Real-world evidence from Germany and the United States: Treatment initiation on low-efficacy versus high-efficacy therapies in patients with multiple sclerosis.

BACKGROUND: The hit-hard-and-early (HHAE) strategy where treatment is initiated with high-efficacy therapies opposed to low-efficacy therapies presents a potential paradigm shift in multiple sclerosis (MS) management. This study aimed to assess the adoption of the HHAE strategy in Germany and the United States (US) from 2020 to 2022 based on real-world data. METHODS: The analysis was based on longitudinal, patient-level data from Germany and the US. For Germany, data was extracted from the Permea platform covering approximately 44 % of all German community pharmacy dispensing. For the US, data from the Komodo Healthcare Map™ was utilized, covering medical benefit data from around 88 % of the US patient population. Patients ≥18 years old and who had at least 2 prescriptions for MS-related disease-modifying drugs (DMDs) between January 2020 and December 2022 were included. To approximate therapy beginners, a washout period of one year before treatment start was applied, excluding all patients who had an MS-related DMD prescription or claim in 2019. Cohort entry date was the day of the first MS-related DMD dispense or claim. DMDs were classified as high-efficacy and low-efficacy based on the Multiple Sclerosis Therapy Consensus Group (MSTCG). Group differences were assessed with two-sided χ2-square and t-tests. RESULTS: 29,604 MS therapy beginners were identified in the German and 49,791 MS therapy beginners were identified in the US dataset. 29.6 % of MS therapy beginners in Germany and 61.6 % in the US followed the HHAE strategy. Between 2020 and 2022, a significant 14 % increase in the HHAE strategy was observed in both countries (p < 0.0001). High-efficacy therapy beginners switched from their initially prescribed therapy less frequently than low-efficacy therapy beginners: 6.9 % of high-efficacy vs. 19.5 % of low-efficacy therapy beginners in Germany (p < 0.0001) and 5.5 % of high-efficacy vs. 25.0 % low-efficacy therapy beginners in the US (p < 0.0001) switched from their first prescribed DMD. CONCLUSION: Between 2020 and 2022, the adoption of the HHAE strategy increased in both countries, with the US exhibiting nearly double the adoption rates. High-efficacy therapy beginners were less likely to switch from their initially prescribed medication than low-efficacy therapy beginners. Real world evidence can provide valuable insights into rapidly changing treatment patterns in patients with MS.

Exploring existing malaria services and the feasibility of implementing community engagement approaches amongst conflict-affected communities in Cameroon: a qualitative study.

BACKGROUND: Cameroon is one of the countries with the highest burden of malaria. Since 2018, there has been an ongoing conflict in the country, which has reduced access to healthcare for populations in affected regions, and little is known about the impact on access to malaria services. The objective of this study was to understand the current situation regarding access to malaria services in Cameroon to inform the design of interventions to remove barriers and encourage the use of available services. METHODS: A qualitative research study was carried out to understand the barriers preventing communities accessing care, the uptake of community health worker (CHW) services, and to gather perceptions on community engagement approaches, to assess whether these could be an appropriate mechanism to encourage uptake of community health worker (CHW) services. Twenty-nine focus group discussions and 11 in-depth interviews were carried out between May and July 2021 in two regions of Cameroon, Southwest and Littoral. Focus group discussions were held with CHWs and community members and semi-structured, in-depth interviews were conducted with key stakeholders including regional government staff, council staff, community leaders and community-based organisations. The data were analysed thematically; open, descriptive coding was combined with exploration of pre-determined investigative areas. RESULTS: The study confirmed that access to healthcare has become increasingly challenging in conflict-affected areas. Although the Ministry of Health are providing CHWs to improve access, several barriers remain that limit uptake of these services including awareness, availability, cost, trust in competency, and supply of testing and treatment. This study found that communities were supportive of community engagement approaches, particularly the community dialogue approach. CONCLUSION: Communities in conflict-affected regions of Cameroon continue to have limited access to healthcare services, in part due to poor use of CHW services provided. Community engagement approaches can be an effective way to improve the awareness and use of CHWs. However, these approaches alone will not be sufficient to resolve all the challenges faced by conflict-affected communities when accessing health and malaria services. Additional interventions are needed to increase the availability of CHWs, improve the supply of diagnostic tests and treatments and to reduce the cost of treatment for all.

A formative cross-sectional study to assess caregiver's health-seeking behaviour and knowledge surrounding malaria, and understand the burden of malaria among children under-five in conflict-affected communities of Cameroon.

