The challenge of global elimination policies : a case study of malaria and other diseases of poverty

Malaria is a priority disease on the global public health agenda, with between 800 thousand and one million deaths reported annually. The endemic areas most affected by this parasitic disease have high poverty rates across broad population groups. Children and pregnant women suffer the biggest impacts from this disease, which is transmitted by Anopheles spp. mosquitoes. About 90 countries worldwide report indigenous cases with active transmission. Enormous efforts are ongoing to alleviate the disease burden and its devastating effect on health in vulnerable populations. This research presents a combination of methodological, ontological, and axiological approaches in order to further understand the intrinsic and extrinsic components of malaria which affect the dynamics of transmission and control measures. Limitations are inherent in the ability of the researcher, and this document is unlikely to fully present all factors and determinants which interact in the complex system of malaria. Nonetheless, it reflects a major effort to combine paradigms from positivism to historical constructivism. The purpose of this work is to contribute to the understanding of this phenomenon and compare qualitative and quantitative evidence in malaria-endemic areas of Colombia and the Americas. Additional effort is made to reconstruct the trajectories and experiences of control and prevention and recognize elements to improve models of control, considering the specific contexts where malaria and other diseases of poverty persist. In Chapters I and II, the realities and nature of the problem are defined, specifically to establish paradigms as well as ontological, epistemological, axiological and methodological questions, while the objective of the research is defined in terms of variables such as time, people and places. The analysis process begins with a narrative review of gray literature and indexed texts covering the historical transformations of concepts of control, elimination and eradication of malaria. The compilation of sources interprets the effect of political, economic, social and cultural structures on trends of malaria and diseases of poverty. Additionally, the problem of elimination of infectious diseases is followed from a “biologist model” to a more inclusive and broad bio-socio-political context. Malaria is a complex phenomenon, and control/ elimination /eradication strategies should not underestimate the importance of partial achievements from interventions implemented over time. The search for "magic bullets" is a constant and continual process of recognition by all involved actors, including researchers, academic and public-private institutions, as well as sustained active participation by the affected communities. The detailed description of this process is presented in Chapter III, Concepts evolution of malaria control, elimination and eradication. Historical Review, as submitted to the Journal of Malaria. vii In order to correlate and triangulate the primary and secondary evidence, field work to identify epidemiological markers of advancement and a narrative review on the status of elimination of malaria in Colombia and Latin America are analyzed. These findings are reported in Chapter IV, Proportion of fever attributable to malaria in Colombia: Potential indicators for tracking progress towards malaria elimination. A cross-sectional survey descriptive study, conducted in two regions of Colombia, aimed to identify risk factors (epidemiological and socio-demographic) and baseline characteristics related to the dynamics of malaria transmission. These two regions shared similar structural problems with other malaria endemic regions of Latin America. The field results are strongly correlated with the narrative review. Part of the problem is explained through the primary productive sector, which consists of farmers, miners, fishermen, and migrants/displaced persons, reflecting social injustice and inequalities between regions under the same public policies. Poor governance and reduced infrastructure investment for the health and education sectors, combined with scarce development models for rural and peri-urban areas, produce inadequate living conditions which perpetuate diseases of poverty and high rates of maternal and infant mortality. Information systems for early prediction of outbreaks and epidemics are inadequate or non-existent. Recording of cases on a weekly basis and monitoring of therapeutic failures and insecticide resistance are poorly documented. The proportion of asymptomatic individuals, despite the low reported rates, remains a clinical and epidemiological problem. In the objectives of the Millennium Development Goals, the concepts of elimination particularly focused interest on public health programs. In the case of Colombia, other diseases of poverty can be used as epidemiological markers of the goals achieved. Using the example of endemic goiter, the policy of salt iodization has been adapted as the most cost effective strategy for elimination. By 1998, Colombia declared the country free of goiter. Unfortunately, the lack of monitoring and evaluation programs has hindered appropriate follow up to ensure continued iodization of salt. This study indicates that the disease is still prevalent in school children and pregnant women. In Chapter V, entitled Historical review of the current sanitary policy of goiter elimination in Colombia, 1990-2012, a review on the control policy addresses the decline from a constructivism paradigm. In Chapter VI, the impact of this research to improve the policy of elimination, considering local examples which are widely generalizable to other endemic areas in the same region of the Americas, is presented. New research questions for additional operational research and the development of novel interventions which impact on the incidence of disease are articulated. In conclusion, these results confirm the need to define mechanisms for monitoring and evaluation of programs for elimination. Given the complexity of the health problems, strategies of control must consider reducing inequities, social injustice, and, importantly, the gender component, which are consequences of violence in Colombia

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997Ł2010

Abstract Background: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIVinfected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. Methods: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 personyears (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. Results: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997. Conclusion: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Efficacy of the prescription of physical activity in the obese child population

