A library of quantitative markers of seizure severity.

OBJECTIVE: Understanding fluctuations in seizure severity within individuals is important for determining treatment outcomes and responses to therapy, as well as assessing novel treatments for epilepsy. Current methods for grading seizure severity rely on qualitative interpretations from patients and clinicians. Quantitative measures of seizure severity would complement existing approaches to electroencephalographic (EEG) monitoring, outcome monitoring, and seizure prediction. Therefore, we developed a library of quantitative EEG markers that assess the spread and intensity of abnormal electrical activity during and after seizures. METHODS: We analyzed intracranial EEG (iEEG) recordings of 1009 seizures from 63 patients. For each seizure, we computed 16 markers of seizure severity that capture the signal magnitude, spread, duration, and postictal suppression of seizures. RESULTS: Quantitative EEG markers of seizure severity distinguished focal versus subclinical seizures across patients. In individual patients, 53% had a moderate to large difference (rank sum r > .3 , p < .05 ) between focal and subclinical seizures in three or more markers. Circadian and longer term changes in severity were found for the majority of patients. SIGNIFICANCE: We demonstrate the feasibility of using quantitative iEEG markers to measure seizure severity. Our quantitative markers distinguish between seizure types and are therefore sensitive to established qualitative differences in seizure severity. Our results also suggest that seizure severity is modulated over different timescales. We envisage that our proposed seizure severity library will be expanded and updated in collaboration with the epilepsy research community to include more measures and modalities.

Assembling a global database of child pneumonia studies to inform WHO pneumonia management algorithm: Methodology and applications.

Background: The existing World Health Organization (WHO) pneumonia case management guidelines rely on clinical symptoms and signs for identifying, classifying, and treating pneumonia in children up to 5 years old. We aimed to collate an individual patient-level data set from large, high-quality pre-existing studies on pneumonia in children to identify a set of signs and symptoms with greater validity in the diagnosis, prognosis, and possible treatment of childhood pneumonia for the improvement of current pneumonia case management guidelines. Methods: Using data from a published systematic review and expert knowledge, we identified studies meeting our eligibility criteria and invited investigators to share individual-level patient data. We collected data on demographic information, general medical history, and current illness episode, including history, clinical presentation, chest radiograph findings when available, treatment, and outcome. Data were gathered separately from hospital-based and community-based cases. We performed a narrative synthesis to describe the final data set. Results: Forty-one separate data sets were included in the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) database, 26 of which were hospital-based and 15 were community-based. The PREPARE database includes 285 839 children with pneumonia (244 323 in the hospital and 41 516 in the community), with detailed descriptions of clinical presentation, clinical progression, and outcome. Of 9185 pneumonia-related deaths, 6836 (74%) occurred in children <1 year of age and 1317 (14%) in children aged 1-2 years. Of the 285 839 episodes, 280 998 occurred in children 0-59 months old, of which 129 584 (46%) were 2-11 months of age and 152 730 (54%) were males. Conclusions: This data set could identify an improved specific, sensitive set of criteria for diagnosing clinical pneumonia and help identify sick children in need of referral to a higher level of care or a change of therapy. Field studies could be designed based on insights from PREPARE analyses to validate a potential revised pneumonia algorithm. The PREPARE methodology can also act as a model for disease database assembly.

Cholera diagnosis in human stool and detection in water: A systematic review and meta-analysis.

BACKGROUND: Cholera continues to pose a problem for low-resource, fragile and humanitarian contexts. Evidence suggests that 2.86 million cholera cases and 95,000 deaths due to cholera are reported annually. Without quick and effective diagnosis and treatment, case-fatality may be 50%. In line with the priorities of the Global Task Force on Cholera Control, we undertook a systematic review and meta-analysis of diagnostic test accuracy and other test characteristics of current tests for cholera detection in stool and water. METHODS: We searched 11 bibliographic and grey literature databases. Data was extracted on test sensitivity, specificity and other product information. Meta-analyses of sensitivity and specificity were conducted for tests reported in three or more studies. Where fewer studies reported a test, estimates were summarised through narrative synthesis. Risk of Bias was assessed using QUADAS-2. RESULTS: Searches identified 6,637 records; 41 studies reporting on 28 tests were included. Twenty-two tests had both sensitivities and specificities reported above 95% by at least one study, but there was, overall, wide variation in reported diagnostic accuracy across studies. For the three tests where meta-analyses were possible the highest sensitivity meta-estimate was found in the Cholera Screen test (98.6%, CI: 94.7%-99.7%) and the highest specificity meta-estimate in the Crystal VC on enriched samples (98.3%, CI: 92.8%-99.6%). There was a general lack of evidence regarding field use of tests, but where presented this indicated trends for lower diagnostic accuracy in field settings, with lesser-trained staff, and without the additional process of sample enrichment. Where reported, mean test turnaround times ranged from over 50% to 130% longer than manufacturer's specification. Most studies had a low to unclear risk of bias. CONCLUSIONS: Currently available Rapid Diagnostic Tests can potentially provide high diagnostic and detection capability for cholera. However, stronger evidence is required regarding the conditions required to secure these levels of accuracy in field use, particularly in low-resource settings. REGISTRATION: PROSPERO (CRD42016048428).