BACKGROUND: Malaria remains a major global health problem often worsened by political instability and armed conflict. The purpose of the study was to explore community knowledge, attitudes and practices on malaria prevention, and to understand the burden of malaria and health-seeking behaviours of caregivers of children under-five in conflict-affected communities of the South West and Littoral Regions of Cameroon. METHODS: A cross-sectional survey involving internally displaced persons (IDPS), host population, and their children under-five was conducted across 80 communities. The survey was conducted from May to June 2021. Participants were interviewed using a structured questionnaire. Malaria prevalence for children under-five was determined using rapid diagnostic tests (RDT) on blood samples. Association between variables and displacement status was measured using chi square test and multivariate logistic regression model was fitted to identify factors associated with adequate knowledge on malaria prevention. RESULTS: A total of 2386 adults participated in the study and 1543 RDTs were conducted for children under-five. Adequate levels of knowledge and attitudes on malaria prevention was recorded among 1258 (52.9%) of the participants, with very strong evidence to suggest the level to be higher among the host (59.5%) compared to the IDPs (49.5%) and returnees (39.7%) (p < 0.001). Good practices towards malaria prevention was 43.3%, with very strong evidence indicating lower levels among IDPs (42.8%) and returnees (28.5%) compared to the host (49.4%) (p < 0.001). Malaria prevalence for children under-five was 54.0% and adequate health-seeking for suspected episodes of malaria was 53.0%, without any difference among IDPs (51.78%) and returnees (48.7%) compared to host populations (55.4%) (p = 0.154). Multivariate logistic regression model showed that there was quite strong evidence to suggest primary and secondary levels of education have higher odds of having correct knowledge of malaria prevention (adjusted odds ratio (AOR) 1.71, 95% confidence interval (CI): 1.11-2.64, p = 0.015 and AOR 1.80, 95% CI 1.15-2.82, p = 0.010 respectively). There was very strong evidence to suggest that owning a radio or a television was associated with greater odds of having a higher knowledge on malaria prevention (AOR 1.49, 95% CI 1.233-1.81, p = 0.000 and AOR 1.47, 95% CI 1.18-1.84, p = 0.001). CONCLUSION: Over half of the population have correct knowledge and attitudes towards malaria prevention but gaps in complete knowledge remained. Some of the caregivers know the correct malaria preventive practices coupled with largely unsatisfactory treatment approaches and reflected by the high prevalence of malaria among their children. In order to effectively treat malaria, innovative strategies should target community participation.

Shifting from the treat-to-target to the early highly effective treatment approach in patients with multiple sclerosis - real-world evidence from Germany.

Background: While evidence highlights the effectiveness of initiating disease-modifying therapy with a high-efficacy medication for multiple sclerosis (MS) patients with poor prognostic factors, it remains unclear whether this approach has been adopted by a broad range of MS providers in Germany yet. Objective: To assess the adoption of the early highly effective treatment (EHT) compared to the treat-to-target treatment approach with the option of escalating treatment efficacy over time in Germany based on real-world evidence data. Design: Patient-level pharmacy dispensing data from the Permea platform were analysed from 2020 to 2022. Methods: In total, 29,529 therapy beginners (>18 years) were included to analyse shifts in treatment approaches over time and switching behaviour. Medication classification adhered to the German Society of Neurology guidelines and designated fumarates, glatiramer acetate, teriflunomide and interferons as low-efficacy category 1 medications; cladribine and S1P-modulators as medium-efficacy category 2 medications; and alemtuzumab, natalizumab, ocrelizumab, ofatumumab and rituximab (off-label) as high-efficacy category 3 medications. Results: Our results show that 70.0% of patients redeemed their first prescription for category 1 medication, 16.3% for category 2 and 13.7% for category 3 medications. The proportion of prescriptions filled shifted from 2020 to 2022 with a decrease of 14.7% for category 1 drugs and an increase of 12.5% for category 3 drugs. 93.2% of patients stayed on their initially prescribed medication category. 3.2% of category 1 and 3.7% of category 2 therapy beginners escalated to category 3 medication. 3.4% of category 3 medication users de-escalated their treatment to category 1 or category 2. Conclusion: While most individuals started their treatment according to the treat-to-target approach and remained on their initially prescribed medication category, there has been a steadily increasing shift towards the EHT approach since 2020. These insights demonstrate that, while not officially recommended by German guidelines, MS providers increasingly adopt the EHT approach.

Improving the Quality and Use of Malaria Surveillance Data: Results from Evaluating an Integrated Malaria Information Storage System at the Health Facility Level in Selected Districts in Mozambique.

