A deterministic model to assess the impact of AIDS interventions in countries with generalized HIV epidemic. An application to Botswana

General introductionThe Human Immunodeficiency/Acquired Immunodeficiency Syndrome (HIV/AIDS) epidemic, despite recent encouraging announcements by the World Health Organization (WHO) is still today one of the world's major health care challenges.The present work lies in the field of health care management, in particular, we aim to evaluate the behavioural and non-behavioural interventions against HIV/AIDS in developing countries through a deterministic simulation model, both in human and economic terms. We will focus on assessing the effectiveness of the antiretroviral therapies (ART) in heterosexual populations living in lesser developed countries where the epidemic has generalized (formerly defined by the WHO as type II countries). The model is calibrated using Botswana as a case study, however our model can be adapted to other countries with similar transmission dynamics.The first part of this thesis consists of reviewing the main mathematical concepts describing the transmission of infectious agents in general but with a focus on human immunodeficiency virus (HIV) transmission. We also review deterministic models assessing HIV interventions with a focus on models aimed at African countries. This review helps us to recognize the need for a generic model and allows us to define a typical structure of such a generic deterministic model.The second part describes the main feed-back loops underlying the dynamics of HIV transmission. These loops represent the foundation of our model. This part also provides a detailed description of the model, including the various infected and non-infected population groups, the type of sexual relationships, the infection matrices, important factors impacting HIV transmission such as condom use, other sexually transmitted diseases (STD) and male circumcision. We also included in the model a dynamic life expectancy calculator which, to our knowledge, is a unique feature allowing more realistic cost-efficiency calculations. Various intervention scenarios are evaluated using the model, each of them including ART in combination with other interventions, namely: circumcision, campaigns aimed at behavioral change (Abstain, Be faithful or use Condoms also named ABC campaigns), and treatment of other STD. A cost efficiency analysis (CEA) is performed for each scenario. The CEA consists of measuring the cost per disability-adjusted life year (DALY) averted. This part also describes the model calibration and validation, including a sensitivity analysis.The third part reports the results and discusses the model limitations. In particular, we argue that the combination of ART and ABC campaigns and ART and treatment of other STDs are the most cost-efficient interventions through 2020. The main model limitations include modeling the complexity of sexual relationships, omission of international migration and ignoring variability in infectiousness according to the AIDS stage.The fourth part reviews the major contributions of the thesis and discusses model generalizability and flexibility. Finally, we conclude that by selecting the adequate interventions mix, policy makers can significantly reduce the adult prevalence in Botswana in the coming twenty years providing the country and its donors can bear the cost involved.Part I: Context and literature reviewIn this section, after a brief introduction to the general literature we focus in section two on the key mathematical concepts describing the transmission of infectious agents in general with a focus on HIV transmission. Section three provides a description of HIV policy models, with a focus on deterministic models. This leads us in section four to envision the need for a generic deterministic HIV policy model and briefly describe the structure of such a generic model applicable to countries with generalized HIV/AIDS epidemic, also defined as pattern II countries by the WHO.

N-3 fatty acids, cancer and cachexia: a systematic review of the literature.

Use of n-3 fatty acids (FA) has been reported to be beneficial for cancer patients. We performed a systematic review of the literature in order to issue recommendations on the clinical use of n-3 FA in the cancer setting. A systematic search was performed in MEDLINE, EMBASE, Cochrane and Healthstar databases. We selected clinical trials or prospective observational studies including patients with cancer and life expectancy >2 months, in which enteral supplements with n-3 FA were administered. Parameters evaluated individually were clinical (nutritional status, tolerance, survival and hospital stays), biochemical (inflammatory mediators), and functional (functional status, appetite and quality of life (QoL)). Seventeen studies met the inclusion criteria; eight were of high quality. The panel of experts established the following evidence: (1) oral supplements with n-3 FA benefit patients with advanced cancer and weight loss, and are indicated in tumours of the upper digestive tract and pancreas; (2) the advantages observed were: increased weight and appetite, improved QoL, and reduced post-surgical morbidity; (3) there is no defined pattern for combining different n-3 FA, and it is recommended to administer > 1.5 g/day; and (4) better tolerance is obtained administering low-fat formulas for a period of at least 8 weeks. All the evidences were grade B but for 'length of treatment' and 'advantage of survival' it was grade C. Our findings suggest that administration of n-3 FA (EPA and DHA) in doses of at least 1.5 g/day for a prolonged period of time to patients with advanced cancer is associated with an improvement in clinical, biological and QoL parameters.