External validation of the RISC, RISC-Malawi, and PERCH clinical prediction rules to identify risk of death in children hospitalized with pneumonia.

BACKGROUND: Existing scores to identify children at risk of hospitalized pneumonia-related mortality lack broad external validation. Our objective was to externally validate three such risk scores. METHODS: We applied the Respiratory Index of Severity in Children (RISC) for HIV-negative children, the RISC-Malawi, and the Pneumonia Etiology Research for Child Health (PERCH) scores to hospitalized children in the Pneumonia REsearch Partnerships to Assess WHO REcommendations (PREPARE) data set. The PREPARE data set includes pooled data from 41 studies on pediatric pneumonia from across the world. We calculated test characteristics and the area under the curve (AUC) for each of these clinical prediction rules. RESULTS: The RISC score for HIV-negative children was applied to 3574 children 0-24 months and demonstrated poor discriminatory ability (AUC = 0.66, 95% confidence interval (CI) = 0.58-0.73) in the identification of children at risk of hospitalized pneumonia-related mortality. The RISC-Malawi score had fair discriminatory value (AUC = 0.75, 95% CI = 0.74-0.77) among 17 864 children 2-59 months. The PERCH score was applied to 732 children 1-59 months and also demonstrated poor discriminatory value (AUC = 0.55, 95% CI = 0.37-0.73). CONCLUSIONS: In a large external application of the RISC, RISC-Malawi, and PERCH scores, a substantial number of children were misclassified for their risk of hospitalized pneumonia-related mortality. Although pneumonia risk scores have performed well among the cohorts in which they were derived, their performance diminished when externally applied. A generalizable risk assessment tool with higher sensitivity and specificity to identify children at risk of hospitalized pneumonia-related mortality may be needed. Such a generalizable risk assessment tool would need context-specific validation prior to implementation in that setting.

An analysis of policy and funding priorities of global actors regarding noncommunicable disease in low- and middle-income countries.

BACKGROUND: Noncommunicable diseases (NCDs), including mental health, have become a major concern in low- and middle-income countries. Despite increased attention to them over the past decade, progress toward addressing NCDs has been slow. A lack of bold policy commitments has been suggested as one of the contributors to limited progress in NCD prevention and management. However, the policies of key global actors (bilateral, multilateral, and not-for-profit organisations) have been understudied. METHODS: This study aimed to map the key global actors investing in action regarding NCDs and review their policies to examine the articulation of priorities regarding NCDs. Narrative synthesis of 70 documents and 31 policy papers was completed, and related to data collated from the Global Health Data Visualisation Tool. RESULTS: In 2019 41% of development assistance for health committed to NCDs came from private philanthropies, while that for other global health priorities from this source was just 20%. Through a range of channels, bilateral donors were the other major source of NCD funding (contributing 41% of NCD funding). The UK and the US were the largest bilateral investors in NCDs, each contributing 8%. However, NCDs are still under-prioritised within bilateral portfolios - receiving just 0.48% of US funding and 1.66% of the UK. NGOs were the key channels of funding for NCDs, spending 48% of the funds from donors in 2019. The reviewed literature generally focused on NCD policies of WHO, with policies of multilateral and bilateral donors given limited attention. The analysis of policies indicated a limited prioritisation of NCDs in policy documents. NCDs are framed in the policies as a barrier to economic growth, poverty reduction, and health system sustainability. Bilateral donors prioritise prevention, while multilateral actors offer policy options for NCD prevention and care. Even where stated as a priority, however, funding allocations are not aligned. CONCLUSION: The growing threat of NCDs and their drivers are increasingly recognised. However, global actors' policy priorities and funding allocations need to align better to address these NCD threats. Given the level of their investment and engagement, more research is needed into the role of private philanthropies and NGOs in this area.

Paying for performance to improve the delivery of health interventions in low- and middle-income countries.

