GAPS phase II: development and pilot results of the global assessment in pediatric surgery, an evidence-based pediatric surgical capacity assessment tool for low-resource settings.

PURPOSE: Pediatric surgical care in low- and middle-income countries is often hindered by systemic gaps in healthcare resources, infrastructure, training, and organization. This study aims to develop and validate the Global Assessment of Pediatric Surgery (GAPS) to appraise pediatric surgical capacity and discriminate between levels of care across diverse healthcare settings. METHODS: The GAPS Version 1 was constructed through a synthesis of existing assessment tools and expert panel consultation. The resultant GAPS Version 2 underwent international pilot testing. Construct validation categorized institutions into providing basic or advanced surgical care. GAPS was further refined to Version 3 to include only questions with a > 75% response rate and those that significantly discriminated between basic or advanced surgical settings. RESULTS: GAPS Version 1 included 139 items, which, after expert panel feedback, was expanded to 168 items in Version 2. Pilot testing, in 65 institutions, yielded a high response rate. Of the 168 questions in GAPS Version 2, 64 significantly discriminated between basic and advanced surgical care. The refined GAPS Version 3 tool comprises 64 questions on: human resources (9), material resources (39), outcomes (3), accessibility (3), and education (10). CONCLUSION: The GAPS Version 3 tool presents a validated instrument for evaluating pediatric surgical capabilities in low-resource settings.

Modeling the global impact of reducing out-of-pocket costs for children's surgical care.

Over 1.7 billion children lack access to surgical care, mostly in low- and middle-income countries (LMICs), with substantial risks of catastrophic health expenditures (CHE) and impoverishment. Increasing interest in reducing out-of-pocket (OOP) expenditures as a tool to reduce the rate of poverty is growing. However, the impact of reducing OOP expenditures on CHE remains poorly understood. The purpose of this study was to estimate the global impact of reducing OOP expenditures for pediatric surgical care on the risk of CHE within and between countries. Our goal was to estimate the impact of reducing OOP expenditures for surgical care in children for 149 countries by modeling the risk of CHE under various scale-up scenarios using publicly available World Bank data. Scenarios included reducing OOP expenditures from baseline levels to paying 70%, 50%, 30%, and 10% of OOP expenditures. We also compared the impact of these reductions across income quintiles (poorest, poor, middle, rich, richest) and differences by country income level (low-income, lower-middle-income, upper-middle-income, and high-income countries).Reducing OOP expenditures benefited people from all countries and income quintiles, although the benefits were not equal. The risk of CHE due to a surgical procedure for children was highest in low-income countries. An unexpected observation was that upper-middle income countries were at higher risk for CHE than LMICs. The most vulnerable regions were Africa and Latin America. Across all countries, the poorest quintile had the greatest risk for CHE. Increasing interest in financial protection programs to reduce OOP expenditures is growing in many areas of global health. Reducing OOP expenditures benefited people from all countries and income quintiles, although the benefits were not equal across countries, wealth groups, or even by wealth groups within countries. Understanding these complexities is critical to develop appropriate policies to minimize the risks of poverty.

The Brighton collaboration standardized module for vaccine benefit-risk assessment.

Vaccine Benefit-Risk (B-R) assessment consists of evaluating the benefits and risks of a vaccine and making a judgment whether the expected key benefits outweigh the potential key risks associated with its expected use. B-R supports regulatory and public health decision-making throughout the vaccine's lifecycle. In August 2021, the Brighton Collaboration's Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Benefit-Risk Assessment Module working group was established to develop a standard module to support the planning, conduct and evaluation of structured B-R assessments for vaccines from different platforms, based on data from clinical trials, post-marketing studies and real-world evidence. It enables sharing of relevant information via value trees, effects tables and graphical depictions of B-R trade-offs. It is intended to support vaccine developers, funders, regulators and policy makers in high-, middle- or low-income countries to help inform decision-making and facilitate transparent communication concerning development, licensure, deployment and other lifecycle decisions.

Scaling up antivenom for snakebite envenoming in the Brazilian Amazon: a cost-effectiveness analysis.

