Direct patient costs for drugs and consumables at fifteen health facilities in Southern Madagascar, a secondary analysis of patient invoices.

BACKGROUND: Financial risk protection in health is a key objective of the Sustainable Development Goals. However, financial risk protection mechanisms are limited, especially in low-income countries, such as Madagascar. To design effective financial risk protection mechanisms, solid and reliable data on the costs patients incur when seeking care are essential. With this study, we therefore aim to describe medical costs for drugs and consumables for patients as well as model the likelihood of catastrophic health expenditure at fifteen health facilities in Southern Madagascar. METHODS: We conducted a costing analysis of patient invoices from fifteen health facilities (four primary and eleven secondary facilities) in Southern Madagascar, including public, private, and faith-based facilities. We included invoices from patients accessing care for life-threatening conditions, accidents and injuries, paediatric, or maternity care between February 2021 and July 2022. Costing data were limited to costs for drugs and consumables. We used regional household expenditure data from a representative household survey to calculate the incidence of catastrophic health expenditure in our sample. RESULTS: We analysed data from 9,855 cases, including 4,980 outpatient cases, 3,447 inpatient cases without surgical intervention, and 1,419 surgical cases. The average patient cost for drugs and medical consumables across all cases was USD 39.52 (range: USD 0.13-1,381.18, IQR: USD 9.07-46.91). Average costs for surgical treatment were USD 119.33 (range: USD 8.10-522.88, IQR: USD 73.81-160.49), for inpatient treatment USD 47.07 (range: USD 1.82-1,381.19, IQR: USD 22.38-58.91), and for outpatient treatment USD 11.73 (range: USD 0.15-207.79, IQR USD: 6.00-15.53). On average patients at faith-based facilities paid USD 47.20 (range: USD 0.49-530.33, IQR: 10.74-58.54), USD19.47 (range: USD 0.40-1,381.23, IQR: 6.77-24.07) at private facilities, and USD 34.65 (range: USD 0.58-245.24, IQR: USD 6.08-60.11) at public facilities. Patients requiring surgical care were most likely to experience catastrophic health expenditure and average costs for maternity care were significantly higher than for other patient groups. CONCLUSIONS: Financial risk protection schemes in Madagascar, such as the national UHC policy, and the national solidarity fund, as well as interventions by non-governmental and multilateral organisations, need to focus on surgical cases and maternity care to protect vulnerable populations from catastrophic health expenditures for life-threatening conditions, accidents and injuries, and maternity and paediatric care.

Effect of the COVID-19 Lockdown on Mobile Payments for Maternal Health: Regression Discontinuity Analysis.

BACKGROUND: The COVID-19 pandemic resulted in the unprecedented popularity of digital financial services for contactless payments and government cash transfer programs to mitigate the economic effects of the pandemic. The effect of the pandemic on the use of digital financial services for health in low- and middle-income countries, however, is poorly understood. OBJECTIVE: This study aimed to assess the effect of the first COVID-19 lockdown on the use of a mobile maternal health wallet, with a particular focus on delineating the age-dependent differential effects, and draw conclusions on the effect of lockdown measures on the use of digital health services. METHODS: We analyzed 819,840 person-days of health wallet use data from 3416 women who used health care at 25 public sector primary care facilities and 4 hospitals in Antananarivo, Madagascar, between January 1 and August 27, 2020. We collected data on savings, payments, and voucher use at the point of care. To estimate the effects of the first COVID-19 lockdown in Madagascar, we used regression discontinuity analysis around the starting day of the first COVID-19 lockdown on March 23, 2020. We determined the bandwidth using a data-driven method for unbiased bandwidth selection and used modified Poisson regression for binary variables to estimate risk ratios as lockdown effect sizes. RESULTS: We recorded 3719 saving events, 1572 payment events, and 3144 use events of electronic vouchers. The first COVID-19 lockdown in Madagascar reduced mobile money savings by 58.5% (P<.001), payments by 45.8% (P<.001), and voucher use by 49.6% (P<.001). Voucher use recovered to the extrapolated prelockdown counterfactual after 214 days, while savings and payments did not cross the extrapolated prelockdown counterfactual. The recovery duration after the lockdown differed by age group. Women aged >30 years recovered substantially faster, returning to prelockdown rates after 34, 226, and 77 days for savings, payments, and voucher use, respectively. Younger women aged <25 years did not return to baseline values. The results remained robust in sensitivity analyses using ±20 days of the optimal bandwidth. CONCLUSIONS: The COVID-19 lockdown greatly reduced the use of mobile money in the health sector, affecting savings, payments, and voucher use. Savings were the most significantly reduced, implying that the lockdown affected women's expectations of future health care use. Declines in payments and voucher use indicated decreased actual health care use caused by the lockdown. These effects are crucial since many maternal and child health care services cannot be delayed, as the potential benefits will be lost or diminished. To mitigate the adverse impacts of lockdowns on maternal health service use, digital health services could be leveraged to provide access to telemedicine and enhance user communication with clear information on available health care access options and adherence to safety protocols.