Mozambique addressed critical malaria surveillance system challenges by rolling out an integrated malaria information storage system (iMISS) at the district level in February 2021. The iMISS integrates malaria data from existing systems across thematic program areas to improve data availability and use. In seven districts, the platform was extended to health facilities (HFs), allowing HFs to access iMISS and use tablets to submit monthly malaria reports to a central database, eliminating the need for paper-based reporting to districts. A structured evaluation of the iMISS rollout to HFs was carried out in February-July 2021. The four evaluation areas were data quality (reporting rate, timeliness, and fidelity) of monthly malaria reports electronically submitted to the iMISS, adoption of the iMISS for data-informed decision-making, system maintenance, and acceptability of the iMISS among target users. All 94 HFs in the seven targeted districts were assessed. Over the 6-month period, 86.1% of reported cases on the iMISS were consistent with cases recorded in paper-based reports, allowing for up to 10% discrepancy. In addition, 69.0% of expected monthly district meetings were held, and information from iMISS was discussed during 58.6% of these meetings. Maintenance issues, mostly related to tablet access and internet connectivity, were experienced by 74.5% of HFs; 33.7% of issues were resolved within 1 month. The iMISS and electronic submission of malaria reports were well accepted by HF- and district-level users. Continued political commitment and timely execution of issue management workflows are crucial to ensure trust in the new platform and facilitate higher levels of data use.

Improving the Quality and Use of Malaria Surveillance Data: Results from Evaluating an Integrated Malaria Information Storage System at the Health Facility Level in Selected Districts in Mozambique

Mozambique addressed critical malaria surveillance system challenges by rolling out an integrated malaria information storage system (iMISS) at the district level in February 2021. The iMISS integrates malaria data from existing systems across thematic program areas to improve data availability and use. In seven districts, the platform was extended to health facilities (HFs), allowing HFs to access iMISS and use tablets to submit monthly malaria reports to a central database, eliminating the need for paper-based reporting to districts. A structured evaluation of the iMISS rollout to HFs was carried out in February-July 2021. The four evaluation areas were data quality (reporting rate, timeliness, and fidelity) of monthly malaria reports electronically submitted to the iMISS, adoption of the iMISS for data-informed decision-making, system maintenance, and acceptability of the iMISS among target users. All 94 HFs in the seven targeted districts were assessed. Over the 6-month period, 86.1% of reported cases on the iMISS were consistent with cases recorded in paper-based reports, allowing for up to 10% discrepancy. In addition, 69.0% of expected monthly district meetings were held, and information from iMISS was discussed during 58.6% of these meetings. Maintenance issues, mostly related to tablet access and internet connectivity, were experienced by 74.5% of HFs; 33.7% of issues were resolved within 1 month. The iMISS and electronic submission of malaria reports were well accepted by HF- and district-level users. Continued political commitment and timely execution of issue management workflows are crucial to ensure trust in the new platform and facilitate higher levels of data use.

Optimizing Routine Malaria Surveillance Data in Urban Environments: A Case Study in Maputo City, Mozambique.

In urban settings in malaria-endemic countries, malaria incidence is not well characterized and assumed to be typically very low and consisting largely of imported infections. In such contexts, surveillance systems should adapt to ensure that data are of sufficient spatial and temporal resolution to inform appropriate programmatic interventions. The aim of this research was to 1) assess spatial and temporal trends in reported malaria cases in Maputo City, Mozambique, using an expanded case notification form and 2) to determine how malaria surveillance can be optimized to characterize the local epidemiological context, which can then be used to inform targeted entomological investigations and guide implementation of localized malaria responses. This study took place in all six health facilities of KaMavota District in Maputo City, Mozambique. A questionnaire was administered to all confirmed cases from November 2019 to August 2021. Households of cases were retrospectively geolocated using local landmarks as reference. Overall, 2,380 malaria cases were reported, with the majority being uncomplicated (97.7%) and a median age of 21 years; 70.8% of cases had reported traveling outside the city in the past month with nine reporting traveling internationally. Maps of the 1,314 malaria cases that were geolocated showed distinct spatial patterns. The expanded case notification form enables a more granular overview of the malaria epidemiology in Maputo City; the geolocation data clearly show the areas where endemic transmission is likely, thus informing where resources should be prioritized. As urbanization is rapidly increasing in malaria endemic areas, identifying systems and key variables to collect ensures an operational way to characterize urban malaria through optimization of routine data to inform decision-making.

Evaluating the Interrater Agreement and Acceptability of a New Reference Tool for Assessing Respiratory Rate in Children under Five with Cough and/or Difficulty Breathing.