BACKGROUND: There is growing interest in paying for performance (P4P) as a means to align the incentives of healthcare providers with public health goals. Rigorous evidence on the effectiveness of these strategies in improving health care and health in low- and middle-income countries (LMICs) is lacking; this is an update of the 2012 review on this topic. OBJECTIVES: To assess the effects of paying for performance on the provision of health care and health outcomes in low- and middle-income countries. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and 10 other databases between April and June 2018. We also searched two trial registries, websites, online resources of international agencies, organizations and universities, and contacted experts in the field. Studies identified from rerunning searches in 2020 are under 'Studies awaiting classification.' SELECTION CRITERIA: We included randomized or non-randomized trials, controlled before-after studies, or interrupted time series studies conducted in LMICs (as defined by the World Bank in 2018). P4P refers to the transfer of money or material goods conditional on taking a measurable action or achieving a predetermined performance target. To be included, a study had to report at least one of the following outcomes: patient health outcomes, changes in targeted measures of provider performance (such as the delivery of healthcare services), unintended effects, or changes in resource use. DATA COLLECTION AND ANALYSIS: We extracted data as per original review protocol and narratively synthesised findings. We used standard methodological procedures expected by Cochrane. Given diversity and variability in intervention types, patient populations, analyses and outcome reporting, we deemed meta-analysis inappropriate. We noted the range of effects associated with P4P against each outcome of interest. Based on intervention descriptions provided in documents, we classified design schemes and explored variation in effect by scheme design. MAIN RESULTS: We included 59 studies: controlled before-after studies (19), non-randomized (16) or cluster randomized trials (14);  and interrupted time-series studies (9). One study included both an interrupted time series and a controlled before-after study. Studies focused on a wide range of P4P interventions, including target payments and payment for outputs as modified by quality (or quality and equity assessments). Only one study assessed results-based aid. Many schemes were funded by national governments (23 studies) with the World Bank funding most externally funded schemes (11 studies). Targeted services varied; however, most interventions focused on reproductive, maternal and child health indicators. Participants were predominantly located in public or in a mix of public, non-governmental and faith-based facilities (54 studies). P4P was assessed predominantly at health facility level, though districts and other levels were also involved. Most studies assessed the effects of P4P against a status quo control (49 studies); however, some studies assessed effects against comparator interventions (predominantly enhanced financing intended to match P4P funds (17 studies)). Four studies reported intervention effects against both comparator and status quo. Controlled before-after studies were at higher risk of bias than other study designs. However, some randomised trials were also downgraded due to risk of bias. The interrupted time-series studies provided insufficient information on other concurrent changes in the study context. P4P compared to a status quo control For health services that are specifically targeted, P4P may slightly improve health outcomes (low certainty evidence), but few studies assessed this. P4P may also improve service quality overall (low certainty evidence); and probably increases the availability of health workers, medicines and well-functioning infrastructure and equipment (moderate certainty evidence). P4P may have mixed effects on the delivery and use of services (low certainty evidence) and may have few or no distorting unintended effects on outcomes that were not targeted (low-certainty evidence), but few studies assessed these. For secondary outcomes, P4P may make little or no difference to provider absenteeism, motivation or satisfaction (low certainty evidence); but may improve patient satisfaction and acceptability (low certainty evidence); and may positively affect facility managerial autonomy (low certainty evidence). P4P probably makes little to no difference to management quality or facility governance (low certainty evidence). Impacts on equity were mixed (low certainty evidence). For health services that are untargeted, P4P probably improves some health outcomes (moderate certainty evidence); may improve the delivery, use and quality of some health services but may make little or no difference to others (low certainty evidence); and may have few or no distorting unintended effects (low certainty evidence). The effects of P4P on the availability of medicines and other resources are uncertain (very low certainty evidence). P4P compared to other strategies For health outcomes and services that are specifically targeted, P4P may make little or no difference to health outcomes (low certainty evidence), but few studies assessed this. P4P may improve service quality (low certainty evidence); and may have mixed effects on the delivery and use of health services and on the availability of equipment and medicines (low certainty evidence). For health outcomes and services that are untargeted, P4P may make little or no difference to health outcomes and to the delivery and use of health services (low certainty evidence). The effects of P4P on service quality, resource availability and unintended effects are uncertain (very low certainty evidence). Findings of subgroup analyses Results-based aid, and schemes using payment per output adjusted for service quality, appeared to yield the greatest positive effects on outcomes. However, only one study evaluated results-based aid, so the effects may be spurious. Overall, schemes adjusting both for quality of service and rewarding equitable delivery of services appeared to perform best in relation to service utilization outcomes. AUTHORS' CONCLUSIONS: The evidence base on the impacts of P4P schemes has grown considerably, with study quality gradually increasing. P4P schemes may have mixed effects on outcomes of interest, and there is high heterogeneity in the types of schemes implemented and evaluations conducted. P4P is not a uniform intervention, but rather a range of approaches. Its effects depend on the interaction of several variables, including the design of the intervention (e.g., who receives payments ), the amount of additional funding,  ancillary components (such as technical support) and contextual factors (including organizational context).