Digital technologies for health financing in low-income and middle-income countries: a scoping review protocol.

INTRODUCTION: Universal health coverage (UHC) is a global priority, ensuring equitable access to quality healthcare services without financial hardship. Many countries face challenges in progressing towards UHC. Health financing is pivotal for advancing UHC by raising revenues, enabling risk-sharing through pooling of funds and allocating resources. Digital technologies in the healthcare sector offer promising opportunities for health systems. In low-income and middle-income countries (LMICs), digital technologies for health financing (DTHF) have gained traction, supporting these three main functions of health financing for UHC. As existing information on DTHF in LMICs is limited, our scoping review aims to provide a comprehensive overview of DTHF in LMICs. Our objectives include identifying and describing existing DTHF, exploring evaluation approaches, examining their positive and negative effects, and investigating facilitating factors and barriers to implementation at the national level. METHODS AND ANALYSIS: Our scoping review follows the six stages proposed by Arksey and O'Malley, further developed by Levac et al and the Joanna Briggs Institute. The reporting adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews framework. Eligibility criteria for studies reflect the three core elements of the search: (1) health financing, (2) digital technologies and (3) LMICs. We search multiple databases, including Medline via PubMed, EMBASE via Ovid, the Web of Science Core Collection, CENTRAL via Cochrane and the Global Index Medicus by the WHO. The extracted information is synthesised from both quantitative and qualitative studies. ETHICS AND DISSEMINATION: As our scoping review is based solely on information gathered from previously published studies, documents and publicly available scientific literature, ethical clearance is not required for its conduct. The findings are presented and discussed in a peer-reviewed article, as well as shared at conferences relevant to the topic.

Inter-facility transfers for emergency obstetrical and neonatal care in rural Madagascar: a cost-effectiveness analysis.

CONTEXT: There is a substantial lack of inter-facility referral systems for emergency obstetrical and neonatal care in rural areas of sub-Saharan Africa. Data on the costs and cost-effectiveness of such systems that reduce preventable maternal and neonatal deaths are scarce. SETTING: We aimed to determine the cost-effectiveness of a non-governmental organisation (NGO)-run inter-facility referral system for emergency obstetrical and neonatal care in rural Southern Madagascar by analysing the characteristics of cases referred through the intervention as well as its costs. DESIGN: We used secondary NGO data, drawn from an NGO's monitoring and financial administration database, including medical and financial records. OUTCOME MEASURES: We performed a descriptive and a cost-effectiveness analysis, including a one-way deterministic sensitivity analysis. RESULTS: 1172 cases were referred over a period of 4 years. The most common referral reasons were obstructed labour, ineffective labour and eclampsia. In total, 48 neonates were referred through the referral system over the study period. Estimated cost per referral was US$336 and the incremental cost-effectiveness ratio (ICER) was US$70 per additional life-year saved (undiscounted, discounted US$137). The sensitivity analysis showed that the intervention was cost-effective for all scenarios with the lowest ICER at US$99 and the highest ICER at US$205 per additional life-year saved. When extrapolated to the population living in the study area, the investment costs of the programme were US$0.13 per person and annual running costs US$0.06 per person. CONCLUSIONS: In our study, the inter-facility referral system was a very cost-effective intervention. Our findings may inform policies, decision-making and implementation strategies for emergency obstetrical and neonatal care referral systems in similar resource-constrained settings.

Dataset for: Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune-related adverse events.