BACKGROUND: Manual assessment of respiratory rate (RR) in children is unreliable, but remains the main method to diagnose pneumonia in low-resource settings. While automated RR counters offer a potential solution, there is currently no gold standard to validate these diagnostic aids. A video-based reference tool is proposed that allows users to annotate breaths and distortions including movement periods, allowing the exclusion of distortions from the computation of RR measures similar to how new diagnostic aids account for distortions automatically. This study evaluated the interrater agreement and acceptability of the new reference tool. METHODS: Annotations were based on previously recorded reference videos of children under five years old with cough and/or difficulty breathing (n = 50). Five randomly selected medical experts from a panel of ten annotated each video. RR measures (breaths per minute, bpm) were computed as the number of annotated certain breaths divided by the length of calm periods after removing annotated distorted periods. RESULTS: Reviewers showed good interrater agreement on continuous RR {standard error of measurement (SEM) [4.8 (95%CI 4.4-5.3)]} and substantial agreement on classification of fast breathing (Fleiss kappa, κ 0.71). Agreement was lowest in the youngest age group [< 2 months: SEM 6.2 (5.4-7.4) bpm, κ 0.48; 2-11 months: 4.7 (4.0-5.8) bpm, κ 0.84; 12-59 months: 2.6 (2.2-3.1) bpm, κ 0.8]. Reviewers found the functionalities of the tool helpful in annotating breaths, but remained uncertain about the validity of their annotations. CONCLUSIONS: Before the new tool can be considered a reference standard for RR assessments, interrater agreement in children younger than 2 months must be improved.

Eliminating Plasmodium falciparum malaria: results from tailoring active case detection approaches to remote populations in forested border areas in north-eastern Cambodia.

BACKGROUND: Remaining Plasmodium falciparum cases in Cambodia are concentrated in forested border areas and in remote populations who are hard to reach through passive case detection. A key approach to reach these populations is active case detection by mobile malaria workers (MMWs). However, this is operationally challenging because of changing movement patterns of the target population moving into less accessible areas. From January 2018 to December 2020, a tailored package of active case detection approaches was implemented in forested border areas of three provinces in north-eastern Cambodia to reach remote populations and support the elimination of falciparum malaria. METHODS: Key elements of this project were to tailor approaches to local populations, use responsive monitoring systems, maintain operational flexibility, build strong relationships with local communities, and implement close supervision practices. MMWs were recruited from local communities. Proactive case detection approaches included mobile malaria posts positioned at frequented locations around and within forests, and locally informed outreach activities targeting more remote locations. Reactive case detection was conducted among co-travellers of confirmed cases. Testing for malaria was conducted independent of fever symptoms. Routine monitoring of programmatic data informed tactical adaptations, while supervision exercises ensured service quality. RESULTS: Despite operational challenges, service delivery sites were able to maintain consistently high testing rates throughout the implementation period, with each of 45 sites testing a monthly average of 64 (SD 6) people in 2020. In 2020, project MMWs detected only 32 P. falciparum cases. Over the project period, the P. falciparum/P. vivax ratio steadily inversed. Including data from neighbouring health centres and village malaria workers, 45% (80,988/180,732) of all people tested and 39% (1280/3243) of P. falciparum cases detected in the area can be attributed to project MMWs. Remaining challenges of the last elimination phase include maintaining intensified elimination efforts, addressing the issue of detecting low parasitaemia cases and shifting focus to P. vivax malaria. CONCLUSIONS: Reaching remote populations through active case detection should remain a key strategy to eliminate P. falciparum malaria. This case study presented a successful approach combining tailored proactive and reactive strategies that could be transferred to similar settings in other areas of the Greater Mekong Subregion.

Illusory face detection in pure noise images: The role of interindividual variability in fMRI activation patterns.

Illusory face detection tasks can be used to study the neural correlates of top-down influences on face perception. In a typical functional magnetic resonance imaging (fMRI) study design, subjects are presented with pure noise images, but are told that half of the stimuli contain a face. The illusory face perception network is assessed by comparing blood oxygenation level dependent (BOLD) responses to images in which a face has been detected against BOLD activity related to images in which no face has been detected. In the present study, we highlight the existence of strong interindividual differences of BOLD activation patterns associated with illusory face perception. In the core system of face perception, 4 of 9 subjects had highly significant (p<0.05, corrected for multiple comparisons) activity in the bilateral occipital face area (OFA) and fusiform face area (FFA). In contrast, 5 of 9 subjects did not show any activity in these regions, even at statistical thresholds as liberal as p = 0.05, uncorrected. At the group level, this variability is reflected by non-significant activity in all regions of the core system. We argue that these differences might be related to individual differences in task execution: only some participants really detected faces in the noise images, while the other subjects simply responded in the desired way. This has several implications for future studies on illusory face detection. First, future studies should not only analyze results at the group level, but also for single subjects. Second, subjects should be explicitly queried after the fMRI experiment about whether they really detected faces or not. Third, if possible, not only the overt response of the subject, but also additional parameters that might indicate the perception of a noise stimulus as face should be collected (e.g., behavioral classification images).