Leveraging an epidemic-economic mathematical model to assess human responses to COVID-19 policies and disease progression.

It is imperative that resources are channelled towards programs that are efficient and cost effective in combating the spread of COVID-19, the disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This study proposed and analyzed control strategies for that purpose. We developed a mathematical disease model within an optimal control framework that allows us to investigate the best approach for curbing COVID-19 epidemic. We address the following research question: what is the role of community compliance as a measure for COVID-19 control? Analyzing the impact of community compliance of recommended guidelines by health authorities-examples, social distancing, face mask use, and sanitizing-coupled with efforts by health authorities in areas of vaccine provision and effective quarantine-showed that the best intervention in addition to implementing vaccination programs and effective quarantine measures, is the active incorporation of individuals' collective behaviours, and that resources should also be directed towards community campaigns on the importance of face mask use, social distancing, and frequent sanitizing, and any other collective activities. We also demonstrated that collective behavioral response of individuals influences the disease dynamics; implying that recommended health policy should be contextualized.

A cross-country analysis of macroeconomic responses to COVID-19 pandemic using Twitter sentiments.

The COVID-19 pandemic has had a devastating impact on the global economy. In this paper, we use the Phillips curve to compare and analyze the macroeconomics of three different countries with distinct income levels, namely, lower-middle (Nigeria), upper-middle (South Africa), and high (Canada) income. We aim to (1) find macroeconomic changes in the three countries during the pandemic compared to pre-pandemic time, (2) compare the countries in terms of response to the COVID-19 economic crisis, and (3) compare their expected economic reaction to the COVID-19 pandemic in the near future. An advantage to our work is that we analyze macroeconomics on a monthly basis to capture the shocks and rapid changes caused by on and off rounds of lockdowns. We use the volume and social sentiments of the Twitter data to approximate the macroeconomic statistics. We apply four different machine learning algorithms to estimate the unemployment rate of South Africa and Nigeria on monthly basis. The results show that at the beginning of the pandemic the unemployment rate increased for all the three countries. However, Canada was able to control and reduce the unemployment rate during the COVID-19 pandemic. Nonetheless, in line with the Phillips curve short-run, the inflation rate of Canada increased to a level that has never occurred in more than fifteen years. Nigeria and South Africa have not been able to control the unemployment rate and did not return to the pre-COVID-19 level. Yet, the inflation rate has increased in both countries. The inflation rate is still comparable to the pre-COVID-19 level in South Africa, but based on the Phillips curve short-run, it will increase further, if the unemployment rate decreases. Unfortunately, Nigeria is experiencing a horrible stagflation and a wild increase in both unemployment and inflation rates. This shows how vulnerable lower-middle-income countries could be to lockdowns and economic restrictions. In the near future, the main concern for all the countries is the high inflation rate. This work can potentially lead to more targeted and publicly acceptable policies based on social media content.

Global, regional, and national burden of Guillain-Barré syndrome and its underlying causes from 1990 to 2019.

BACKGROUND: This article presents the first detailed analysis of the prevalence and disability burden of Guillain-Barré syndrome (GBS) from 1990 to 2019 by cause, age, sex, and Socio-demographic Index (SDI) in 204 countries and territories. METHODS: Data from the Global Burden of Diseases Study (GBD) 2019 were used. GBD 2019 modelled the prevalence of GBS using hospital and claims data. Years lived with disability (YLDs) were estimated as the product of the GBS prevalence and the disability weight. This article also reported proportions in the age-standardised prevalence rate that were due to six underlying causes of GBS. RESULTS: In 2019, there were 150,095 [95% uncertainty intervals (UI) 119,924 to 188,309] total cases of GBS worldwide, which resulted in 44,407 (95% UI 28,016 to 64,777) YLDs. Globally, there was a 6.4% (95% UI 3.6 to 9.5) increase in the age-standardised prevalence of GBS per 100,000 population between 1990 and 2019. High-income Asia Pacific [1.9 (95% UI: 1.5 to 2.4)] and East Asia [0.8 (95% UI: 0.6 to 1.0)] had the highest and lowest age-standardised prevalence rates (per 100,000), respectively, in 2019. Nationally, Japan [6.4 (95% UI: 5.3 to 7.7)] and China [0.8 (95% UI: 0.6 to 1.0)] had the highest and lowest age-standardised prevalence rates (per 100,000). The age-standardised burden of GBS increased with increasing age and was higher in males in all age groups. Furthermore, the age-standardised prevalence of GBS (per 100,000) had a positive association with the level of development, as measured by SDI, although this association was not strong. Upper respiratory infections and unknown causes accounted for the highest proportions of underlying causes. CONCLUSIONS: Globally, the prevalence of GBS continues to increase. Geographical differences and strategies aimed at preventing infectious diseases should be considered in future health policy planning and decision-making processes. This study had several limitations, such as using the same disability weight for all causes and a reliance on hospital- and self-reported data, which should be addressed in future research.

