Ecology and Epidemiology of Integrated Malaria Vector Management in Dar es Salaam, Tanzania

Malaria remains one of the major contributors to the global burden of disease with approximately 70% of the clinical malaria attacks occurring in sub-Saharan Africa. Sub- Saharan Africa has the highest risk as ideal climatic conditions for transmission coincide with occurrence of some of the most efficient malaria vectors, namely Anopheles gambiae s.s., Anopheles arabiensis and Anopheles funestus.. Even though it is estimated that by the year 2030 more than 50% of the African population will live in towns and cities, relatively little is known about urban malaria epidemiology, larval ecology and adult mosquito behaviour. Although integrated malaria control programs including environmental management and larviciding have proven successful before the Global Eradication Campaign started in 1955, they were neglected after the invention of DDT. Lately interest into these control measures has revived but it remains to be determined whether they are feasible and cost-effective in urban Africa. The overall goal of the research presented in this thesis was to enhance current understanding of urban malaria epidemiology and ecology and to take an in-depth look at the effectiveness of larviciding with Bacillus thuringiensis (Bti) in the context of the Urban Malaria Control Program (UMCP) in Dar es Salaam, Tanzania. Our findings are based on data derived from the first 3 years of the UMCP, where data collection started in March 2004. The project area includes 5 wards in each of the 3 municipalities which consist of 67 mitaa covering an area of 55 km2 in which 611,871 people lived during the population census of 2002. Achieving the UMCPs objectives fundamentally relies on three component activities: 1) Mapping and surveillance of potential Anopheles breeding sites, 2) Monitoring of adult mosquito densities, and 3) Household surveys with questionnaires and blood smears testing for malaria parasite infection. In the third year of the UMCP, beginning in March 2006, the routine application of the microbial larvicides Bti in open habitats and Bs in closed habitats was initiated in 3 of the 15 wards in the study area, adding to existing interventions such as bednets, house screening, ceiling boards, repellents, spray and coils. At the same time a detailed survey of mosquito biting behaviour, human behaviour and domestic protection measures was conducted in 12 Ten Cell Units (TCU), the smallest subunit of local government in Tanzania, which presented the highest An. gambiae s.l. densities during the early period of the UMCP surveillance system. Human landing catch (HLC) was conducted in 216 houses on an hourly basis indoors and outdoors from 6 pm till 7 am and residents were interviewed about their sleeping behaviour, where they spend their evenings and what kind of preventive measures against malaria they use. Personal protection of an insecticide treated net (ITN) was evaluated using an extension of a recently developed mathematical model. Overall An. gambiae s.l. exhibited a classical hourly biting pattern. In contrast one of the complex’s component sibling species, namely An. arabiensis, had an early biting peak before 10 pm. Both sibling species, namely An. gambiae s.s. and An. arabiensis, as well as An. funestus and An. coustani were highly exophagic. This behaviour led to a reduced personal protection against exposure to An. gambiae s.s. by ITNs which conferred 59% reduction of exposure in Dar es Salaam compared to 70% in rural Tanzania. An. arabiensis is a vector of only modest importance in Dar es Salaam which is fortunate because ITNs only conferred 38% protection against exposure to this species of mosquito. ITNs conferred slightly less protection against exposure to malaria vectors in good quality houses. This is mainly because people living in good houses tend to spend more time indoors before they go to bed. An. gambiae s.l. is the most important vector in Dar es Salaam , responsible for an EIR (entomological inoculation rate) of 1.00 infectious bites per person per year whereas An. funestus has an EIR of 0.13. Surprisingly, An. coustani also acts as a notable vector in Dar es Salaam with an EIR of 0.20 infectious bites per person per year. Malaria transmission is seasonal with two peaks of malaria prevalence during and after the two rainy seasons. Malaria prevalence was only related to EIR in children under 5 years of age, with a classical ageprevalence distribution similar to most of rural Africa. Malaria prevalence steadily declined from 2004 onwards as the use of window screenings, ceiling boards and more effective drugs like amodiaquine and artemisin-based drugs increased. ITNs (prevalence reduction estimate 20%, 95% CI 0%-36%; P=0.060; year 1) and ceiling boards (prevalence reduction estimate 22%, 95% CI 3%-38%; P=0.026; year 2) conferred modest personal protection and reduced malaria prevalence by approximately one fifth. By comparison, a much greater reduction (prevalence reduction estimate 50%, 95% CI 20%-64%; P=0.002) of malaria prevalence was achieved by larviciding with Bti. This was mainly achieved through major reductions of An. gambiae during July and August when most of the sporozoite infected mosquitoes were caught, combined with all-year-round suppression of the secondary vectors, namely An. funestus and An. coustani. This major achievement was only possible through the novel surveillance and staff management procedures developed by the UMCP to enable effective community based implementation in a decentralized manner. Standards of the surveillance improved greatly after the onset of the program with realized reaction times to vector surveillance at observations being one day, week and month at ward, municipality and city level, respectively. These results of changing biting behaviour of the main malaria vectors in urban settings and the therefore lower but still useful personal protection offered by ITNs call for additional complementary vector control methods such as environmental management or larviciding. The UMCP demonstrated that major reductions in malaria prevalence can be achieved through routine application of microbial larvicides with its new practical management and surveillance system. As these represent the early results of the program, we expect substantial improvement with time and investment. Here we demonstrated for the first time since before the Global Eradication Campaign era, a success story of a malaria control program integrating larviciding, which could be easily adapted by other African cities as a cost-effective option for malaria prevention