Background: Snakebite envenoming (SBE) affects nearly three million people yearly, causing up to 180,000 deaths and 400,000 cases of permanent disability. Brazil's state of Amazonas is a global hotspot for SBE, with one of the highest annual incidence rates per 100,000 people, worldwide. Despite this burden, snake antivenom remains inaccessible to a large proportion of SBE victims in Amazonas. This study estimates the costs, and health and economic benefits of scaling up antivenom to community health centers (CHCs) and hospitals in the state. Methods: We built a decision tree model to simulate three different antivenom scale-up scenarios: (1) scale up to 95% of hospitals, (2) scale up to 95% of CHCs, and (3) scale up to 95% of hospitals and 95% of CHCs. We consider each scenario with and without a 10% increase in demand for antivenom among SBE victims. For each scenario, we model the treatment costs averted, deaths averted, and disability-adjusted life years (DALYs) averted from a societal, health system, and patient perspective relative to the status quo and over a time horizon of one year. For each scenario and perspective, we also calculate the incremental cost per DALY averted and per death averted. We use a willingness to pay threshold equal to the 2022 gross domestic product (GDP) per capita of Brazil. Findings: Scaling up antivenom to 95% of hospitals averts up to 2022 DALYs, costs up to USD $460 per DALY averted from a health system perspective, but results in net economic benefits up to USD $4.42 million from a societal perspective. Scaling up antivenom to 95% of CHCs averts up to 3179 DALYs, costs up to USD $308 per DALY averted from a health system perspective, but results in net economic benefits up to USD $7.35 million from a societal perspective. Scaling up antivenom to 95% of hospitals and CHCs averts up to 3922 DALYs, costs up to USD $328 per DALY averted from a health system perspective, but results in net economic benefits up to USD $8.98 million from a societal perspective. Interpretation: All three antivenom scale up scenarios - scale up to 95% of hospitals, scale up to 95% of CHCs, and scale up to 95% of hospitals and 95% of CHCs - avert a substantial proportion of the SBE burden in Amazonas and are cost-saving from a societal perspective and cost-effective from a health system perspective. Funding: W.M. and J.S. were funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq productivity scholarships). W.M. was funded by Fundação de Amparo à Pesquisa do Estado do Amazonas (PRÓ-ESTADO, call n. 011/2021-PCGP/FAPEAM, call n. 010/2021-CT&I ÁREAS PRIORITÁRIAS, call n. 003/2022-PRODOC/FAPEAM, POSGRAD/FAPEAM) and by the Ministry of Health, Brazil (Proposal No. 733781/19-035). Research reported in this publication was supported by the Fogarty International Center of the National Institutes of Health under Award Number R21TW011944. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Comparison of Masimo Total Hemoglobin SpHb® continuous non-invasive hemoglobin monitoring device with laboratory complete blood count measurement using venous sample: Protocol for an observational substudy of the Pregnancy Risk and Infant Surveillance and Measurement Alliance Maternal and Newborn Health (PRISMA MNH) study.

Background: The Masimo Total Hemoglobin SpHb® is a continuous and non-invasive handheld device to measure hemoglobin levels. Previous research has found that SpHb is able to accurately detect hemoglobin levels in adult patients with a similar degree of bias and standard deviation to point-of-care invasive method measurements. Generally, limited clinical evidence, lack of validation of Masimo at higher than and lower than hemoglobin threshold values, and scientific consensus supporting the use of Masimo for accurate hemoglobin testing for the diagnosis of anemia during pregnancy calls for further research. Methods and analysis: The proposed prospective cohort will be nested within the ongoing Pregnancy Risk and Infant Surveillance and Measurement Alliance (PRISMA) Maternal and Newborn Health (MNH) study. Three study sites (located in Zambia, Kenya, and Pakistan) will participate and collect hemoglobin data at five time points (<20 weeks, 20 weeks, 28 weeks, 36 weeks' gestation, and six weeks postpartum). We will measure hemoglobin using a venous blood sample via hematology auto-analyzer complete blood count (gold standard) and the non-invasive device. The primary objective is to assess agreement between Masimo total hemoglobin and complete blood count and on a continuous scale using Intraclass Correlation Coefficient and Bland-Altman Analysis. The second objective is to assess agreement between the two measures on a binary scale using Positive Percentage Agreement and Negative Percentage Agreement, Cohen's Kappa, and McNemar Test. On an ordinal scale, agreement will be measured using Weighted Cohen's Kappa and Harrel's Concordance Index. Lastly, we will assess factors that might affect the accuracy of Masimo total hemoglobin using linear mixed models. Conclusions: The primary aim of this study is to assess the validity of the non-invasive Masimo device compared to the gold standard method of invasive hemoglobin measurements during pregnancy and postpartum periods for the diagnosis of anemia.