The rise of cancer immunotherapy has been a milestone in clinical oncology. Above all, immune checkpoint inhibitor treatment (ICI) with monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has improved survival rates for an increasing number of malignancies. However, despite the clinical benefits, ICI-related autoimmunity has become a significant cause of non-relapse-related morbidity and mortality. Neurological immune-related adverse events (irAE-n) are particularly severe toxicities with a high risk for chronic illness, long-term steroid dependency, and early ICI treatment termination. While the clinical characteristics of irAE-n are well described, little is known about underlying immune mechanisms and potential biomarkers. Recently, high frequencies of neuronal autoantibodies in patients with irAE-n have been reported, however, their clinical relevance is unclear. Here, we present a dataset on neuronal autoantibody profiles in ICI-treated cancer patients with and without irAE-n, which was generated to investigate the potential role of neuronal autoantibodies in ICI-induced autoimmunity. Between September 2017 and January 2022 serum samples of 29 cancer patients with irAE-n post-ICI treatment) and 44 cancer control patients without high-grade immune-related adverse events (irAEs, n = 44 pre- and post-ICI treatment) were collected and tested for a large panel of brain-reactive and neuromuscular autoantibodies using indirect immunofluorescence and immunoblot assays. Prevalence of autoantibodies was compared between the groups and correlated with clinical characteristics such as outcome and irAE-n manifestation. These data represent the first systematic comparison of neuronal autoantibody profiles between ICI-treated cancer patients with and without irAE-n, providing valuable information for both researchers and clinicians. In the future, this dataset may be valuable for meta-analyses on the prevalence of neuronal autoantibodies in cancer patients.

A cross-sectional analysis of the effectiveness of a nutritional support programme for people with tuberculosis in Southern Madagascar using secondary data from a non-governmental organisation.

BACKGROUND: There is a strong, bi-directional link between tuberculosis (TB) and undernutrition: TB often causes undernutrition, and undernourished people are more likely to contract TB and experience worse outcomes. Globally, several TB nutritional support programmes exist; however, evidence on their effectiveness is limited and contested. This study evaluates the effect of a nutritional support programme implemented for people with TB in the Atsimo-Andrefana region, Madagascar in 2022. Within this programme, undernourished people with TB [with a body mass index (BMI) of < 18.5 kg/m2] receive 0.6 L of vegetable oil and 6.0 kg of a soy-wheat blend per month throughout their TB treatment. METHODS: We analysed secondary non-governmental organisation data collected between January and November 2022 in the Atsimo-Andrefana region, Southern Madagascar, including information on an individual's medical conditions (e.g., type of TB, treatment outcomes) and nutritional status measured prior to, during, and after completion of treatment (e.g., height, weight, mid-upper arm circumference). We conducted descriptive analyses of patient baseline characteristics and outcomes to assess the impact of the provided nutritional support on the BMI of people with TB. RESULTS: A total of 1310 people with TB were included in the study [9.9% (130) children under the age of 5, 32.1% (420) children between 5 and 18 years, 58.0% (760) adults]. 55.4% of children under 5, 28.1% of children between ages 5 and 18, and 81.3% of adults were undernourished at treatment initiation. 42.3% (55/130) of children under 5 experienced severe acute malnutrition at treatment uptake. While the average BMI of adults with TB receiving food support increased over time, from 17.1 kg/m2 (interquartile range: 15.8-18.3, range: 10.3-22.5) to 17.9 kg/m2 (interquartile range: 16.6-19.1, range: 11.9-24.1), most adults remained undernourished even after completing TB treatment. CONCLUSIONS: The current TB nutritional support programme falls short of sufficiently increasing the BMI of people with TB to overcome malnutrition. There is an urgent need to revise the nutritional support available for people with TB, particularly for children under 5.

Immune signatures of checkpoint inhibitor-induced autoimmunity-A focus on neurotoxicity.

BACKGROUND: Neurologic immune-related adverse events (irAE-n) are rare but severe toxicities of immune checkpoint inhibitor (ICI) treatment. To overcome diagnostic and therapeutic challenges, a better mechanistic understanding of irAE-n is paramount. METHODS: In this observational cohort study, we collected serum and peripheral blood samples from 34 consecutive cancer patients with irAE-n (during acute illness) and 49 cancer control patients without irAE-n (pre- and on-ICI treatment, n = 44 without high-grade irAEs, n = 5 with high-grade nonneurologic irAEs). Patients received either anti-programmed cell death protein (PD)-1 or anti-PD ligand-1 monotherapy or anti-PD-1/anti-cytotoxic T-lymphocyte-associated protein-4 combination therapy. Most common cancers were melanoma, lung cancer, and hepatocellular carcinoma. Peripheral blood immune profiling was performed using 48-marker single-cell mass cytometry and a multiplex cytokine assay. RESULTS: During acute illness, patients with irAE-n presented higher frequencies of cluster of differentiation (CD)8+ effector memory type (EM-)1 and central memory (CM) T cells compared to controls without irAEs. Multiorgan immunotoxicities (neurologic + nonneurologic) were associated with higher CD8+ EM1 T cell counts. While there were no B cell changes in the overall cohort, we detected a marked decrease of IgD- CD11c+ CD21low and IgD- CD24+ CD21high B cells in a subgroup of patients with autoantibody-positive irAE-n. We further identified signatures indicative of enhanced chemotaxis and inflammation in irAE-n patients and discovered C-X-C motif chemokine ligand (CXCL)10 as a promising marker to diagnose high-grade immunotoxicities such as irAE-n. CONCLUSIONS: We demonstrate profound and partly subgroup-specific immune cell dysregulation in irAE-n patients, which may guide future biomarker development and targeted treatment approaches.