Determinants of Aedes mosquito density as an indicator of arbovirus transmission risk in three sites affected by co-circulation of globally spreading arboviruses in Colombia, Ecuador and Argentina.

BACKGROUND: The global impact of Zika virus in Latin America has drawn renewed attention to circulating mosquito-borne viruses in this region, such as dengue and chikungunya. Our objective was to assess socio-ecological factors associated with Aedes mosquito vector density as a measure of arbovirus transmission risk in three cities of potentially recent Zika virus introduction: Ibagué, Colombia; Manta, Ecuador; and Posadas, Argentina, in order to inform disease mitigation strategies. METHODS: We sampled Aedes mosquito populations in a total of 1086 households, using indoor and peridomestic mosquito collection methods, including light traps, resting traps, traps equipped with chemical attractant and aspirators. For each sampled household, we collected socio-economic data using structured questionnaires and data on microenvironmental conditions using iButton data loggers. RESULTS: A total of 3230 female Aedes mosquitoes were collected, of which 99.8% were Aedes aegypti and 0.2% were Aedes albopictus. Mean female Aedes mosquito density per household was 1.71 (standard deviation: 2.84). We used mixed-effects generalized linear Poisson regression analyses to identify predictors of Aedes density, using month, neighborhood and country as random-effects variables. Across study sites, the number of household occupants [incidence rate ratio (IRR): 1.08, 95% confidence interval (CI): 1.01-1.14], presence of entry points for mosquitoes into the household (IRR: 1.51, 95% CI: 1.30-1.76) and presence of decorative vegetation (IRR: 1.52, 95% CI: 1.22-1.88) were associated with higher Aedes density; while being in the highest wealth tertile of household wealth (IRR: 0.78, 95% CI: 0.66-0.92), knowledge of how arboviruses are transmitted (IRR: 0.94, 95% CI: 0.89-1.00) and regular emptying of water containers by occupants (IRR: 0.79, 95% CI: 0.67-0.92) were associated with lower Aedes density. CONCLUSIONS: Our study addresses the complexities of arbovirus vectors of global significance at the interface between human and mosquito populations. Our results point to several predictors of Aedes mosquito vector density in countries with co-circulation of multiple Aedes-borne viruses, and point to modifiable risk factors that may be useful for disease prevention and control.

Trends and Regional Variation in Prevalence of Cardiovascular Risk Factors and Association With Socioeconomic Status in Canada, 2005-2016.