An analysis of clinical predictive values for radiographic pneumonia in children.

INTRODUCTION: Healthcare providers in resource-limited settings rely on the presence of tachypnoea and chest indrawing to establish a diagnosis of pneumonia in children. We aimed to determine the test characteristics of commonly assessed signs and symptoms for the radiographic diagnosis of pneumonia in children 0-59 months of age. METHODS: We conducted an analysis using patient-level pooled data from 41 shared datasets of paediatric pneumonia. We included hospital-based studies in which >80% of children had chest radiography performed. Primary endpoint pneumonia (presence of dense opacity occupying a portion or entire lobe of the lung or presence of pleural effusion on chest radiograph) was used as the reference criterion radiographic standard. We assessed the sensitivity, specificity, and likelihood ratios for clinical findings, and combinations of findings, for the diagnosis of primary endpoint pneumonia among children 0-59 months of age. RESULTS: Ten studies met inclusion criteria comprising 15 029 children; 24.9% (n=3743) had radiographic pneumonia. The presence of age-based tachypnoea demonstrated a sensitivity of 0.92 and a specificity of 0.22 while lower chest indrawing revealed a sensitivity of 0.74 and specificity of 0.15 for the diagnosis of radiographic pneumonia. The sensitivity and specificity for oxygen saturation <90% was 0.40 and 0.67, respectively, and was 0.17 and 0.88 for oxygen saturation <85%. Specificity was improved when individual clinical factors such as tachypnoea, fever and hypoxaemia were combined, however, the sensitivity was lower. CONCLUSIONS: No single sign or symptom was strongly associated with radiographic primary end point pneumonia in children. Performance characteristics were improved by combining individual signs and symptoms.

Understanding fragility: implications for global health research and practice.

Advances in population health outcomes risk being slowed-and potentially reversed-by a range of threats increasingly presented as 'fragility'. Widely used and critiqued within the development arena, the concept is increasingly used in the field of global health, where its relationship to population health, health service delivery, access and utilization is poorly specified. We present the first scoping review seeking to clarify the meaning, definitions and applications of the term in the global health literature. Adopting the theoretical framework of concept analysis, 10 bibliographic and grey literature sources, and five key journals, were searched to retrieve documents relating to fragility and health. Reviewers screened titles and abstracts and retained documents applying the term fragility in relation to health systems, services, health outcomes and population or community health. Data were extracted according to the protocol; all documents underwent bibliometric analysis. Narrative synthesis was then used to identify defining attributes of the concept in the field of global health. A total of 377 documents met inclusion criteria. There has been an exponential increase in applications of the concept in published literature over the last 10 years. Formal definitions of the term continue to be focused on the characteristics of 'fragile and conflict-affected states'. However, synthesis indicates diverse use of the concept with respect to: level of application (e.g. from state to local community); emphasis on particular antecedent stressors (including factors beyond conflict and weak governance); and focus on health system or community resources (with an increasing tendency to focus on the interface between two). Amongst several themes identified, trust is noted as a key locus of fragility at this interface, with critical implications for health seeking, service utilization and health system and community resilience.

Cholera diagnosis in human stool and detection in water: protocol for a systematic review of available technologies.

BACKGROUND: Cholera is a highly infectious diarrheal disease spread via fecal contamination of water and food sources; it is endemic in parts of Africa and Asia and recent outbreaks have been reported in Haiti, the Zambia and Democratic Republic of the Congo. If left untreated, the disease can be fatal in less than 24 h and result in case fatality ratios of 30-50%. Cholera disproportionately affects those living in areas with poor access to water and sanitation: the long-term public health response is focused on improving water and hygiene facilities and access. Short-term measures for infection prevention and control, and disease characterization and surveillance, are impaired by diagnostic delays: culture methods are slow and rely on the availability of infrastructure and specialist equipment. Rapid diagnostic tests have shown promise under field conditions and further innovations in this area have been proposed. METHODS: This paper is the protocol for a systematic review focused on identifying current technologies and methods used for cholera diagnosis in stool, and detection in water. We will synthesize and appraise information on product technical specifications, accuracy and design features in order to inform infection prevention and control and innovation development. Embase, MEDLINE, CINAHL, Proquest, IndMed and the WHO and Campbell libraries will be searched. We will include studies reporting on field evaluations, including within-study comparisons against a reference standard, and laboratory evaluations reporting on product validation against field stool or water samples. We will extract data according to protocol and attempt meta-analyses if appropriate given data availability and quality. DISCUSSION: The systematic review builds on a previous scoping review in this field and expands upon this by synthesising data on both product technical characteristics and design features. The review will be of particular value to stakeholders engaged in diagnostic procurement and manufacturers interested in developing cholera or diarrheal disease diagnostics. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016048428 .