Design Research to Embed mHealth into a Community-Led Blood Pressure Management System in Uganda: Protocol for a Mixed Methods Study.

BACKGROUND: Uncontrolled hypertension is a leading risk factor for cardiovascular diseases. In Uganda, such diseases account for approximately 10% of all deaths, with 1 in 5 adults having hypertension (>90% of the hypertensive cases are uncontrolled). Although basic health care in the country is available free of cost at government facilities, regularly accessing medication to control hypertension is difficult because supply chain challenges impede availability. Clients therefore frequently suspend treatment or buy medication individually at private facilities or pharmacies (incurring significant costs). In recent years, mobile health (mHealth) interventions have shown increasing potential in addressing health system challenges in sub-Saharan Africa, but the acceptability, feasibility, and uptake conditions of mobile money approaches to chronic disease management remain understudied. OBJECTIVE: This study aims to design and pilot-test a mobile money-based intervention to increase the availability of antihypertensive medication and lower clients' out-of-pocket payments. We will build on existing local approaches and assess the acceptability, feasibility, and uptake of the designed intervention. Furthermore, rather than entering the study setting with a ready-made intervention, this research will place emphasis on gathering applied ethnographic insights early, which can then inform the parameters of the intervention prototype and concurrent trial. METHODS: We will conduct a mixed methods study following a human-centered design approach. We will begin by conducting extensive qualitative research with a range of stakeholders (clients; health care providers; religious, cultural, and community leaders; academics; and policy makers at district and national levels) on their perceptions of hypertension management, money-saving systems, and mobile money in the context of health care. Our results will inform the design, iterative adaptation, and implementation of an mHealth-facilitated pooled financing intervention prototype. At study conclusion, the finalized prototype will be evaluated quantitatively via a randomized controlled trial. RESULTS: As of August 2023, qualitative data collection, which started in November 2022, is ongoing, with data analysis of the first qualitative interviews underway to inform platform and implementation design. Recruitment for the quantitative part of this study began in August 2023. CONCLUSIONS: Our results aim to inform the ongoing discourse on novel and sustainable pathways to facilitate access to medication for the management of hypertension in resource-constrained settings. TRIAL REGISTRATION: German registry of clinical trials DRKS00030922; https://drks.de/search/en/trial/DRKS00030922. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46614.

Final-year medical students' perspective: a survey on the use of computed tomography in sepsis.

OBJECTIVES: To determine the perspective of final-year medical students on the use of computed tomography (CT) in patients with sepsis. METHODS: A total of 207 questionnaires were distributed to final-year medical students at a large university medical center, and 113 returned questionnaires met the criteria for inclusion in the analysis. Questions referred to sepsis guidelines, CT indications, and the use of contrast agents. Control variables included a level of practical experience as a final-year student (trimester of student's practical year) and previous radiological experience. Statistical hypothesis tests such as the Mann-Whitney U test and chi-square test were performed. RESULTS: The majority of participating students, 85% (n = 91/107), considered a Systemic Organ Failure Assessment (SOFA) score ≥ 2 as a diagnostic criterion for sepsis. The presence of ≥ 2 positive systemic inflammatory response syndrome (SIRS) criteria was considered relevant for diagnosing sepsis by 34% (n = 34/100). Ninety-nine percent (n = 64/65) of the participants who fully agreed with a SOFA score ≥ 2 being relevant for diagnosing sepsis would also use it as an indication for a CT scan. Seventy-six percent (n = 78/103) of the students rated a known severe allergic reaction to contrast agents as an absolute contraindication for its administration. Ninety-five percent (n = 78/82) considered radiation exposure as problematic in CT examinations, especially in repeat CTs. CONCLUSION: Most final-year medical students were familiar with the sepsis criteria. Still, some referred to outdated diagnostic criteria. Participants saw the ability to plan further patient management based on CT as a major benefit. Most participants were aware of radiation as a risk of CT. CRITICAL RELEVANCE STATEMENT: More detailed knowledge of CT in septic patients should be implemented in the medical curriculum. Retraining of medical students could help increase student confidence potentially improving patient care. KEY POINTS: 1. Whereas the majority of final-year medical students were familiar with sepsis criteria, some referred to outdated diagnostic criteria. 2. Participants saw the ability to plan further patient management based on CT as a major benefit. 3. Most participants were aware of radiation as a risk of CT.

