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

Background: 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 (ß = -0.05, P < 0.001) form, and directly associated with CCM (ß = 0.06, P < 0.001) and digestive (ß = 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. Funding: This study was funded by the World Heart Federation, through a research collaboration with Novartis Pharma AG.

The Burden of Chagas Disease in the Contemporary World: The RAISE Study.

Chagas disease (ChD), a Neglected Tropical Disease, has witnessed a transformative epidemiological landscape characterized by a trend of reduction in prevalence, shifting modes of transmission, urbanization, and globalization. Historically a vector-borne disease in rural areas of Latin America, effective control measures have reduced the incidence in many countries, leading to a demographic shift where most affected individuals are now adults. However, challenges persist in regions like the Gran Chaco, and emerging oral transmission in the Amazon basin adds complexity. Urbanization and migration from rural to urban areas and to non-endemic countries, especially in Europe and the US, have redefined the disease's reach. These changing patterns contribute to uncertainties in estimating ChD prevalence, exacerbated by the lack of recent data, scarcity of surveys, and reliance on outdated models. Besides, ChD's lifelong natural history, marked by acute and chronic phases, introduces complexities in diagnosis, particularly in non-endemic regions where healthcare provider awareness is low. The temporal dissociation of infection and clinical manifestations, coupled with underreporting, has rendered ChD invisible in health statistics. Deaths attributed to ChD cardiomyopathy often go unrecognized, camouflaged under alternative causes. Understanding these challenges, the RAISE project aims to reassess the burden of ChD and ChD cardiomyopathy. The project is a collaborative effort of the World Heart Federation, Novartis Global Health, the University of Washington's Institute for Health Metrics and Evaluation, and a team of specialists coordinated by Brazil's Federal University of Minas Gerais. Employing a multidimensional strategy, the project seeks to refine estimates of ChD-related deaths, conduct systematic reviews on seroprevalence and prevalence of clinical forms, enhance existing modeling frameworks, and calculate the global economic burden, considering healthcare expenditures and service access. The RAISE project aspires to bridge knowledge gaps, raise awareness, and inform evidence-based health policies and research initiatives, positioning ChD prominently on the global health agenda.

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.

The economic burden of Chagas disease: A systematic review.

BACKGROUND: Chagas disease (CD) is a neglected disease affecting millions worldwide, yet little is known about its economic burden. This systematic review is part of RAISE project, a broader study that aims to estimate the global prevalence, mortality, and health and economic burden attributable to chronic CD and Chronic Chagas cardiomyopathy. The objective of this study was to assess the main costs associated with the treatment of CD in both endemic and non-endemic countries. METHODS: An electronic search of the Medline, Lilacs, and Embase databases was conducted until 31st, 2022, to identify and select economic studies that evaluated treatment costs of CD. No restrictions on place or language were made. Complete or partial economic analyses were included. RESULTS: Fifteen studies were included, with two-thirds referring to endemic countries. The most commonly investigated cost components were inpatient care, exams, surgeries, consultation, drugs, and pacemakers. However, significant heterogeneity in the estimation methods and presentation of data was observed, highlighting the absence of standardization in the measurement methods and cost components. The most common component analyzed using the same metric was hospitalization. The mean annual hospital cost per patient ranges from $25.47 purchasing power parity US dollars (PPP-USD) to $18,823.74 PPP-USD, and the median value was $324.44 PPP-USD. The lifetime hospital cost per patient varies from $209,44 PPP-USD for general care to $14,351.68 PPP-USD for patients with heart failure. DISCUSSION: Despite the limitations of the included studies, this study is the first systematic review of the costs of CD treatment. The findings underscore the importance of standardizing the measurement methods and cost components for estimating the economic burden of CD and improving the comparability of cost components magnitude and cost composition analysis. Finally, assessing the economic burden is essential for public policies designed to eliminate CD, given the continued neglect of this disease.

Disease Burden and Treatment Patterns Among US Patients with Hidradenitis Suppurativa: A Retrospective Cohort Study.