Importance: Cardiovascular disease remains the second leading cause of death in Canada. Monitoring and tracking the trends and disparities in major cardiovascular risk factors could provide benchmarks for future cardiovascular health strategies. Objective: To investigate the temporal trends, regional variations, and socioeconomic disparities in major cardiovascular risk factors in Canada from 2005 to 2016. Design, Setting, and Participants: This repeated cross-sectional survey study included adults aged 20 years and older from 6 Canadian Community Health Survey cycles between 2005 and 2016. Cardiovascular risk factors included hypertension, diabetes, obesity, and current smoking. Socioeconomic status was measured using equivalized household income. Data analysis was performed from September 2019 to April 2020. Exposures: A total of 112 health regions and socioeconomic status. Main Outcomes and Measures: Age- and sex-adjusted prevalence of hypertension, diabetes, obesity, and current smoking by year; health regions; and socioeconomic status. Absolute numbers were rounded to base 100 for confidentiality purposes, and percentages were based on weighted numbers. Slope index of inequality (SII) and relative index of inequality (RII) were calculated to assess absolute and relative socioeconomic inequalities, respectively. Results: A total of 670 000 respondents (329 000 [49.1%] men; 341 000 [50.9%] women) aged 20 years and older from 6 survey cycles were enrolled for this study. The largest age group was those aged 40 to 59 years (eg, 2005 cycle: 40.2% [95% CI, 39.9%-40.6%]). In the 2015/2016 cycle, the overall age- and sex-adjusted prevalence rates of hypertension, diabetes, obesity, and current smoking were 20.7% (95% CI, 20.4%-21.1%), 7.2% (95% CI, 7.0%-7.5%), 20.1% (95% CI, 19.7%-20.6%), and 17.8% (95% CI, 17.4%-18.2%), respectively. From 2005 to 2016, there was a significant increase in the prevalence of hypertension, diabetes, and obesity (eg, prevalence of diabetes in both sexes, 2005: 5.8% [95% CI, 5.6%-6.0%]; 2015/2016: 7.2% [95% CI, 7.0%-7.5%]; P < .001) but a significant decrease in the prevalence of current smoking (both sexes, 2005: 22.1% [95% CI, 21.7%-22.5%]; 2015/2016: 17.8% [95% CI, 17.4%-18.2%]; P < .001). The prevalence of all the risk factors varied widely across health regions (eg, obesity, Vancouver Health Service Delivery Area: 6.7% [95% CI, 4.5%-9.0%]; Miramichi Area: 36.8% [95% CI, 27.3%-46.3%]). In addition to obesity among men, all risk factors tended to be more common among those with lower income (eg, prevalence of hypertension in both sexes, 2015/2016, lowest income group: 23.2% [95% CI, 22.4%-24.0%]; highest income group: 18.4% [95% CI, 17.7%-19.1%]). The SII and RII indicated consistent absolute and relative socioeconomic inequalities in hypertension, diabetes, and current smoking over time (eg, RII for hypertension in both sexes, 2005: 1.25; 95% CI, 1.18-1.33; 2015/2016: 1.34; 95% CI, 1.26-1.43). However, the phenomenon of absolute and relative socioeconomic inequalities in obesity was only observed among women (eg, RII for 2015/2016 for obesity in women; 1.74 (95% CI, 1.56-1.93); men: 1.09; 95% CI, 0.99-1.21). Conclusions and Relevance: During the study period, the prevalence of hypertension, diabetes, and obesity significantly increased, while the prevalence of current smoking significantly decreased. Geographic and socioeconomic gaps should be considered and addressed in future interventions and policies targeted at reducing these cardiovascular risk factors in Canada.

Worldwide Trends in Prevalence, Mortality, and Disability-Adjusted Life Years for Hypertensive Heart Disease From 1990 to 2017.

[Figure: see text].

Global, regional, and national prevalence, incidence, mortality, and risk factors for atrial fibrillation, 1990-2017: results from the Global Burden of Disease Study 2017.

AIMS: To estimate the prevalence, incidence, mortality, and risk factors for atrial fibrillation (AF) in 195 countries and territories from 1990 to 2017. METHODS AND RESULTS: Following the methodologies used in the Global Burden of Disease Study 2017, the prevalence, incidence, and mortality of AF were analysed by age, sex, year, socio-demographic index (SDI), and location. The percentage contributions of major risk factors to age-standardized AF deaths were measured by population attributable fractions. In 2017, there were 37.57 million [95% uncertainty interval (UI) 32.55-42.59] prevalent cases and 3.05 million (95% UI 2.61-3.51) incident cases of AF globally, contributing to 287 241 (95% UI 276 355-304 759) deaths. The age-standardized rates of prevalent cases, incident cases, and deaths of AF in 2017 and their temporal trends from 1990 to 2017 varied significantly by SDI quintile and location. High systolic blood pressure was the leading risk factor for AF age-standardized deaths [34.3% (95% UI 27.4-41.5)] in 2017, followed by high body mass index [20.7% (95% UI 11.5-32.2)] and alcohol use [9.4% (95% UI 7.0-12.2)]. CONCLUSION: Our study has systematically and globally assessed the temporal trends of AF, which remains a major public heath challenge. Although AF mainly occurred in developed countries, the unfavourable trend in countries with lower SDI also deserves particular attention. More effective prevention and treatment strategies aimed at counteracting the increase in AF burden should be established in some countries.