Prediction of Stroke Outcome in Mice Based on Noninvasive MRI and Behavioral Testing.

BACKGROUND: Prediction of poststroke outcome using the degree of subacute deficit or magnetic resonance imaging is well studied in humans. While mice are the most commonly used animals in preclinical stroke research, systematic analysis of outcome predictors is lacking. METHODS: We intended to incorporate heterogeneity into our retrospective study to broaden the applicability of our findings and prediction tools. We therefore analyzed the effect of 30, 45, and 60 minutes of arterial occlusion on the variance of stroke volumes. Next, we built a heterogeneous cohort of 215 mice using data from 15 studies that included 45 minutes of middle cerebral artery occlusion and various genotypes. Motor function was measured using a modified protocol for the staircase test of skilled reaching. Phases of subacute and residual deficit were defined. Magnetic resonance images of stroke lesions were coregistered on the Allen Mouse Brain Atlas to characterize stroke topology. Different random forest prediction models that either used motor-functional deficit or imaging parameters were generated for the subacute and residual deficits. RESULTS: Variance of stroke volumes was increased by 45 minutes of arterial occlusion compared with 60 minutes. The inclusion of various genotypes enhanced heterogeneity further. We detected both a subacute and residual motor-functional deficit after stroke in mice and different recovery trajectories could be observed. In mice with small cortical lesions, lesion volume was the best predictor of the subacute deficit. The residual deficit could be predicted most accurately by the degree of the subacute deficit. When using imaging parameters for the prediction of the residual deficit, including information about the lesion topology increased prediction accuracy. A subset of anatomic regions within the ischemic lesion had particular impact on the prediction of long-term outcomes. Prediction accuracy depended on the degree of functional impairment. CONCLUSIONS: For the first time, we developed and validated a robust tool for the prediction of functional outcomes after experimental stroke in mice using a large and genetically heterogeneous cohort. These results are discussed in light of study design and imaging limitations. In the future, using outcome prediction can improve the design of preclinical studies and guide intervention decisions.

Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune related adverse events.

Background: Neurological immune-related adverse events (irAE-n) are severe and potentially fatal toxicities of immune checkpoint inhibitors (ICI). To date, the clinical significance of neuronal autoantibodies in irAE-n is poorly understood. Here, we characterize neuronal autoantibody profiles in patients with irAE-n and compare these with ICI-treated cancer patients without irAE-n. Methods: In this cohort study (DRKS00012668), we consecutively collected clinical data and serum samples of 29 cancer patients with irAE-n (n = 2 pre-ICI, n = 29 post-ICI) and 44 cancer control patients without irAE-n (n = 44 pre- and post-ICI). Using indirect immunofluorescence and immunoblot assays, serum samples were tested for a large panel of neuromuscular and brain-reactive autoantibodies. Results: IrAE-n patients and controls received ICI treatment targeting programmed death protein (PD-)1 (61% and 62%), programmed death ligand (PD-L)1 (18% and 33%) or PD-1 and cytotoxic T-lymphocyte-associated protein (CTLA-)4 (21% and 5%). Most common malignancies were melanoma (both 55%) and lung cancer (11% and 14%). IrAE-n affected the peripheral nervous system (59%), the central nervous system (21%), or both (21%). Prevalence of neuromuscular autoantibodies was 63% in irAE-n patients, which was higher compared to ICI-treated cancer patients without irAE-n (7%, p <.0001). Brain-reactive autoantibodies targeting surface (anti-GABABR, -NMDAR, -myelin), intracellular (anti-GFAP, -Zic4, -septin complex), or unknown antigens were detected in 13 irAE-n patients (45%). In contrast, only 9 of 44 controls (20%) presented brain-reactive autoantibodies before ICI administration. However, seven controls developed de novo brain-reactive autoantibodies after ICI initiation, therefore, prevalence of brain-reactive autoantibodies was comparable between ICI-treated patients with and without irAE-n (p = .36). While there was no clear association between specific brain-reactive autoantibodies and clinical presentation, presence of at least one of six selected neuromuscular autoantibodies (anti-titin, anti-skeletal muscle, anti-heart muscle, anti-LRP4, anti-RyR, anti-AchR) had a sensitivity of 80% (95% CI 0.52-0.96) and a specificity of 88% (95% CI 0.76-0.95) for the diagnosis of myositis, myocarditis, or myasthenia gravis. Conclusion: Neuromuscular autoantibodies may serve as a feasible marker to diagnose and potentially predict life-threatening ICI-induced neuromuscular disease. However, brain-reactive autoantibodies are common in both ICI-treated patients with and without irAE-n, hence, their pathogenic significance remains unclear.