Do socioeconomic factors shape weight and obesity trajectories over the transition from midlife to old age? Results from the French GAZEL cohort study

BACKGROUND: Obesity is a contemporary epidemic that does not affect all age groups and sections of society equally. OBJECTIVE: The objective was to examine socioeconomic differences in trajectories of body mass index (BMI; in kg/m(2)) and obesity between the ages of 45 and 65 y. DESIGN: A total of 13,297 men and 4532 women from the French GAZEL (Gaz de France Electricité de France) cohort study reported their height in 1990 and their weight annually over the subsequent 18 y. Changes in BMI and obesity between ages 45 and 49 y, 50 and 54 y, 55 and 59 y, and 60 and 65 y as a function of education and occupational position (at age 35 y) were modeled by using linear mixed models and generalized estimating equations. RESULTS: BMI and obesity rates increased between the ages of 45 and 65 y. In men, BMI was higher in unskilled workers than in managers at age 45 y; this difference in BMI increased from 0.82 (95% CI: 0.66, 0.99) at 45 y to 1.06 (95% CI: 0.85, 1.27) at 65 y. Men with a primary school education compared with those with a high school degree at age 45 y had a 0.75 (95% CI: 0.51, 1.00) higher BMI, and this difference increased to 1.32 (95% CI: 1.03,1.62) at age 65 y. Obesity rates were 3.35% and 7.68% at age 45 y and 9.52% and 18.10% at age 65 y in managers and unskilled workers, respectively; the difference in obesity increased by 4.25% (95% CI: 1.87, 6.52). A similar trend was observed in women. Conclusions: Weight continues to increase in the transition between midlife and old age; this increase is greater in lower socioeconomic groups.

Principes d'evaluation et de prise en charge des patients agés polymorbides: guide a l'intention des cliniciens [Principles for the assessment and management of polymorbid elderly patients: a guide for clinicians].

Providing care to multimorbid older patients is complex, not only because of the coexistence of multiple chronic conditions, but also because of their frequent intrication with psychological and social problems. This article describes a guide for clinicians to assess and manage multimorbid older patients. This guide was adapted from the work of a group of expert US geriatricians. It proposes seven steps: identification of the main problem; identification of patients' preferences; setting of goals of care; estimation of life expectancy; identification of relevant evidence in the literature; revision of the plan of care; and discussion of the options with the patient. The use of this guide is illustrated by a clinical case.

Estimation of Aedes aegypti (Diptera: Culicidae) population size and adult male survival in an urban area in Panama

Traditional mosquito control strategies rely heavily on the use of chemical insecticides. However, concerns about the efficiency of traditional control methods, environmental impact and emerging pesticide resistance have highlighted the necessity for developing innovative tools for mosquito control. Some novel strategies, including release of insects carrying a dominant lethal gene (RIDL®), rely on the sustained release of modified male mosquitoes and therefore benefit from a thorough understanding of the biology of the male of the species. In this report we present the results of a mark-release-recapture study aimed at: (i) establishing the survival in the field of laboratory-reared, wild-type male Aedes aegypti and (b) estimating the size of the local adult Ae. aegypti population. The study took place in Panama, a country where recent increases in the incidence and severity of dengue cases have prompted health authorities to evaluate alternative strategies for vector control. Results suggest a life expectancy of 2.3 days for released male mosquitoes (confidence interval: 1.78-2.86). Overall, the male mosquito population was estimated at 58 males/ha (range 12-81 males/ha), which can be extrapolated to an average of 0.64 pupae/person for the study area. The practical implications of these results are discussed.