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for the Novavax COVID-19 Vaccine (NVX-CoV2373), a recombinant spike protein vaccine with Matrix-M adjuvant to prevent disease caused by SARS-CoV-2 viruses.

Novavax, a global vaccine company, began evaluating NVX-CoV2373 in human studies in May 2020 and the pivotal placebo-controlled phase 3 studies started in November 2020; five clinical studies provided adult and adolescent clinical data for over 31,000 participants who were administered NVX-CoV2373. This extensive data has demonstrated a well-tolerated response to NVX-CoV2373 and high vaccine efficacy against mild, moderate, or severe COVID-19 using a two-dose series (Dunkle et al., 2022) [1], (Heath et al., 2021) [2], (Keech et al., 2020) [3], (Mallory et al., 2022) [4]. The most common adverse events seen after administration with NVX-CoV2373 were injection site tenderness, injection site pain, fatigue, myalgia, headache, malaise, arthralgia, nausea, or vomiting. In addition, immunogenicity against variants of interest (VOI) and variants of concern (VOC) was established with high titers of ACE2 receptor-inhibiting and neutralizing antibodies in these studies (EMA, 2022) [5], (FDA, 2023) [6]. Further studies on correlates of protection determined that titers of anti-Spike IgG and neutralizing antibodies correlated with efficacy against symptomatic COVID-19 established in clinical trials (p < 0.001 for recombinant protein vaccine and p = 0.005 for mRNA vaccines for IgG levels) (Fong et al., 2022) [7]. Administration of a booster dose of the recombinant protein vaccine approximately 6 months following the primary two-dose series resulted in substantial increases in humoral antibodies against both the prototype strain and all evaluated variants, similar to or higher than the antibody levels observed in phase 3 studies that were associated with high vaccine efficacy (Dunkle et al., 2022) [1], (Mallory et al., 2022) [4]. These findings, together with the well tolerated safety profile, support use of the recombinant protein vaccine as primary series and booster regimens.

Evaluating the status of the Lancet Commission on Global Surgery indicators for India.

For universal surgical, obstetric, trauma, and anesthesia care by 2030, the Lancet Commission on Global Surgery (LCoGS) suggested tracking six indicators. We reviewed academic and policy literature to investigate the current state of LCoGS indicators in India. There was limited primary data for access to timely essential surgery, risk of impoverishing and catastrophic health expenditures due to surgery, though some modeled estimates are present. Surgical specialist workforce estimates are heterogeneous across different levels of care, urban and rural areas, and diverse health sectors. Surgical volumes differ widely across demographic, socio-economic, and geographic cohorts. Perioperative mortality rates vary across procedures, diagnoses, and follow-up time periods. Available data suggest India falls short of achieving global targets. This review highlights the evidence gap for India's surgical care planning. India needs a systematic subnational mapping of indicators and adaptation of targets as per the country's health needs for equitable and sustainable planning.

Does reducing out-of-pocket costs for children's surgical care protect families from poverty in Somaliland? A cross-sectional, national, economic evaluation modelling study.