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic, autoinflammatory skin disease associated with many comorbidities. One biologic (adalimumab) is approved for HS. This study assessed the sociodemographic characteristics, comorbidities, treatment patterns, healthcare resource utilization (HCRU) and associated costs of patients with HS following biologic approval. METHODS: This non-interventional, retrospective cohort study involved adult (≥ 18 years) and adolescent (12-17 years) patients diagnosed with HS in the United States (US) using Optum's de-identified Clinformatics® Data Mart Database during the period 1 January 2016 to 31 December 2018. RESULTS: Of 42,843 identified patients, 10,909 met the incident HS patient criteria (10,230 adults, 628 adolescents, 51 patients aged <12 years). Patients were mostly diagnosed by a general practitioner/pediatrician (adults: 41.6%; adolescents: 39.6%) or dermatologist (adults: 22.1%; adolescents: 30.6%). Commonly reported Charlson comorbidities at pre-index in adult patients were diabetes without complications (20.4%), chronic pulmonary disease (16.4%) and diabetes with complications (9.0%), and the most frequent Elixhauser comorbidities were uncomplicated hypertension (38.3%), obesity (22.5%), uncomplicated diabetes (19.0%) and depression (17.4%). The burden of comorbidities generally increased over time after diagnosis in both adults and adolescents. HS-related surgical procedures were uncommon in the 2-years post-index period: an incision and drainage procedure was reported in 7.6% of adults and 6.4% of adolescents. Patients were predominantly treated with both topical and systemic antibiotic treatments (adults: 25.0% and 65.1%, respectively; adolescents: 41.7% and 74.5%, respectively). Biologic prescription was higher in adults than adolescents (3.5% vs. 1.8%). Total healthcare costs for adult and adolescent patients in the 2-years post-index period were US$42,143 and US$16,057, respectively, with outpatient costs accounting for the majority of these costs (US$20,980 and US$8408, respectively). CONCLUSION: In adult and adolescent patients with HS, comorbidity burden continues to increase after diagnosis. All-cause and HS-specific HCRU and costs are high in adults and adolescents with HS. These findings support the need for a multidisciplinary comprehensive care strategy for patients with HS.

Core Data Elements for Pregnancy Pharmacovigilance Studies Using Primary Source Data Collection Methods: Recommendations from the IMI ConcePTION Project.

INTRODUCTION AND OBJECTIVE: The risks and benefits of medication use in pregnancy are typically established through post-marketing observational studies. As there is currently no standardised or systematic approach to the post-marketing assessment of medication safety in pregnancy, data generated through pregnancy pharmacovigilance (PregPV) research can be heterogenous and difficult to interpret. The aim of this article is to describe the development of a reference framework of core data elements (CDEs) for collection in primary source PregPV studies that can be used to standardise data collection procedures and, thereby, improve data harmonisation and evidence synthesis capabilities. METHODS: This CDE reference framework was developed within the Innovative Medicines Initiative (IMI) ConcePTION project by experts in pharmacovigilance, pharmacoepidemiology, medical statistics, risk-benefit communication, clinical teratology, reproductive toxicology, genetics, obstetrics, paediatrics, and child psychology. The framework was produced through a scoping review of data collection systems used by established PregPV datasets, followed by extensive discussion and debate around the value, definition, and derivation of each data item identified from these systems. RESULTS: The finalised listing of CDEs comprises 98 individual data elements, arranged into 14 tables of related fields. These data elements are openly available on the European Network of Teratology Information Services (ENTIS) website ( http://www.entis-org.eu/cde ). DISCUSSION: With this set of recommendations, we aim to standardise PregPV primary source data collection processes to improve the speed at which high-quality evidence-based statements can be provided about the safety of medication use in pregnancy.

Emulation of the control cohort of a randomized controlled trial in pediatric kidney transplantation with Real-World Data from the CERTAIN Registry.

BACKGROUND: Randomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far. METHODS: In this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554). RESULTS: Most baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2 P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable. CONCLUSIONS: In conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Predicting Clinical Remission of Chronic Urticaria Using Random Survival Forests: Machine Learning Applied to Real-World Data.

INTRODUCTION: The time required to reach clinical remission varies in patients with chronic urticaria (CU). The objective of this study is to develop a predictive model using a machine learning methodology to predict time to clinical remission for patients with CU. METHODS: Adults with ≥ 2 ICD-9/10 relevant CU diagnosis codes/CU-related treatment > 6 weeks apart were identified in the Optum deidentified electronic health record dataset (January 2007 to June 2019). Clinical remission was defined as ≥ 12 months without CU diagnosis/CU-related treatment. A random survival forest was used to predict time from diagnosis to clinical remission for each patient based on clinical and demographic features available at diagnosis. Model performance was assessed using concordance, which indicates the degree of agreement between observed and predicted time to remission. To characterize clinically relevant groups, features were summarized among cohorts that were defined based on quartiles of predicted time to remission. RESULTS: Among 112,443 patients, 73.5% reached clinical remission, with a median of 336 days from diagnosis. From 1876 initial features, 176 were retained in the final model, which predicted a median of 318 days to remission. The model showed good performance with a concordance of 0.62. Patients with predicted longer time to remission tended to be older with delayed CU diagnosis, and have more comorbidities, more laboratory tests, higher body mass index, and polypharmacy during the 12-month period before the first CU diagnosis. CONCLUSIONS: Applying machine learning to real-world data enabled accurate prediction of time to clinical remission and identified multiple relevant demographic and clinical variables with predictive value. Ongoing work aims to further validate and integrate these findings into clinical applications for CU management.