Unanswered clinical questions in the management of cardiometabolic risk in the elderly: a statement of the Spanish society of internal medicine.

BACKGROUND Despite the progressive increase in life expectancy and the relationship between aging with multi-morbidities and the increased use of healthcare resources, current clinical practice guidelines (CPG) on cardiometabolic risk cannot be adequately applied to elderly subjects with multiple chronic conditions. Its management frequently becomes complicated by both, an excessive use of medications that may lead to overtreatment, drug interactions and increased toxicity, and errors in dosage and non-compliance. Concerned by this gap, the Spanish Society of Internal Medicine created a group of independent experts on cardiometabolic risk who discussed what they considered to be unanswered questions in the management of elderly patients. DISCUSSION Current guidelines do not specifically address the problem of elderly with multiple chronic conditions. For this reason, the combined use of the limited available evidence, clinical experience and common sense, could all help us to address this unmet need. In very old people, life expectancy and functionality are the most important factors for guiding potential treatments. Their higher propensity to develop serious adverse events and their shorter lifespan could prevent them from obtaining the potential benefits of the interventions administered. SUMMARY In this document, experts on cardiometabolic risk factors have established a number of consensual recommendations that have taken into account international guidelines and clinical experience, and have also considered the more effective use of healthcare resources. This document is intended to provide general recommendations for clinicians and to promote the effective use of procedures and medications.

Managing diabetes in Switzerland : a systemic approach

Executive summaryThe increasing prevalence of chronic diseases is one of the major causes of rising health expenditure, as stated by the WHO. Not only chronic diseases are very costly, but they are by far the leading cause of mortality in the world, representing 60% of all deaths. Diabetes in particular is becoming a major burden of disease. In Switzerland around 5% of the population suffer of type 2 diabetes and 5 to 10% of the annual health care budget is attributable to diabetes. If the predictions of WHO do realise, the prevalence of diabetes will double until 2030 and so is expected the attributable health expenditure.The objective of this thesis is to provide policy recommendations as to slow down the disease progression and its costly complication. We study the factors that influence diabetes dynamics and the interventions that improve health outcomes while decreasing costs according to different time horizon and use systems thinking and system dynamic.Our results show that managing diabetes requires using integrated care interventions that are effective on three fronts: (1) delaying the onset of complications, (2) slowing down the disease progression and (3) accelerating the time to diagnosis of diabetes and its complications. We recommend firstly the implementation of those interventions targeted at changing patients' behaviour which are also less expensive, but require a change in the delivery of care and medical practices. Then policies targeted at an earlier diagnosis of diabetes, its prevention and the diagnosis of complications are to be considered. This sequence of interventions allows saving money, as total costs decrease, even including the costs of interventions and result in longer life expectancy of diabetics in the long term.In diabetes management there is therefore a trade-off between medical costs and patients' benefits on the one hand and between the objectives of obtaining results in the short or long term on the other hand. Decision makers need to deliver acceptable outcomes in the short term. Considering this criterion, the preferred policy may be to focus only on diagnosed diabetics, thus attempting to slow down the progression of their disease, compared to an integrated care approach addressing all the aspects of the disease. Such a policy also yields desirable results in terms of costs and patients' benefits.

Current concepts and management of glioblastoma.

Glioblastoma is the most common malignant primary brain tumor in adults. Its often rapid clinical course, with many medical and psychosocial challenges, requires a multidisciplinary management. Modern multimodality treatment and care improve patients' life expectancy and quality of life. This review covers major aspects of care of glioblastoma patients with a focus on the management of common symptoms and complications. We aim to provide a guide for clinicians confronted with glioblastoma patients in their everyday practice. Ann Neurol 2011;

Dépistage et prévention chez les aînés: quelles interventions proposer, à qui, et jusqu'à quel âge [Screening and prevention in the elderly: which interventions should be proposed, to whom, and up to what age?].