OBJECTIVES: An estimated 1.7 billion children around the world do not have access to safe, affordable and timely surgical care, with the financing through out-of-pocket (OOP) expenses being one of the main barriers to care. Our study modelled the impact of reducing OOP costs related to surgical care for children in Somaliland on the risk of catastrophic expenditures and impoverishment. DESIGN AND SETTING: This cross-sectional nationwide economic evaluation modelled several different approaches to reduction of paediatric OOP surgical costs in Somaliland. PARTICIPANTS AND OUTCOME MEASURES: A surgical record review of all procedures on children up to 15 years old was conducted at 15 surgically capable hospitals. We modelled two rates of OOP cost reduction (reduction of OOP proportion from 70% to 50% and from 70% to 30% reduction in OOP costs) across five wealth quintiles (poorest, poor, neutral, rich, richest) and two geographical areas (urban and rural). The outcome measures of the study are catastrophic expenditures and risk of impoverishment due to surgery. We followed the Consolidated Health Economic Evaluation Reporting Standards. RESULTS: We found that the risk of catastrophic and impoverishing expenditures related to OOP expenditures for paediatric surgery is high across Somaliland, but most notable in the rural areas and among the poorest quintiles. Reducing OOP expenses for surgical care to 30% would protect families in the richest wealth quintiles while minimally affecting the risk of catastrophic expenditure and impoverishment for those in the lowest wealth quintiles, particularly those in rural areas. CONCLUSION: Our models suggest that the poorest communities in Somaliland lack protection against the risk of catastrophic health expenditure and impoverishment, even if OOP payments are reduced to 30% of surgical costs. A comprehensive financial protection in addition to reduction of OOP costs is required to prevent risk of impoverishment in these communities.

Antenatal multiple micronutrient supplements versus iron-folic acid supplements and birth outcomes: Analysis by gestational age assessment method.

Meta-analyses consistently have found that antenatal multiple micronutrient supplementation (MMS) compared with iron and folic acid (IFA) alone reduce adverse birth outcomes. In 2020, the World Health Organization (WHO) placed a conditional recommendation for MMS and requested additional trials using ultrasounds to establish gestational age, because the evidence on low birthweight (LBW), preterm birth and small for gestational age (SGA) was considered inconsistent. We conducted meta-analyses to determine if the effects of MMS on LBW, preterm birth and SGA differed by gestational age assessment method. Using data from the 16 trials in the WHO analyses, we calculated the effect estimates of MMS versus IFA on birth outcomes (generic inverse variance method and random effects model) stratified by method of gestational age assessment: ultrasound, prospective collection of the date of last menstrual period (LMP) and confirmation of pregnancy by urine test and recall of LMP. The effects of MMS versus IFA on birthweight, preterm birth and SGA appeared consistent across subgroups with no evidence of subgroup differences (p > 0.05). When limited to the seven trials that used ultrasound, the beneficial effects of MMS were demonstrated: risk ratios of 0.87 (95% confidence interval [CI] 0.78-0.97) for LBW, 0.90 (95% CI, 0.79-1.03) for preterm birth and 0.9 (95% CI, 0.83-0.99) for SGA. Sensitivity analyses indicated consistency in the results. These results, together with recent analyses demonstrating comparable effects of MMS (vs. IFA) on maternal anaemia outcomes, strengthen the evidence to support a transition from IFA to MMS programmes in low- and middle-income countries.

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for the Medigen COVID-19 protein vaccine.

