based on publicly available sources as of July 31, 2020. Results: Compared with its Nordic peers, Sweden had a higher incidence rate across all ages, a higher COVID-19-related death rate only partially explained by population demographics, a higher death rate in seniors' care, and higher all-cause mortality. Sweden had approximately half as much mobility change as its Nordic neighbours until April and followed similar rates as its neighbours from April to July. Denmark led its Nordic peers in testing rates, while Sweden had the highest cumulative test-positivity rate continuously from mid-March. Conclusions: COVID-19 pushed Sweden's health system to its capacity, exposed systemic weaknesses in the seniors' care system, and revealed challenges with implementing effective contact tracing and testing strategies while experiencing a high case burden. Looser government restrictions at the beginning of the outbreak are likely to have played a role in the impact of COVID-19 in Sweden. In an effort to improve epidemic control, Sweden has increased testing rates, implemented more restrictive prevention measures, and increased their intensive care unit bed capacity.

Multifaceted strategies for the control of COVID-19 outbreaks in long-term care facilities in Ontario, Canada.

The novel coronavirus disease 2019 (COVID-19) has caused severe outbreaks in Canadian long-term care facilities (LTCFs). In Canada, over 80% of COVID-19 deaths during the first pandemic wave occurred in LTCFs. We sought to evaluate the effect of mitigation measures in LTCFs including frequent testing of staff, and vaccination of staff and residents. We developed an agent-based transmission model and parameterized it with disease-specific estimates, temporal sensitivity of nasopharyngeal and saliva testing, results of vaccine efficacy trials, and data from initial COVID-19 outbreaks in LTCFs in Ontario, Canada. Characteristics of staff and residents, including contact patterns, were integrated into the model with age-dependent risk of hospitalization and death. Estimates of infection and outcomes were obtained and 95% credible intervals were generated using a bias-corrected and accelerated bootstrap method. Weekly routine testing of staff with 2-day turnaround time reduced infections among residents by at least 25.9% (95% CrI: 23.3% - 28.3%), compared to baseline measures of mask-wearing, symptom screening, and staff cohorting alone. A similar reduction of hospitalizations and deaths was achieved in residents. Vaccination averted 2-4 times more infections in both staff and residents as compared to routine testing, and markedly reduced hospitalizations and deaths among residents by 95.9% (95% CrI: 95.4% - 96.3%) and 95.8% (95% CrI: 95.5% - 96.1%), respectively, over 200 days from the start of vaccination. Vaccination could have a substantial impact on mitigating disease burden among residents, but may not eliminate the need for other measures before population-level control of COVID-19 is achieved.

Optimal Allocation of Research Funds under a Budget Constraint.

Purpose. Health economic evaluations that include the expected value of sample information support implementation decisions as well as decisions about further research. However, just as decision makers must consider portfolios of implementation spending, they must also identify the optimal portfolio of research investments. Methods. Under a fixed research budget, a decision maker determines which studies to fund; additional budget allocated to one study to increase the study sample size implies less budget available to collect information to reduce decision uncertainty in other implementation decisions. We employ a budget-constrained portfolio optimization framework in which the decisions are whether to invest in a study and at what sample size. The objective is to maximize the sum of the studies' population expected net benefit of sampling (ENBS). We show how to determine the optimal research portfolio and study-specific levels of investment. We demonstrate our framework with a stylized example to illustrate solution features and a real-world application using 6 published cost-effectiveness analyses. Results. Among the studies selected for nonzero investment, the optimal sample size occurs at the point at which the marginal population ENBS divided by the marginal cost of additional sampling is the same for all studies. Compared with standard ENBS optimization without a research budget constraint, optimal budget-constrained sample sizes are typically smaller but allow more studies to be funded. Conclusions. The budget constraint for research studies directly implies that the optimal sample size for additional research is not the point at which the ENBS is maximized for individual studies. A portfolio optimization approach can yield higher total ENBS. Ultimately, there is a maximum willingness to pay for incremental information that determines optimal sample sizes.

Post-mortem 7 Tesla MRI detection of white matter hyperintensities: A multidisciplinary voxel-wise comparison of imaging and histological correlates.

White matter hyperintensities (WMH) occur in normal aging and across diagnostic categories of neurodegeneration. Ultra-high field imaging (UHF) MRI machines offer the potential to improve our understanding of WMH. Post-mortem imaging using UHF magnetic resonance imaging (MRI) is a useful way of assessing WMH, however, the responsiveness of UHF-MRI to pathological changes within the white matter has not been characterized. In this study we report post-mortem MRI sequences of white matter hyperintensities in normal aging, Alzheimer's disease, and cerebrovascular disease. Seven Tesla post-mortem MRI reliably detected periventricular WMH using both FLAIR and T2 sequences and reflects underlying pathology of myelin and axon density despite prolonged fixation time. Co-registration of histological images to MRI allowed for direct voxel- wise comparison of imaging findings and pathological changes. Myelin content and cerebrovascular pathology were the most significant predictors of MRI white matter intensity as revealed by linear mixed models. Future work investigating the utility of UHF- MRI in studying cell-specific changes within WMH is required to better understand radio-pathologic correlations.