The global burden of disease attributable to high body mass index in 195 countries and territories, 1990-2017: An analysis of the Global Burden of Disease Study.

BACKGROUND: Obesity represents an urgent problem that needs to be properly addressed, especially among children. Public and global health policy- and decision-makers need timely, reliable quantitative information to develop effective interventions aimed at counteracting the burden generated by high body mass index (BMI). Few studies have assessed the high-BMI-related burden on a global scale. METHODS AND FINDINGS: Following the methodology framework and analytical strategies used in the Global Burden of Disease Study (GBD) 2017, the global deaths and disability-adjusted life years (DALYs) attributable to high BMI were analyzed by age, sex, year, and geographical location and by Socio-demographic Index (SDI). All causes of death and DALYs estimated in GBD 2017 were organized into 4 hierarchical levels: level 1 contained 3 broad cause groupings, level 2 included more specific categories within the level 1 groupings, level 3 comprised more detailed causes within the level 2 categories, and level 4 included sub-causes of some level 3 causes. From 1990 to 2017, the global deaths and DALYs attributable to high BMI have more than doubled for both females and males. However, during the study period, the age-standardized rate of high-BMI-related deaths remained stable for females and only increased by 14.5% for males, and the age-standardized rate of high-BMI-related DALYs only increased by 12.7% for females and 26.8% for males. In 2017, the 6 leading GBD level 3 causes of high-BMI-related DALYs were ischemic heart disease, stroke, diabetes mellitus, chronic kidney disease, hypertensive heart disease, and low back pain. For most GBD level 3 causes of high-BMI-related DALYs, high-income North America had the highest attributable proportions of age-standardized DALYs due to high BMI among the 21 GBD regions in both sexes, whereas the lowest attributable proportions were observed in high-income Asia Pacific for females and in eastern sub-Saharan Africa for males. The association between SDI and high-BMI-related DALYs suggested that the lowest age-standardized DALY rates were found in countries in the low-SDI quintile and high-SDI quintile in 2017, and from 1990 to 2017, the age-standardized DALY rates tended to increase in regions with the lowest SDI, but declined in regions with the highest SDI, with the exception of high-income North America. The study's main limitations included the use of information collected from some self-reported data, the employment of cutoff values that may not be adequate for all populations and groups at risk, and the use of a metric that cannot distinguish between lean and fat mass. CONCLUSIONS: In this study, we observed that the number of global deaths and DALYs attributable to high BMI has substantially increased between 1990 and 2017. Successful population-wide initiatives targeting high BMI may mitigate the burden of a wide range of diseases. Given the large variations in high-BMI-related burden of disease by SDI, future strategies to prevent and reduce the burden should be developed and implemented based on country-specific development status.

Canada needs to rapidly escalate public health interventions for its COVID-19 mitigation strategies.

BACKGROUND: After the declaration of COVID-19 pandemic on March 11th, 2020, local transmission chains starting in different countries including Canada are forcing governments to take decisions on public health interventions to mitigate the spread of the epidemic. METHODS: We conduct data-driven and model-free estimations for the growth rates of the COVID-19 epidemics in Italy and Canada, by fitting an exponential curve to the daily reported cases. We use these estimates to predict epidemic trends in Canada under different scenarios of public health interventions. RESULTS: In Italy, the initial growth rate (0.22) has reduced to 0.1 two weeks after the lockdown of the country on March 8th, 2020. This corresponds to an increase of the doubling time from about 3.15 to almost 7 days. In comparison, the growth rate in Canada has increased from 0.13 between March 1st and 13th, to 0.25 between March 13th to 22nd. This current growth rate corresponds to a doubling time of 2.7 days, and therefore, unless further public health interventions are escalated in Canada, we project 15,000 cases by March 31st. However, the case number may be reduced to 4000 if escalated public health interventions could instantly reduce the growth rate to 0.1, the same level achieved in Italy. INTERPRETATION: Prompt and farsighted interventions are critical to counteract the very rapid initial growth of the COVID-19 epidemic in Canada. Mitigation plans must take into account the delayed effect of interventions by up to 2-weeks and the short doubling time of 3-4 days.