The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit-risk assessment of several vaccine platform technologies, including protein subunit vaccines. This article uses the BRAVATO template to review the features of the MVC-COV1901 vaccine, a recombinant protein subunit vaccine based on the stabilized pre-fusion SARS-CoV-2 spike protein S-2P, adjuvanted with CpG 1018 and aluminum hydroxide, manufactured by Medigen Vaccine Biologics Corporation in Taiwan. MVC-COV1901 vaccine is indicated for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 12 years of age and older. The template offers details on basic vaccine information, target pathogen and population, characteristics of antigen and adjuvant, preclinical data, human safety and efficacy data, and overall benefit-risk assessment. The clinical development program began in September 2020 and based on demonstration of favorable safety and immunogenicity profiles in 11 clinical trials in over 5,000 participants, it has been approved for emergency use based on immunobridging results for adults in Taiwan, Estwatini, Somaliland, and Paraguay. The main clinical trials include placebo-controlled phase 2 studies in healthy adults (CT-COV-21), adolescents (CT-COV-22), and elderly population (CT-COV-23) as well as 3 immunobridging phase 3 trials (CT-COV-31, CT-COV-32, and CT-COV-34) in which MVC-COV1901 was compared to AZD1222. There are also clinical trials studying MVC-COV1901 as homologous and heterologous boosters (CT-COV-24 and CT-COV-25). The totality of evidence based on ∼3 million vaccinees to date includes a mostly clean safety profile, with adverse events mostly being mild and self-limiting in both clinical development and post-marketing experience, proven immunogenic response, and real-world effectiveness data. The immunogenic profile demonstrates that MVC-COV1901 induces high levels of neutralizing and binding antibodies against SARS-CoV-2. There is a dose-dependent response and a significant correlation between binding and neutralizing antibody activity. Antigen-specific T-cell responses, particularly a Th1-biased immune response characterized by high levels of interferon gamma and IL-2 cytokines, have also been observed. Coupled with this, MVC-COV1901 has favorable thermostability and better safety profiles when compared to other authorized vaccines from different platforms, which make it potentially a good candidate for vaccine supply chains in global markets.

Picture Cards Versus Physical Examination: A Proof-of-Concept Study to Improve the SOSAS Survey Tool.

INTRODUCTION: The Surgeons OverSeas Assessment of Surgical Needs (SOSAS) survey tool is used to determine the unmet surgical needs in the community and has been validated in several countries. A major weakness is the absence of an objective assessment to verify patient-reported surgically treatable conditions. The goal of this study was to determine whether a picture portfolio, a tool previously shown to improve parental recognition of their child's congenital deformity, could improve the accuracy of the SOSAS tool by how it compares with physical examination. This study focused on children as many surgical conditions in them require prompt treatment but are often not promptly diagnosed. METHODS: We conducted a descriptive cross-sectional community-based study to determine the prevalence of congenital and acquired surgical conditions among children and adults in a mixed rural-urban area of Lagos, Southwest Nigeria. The picture portfolio was administered only to children and the surgical conditions to be assessed were predetermined using an e-Delphi process among pediatric surgeons. The modified The Surgeons OverSeas Assessment of Surgical Needs-Nigeria Survey Tool (SOSAS-NST) was administered to household members to collect other relevant data. Data were analyzed using the REDCap analytic tool. RESULTS: Eight hundred and fifty-six households were surveyed. There were 1984 adults (49.5%) and 2027 children (50.5%). Thirty-six children met the predetermined criteria for the picture portfolio-hydrocephalus (n = 1); lymphatic malformation (n = 1); umbilical hernia (n = 14); Hydrocele (n = 5); inguinal hernia (n = 10) and undescended testes (n = 5). The picture portfolio predicted all correctly except a case of undescended testis that was mistaken for a hernia. The sensitivity of the picture portfolio was therefore 35/36 or 97.2%. CONCLUSIONS: The SOSAS-NST has improved on the original SOSAS tool and within the limits of the small numbers, the picture portfolio has a high accuracy in predicting diagnosis in children in lieu of physical examination.

Modeling the Scale-up of Surgical Services for Children with Surgically Treatable Congenital Conditions in Somaliland.

BACKGROUND: Congenital conditions comprise a significant portion of the global burden of surgical conditions in children. In Somaliland, over 250,000 children do not receive required surgical care annually, although the estimated costs and benefits of scale-up of children's surgical services to address this disease burden is not known. METHODS: We developed a Markov model using a decision tree template to project the costs and benefits of scale-up of surgical care for children across Somaliland. We used a proxy set of congenital anomalies across Somaliland to estimate scale-up costs using three different scale-up rates. The cost-effectiveness ratio and net societal monetary benefit were estimated using these models, supported by disability weights in existing literature. RESULTS: Overall, we found that scale-up of surgical services at an aggressive rate (22.5%) over a 10-year time horizon is cost effective. Although the scale-up of surgical care for most conditions in the proxy set was cost effective, scale-up of hydrocephalus and spina bifida are not as cost effective as other conditions. CONCLUSIONS: Our analysis concludes that it is cost effective to scale-up surgical services for congenital anomalies for children in Somaliland.