Objective To determine the effectiveness of prescribing physical activity to the population of overweight and obese children, in accordance with the levels of evidence.Methods To find literature pertaining to the intervention of physical activity in overweight and obese children. four electronic databases were used: Pubmed, Embase, Cochrane and Lilacs. The search was conducted with a cut-off date of June 2012. Randomized controlled clinical trials of intervention programs involving physical activity for both overweight and obese children were selected. Two independent researchers reviewed and evaluated the quality of the studies, and extracted intervention and result data.Results A total of 204 studies were identified. 19 randomized controlled studies which complied with inclusion and exclusion criteria were included. These studies evaluated the impact of physical activity among obese children and compared different types of intervention based on exercise and diet or both with the objective of reducing weight in obese children.Conclusions It is necessary to conduct studies on obese children with bigger sample sizes to determine the effects of the treatment, and more importantly, to devise comprehensive programs that include a structured exercise program complemented by a dietary program. Likewise, the development of public health policies that allow for the development of national programs for weight and obesity control in Colombian children and adults should be developed, taking into account that the causes of obesity are multiple, including social, familiar, metabolic, and dietary aspects

How do women living with HIV experience menopause? Menopausal symptoms, anxiety and depression according to reproductive age in a multicenter cohort

CatedresBackground: To estimate the prevalence and severity of menopausal symptoms and anxiety/depression and to assess the differences according to menopausal status among women living with HIV aged 45-60 years from the cohort of Spanish HIV/AIDS Research Network (CoRIS). Methods: Women were interviewed by phone between September 2017 and December 2018 to determine whether they had experienced menopausal symptoms and anxiety/depression. The Menopause Rating Scale was used to evaluate the prevalence and severity of symptoms related to menopause in three subscales: somatic, psychologic and urogenital; and the 4-item Patient Health Questionnaire was used for anxiety/depression. Logistic regression models were used to estimate odds ratios (ORs) of association between menopausal status, and other potential risk factors, the presence and severity of somatic, psychological and urogenital symptoms and of anxiety/depression. Results: Of 251 women included, 137 (54.6%) were post-, 70 (27.9%) peri- and 44 (17.5%) pre-menopausal, respectively. Median age of onset menopause was 48 years (IQR 45-50). The proportions of pre-, peri- and post-menopausal women who had experienced any menopausal symptoms were 45.5%, 60.0% and 66.4%, respectively. Both peri- and post-menopause were associated with a higher likelihood of having somatic symptoms (aOR 3.01; 95% CI 1.38-6.55 and 2.63; 1.44-4.81, respectively), while post-menopause increased the likelihood of having psychological (2.16; 1.13-4.14) and urogenital symptoms (2.54; 1.42-4.85). By other hand, post-menopausal women had a statistically significant five-fold increase in the likelihood of presenting severe urogenital symptoms than pre-menopausal women (4.90; 1.74-13.84). No significant differences by menopausal status were found for anxiety/depression. Joint/muscle problems, exhaustion and sleeping disorders were the most commonly reported symptoms among all women. Differences in the prevalences of vaginal dryness (p = 0.002), joint/muscle complaints (p = 0.032), and sweating/flush (p = 0.032) were found among the three groups. Conclusions: Women living with HIV experienced a wide variety of menopausal symptoms, some of them initiated before women had any menstrual irregularity. We found a higher likelihood of somatic symptoms in peri- and post-menopausal women, while a higher likelihood of psychological and urogenital symptoms was found in post-menopausal women. Most somatic symptoms were of low or moderate severity, probably due to the good clinical and immunological situation of these women

COVID-19 in hospitalized HIV-positive and HIV-negative patients : A matched study

CatedresObjectives: We compared the characteristics and clinical outcomes of hospitalized individuals with COVID-19 with [people with HIV (PWH)] and without (non-PWH) HIV co-infection in Spain during the first wave of the pandemic. Methods: This was a retrospective matched cohort study. People with HIV were identified by reviewing clinical records and laboratory registries of 10 922 patients in active-follow-up within the Spanish HIV Research Network (CoRIS) up to 30 June 2020. Each hospitalized PWH was matched with five non-PWH of the same age and sex randomly selected from COVID-19@Spain, a multicentre cohort of 4035 patients hospitalized with confirmed COVID-19. The main outcome was all-cause in-hospital mortality. Results: Forty-five PWH with PCR-confirmed COVID-19 were identified in CoRIS, 21 of whom were hospitalized. A total of 105 age/sex-matched controls were selected from the COVID-19@Spain cohort. The median age in both groups was 53 (Q1-Q3, 46-56) years, and 90.5% were men. In PWH, 19.1% were injecting drug users, 95.2% were on antiretroviral therapy, 94.4% had HIV-RNA < 50 copies/mL, and the median (Q1-Q3) CD4 count was 595 (349-798) cells/μL. No statistically significant differences were found between PWH and non-PWH in number of comorbidities, presenting signs and symptoms, laboratory parameters, radiology findings and severity scores on admission. Corticosteroids were administered to 33.3% and 27.4% of PWH and non-PWH, respectively (P = 0.580). Deaths during admission were documented in two (9.5%) PWH and 12 (11.4%) non-PWH (P = 0.800). Conclusions: Our findings suggest that well-controlled HIV infection does not modify the clinical presentation or worsen clinical outcomes of COVID-19 hospitalization