The human cost of global warming: Deadly landslides and their triggers (1995-2014).

Worldwide, landslides incur catastrophic and significant economic and human losses. Previous studies have characterized the patterns in landslides' fatalities, from all kinds of triggering causes, at a continental or global scale, but they were based on data from periods of <10 years. The research herein presented hypothesizes that climate change associated with extreme rainfall and population distribution is contributing to a higher number of deadly landslides worldwide. This study maps and identified deadly landslides in 128 countries and it encompasses their role, for a 20 years' period from January/1995 to December/2014, considered representative for establishing a relationship between landslides and their meteorological triggers. A database of georeferenced landslides, their date, and casualties' information, duly validated, was implemented. A hot spot analysis for the daily record of landslide locations was performed, as well as a percentile-based approach to evaluate the trend of extreme rainfall events for each occurrence. The relationship between casualty, population distribution, and rainfall was also evaluated. For 20 years, 3876 landslides caused a total of 163,658 deaths and 11,689 injuries globally. They occurred most frequently between June and December in the Northern Hemisphere, and between December and February in the Southern Hemisphere. A significant global rise in the number of deadly landslides and hotspots across the studied period was observed. Analysis of daily rainfall confirmed that more than half of the events were in areas exposed to the risk of extreme rainfall. The relationships established between extreme rainfall, population distribution, seasonality, and landslides provide a useful basis for efforts to model the adverse impacts of extreme rainfall due to climate change and human activities and thus contribute towards a more resilient society.

Advancing risk assessment: mechanistic dose-response modelling of Listeria monocytogenes infection in human populations.

The utility of characterizing the effects of strain variation and individual/subgroup susceptibility on dose-response outcomes has motivated the search for new approaches beyond the popular use of the exponential dose-response model for listeriosis. While descriptive models can account for such variation, they have limited power to extrapolate beyond the details of particular outbreaks. By contrast, this study exhibits dose-response relationships from a mechanistic basis, quantifying key biological factors involved in pathogen-host dynamics. An efficient computational algorithm and geometric interpretation of the infection pathway are developed to connect dose-response relationships with the underlying bistable dynamics of the model. Relying on in vitro experiments as well as outbreak data, we estimate plausible parameters for the human context. Despite the presence of uncertainty in such parameters, sensitivity analysis reveals that the host response is most influenced by the pathogen-immune system interaction. In particular, we show how variation in this interaction across a subgroup of the population dictates the shape of dose-response curves. Finally, in terms of future experimentation, our model results provide guidelines and highlight vital aspects of the interplay between immune cells and particular strains of Listeria monocytogenes that should be examined.

The Preventive Control of Zoonotic Visceral Leishmaniasis: Efficacy and Economic Evaluation.

Zoonotic Visceral Leishmaniasis (ZVL) is one of the world's deadliest and neglected infectious diseases, according to World Health Organization. This disease is one of major human and veterinary medical significance. The sandfly and the reservoir in urban areas remain among the major challenges for the control activities. In this paper, we evaluated five control strategies (positive dog elimination, insecticide impregnated dog collar, dog vaccination, dog treatment, and sandfly population control), considering disease control results and cost-effectiveness. We elaborated a mathematical model based on a set of differential equations in which three populations were represented (human, dog, and sandfly). Humans and dogs were divided into susceptible, latent, clinically ill, and recovery categories. Sandflies were divided into noninfected, infected, and infective. As the main conclusions, the insecticide impregnated dog collar was the strategy that presented the best combination between disease control and cost-effectiveness. But, depending on the population target, the control results and cost-effectiveness of each strategy may differ. More and detailed studies are needed, specially one which optimizes the control considering more than one strategy in activity.