Recommendations on preventive services rarely mention how to apply them to older people. Even though general criteria (prevalence of disease, quality of screening tests) that influence screening's efficacy remain important, appropriateness of screening in older persons depends much more on individual criteria, such as comorbidity, functional status, and life expectancy. More than with any other age group, patients preferences regarding future investigation and treatment guide the clinical decision. This article focuses on primary and secondary prevention, and discusses specific criteria to consider in each patient. A table summarizes the appropriate recommendations.

Age above 60 years is not a negative predictive factor for combined antiviral therapy with pegylated interferon alpha and ribavirin in hepatitis C patients

Background: Age is frequently discussed as negative host factor to achieve a sustained virological response (SVR) to antiviral hepatitis C therapy. However, elderly patients often show relevant fibrosis or cirrhosis which is a known negative predictive factor, making it difficult to interpret age as an independent predictive factor. Methods: From the framework of the Swiss hepatitis C cohort (SCCS), we collected data from 545 antiviral hepatitis C therapies, including data from 67 hepatitis C patients ≥ 60 y who had been treated with PEG-interferon and ribavirin. We analyzed host factors (age, gender, fibrosis, haemoglobin, depression, earlier hepatitis C treatment), viral factors (genotype, viral load) and treatment course (early virological response, end of treatment response, SVR). Generalised estimating equations (GEE) regression modelling was used for the primary end point (SVR), with age ≥ 60 y and < 60 y as independent variable and gender, presence of cirrhosis, genotype, earlier treatment and viral load as confounders. SVR was analysed in young and elderly patients after matching for these confounders. Additionally, classification tree analysis was done in elderly patients using these confounders. Results: SVR analyzed in 545 patients was 55%. In genotype 1/4, SVR was 42.9% in 259 patients < 60 y and 26.1% in 46 patients ≥ 60 y. In genotype 2/3, SVR was 74.4% in 215 patients < 60 y and 84% in 25 patients ≥ 60 y. However, GEE model showed that age had no influence on achieving SVR (Odds ratio 0.91). Confounders influenced SVR as known from previous studies (cirrhosis, genotype 1/4, previous treatment and viral load >600'000 IE/ml as negative predictive factors). When young and elderly patients were matched (analysis in 59 elderly patients), SVR was not different in these patient groups (54.2% and 55.9%, resp.; p=0.795 in binomial test). The classification tree-derived best criterion for SVR in elderly patients was genotype, with no further criteria relevant for predicting SVR in genotype 2/3. In patients with genotype 1/4, further criteria were presence of cirrhosis and low viral load <600'000 IE/ml in non-cirrhotic patients. Conclusions: Age is not a relevant predictive factor for achieving SVR, when confounders were taken into account. In terms of effectiveness of antiviral therapy, age does not play a major role and should not be regarded as relevant negative predictive factor. Since life expectancy in Switzerland at age 60 is more than 22 y, hepatitis C therapy is reasonable in elderly patients with known relevant fibrosis or cirrhosis, because interferon-based hepatitis C therapy improves survival and reduces carcinogenesis.

Passive modernization? the new human development index and its components in Italy’s regions (1871-2007)

The article presents and discusses estimates of social and economic indicators for Italy’s regions in benchmark years roughly from Unification to the present day: life expectancy, education, GDP per capita at purchasing power parity, and the new Human Development Index (HDI). A broad interpretative hypothesis, based on the distinction between passive and active modernization, is proposed to account for the evolution of regional imbalances over the long-run. In the lack of active modernization, Southern Italy converged thanks to passive modernization, i.e., State intervention: however, this was more effective in life expectancy, less successful in education, expensive and as a whole ineffective in GDP. As a consequence, convergence in the HDI occurred from the late XIX century to the 1970s, but came to a sudden halt in the last decades of the XX century.