Demonstrating Benefit-Risk Profiles of Novel Therapeutic Strategies in Kidney Transplantation: Opportunities and Challenges of Real-World Evidence.

While great progress has been made in transplantation medicine, long-term graft failure and serious side effects still pose a challenge in kidney transplantation. Effective and safe long-term treatments are needed. Therefore, evidence of the lasting benefit-risk of novel therapies is required. Demonstrating superiority of novel therapies is unlikely via conventional randomized controlled trials, as long-term follow-up in large sample sizes pose statistical and operational challenges. Furthermore, endpoints generally accepted in short-term clinical trials need to be translated to real-world (RW) care settings, enabling robust assessments of novel treatments. Hence, there is an evidence gap that calls for innovative clinical trial designs, with RW evidence (RWE) providing an opportunity to facilitate longitudinal transplant research with timely translation to clinical practice. Nonetheless, the current RWE landscape shows considerable heterogeneity, with few registries capturing detailed data to support the establishment of new endpoints. The main recommendations by leading scientists in the field are increased collaboration between registries for data harmonization and leveraging the development of technology innovations for data sharing under high privacy standards. This will aid the development of clinically meaningful endpoints and data models, enabling future long-term research and ultimately establish optimal long-term outcomes for transplant patients.

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 >8 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.

Prevalence of adverse pregnancy outcomes after exposure to interferon beta prior to or during pregnancy in women with MS: Stratification by maternal and newborn characteristics in a register-based cohort study in Finland and Sweden.

BACKGROUND: Previous studies reported no increase in the prevalence of adverse pregnancy outcomes after exposure to interferon-beta (IFN-beta). However, no study has investigated if the prevalence of these outcomes after IFN-beta exposure is modified by maternal and newborn characteristics. Our objective was to describe the stratified prevalence of adverse pregnancy outcomes among women with multiple sclerosis (MS) exposed only to IFN-beta or unexposed to any MS disease modifying drugs (MSDMDs). METHODS: This population-based cohort study using Finnish (1996-2014) and Swedish (2005-2014) register data included pregnancies of women with MS exposed only to IFN-beta 6 months before or during pregnancy (n=718) or unexposed to MSDMDs (n=1397). The outcome prevalences were described stratified by maternal and newborn characteristics, with 95% confidence intervals (CIs). Confounder-adjusted analyses were performed if the prevalence results indicated modified effect of IFN-beta in specific strata. RESULTS: The stratified analysis indicated that the prevalence of serious (anomaly or stillbirth) and other adverse pregnancy outcomes was similar among the exposed and unexposed, with no statistically significant difference. Among women treated for MS >5 years, serious adverse pregnancy outcomes occurred in 4.3% (95%CI: 1.9-8.3%) of pregnancies exposed only to IFN-beta 6 months before or during pregnancy and in 2.7% (95%CI: 1.2-5.0%) of unexposed pregnancies. The confounder adjusted analyses did not support the hypothesis that MS treatment duration before pregnancy would modify the risk of adverse pregnancy outcomes after exposure to IFN-beta 6 months before or during pregnancy. CONCLUSION: The prevalence of adverse pregnancy outcomes was not increased after IFN-beta exposure, when pregnancies of women with MS were stratified by maternal and newborn characteristics. The stratified results were similar to the unstratified results in the same population.