Evaluation of pregnancy outcomes in patients with multiple sclerosis after fingolimod exposure

Background and Methods: Limited data are available on the safety of fingolimod in pregnant women. We estimated the risk of adverse pregnancy outcomes in women with multiple sclerosis (MS) exposed to fingolimod either shortly before or during pregnancy in prospectively collected cases from clinical trials, observational studies, surveillance programs, and spontaneous reports.Results: The prevalence of major malformations among live births does not appear to be significantly higher than those in the general population and the unexposed MS population. Similarly, the prevalence of cardiac malformations observed in this analysis was not significantly different from that of the general population. Proportions of miscarriage were in line with those of the general and unexposed MS population and no specific pattern of birth defects was identified.Conclusions: These data can help inform healthcare professionals and women with MS exposed to fingolimod during conception.</p

Prevalence of clinical forms of Chagas disease: a systematic review and meta-analysis – data from the RAISE study

Chagas disease; PrevalenceEnfermedad de Chagas; PrevalenciaMalaltia de Chagas; PrevalençaBackground There is a lack of up-to-date estimates about the prevalence of Chagas disease (ChD) clinical presentations and, therefore, we aimed to assess the prevalence of clinical forms of ChD among seropositive adults, pooling available data. Methods A systematic review was conducted in Medline, Embase, Biblioteca Virtual em Saúde and Cochrane databases looking for studies published from 1990 to August 2023, which investigated the prevalence of ChD clinical forms among seropositive adults, including: (i) indeterminate phase, (ii) chronic Chagas cardiomyopathy (CCM), (iii) digestive and (iv) mixed (CCM + digestive) forms. Pooled estimates and 95% confidence intervals (CI) were calculated using random-effects models. Studies quality and risk of bias was assessed with the Leboeuf-Yde and Lauritsen tool. Heterogeneity was assessed with the I2 statistic. The study was registered in the PROSPERO database (CRD42022354237). Findings 1246 articles were selected for screening and 73 studies were included in the final analysis (17,132 patients, 44% men). Most studies were conducted with outpatients (n = 50), followed by population-based studies (n = 15). The pooled prevalence of the ChD clinical forms was: indeterminate 42.6% (95% CI: 36.9–48.6), CCM 42.7% (95% CI: 37.3–48.3), digestive 17.7% (95% CI: 14.9–20.9), and mixed 10.2% (95% CI: 7.9–13.2). In population-based studies, prevalence was lower for CCM (31.2%, 95% CI: 24.4–38.9) and higher for indeterminate (47.2%, 95% CI: 39.0–55.5) form. In meta-regression, age was inversely associated with the prevalence of indeterminate (β = −0.05, P < 0.001) form, and directly associated with CCM (β = 0.06, P < 0.001) and digestive (β = 0.02, P < 0.001) forms. Heterogeneity was overall high. Interpretation Compared to previous publications, our pooled estimates show a higher prevalence of CCM among ChD seropositive patients, but similar rates of the digestive form.This study was funded by Novartis Pharma AG as part of a research collaboration with the World Heart Federation, project number CLCZ696D2010R. The World Heart Federation funded the Federal University of Minas Gerais to lead the study. Dr Pinho Ribeiro is supported in part by CNPq (310790/2021-2 and 465518/2014-1). Dr. Ramos Nascimento is supported in part by CNPq (Bolsa de produtividade em pesquisa, 310749/2022-0), by the Edwards Lifesciences Foundation (Improving the Prevention and Detection of Heart Valve Disease Across the Lifespan, 2023) and by FAPEMIG (grant APQ-000627-20)

Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US Department of Defense administrative claims database

AbstractBackgroundData are limited for mortality and comorbidities in patients with multiple sclerosis (MS).ObjectivesCompare mortality rates and event rates for comorbidities in MS (n=15,684) and non-MS (n=78,420) cohorts from the US Department of Defense (DoD) database.MethodsComorbidities and all-cause mortality were assessed using the database. Causes of death (CoDs) were assessed through linkage with the National Death Index. Cohorts were compared using mortality (MRR) and event (ERR) rate ratios.ResultsAll-cause mortality was 2.9-fold higher in the MS versus non-MS cohort (MRR, 95% confidence interval [CI]: 2.9, 2.7–3.2). Frequent CoDs in the MS versus non-MS cohort were infectious diseases (6.2, 4.2–9.4), diseases of the nervous (5.8, 3.7–9.0), respiratory (5.0, 3.9–6.4) and circulatory (2.1, 1.7–2.7) systems and suicide (2.6, 1.3–5.2). Comorbidities including sepsis (ERR, 95% CI: 5.7, 5.1–6.3), ischemic stroke (3.8, 3.5–4.2), attempted suicide (2.4, 1.3–4.5) and ulcerative colitis (2.0, 1.7–2.3), were higher in the MS versus non-MS cohort. The rate of cancers was also higher in the MS versus the non-MS cohort, including lymphoproliferative disorders (2.2, 1.9–2.6) and melanoma (1.7, 1.4–2.0).ConclusionsRates of mortality and several comorbidities are higher in the MS versus non-MS cohort. Early recognition and management of comorbidities may reduce premature mortality and improve quality of life in patients with MS

Improving Data Collection in Pregnancy Safety Studies: Towards Standardisation of Data Elements in Pregnancy Reports from Public and Private Partners, A Contribution from the ConcePTION Project.

INTRODUCTION AND OBJECTIVE The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. METHODS Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. RESULTS The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs). CONCLUSIONS Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible

Comorbid disease burden among MS patients 1968–2012: A Swedish register–based cohort study

10.1177/1352458520910497Multiple Sclerosis Journal135245852091049-13524585209104

Safety of Fingolimod in Patients with Multiple Sclerosis Switched from Natalizumab: Results from TRANSITION-A 2-Year, Multicenter, Observational, Cohort Study.

Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to evaluate the safety of fingolimod over two years in patients with MS after switching from natalizumab in a real-world setting. The safety and effectiveness were assessed by monitoring serious and other adverse events (SAEs, AEs). We assessed effectiveness by recording relapses, Expanded Disability Status Scale (EDSS) scores, and MRI activity. Of 637 patients enrolled, 505 completed the study (mean age, 42 years). Overall, 72.8% and 12.7% experienced AEs and SAEs respectively. The most common AEs were fatigue, headache, and urinary tract infection; no cases of PML were observed. Fingolimod treatment resulted in low disease activity. Patients with ≤8 weeks washout period had a markedly lower risk of relapses (4.5%) than those with \u3e8 weeks (51.4%). In patients switching from natalizumab to fingolimod, no new safety signals with overall low relapse activity were observed in patients with washout latencies of ≤8 weeks before fingolimod initiation. Fingolimod was found to be safe and effective in patients transitioning from natalizumab