Healthy Iowans 2010 Mid-Course Revision, July 2005

In the past century, public health has been credited with adding 25 years to life expectancy by contributing to the decline in illness and injury. Progress has been made, for example, in smoking reduction, infectious disease, and motor vehicle and workplace injuries. Besides its focus on traditional concerns such as clean water and safe food, public health is adapting to meet emerging health problems. Particular troublesome are health threats to youth: teenage pregnancies, violence, substance abuse, sexually transmitted diseases, and other conditions associated with high-risk behaviors. These threats add to burgeoning health care costs. A conservative estimate of $69 billion in medical spending could be averted through the impact of public health strategies aimed at heart disease, stroke, fatal and nonfatal occupational injuries, motor vehicle-related injuries, low birth weight, and violence. These strategies require the collaboration of many groups in the public and private sectors. Collaboration is the bedrock of public health and Healthy Iowans planning. At the core of Healthy Iowans 2000 and its successor, Healthy Iowans 2010, is the idea that all Iowans benefit when stakeholders decide on disease prevention and health promotion strategies and agree to work together on them. These strategies can improve the quality of life and hold down health care costs. The payoff for health promotion and disease prevention is not immediate, but it has long-lasting benefits. The Iowa plan is a companion to the national plan, Healthy People 2010. An initiative to improve the health of Americans, the national plan is the driving force for federal resource allocation for disease prevention and health promotion. The state plan is used in the same way. Both plans have received broad support from Republican and Democratic administrations. Community planners are using the state plan to help assess health needs and craft health improvement plans. Healthy Iowans 2010 was written at an unusual point in history – a new decade, a new century, a new millennium. The introduction was optimistic. “The 21st century,” it says, “promises to add life as well as years through improved health habits coupled with medical advances. Scientists have suggested that if these changes occur, the definition of adulthood will also change. An extraordinary number of people will live fuller, more active lives beyond that expected in the late 20th century.” At the same time, the country has spawned a new generation of health hazards. According to Dr. William Dietz of the Centers for Disease Control and Prevention (CDC), it has replaced “the diseases of deficiency with diseases of excess” (Newsweek, August 2, 1999). New threats, such as childhood overweight, can reverse progress made in the last century. This demands concerted action.

A Th17- and Th2-skewed Cytokine Profile in Cystic Fibrosis Lungs Represents a Potential Risk Factor for Pseudomonas aeruginosa Infection.

Rationale: Cystic fibrosis (CF) is characterized by progressive pulmonary inflammation that is infection-triggered. Pseudomonas aeruginosa represents a risk factor for deterioration of lung function and reduced life expectancy. Objectives: To assess T-cell cytokine/chemokine production in clinically stable children with CF and evaluate the association between T-cell subtypes and susceptibility for infection with P. aeruginosa. Methods: T-cell cytokine/chemokine profiles were measured in bronchoalveolar lavage fluid (BALF) from children with CF (n = 57; 6.1 ± 5.9 yr) and non-CF control subjects (n = 18; 5.9 ± 4.3 yr). Memory responses to Aspergillus fumigatus and P. aeruginosa were monitored. High-resolution computed tomography-based Helbich score was assessed. In a prospective observational trial the association between BALF cytokine/chemokine profiles and subsequent infection with P. aeruginosa was studied. Measurements and Main Results: Th1- (INF-γ), Th2- (IL-5, IL-13), Th17- (IL-17A), and Th17-related cytokines (IL-1β, IL-6) were significantly up-regulated in airways of patients with CF. IL-17A, IL-13, and IL-5 were significantly higher in BALF of symptomatic as compared with clinically asymptomatic patients with CF. IL-17A and IL-5 correlated with the percentage of neutrophils in BALF (r = 0.41, P < 0.05 and r = 0.46, P < 0.05, respectively). Th17- (IL-17A, IL-6, IL-1β, IL-8) and Th2-associated cytokines and chemokines (IL-5, IL-13, TARC/CCL17), but not IFN-γ levels, significantly correlated with high-resolution computed tomography changes (Helbich score; P < 0.05). P. aeruginosa- and A. fumigatus-specific T cells from patients with CF displayed significantly higher IL-5 and IL-17A mRNA expression. IL-17A and TARC/CCL17 were significantly augmented in patients that developed P. aeruginosa infection within 24 months. Conclusions: We propose a role for Th17 and Th2 T cells in chronic inflammation in lungs of patients with CF. High concentrations of these cytokines/chemokines in CF airways precede infection with P. aeruginosa.