Usability and acceptance of a mobile health wallet for pregnancy-related healthcare: A mixed methods study on stakeholders' perceptions in central Madagascar.

BACKGROUND: Several sub-Saharan African countries use digital financial services to improve health financing, especially for maternal and child health. In cooperation with the Malagasy Ministry of Health, the NGO Doctors for Madagascar is implementing a mobile health wallet for maternal health care in public-sector health facilities in Madagascar. Our aim was to explore the enabling and limiting factors related to the usability and acceptance of the Mobile Maternal Health Wallet (MMHW) intervention during its implementation. METHODS: We conducted a cross-sectional, mixed methods study with mothers and pregnant women and facility- (FBHWs) and community-based (CHWs) health workers from public-sector health facilities in three districts of the Analamanga region in Madagascar. We used a convergent design in collecting and analyzing quantitative and qualitative data. We performed one-stage proportional sampling of women who had signed up for the MMHW. All FBHWs and CHWs at primary care facilities in the intervention area were eligible to participate. RESULTS AND SIGNIFICANCE: 314 women, 76 FBHWs, and 52 CHWs were included in the quantitative survey. Qualitative data were extracted from in-depth interviews with 12 women and 12 FBHWs and from six focus group discussions with 39 CHWSs. The MMHW intervention was accepted and used by health workers and women from different socioeconomic backgrounds. Main motivations for women to enroll in the intervention were the opportunity to save money for health (30.6%), electronic vouchers for antenatal ultrasound (30.2%), and bonus payments upon reaching a savings goal (27.9%). Main motivation for health workers was enabling pregnant women to save for health, thus encouraging facility-based deliveries (57.9%). Performance-based payments had low motivational value for health workers. Key facilitators were community sensitization, strong women-health worker relationship, decision making at the household level, and repetitive training on the use of the MMHW. Key barriers included limited phone ownership, low level of digital literacy, disinformation concerning the effects of the intervention, and technical problems like slow payout processes.

Dataset of a retrospective multicenter cohort study on characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis.

Over the past decade, cancer immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved the outcome of many malignancies. However, with the broad use of ICIs, neurological immune related adverse events (irAE) are increasingly recognized. ICI-induced encephalitis (ICI-iE) is a particularly severe irAE, often leading to treatment termination, long-term sequalae or death. Despite its high morbidity and mortality, data on clinical features and diagnostic criteria are limited. We aimed to define clinical, radiologic and laboratory characteristics of ICI-iE and identify factors that discriminate it from anti-leucine-rich glioma-inactivated (anti-LGI)-1 encephalitis and herpes simplex virus (HSV)-1 encephalitis - two alternative causes of encephalitis - to increase the awareness of ICI-iE and improve its diagnosis and management. To that end, we retrospectively collected 30 cases of ICI-iE that were reported to the Side Effect Registry Immuno-Oncology (SERIO) and 46 cases of anti-LGI1 encephalitis or herpes simplex virus (HSV)-1 encephalitis that presented to a large German neurological referral center (Charité Universitätsmedizin Berlin) between January 2015 and September 2021. Signs and symptoms, imaging and electroencephalogram features, laboratory findings and outcome measures were assessed using standardized case report forms as well as patients' medical records and compared between the groups. The data reported here represents the largest primary cohort of patients with ICI-iE to date and the first comparison with other types of encephalitis. As all three disorders - ICI-iE, HSV-1 encephalitis and anti-LGI1 encephalitis - are rare neurological entities, this dataset can be used as a reference in future clinical studies on ICI-induced neurotoxicity, neurological autoimmune disorders, and central nervous system infections.

Proportion of stroke types in Madagascar: A tertiary-level hospital-based case series.