Defining Surgical Workforce Density Targets to Meet Child and Neonatal Mortality Rate Targets in the Age of the Sustainable Development Goals: A Global Cross-Sectional Study.

OBJECTIVES: To reduce preventable deaths of newborns and children, the United Nations set a target rate per 1000 live births of 12 for neonatal mortality (NMR) and 25 for under-5 mortality (U5MR). The purpose of this paper is to define the minimum surgical workforce needed to meet these targets and evaluate the relative impact of increasing surgeon, anesthesia, and obstetrician (SAO) density on reducing child mortality. METHODS: We conducted a cross-sectional study of 192 countries to define the association between surgical workforce density and U5MR as well as NMR using unadjusted and adjusted B-spline regression, adjusting for common non-surgical causes of childhood mortality. We used these models to estimate the minimum surgical workforce to meet the sustainable development goals (SDGs) for U5MR and NMR and marginal effects plots to determine over which range of SAO densities the largest impact is seen as countries scale-up SAO workforce. RESULTS: We found that increased SAO density is associated with decreased U5MR and NMR (P < 0.05), adjusting for common non-surgical causes of child mortality. A minimum SAO density of 10 providers per 100,000 population (95% CI: 7-13) is associated with an U5MR of < 25 per 1000 live births. A minimum SAO density of 12 (95% CI: 9-20) is associated with an NMR of < 12 per 1000 live births. The maximum decrease in U5MR, on the basis of our adjusted B-spline model, occurs from 0 to 20 SAO per 100,000 population. The maximum decrease in NMR based on our adjusted B-spline model occurs up from 0 to 18 SAO, with additional decrease seen up to 80 SAO. CONCLUSIONS: Scale-up of the surgical workforce to 12 SAO per 100,000 population may help health systems meet the SDG goals for childhood mortality rates. Increases in up to 80 SAO/100,000 continue to offer mortality benefit for neonates and would help to achieve the SDGs for neonatal mortality reduction.

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for the Moderna COVID-19 Vaccine (mRNA-1273).

The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit-risk assessment of several vaccine platform technologies, including nucleic acid (RNA and DNA) vaccines. This paper uses the BRAVATO template to review the features of a vaccine employing a proprietary mRNA vaccine platform to develop Moderna COVID-19 Vaccine (mRNA-1273); a highly effective vaccine to prevent coronavirus disease 2019 (Covid-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In response to the pandemic the first in human studies began in March 2020 and the pivotal, placebo-controlled phase 3 efficacy study in over 30,000 adults began in July 2020. Based on demonstration of efficacy and safety at the time of interim analysis in November 2020 and at the time of trial unblinding in March 2021, the mRNA-1273 received Emergency Use Authorization in December 2020 and full FDA approval in January 2022.

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for an inactivated viral vaccine against Chikungunya virus.

Inactivated viral vaccines have long been used in humans for diseases of global health threat (e.g., poliomyelitis and pandemic and seasonal influenza) and the technology of inactivation has more recently been used for emerging diseases such as West Nile, Chikungunya, Ross River, SARS and especially for COVID-19. The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit and risk of several vaccine platform technologies, including inactivated viral vaccines. This paper uses the BRAVATO inactivated virus vaccine template to review the features of an inactivated whole chikungunya virus (CHIKV) vaccine that has been evaluated in several preclinical studies and clinical trials. The inactivated whole CHIKV vaccine was cultured on Vero cells and inactivated by ß-propiolactone. This provides an effective, flexible system for high-yield manufacturing. The inactivated whole CHIKV vaccine has favorable thermostability profiles, compatible with vaccine supply chains. Safety data are compiled in the current inactivated whole CHIKV vaccine safety database with unblinded data from the ongoing studies: 850 participants from phase II study (parts A and B) outside of India, and 600 participants from ongoing phase II study in India, and completed phase I clinical studies for 60 subjects. Overall, the inactivated whole CHIKV vaccine has been well tolerated, with no significant safety issues identified. Evaluation of the inactivated whole CHIKV vaccine is continuing, with 1410 participants vaccinated as of 20 April 2022. Extensive evaluation of immunogenicity in humans shows strong, durable humoral immune responses.