Pregnancy outcomes in interferon-beta-exposed patients with multiple sclerosis

$\bf Background$ Family planning is an important consideration for women with multiple sclerosis (MS), who are often diagnosed during their reproductive years. Currently, limited data are available on pregnancy outcomes in patients exposed to interferon-beta (IFN-beta) before or during pregnancy. Here, we present the cumulative pregnancy exposure data and prevalence of pregnancy and infant outcomes in IFN-beta-exposed pregnant women with MS from the European IFN-beta Pregnancy Registry. $\bf Methods$ Using spontaneous and solicited reports, the registry collected data from 26 countries of the European Economic Area, consisting of information on women with MS identifying themselves to one of the Marketing Authorisation Holders (Bayer, Biogen, Merck KGaA, and Novartis) or healthcare professionals as pregnant and exposed to IFN-beta during pregnancy or within 1 month before conception. The outcomes collected by the registry included ectopic pregnancies, spontaneous abortions, elective terminations, live, and stillbirths with or without congenital anomalies. The prevalence of pregnancy outcomes was put in context with those reported in the general population. $\bf Results$ Between 2009 and 2017, the registry collected 948 pregnancy reports with a known pregnancy outcome. Overall, 82.0% (777/948) of pregnancies resulted in live birth without congenital anomaly. When comparing IFN-beta-exposed pregnancies with the general population, the prevalence of spontaneous abortions (10.7% vs. 10–21%) and congenital anomalies in live births (2.1% vs. 2.1–4.1%) were found to be within reported ranges. $\bf Conclusions$ The data gathered from these pregnancy cases suggest no evidence that IFN-beta exposure before conception and/or during pregnancy adversely increases the rate of congenital anomalies or spontaneous abortions

Pregnancy outcomes after exposure to interferon beta: a register-based cohort study among women with MS in Finland and Sweden

Background Our aim was to estimate and compare the prevalence of adverse pregnancy outcomes among pregnant women with multiple sclerosis (MS) exposed to interferon beta (IFNB) and among women with MS unexposed to any MS disease-modifying drug (MSDMD). Methods This cohort study used Finnish (1996–2014) and Swedish (2005–2014) national register data. Women with MS having IFNB dispensed 6 months before or during pregnancy as the only medication were considered as IFNB exposed (only IFNB-exposed), whereas women with MS unexposed to any MSDMD were considered unexposed (MSDMD-unexposed). Prevalence was described and compared using log-binomial or logistic regression and adjusted for potential confounders including maternal age and comorbidity. Results Among 2831 pregnancies, 2.2% of the only IFNB-exposed and 4.0% of the MSDMD-unexposed women had serious adverse pregnancy outcomes [elective termination of pregnancy due to foetal anomaly (TOPFA), major congenital anomaly (MCA) in live, or stillbirth]. After adjustments, the prevalence of serious adverse pregnancy outcomes was lower among the only IFNB-exposed compared with the MSDMD-unexposed [relative risk 0.55, 95% confidence interval (CI) 0.31–0.96]. The prevalence of individual outcomes, including MCA, spontaneous abortions, and stillbirths was not increased with IFNB exposure. Women with MS exposed to IFNB appeared more likely to terminate their pregnancy for reasons other than foetal anomaly, compared with MSDMD-unexposed pregnant MS patients (odds ratio 1.71, 95% CI 1.06–2.78). Conclusion In this large cohort study, no increase in the prevalence of adverse pregnancy outcomes was observed in women with MS exposed to IFNB compared with MS patients unexposed to any MSDMDs. This study together with other evidence led to a change in the labels of the IFNB products in September 2019 in the European Union, and IFNB use today may be considered during pregnancy, if clinically needed