Conceptualizing type 2 diabetes and its management.

Type 2 diabetes is growing worldwide due to population growth, increased rates of obesity, unhealthy diet, and physical inactivity. Risk assessment methods can effectively evaluate the risk of diabetes, and a healthy lifestyle can significantly reduce risk or prevent complications of type 2 diabetes. However, risk assessment alone has not significantly improved poor adherence to recommended medical interventions and lifestyle changes. This paper focuses on the challenge of nonadherence and posits that improving adherence requires tailoring interventions that explicitly consider the social determinants of health.

Economic evaluation of vaccines in Canada: A systematic review.

BACKGROUND: Economic evaluations should form part of the basis for public health decision making on new vaccine programs. While Canada's national immunization advisory committee does not systematically include economic evaluations in immunization decision making, there is increasing interest in adopting them. We therefore sought to examine the extent and quality of economic evaluations of vaccines in Canada. OBJECTIVE: We conducted a systematic review of economic evaluations of vaccines in Canada to determine and summarize: comprehensiveness across jurisdictions, studied vaccines, funding sources, study designs, research quality, and changes over time. METHODS: Searches in multiple databases were conducted using the terms "vaccine," "economics" and "Canada." Descriptive data from eligible manuscripts was abstracted and three authors independently evaluated manuscript quality using a 7-point Likert-type scale scoring tool based on criteria from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). RESULTS: 42/175 articles met the search criteria. Of these, Canada-wide studies were most common (25/42), while provincial studies largely focused on the three populous provinces of Ontario, Quebec and British Columbia. The most common funding source was industry (17/42), followed by government (7/42). 38 studies used mathematical models estimating expected economic benefit while 4 studies examined post-hoc data on established programs. Studies covered 10 diseases, with 28/42 addressing pediatric vaccines. Many studies considered cost-utility (22/42) and the majority of these studies reported favorable economic results (16/22). The mean quality score was 5.9/7 and was consistent over publication date, funding sources, and disease areas. CONCLUSIONS: We observed diverse approaches to evaluate vaccine economics in Canada. Given the increased complexity of economic studies evaluating vaccines and the impact of results on public health practice, Canada needs improved, transparent and consistent processes to review and assess the findings of the economic evaluations of vaccines.

Optimal isolation strategies of emerging infectious diseases with limited resources.

A classical deterministic SIR model is modified to take into account of limited resources for diagnostic confirmation/medical isolation. We show that this modification leads to four different scenarios (instead of three scenarios in comparison with the SIR model) for optimal isolation strategies, and obtain analytic solutions for the optimal control problem that minimize the outbreak size under the assumption of limited resources for isolation. These solutions and their corresponding optimal control policies are derived explicitly in terms of initial conditions, model parameters and resources for isolation (such as the number of intensive care units). With sufficient resources, the optimal control strategy is the normal Bang-Bang control. However, with limited resources the optimal control strategy requires to switch to time-variant isolation at an optimal rate proportional to the ratio of isolated cases over the entire infected population once the maximum capacity is reached.

Indigenous populations health protection: a Canadian perspective.

The disproportionate effects of the 2009 H1N1 pandemic on many Canadian Aboriginal communities have drawn attention to the vulnerability of these communities in terms of health outcomes in the face of emerging and reemerging infectious diseases. Exploring the particular challenges facing these communities is essential to improving public health planning. In alignment with the objectives of the Pandemic Influenza Outbreak Research Modelling (Pan-InfORM) team, a Canadian public health workshop was held at the Centre for Disease Modelling (CDM) to: (i) evaluate post-pandemic research findings; (ii) identify existing gaps in knowledge that have yet to be addressed through ongoing research and collaborative activities; and (iii) build upon existing partnerships within the research community to forge new collaborative links with Aboriginal health organizations. The workshop achieved its objectives in identifying main research findings and emerging information post pandemic, and highlighting key challenges that pose significant impediments to the health protection and promotion of Canadian Aboriginal populations. The health challenges faced by Canadian indigenous populations are unique and complex, and can only be addressed through active engagement with affected communities. The academic research community will need to develop a new interdisciplinary framework, building upon concepts from 'Communities of Practice', to ensure that the research priorities are identified and targeted, and the outcomes are translated into the context of community health to improve policy and practice.