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

BACKGROUND: People with multiple sclerosis (pwMS) have increased comorbid disease (CMD) risk. Most previous studies have not considered overall CMD burden. OBJECTIVE: To describe lifetime CMD burden among pwMS. METHODS: PwMS identified using Swedish registers between 1968 and 2012 (n = 25,476) were matched by sex, age, and county of residence with general-population comparators (n = 251,170). Prevalence, prevalence ratios (PRs), survival functions, and hazard ratios by MS status, age, and time period compared seven CMD: autoimmune, cardiovascular, depression, diabetes, respiratory, renal, and seizures. RESULTS: The magnitude of the PRs for each CMD and age group decreased across time, with higher PRs in earlier time periods. Before 1990, younger age groups had higher PRs, and after 1990, older age groups had higher PRs. Male pwMS had higher burden compared with females. Overall, renal, respiratory, and seizures had the highest PRs. Before 2001, 50% of pwMS received a first/additional CMD diagnosis 20 years prior to people without MS, which reduced to 4 years after 2001. PwMS had four times higher rates of first/additional diagnoses in earlier time periods, which reduced to less than two times higher in recent time periods compared to people without MS. CONCLUSION: Swedish pwMS have increased CMD burden compared with the general population, but this has reduced over time.

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.

A systematic review and meta-analyses of pregnancy and fetal outcomes in women with multiple sclerosis: a contribution from the IMI2 ConcePTION project.

Neurologists managing women with Multiple Sclerosis (MS) need information about the safety of disease modifying drugs (DMDs) during pregnancy. However, this knowledge is limited. The present study aims to summarize previous studies by performing a systematic review and meta-analyses. The terms "multiple sclerosis" combined with DMDs of interest and a broad profile for pregnancy terms were used to search Embase and Medline databases to identify relevant studies published from January 2000 to July 2019.1260 studies were identified and ten studies met our inclusion criteria. Pooled risk ratios (RR) of pregnancy and birth outcomes in pregnancies exposed to DMDs compared to those not exposed were calculated using a random effects model. For spontaneous abortion RR = 1.14, 95% CI 0.99-1.32, for preterm births RR = 0.93, 95% CI 0.72-1.21 and for major congenital malformations RR = 0.86, 95% CI 0.47-1.56. The most common major congenital malformations reported in MS patients exposed to MS drugs were atrial septal defect (ASD) (N = 4), polydactyly (N = 4) and club foot (N = 3), which are among the most prevalent birth defects observed in the general population. In conclusion, interferons, glatiramer acetate or natalizumab, do not appear to increase the risk for spontaneous abortions, pre-term birth or major congenital malformations. There were very few patients included that were exposed to fingolimod, azathioprine and rituximab; therefore, these results cannot be generalized across drugs. Future studies including internal comparators are needed to enable treating physicians and their patients to decide on the best treatment options.

An alternative to product-specific pregnancy registries? PRIM; PRegnancy outcomes Intensive Monitoring.

Patient safety during pregnancy is an important concern. This article presents a method of using an industry safety database to access prospective pregnancy cases. This method, termed here 'PRegnancy outcomes Intensive Monitoring' (PRIM) was developed for fingolimod (Gilenya ™), a treatment option for multiple sclerosis (MS), due to slow enrollment in the company pregnancy registry. The aim of PRIM was to enhance the process of pregnancy data collection and improve data quality, and in particular to enable estimation of the proportion of major congenital malformation and other pregnancy outcomes. To do this, the spontaneous reports of maternal exposure to fingolimod in pregnancy or in the eight weeks immediately before the last menstrual period of patients not enrolled in the pregnancy registry were identified. Follow up checklists were sent at four time points: initial pregnancy report, end of pregnancy, infant attained 3 and 12 months of age. These focused on core data required for derivation of programmed analyses. From 01 Mar 2014 to 28 Feb 2018, a total of 831 prospective maternal exposures with 843 infants were reported, with fetal outcomes reported in 459/843 (54.4 %) of those infants. This enabled the calculation of proportions of pregnancy cases with the main pregnancy outcomes and of fetal cases with malformation. The number of reported pregnancies was significantly higher in PRIM than in the registry, showing that structured use of pharmacovigilance data enables speedier assessment of risks of maternal drug exposure.

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.

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.

BACKGROUND: Data are limited for mortality and comorbidities in patients with multiple sclerosis (MS). OBJECTIVES: Compare 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. METHODS: Comorbidities 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. RESULTS: All-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). CONCLUSIONS: Rates 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.

New opportunities of real-world data from clinical routine settings in life-cycle management of drugs: example of an integrative approach in multiple sclerosis.

The assessment and demonstration of a positive benefit-risk balance of a drug is a life-long process and includes specific data from preclinical, clinical development and post-launch experience. However, new integrative approaches are needed to enrich evidence from clinical trials and sponsor-initiated observational studies with information from multiple additional sources, including registry information and other existing observational data and, more recently, health-related administrative claims and medical records databases. To illustrate the value of this approach, this paper exemplifies such a cross-package approach to the area of multiple sclerosis, exploring also possible analytic strategies when using these multiple sources of information.