BACKGROUND: Like other countries in sub-Saharan Africa, Madagascar has a high burden of stroke. The Malagasy population is unique in sharing both African and Asian ancestry. The proportion of ischemic and hemorrhagic stroke types is unknown for this population. AIM: Our aim was to establish the proportion of stroke types and known risk factors for the Malagasy population. METHODS: We conducted a single-center, tertiary-level hospital-based case series. We included all patients with a CT-imaging confirmed stroke who presented at the emergency ward of the study hospital between January 1, 2017, and November 20, 2018. RESULTS: Of 223 patients with CT-confirmed stroke, 57.4% (128/223, 95% CI: 51-64%) had an ischemic stroke and 42.6% (95/223, 95% CI: 36-49%) had an intracranial hemorrhage. The majority (89.5%; 85/95, 95% CI: 83-96%) of intracranial hemorrhages were intracerebral; 4.2% (4/95, 95% CI: 0-8%) had a subdural hematoma, 5.3% (5/95, 95% CI: 1-10%) had a subarachnoid hemorrhage, there was one isolated intraventricular hemorrhage (1.1%; 1/95, 95% CI: -1-3%). The prevalence of hypertension among stroke patients was high (86.6%; 187/216, 95% CI: 82-91%). CONCLUSIONS: Our study is the first to report the proportion of stroke types and known risk factors in Madagascar. We find that the proportion of hemorrhagic strokes was unexpectedly higher than that reported from other countries in sub-Saharan Africa. Our findings highlight the need for a country-specific approach to stroke prevention, treatment, and rehabilitation and provide guidance on public health resource allocation in Madagascar.

Characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis: A retrospective multicentre cohort study.

AIM: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. METHODS: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. RESULTS: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). CONCLUSIONS: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.

Direct patient costs of maternal care and birth-related complications at faith-based hospitals in Madagascar: a secondary analysis of programme data using patient invoices.

OBJECTIVES: We aimed to determine the rate of catastrophic health expenditure incurred by women using maternal healthcare services at faith-based hospitals in Madagascar. DESIGN: This was a secondary analysis of programmatic data obtained from a non-governmental organisation. SETTING: Two faith-based, secondary-level hospitals located in rural communities in southern Madagascar. PARTICIPANTS: All women using maternal healthcare services at the study hospitals between 1 March 2019 and 7 September 2020 were included (n=957 women). MEASURES: We collected patient invoices and medical records of all participants. We then calculated the rate of catastrophic health expenditure relative to 10% and 25% of average annual household consumption in the study region. RESULTS: Overall, we found a high rate of catastrophic health expenditure (10% threshold: 486/890, 54.6%; 25% threshold: 366/890, 41.1%). Almost all women who required surgical care, most commonly a caesarean section, incurred catastrophic health expenditure (10% threshold: 279/280, 99.6%; 25% threshold: 279/280, 99.6%). The rate of catastrophic health expenditure among women delivering spontaneously was 5.7% (14/247; 10% threshold). CONCLUSIONS: Our findings suggest that direct patient costs of managing pregnancy and birth-related complications at faith-based hospitals are likely to cause catastrophic health expenditure. Financial risk protection strategies for reducing out-of-pocket payments for maternal healthcare should include faith-based hospitals to improve health-seeking behaviour and ultimately achieve universal health coverage in Madagascar.

The 4MOTHERS trial of the impact of a mobile money-based intervention on maternal and neonatal health outcomes in Madagascar: study protocol of a cluster-randomized hybrid effectiveness-implementation trial.