Optimal control of drug therapy: melding pharmacokinetics with viral dynamics.

Pharmacokinetics were melded with a viral dynamical model to design an optimal drug administration regimen such that the basic reproductive number for the virus was minimized. One-compartmental models with two kinds of drug delivery routes, intravenous and extravascular with multiple dosages, and two drug elimination rates, first order and Michaelis-Menten rates, were considered. We defined explicitly the basic reproductive number for the viral dynamical model melded with pharmacokinetics. When the average plasma drug concentration was constant, intravenous administration of the drug with small dosages applied frequently minimized the basic reproductive number. For extravascular administration, the basic reproductive number initially decreases to a trough point and then increases as the drug dosage increases. When a therapeutic window is considered, numerical studies indicate that the wider the window, the smaller the basic reproductive number. Once the width of the therapeutic window is fixed, the basic reproductive number monotonously declines as the minimum therapeutic level increases. The findings suggest that the existence of drug dosage and drug administration interval that minimize the basic reproductive number could help design the optimal drug administration regimen.

Comparative bioavailability and tolerability of a single 20-mg dose of two fluoxetine hydrochloride dispersible tablet formulations in fasting, healthy Chinese male volunteers: an open-label, randomized-sequence, two-period crossover study.

BACKGROUND: The proprietary formulation of fluoxetine hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. Pharmacokinetic studies investigating the bioequivalence of generic and branded formulations are needed to market generic fluoxetine in China. OBJECTIVE: The aim of this study was to compare the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of fluoxetine hydrochloride 20 mg in a fasting, healthy Chinese male population. METHODS: This 10-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 20-mg dose of the test or reference formulation, followed by a 35-day washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties (including C(max), T(max), AUC(0-t), AUC(0-∞), and t(½)), blood samples were obtained over a 672-hour period after dosing. Plasma concentrations of fluoxetine and its active metabolite, norfluoxetine, were analyzed using a validated LC-MS/MS method. The formulations were to be considered bioequivalent if the ln-transformed ratios (test/ reference) of C(max) and AUC were within the predetermined bioequivalence range of 80% to 125%, as established by the US Food and Drug Administration, and if the P values were <0.05 for the 90% CIs. Signs and symptoms of adverse effects of fluoxetine hydrochloride such as nausea, vomiting, insomnia, somnolence, anxiety, and nervousness, as well as any untoward effects, were collected using a daily written questionnaire and recorded by the study physicians. Tolerability was assessed using monitoring of vital signs, physical ex- amination, ECG, and routine blood and urine tests, along with blood biochemical tests, at the start as well as at the end of the study. RESULTS: Twenty-four subjects were enrolled and completed the study (mean [SD] age, 24.4 [2.3] years [range, 20-30 years]; weight, 63.6 [8.5] kg [range, 51.2-86.8 kg]; height, 1.72 [0.07] m [range, 1.57-1.91 m]). The AUC values for fluoxetine were not consistent with a normal distribution, reflecting the existence of 2 different populations (poor and extensive metabolizers). Data from the one poor metabolizer were excluded from the pharmacokinetics data summarized. In extensive metabolizers, the mean (SD) C(max) for fluoxetine with the test formulation was 11.786 (3.459) ng/mL and T(max) was 5.48 (2.06) hours. With the reference formulation, the corresponding values were 11.754 (3.292) ng/mL and 6.26 (5.77) hours, respectively. The t(½) values with the test and reference formulations were 30.86 (7.61) and 30.96 (6.91) hours, respectively. For norfluoxetine, mean C(max) with the test formulation was 14.177 (4.957) ng/mL and T(max) was 58.48 (31.67) hours; the corresponding values for the reference formulation were 13.828 (4.838) ng/mL and 57.91 (25.75) hours. The t(½) values with the test and reference formulations were 130.91 (42.04) and 128.79 (52.72) hours, respectively. For fluoxetine, the 90% CIs (in extensive metabolizers only) for the In-transformed C(max), AUC(0-168), and AUC(0-∞) were 92.0% to 108.4%, 95.7% to 110.3%, and 97.4% to 111.3%, respectively (all, P < 0.001). For norfluoxetine, the 90% CIs for the ln-transformed C(max), AUC(0-672), and AUC(0-∞) were 93.7% to 110.7%, 98.9% to 111.4%, and 98.8% to 110.9% (all, P < 0.001). No period or sequence effects were observed for any pharmacokinetic variable in the extensive metabolizers. No adverse events were reported by the volunteers or found with results of clinical laboratory testing. CONCLUSIONS: This single-dose study found that the test and reference formulations of fluoxetine hydro- chloride met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated.