A third of community-dwelling elderly with intermediate and high level of Alzheimer's neuropathologic changes are not demented: A meta-analysis.

This systematic review and meta-analysis assessed the bidirectional association between AD pathology and dementia in community-dwelling elderly populations. We searched PubMed/MEDLINE, Embase, Scopus, Web of Science, and references of the pertinent articles for community/population-based longitudinal cohorts with regular assessment of cognitive status of participants followed by postmortem neuropathology data, with no language and date restrictions, until 20 September 2019. Finally, we retrieved 18 articles with data from 17 cohorts comprising 4677 persons. Dementia was twice as likely in participants with definitive neuropathological indicator for AD compared to those without it: moderate/high Braak and Braak (BB) stages III-VI of neurofibrillary tangles (54 % vs. 26 % in participants with BB stages 0-II), the Consortium to Establish a Registry for AD (CERAD) moderate/frequent neuritic plaques scores (64 % vs. 33 % in participants with CERAD none/infrequent), and National Institute on Aging and the Reagan Institute of the Alzheimer's Association criteria intermediate/high AD probability (52 % vs. 28 % in participants with no/low AD probability). Accordingly, a substantial proportion of community-dwelling elderly people with definitive AD pathology may not develop dementia. Brain reserve or contribution of other factors and pathologies, such as vascular and degenerative pathology to dementia might explain this apparent discrepancy. These findings also suggest caution in equating Alzheimer pathology biomarkers with dementia.

Dynamics of Drug Resistance: Optimal Control of an Infectious Disease.

Antimicrobial resistance is a significant public health threat. In the U.S. alone, 2 million people are infected and 23,000 die each year from antibiotic resistant bacterial infections. In many cases, infections are resistant to all but a few remaining drugs. We examine the case where a single drug remains and solve for the optimal treatment policy for an SIS infectious disease model incorporating the effects of drug resistance. The problem is formulated as an optimal control problem with two continuous state variables, the disease prevalence and drug's "quality" (the fraction of infections that are drug-susceptible). The decision maker's objective is to minimize the discounted cost of the disease to society over an infinite horizon. We provide a new generalizable solution approach that allows us to thoroughly characterize the optimal treatment policy analytically. We prove that the optimal treatment policy is a bang-bang policy with a single switching time. The action/inaction regions can be described by a single boundary that is strictly increasing when viewed as a function of drug quality, indicating that when the disease transmission rate is constant, the policy of withholding treatment to preserve the drug for a potentially more serious future outbreak is not optimal. We show that the optimal value function and/or its derivatives are neither C 1 nor Lipschitz continuous suggesting that numerical approaches to this family of dynamic infectious disease models may not be computationally stable. Furthermore, we demonstrate that relaxing the standard assumption of constant disease transmission rate can fundamentally change the shape of the action region, add a singular arc to the optimal control, and make preserving the drug for a serious outbreak optimal. In addition, we apply our framework to the case of antibiotic resistant gonorrhea.

Evidence of Concomitantly Increasing Stroke and Dementia Prevalence among those 80 Years and Older in Ontario, Canada, 2003-04 to 2012-13.

Among those aged 80 years and older in Ontario, Canada, stroke and dementia incidence declined concomitantly from 2002-03 to 2013-14. This study aimed to report the concurrent temporal trends of stroke and dementia prevalence in Ontario among the same age demographic. The prevalence of both stroke and dementia increased from 2003-04 to 2012-13 in both sexes and the magnitude in which prevalence of dementia increased over time exceeded that of stroke. The substantial increase in the prevalence of dementia may be because of increased recognition and diagnoses of dementia and increased survival of stroke patients who are at higher risk of developing dementia.

Des preuves quant à une augmentation simultanée de la prévalence des AVC et de la démence. De 2002-2003 à 2013-2014, on a noté une diminution simultanée de l'incidence des AVC et de la démence parmi les individus âgés de plus de 80 ans vivant en Ontario (Canada). Ce qui nous intéresse dans cette étude, ce sont les tendances temporelles simultanées en ce qui a trait à la prévalence des AVC et de la démence au sein de la même tranche d'âge et dans la même province. On a ainsi noté que tant la prévalence des AVC que celle de la démence ont augmenté entre 2003­2004 et 2012­2013, et ce, tant chez les hommes que chez les femmes. Cela dit, l'ampleur de l'augmentation de la prévalence de la démence a fini par dépasser au fil du temps celle des AVC. Il se pourrait que l'augmentation substantielle de la prévalence des cas de démence puisse être attribuée à un dépistage accru et à l'établissement de plus nombreux diagnostics ainsi qu'à un accroissement de la survie des patients victimes d'AVC, ces derniers étant alors plus susceptibles d'être atteints de démence.