A new tent trap for sampling exophagic and endophagic members of the Anopheles gambiae complex.

BACKGROUND: Mosquito sampling methods are essential for monitoring and evaluating malaria vector control interventions. In urban Dar es Salaam, human landing catch (HLC) is the only method sufficiently sensitive for monitoring malaria-transmitting Anopheles. HLC is labour intensive, cumbersome, hazardous, and requires such intense supervision that is difficulty to sustain on large scales. METHODS: Novel tent traps were developed as alternatives to HLC. The Furvela tent, designed in Mozambique, incorporates a CDC Light trap (LT) components, while two others from Ifakara, Tanzania (designs A and B) require no electricity or moving parts. Their sensitivity for sampling malaria vectors was compared with LT and HLC over a wide range of vector abundances in rural and urban settings in Tanzania, with endophagic and exophagic populations, respectively, using randomised Latin-square and cross- over experimental designs. RESULTS: The sensitivity of LTs was greater than HLC while the opposite was true of Ifakara tent traps (crude mean catch of An. gambiae sensu lato relative to HLC = 0.28, 0.65 and 1.30 for designs A, B and LT in a rural setting and 0.32 for design B in an urban setting). However, Ifakara B catches correlated far better to HLC (r2 = 0.73, P < 0.001) than any other method tested (r2 = 0.04, P = 0.426 and r2 = 0.19, P = 0.006 for Ifakara A and LTs respectively). Only Ifakara B in a rural setting with high vector density exhibited constant sampling efficiency relative to HLC. The relative sensitivity of Ifakara B increased as vector densities decreased in the urban setting and exceeded that of HLC at the lowest densities. None of the tent traps differed from HLC in terms of the proportions of parous mosquitoes (P >or= 0.849) or An. gambiae s.l. sibling species (P >or= 0.280) they sampled but both Ifakara A and B designs failed to reduce the proportion of blood-fed mosquitoes caught (Odds ratio [95% Confidence Interval] = 1.6 [1.2, 2.1] and 1.0 [0.8, 1.2], P = 0.002 and 0.998, respectively), probably because of operator exposure while emptying the trap each morning. CONCLUSION: The Ifakara B trap may have potential for monitoring and evaluating a variety of endophagic and exophagic Afrotropical malaria vectors, particularly at low but epidemiologically relevant population densities. However, operator exposure to mosquito bites remains a concern so additional modifications or protective measures will be required before this design can be considered for widespread, routine use.

Microbial larvicide application by a large-scale, community-based program reduces malaria infection prevalence in urban Dar es Salaam, Tanzania.

BACKGROUND: Malaria control in Africa is most tractable in urban settlements yet most research has focused on rural settings. Elimination of malaria transmission from urban areas may require larval control strategies that complement adult mosquito control using insecticide-treated nets or houses, particularly where vectors feed outdoors. METHODS AND FINDINGS: Microbial larvicide (Bacillus thuringiensis var. israelensis (Bti)) was applied weekly through programmatic, non-randomized community-based, but vertically managed, delivery systems in urban Dar es Salaam, Tanzania. Continuous, randomized cluster sampling of malaria infection prevalence and non-random programmatic surveillance of entomological inoculation rate (EIR) respectively constituted the primary and secondary outcomes surveyed within a population of approximately 612,000 residents in 15 fully urban wards covering 55 km(2). Bti application for one year in 3 of those wards (17 km(2) with 128,000 residents) reduced crude annual transmission estimates (Relative EIR [95% Confidence Interval] = 0.683 [0.491-0.952], P = 0.024) but program effectiveness peaked between July and September (Relative EIR [CI] = 0.354 [0.193 to 0.650], P = 0.001) when 45% (9/20) of directly observed transmission events occurred. Larviciding reduced malaria infection risk among children < or =5 years of age (OR [CI] = 0.284 [0.101 to 0.801], P = 0.017) and provided protection at least as good as personal use of an insecticide treated net (OR [CI] = 0.764 [0.614-0.951], P = 0.016). CONCLUSIONS: In this context, larviciding reduced malaria prevalence and complemented existing protection provided by insecticide-treated nets. Larviciding may represent a useful option for integrated vector management in Africa, particularly in its rapidly growing urban centres.