Community-based measures for mitigating the 2009 H1N1 pandemic in China.

Since the emergence of influenza A/H1N1 pandemic virus in March-April 2009, very stringent interventions including Fengxiao were implemented to prevent importation of infected cases and decelerate the disease spread in mainland China. The extent to which these measures have been effective remains elusive. We sought to investigate the effectiveness of Fengxiao that may inform policy decisions on improving community-based interventions for management of on-going outbreaks in China, in particular during the Spring Festival in mid-February 2010 when nationwide traveling will be substantially increased. We obtained data on initial laboratory-confirmed cases of H1N1 in the province of Shaanxi and used Markov-chain Monte-Carlo (MCMC) simulations to estimate the reproduction number. Given the estimates for the exposed and infectious periods of the novel H1N1 virus, we estimated a mean reproduction number of 1.68 (95% CI 1.45-1.92) and other A/H1N1 epidemiological parameters. Our results based on a spatially stratified population dynamical model show that the early implementation of Fengxiao can delay the epidemic peak significantly and prevent the disease spread to the general population but may also, if not implemented appropriately, cause more severe outbreak within universities/colleges, while late implementation of Fengxiao can achieve nothing more than no implementation. Strengthening local control strategies (quarantine and hygiene precaution) is much more effective in mitigating outbreaks and inhibiting the successive waves than implementing Fengxiao. Either strong mobility or high transport-related transmission rate during the Spring Festival holiday will not reverse the ongoing outbreak, but both will result in a large new wave. The findings suggest that Fengxiao and travel precautions should not be relaxed unless strict measures of quarantine, isolation, and hygiene precaution practices are put in place. Integration and prompt implementation of these interventions can significantly reduce the overall attack rate of pandemic outbreaks.

Revaluation of clopidogrel: let the data speak for themselves.

Clopidogrel was believed to be superior to aspirin by the well-known CAPRIE trial. However, no other large clinical trials demonstrated the same results, but all focused on the combination use of clopidogrel with aspirin, and combination therapy in CREDO was called the "Emperor's New Clothes". However, no one overturned the results of these clinical trials by quantitatively analyzing them. We reviewed ten large-scale clinical trials about clopidogrel. On the basis of results of CAPRIE, CREDO and CHARISMA trials, we re-estimated their minimal sample sizes and their powers by three well-established statistical methodologies. From the results of CAPRIE, we inferred that the minimal sample size should be 85 086 or 84 968 but its power was only 30.70%. A huge gap existed. The same was also true of CREDO and CHARISMA trials. Moreover, in CAPRIE trial, 0 was included in the 95% confidence interval and 1 was included in the 95% confidence interval for the relative risk. There were some paradoxical data in CAPRIE trial. We are led to conclude that the results in CAPRIE, CREDO, and from the subgroup analysis in CHARISMA trials were questionable. These results failed to demonstrate that clopidogrel was superior to aspirin or that clopidogrel used in combination with aspirin was better than aspirin alone. The cost-effectiveness analyses by some previous studies were not reliable.