BACKGROUND: Mobile money-a service enabling users to receive, store, and send electronic money using mobile phones-has been widely adopted across low- and middle-income economies to pay for a variety of services, including healthcare. However, evidence on its effects on healthcare access and health outcomes are scarce and the possible implications of using mobile money for financing and payment of maternal healthcare services-which generally require large one-time out-of-pocket payments-have not yet been systematically assessed in low-resource settings. The aim of this study is to determine the impact on health outcomes, cost-effectiveness, feasibility, acceptability, and usefulness of mobile phone-based savings and payment service, the Mobile Maternal Health Wallet (MMHW), for skilled healthcare during pregnancy and delivery among women in Madagascar. METHODS: This is a hybrid effectiveness-implementation type-1 trial, determining the effectiveness of the intervention while evaluating the context of its implementation in Madagascar's Analamanga region, containing the capital, Antananarivo. Using a stratified cluster randomized design, 61 public-sector primary-care health facilities were randomized within 6 strata to either receive the intervention or not (29 intervention vs. 32 control facilities). The strata were defined by a health facility's antenatal care visit volume and its capacity to offer facility-based deliveries. The registered pre-specified primary outcomes are (i) delivery at a health facility, (ii) antenatal care visits, and (iii) total healthcare expenditure during pregnancy, delivery, and neonatal period. The registered pre-specified secondary outcomes include additional health outcomes, economic outcomes, and measurements of user experience and satisfaction. Our estimated enrolment number is 4600 women, who completed their pregnancy between July 1, 2020, and December 31, 2021. A series of nested mixed-methods studies will elucidate client and provider perceptions on feasibility, acceptability, and usefulness of the intervention to inform future implementation efforts. DISCUSSION: A cluster-randomized, hybrid effectiveness-implementation design allows for a robust approach to determine whether the MMHW is a feasible and beneficial intervention in a resource-restricted public healthcare environment. We expect the results of our study to guide future initiatives and health policy decisions related to maternal and neonatal health and universal healthcare coverage through technology in Madagascar and other countries in sub-Saharan Africa. TRIAL REGISTRATION: This trial was registered on March 12, 2021: Deutsches Register Klinischer Studien (German Clinical Trials Register), identifier: DRKS00014928 . For World Health Organization Trial Registration Data Set see Additional file 1.

Neurological symptoms and complications in predominantly hospitalized COVID-19 patients: Results of the European multinational Lean European Open Survey on SARS-Infected Patients (LEOSS).

BACKGROUND AND PURPOSE: During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry. METHODS: We analyzed COVID-19 patients from 127 centers, diagnosed between January 2020 and February 2021, and registered in the European multinational LEOSS (Lean European Open Survey on SARS-Infected Patients) registry. The effects of prior neurological diseases and the effect of neurological symptoms on outcome were studied using multivariate logistic regression. RESULTS: A total of 6537 COVID-19 patients (97.7% PCR-confirmed) were analyzed, of whom 92.1% were hospitalized and 14.7% died. Commonly, excessive tiredness (28.0%), headache (18.5%), nausea/emesis (16.6%), muscular weakness (17.0%), impaired sense of smell (9.0%) and taste (12.8%), and delirium (6.7%) were reported. In patients with a complicated or critical disease course (53%) the most frequent neurological complications were ischemic stroke (1.0%) and intracerebral bleeding (ICB; 2.2%). ICB peaked in the critical disease phase (5%) and was associated with the administration of anticoagulation and extracorporeal membrane oxygenation (ECMO). Excessive tiredness (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.20-1.68) and prior neurodegenerative diseases (OR 1.32, 95% CI 1.07-1.63) were associated with an increased risk of an unfavorable outcome. Prior cerebrovascular and neuroimmunological diseases were not associated with an unfavorable short-term outcome of COVID-19. CONCLUSION: Our data on mostly hospitalized COVID-19 patients show that excessive tiredness or prior neurodegenerative disease at first presentation increase the risk of an unfavorable short-term outcome. ICB in critical COVID-19 was associated with therapeutic interventions, such as anticoagulation and ECMO, and thus may be an indirect complication of a life-threatening systemic viral infection.

A Semiquantitative Non-invasive Measurement of PcomA Patency in C57BL/6 Mice Explains Variance in Ischemic Brain Damage in Filament MCAo.

Numerous studies on experimental ischemic stroke use the filament middle cerebral artery occlusion (fMCAo) model in C57BL/6 mice, but lesion sizes in this strain are highly variable. A known contributor is variation in the posterior communicating artery (PcomA) patency. We therefore aimed to provide a semiquantitative non-invasive in vivo method to routinely assess PcomA patency. We included 43 male C57BL/6 mice from four independent studies using a transient 45 min fMCAo model. Edema-corrected lesion sizes were measured by magnetic resonance (MR) imaging 24 h after reperfusion. Time-of-flight MR angiography was performed 7 days before and 24 h after fMCAo. Scores of PcomA size measured 24 h after, but not scores measured 7 days before fMCAo were negatively correlated with lesion size. Variability in PcomA patency explained 30% of the variance in our cohort (p < 0.0001, coefficient of determination r 2 = 0.3). In a simulation using parameters typical for experimental stroke research, the power to detect a true effect of d = 1 between two groups increased by 15% when an according covariate was included in the statistical model. We have demonstrated that in vivo measurement of PcomA size is feasible and can lead to increased accuracy in assessing the effect of treatments.