Vaccines based on the replication-deficient simian adenoviral vector ChAdOx1: Standardized template with key considerations for a risk/benefit assessment.

Replication-deficient adenoviral vectors have been under investigation as a platform technology for vaccine development for several years and have recently been successfully deployed as an effective COVID-19 counter measure. A replication-deficient adenoviral vector based on the simian adenovirus type Y25 and named ChAdOx1 has been evaluated in several clinical trials since 2012. The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) was formed to evaluate the safety and other key features of new platform technology vaccines. This manuscript reviews key features of the ChAdOx1-vectored vaccines. The simian adenovirus Y25 was chosen as a strategy to circumvent pre-existing immunity to common human adenovirus serotypes which could impair immune responses induced by adenoviral vectored vaccines. Deletion of the E1 gene renders the ChAdOx1 vector replication incompetent and further genetic engineering of the E3 and E4 genes allows for increased insertional capability and optimizes vaccine manufacturing processes. ChAdOx1 vectored vaccines can be manufactured in E1 complementing cell lines at scale and are thermostable. The first ChAdOx1 vectored vaccines approved for human use, against SARS-CoV-2, received emergency use authorization in the UK on 30th December 2020, and is now approved in more than 180 countries. Safety data were compiled from phase I-III clinical trials of ChAdOx1 vectored vaccines expressing different antigens (influenza, tuberculosis, malaria, meningococcal B, prostate cancer, MERS-CoV, Chikungunya, Zika and SARS-CoV-2), conducted by the University of Oxford, as well as post marketing surveillance data for the COVID-19 Oxford-AstraZeneca vaccine. Overall, ChAdOx1 vectored vaccines have been well tolerated. Very rarely, thrombosis with thrombocytopenia syndrome (TTS), capillary leak syndrome (CLS), immune thrombocytopenia (ITP), and Guillain-Barre syndrome (GBS) have been reported following mass administration of the COVID-19 Oxford-AstraZeneca vaccine. The benefits of this COVID-19 vaccination have outweighed the risks of serious adverse events in most settings, especially with mitigation of risks when possible. Extensive immunogenicity clinical evaluation of ChAdOx1 vectored vaccines reveal strong, durable humoral and cellular immune responses to date; studies to refine the COVID-19 protection (e.g., via homologous/heterologous booster, fractional dose) are also underway. New prophylactic and therapeutic vaccines based on the ChAdOx1 vector are currently undergoing pre-clinical and clinical assessment, including vaccines against viral hemorrhagic fevers, Nipah virus, HIV, Hepatitis B, amongst others.

Problems with evidence assessment in COVID-19 health policy impact evaluation: a systematic review of study design and evidence strength.

INTRODUCTION: Assessing the impact of COVID-19 policy is critical for informing future policies. However, there are concerns about the overall strength of COVID-19 impact evaluation studies given the circumstances for evaluation and concerns about the publication environment. METHODS: We included studies that were primarily designed to estimate the quantitative impact of one or more implemented COVID-19 policies on direct SARS-CoV-2 and COVID-19 outcomes. After searching PubMed for peer-reviewed articles published on 26 November 2020 or earlier and screening, all studies were reviewed by three reviewers first independently and then to consensus. The review tool was based on previously developed and released review guidance for COVID-19 policy impact evaluation. RESULTS: After 102 articles were identified as potentially meeting inclusion criteria, we identified 36 published articles that evaluated the quantitative impact of COVID-19 policies on direct COVID-19 outcomes. Nine studies were set aside because the study design was considered inappropriate for COVID-19 policy impact evaluation (n=8 pre/post; n=1 cross-sectional), and 27 articles were given a full consensus assessment. 20/27 met criteria for graphical display of data, 5/27 for functional form, 19/27 for timing between policy implementation and impact, and only 3/27 for concurrent changes to the outcomes. Only 4/27 were rated as overall appropriate. Including the 9 studies set aside, reviewers found that only four of the 36 identified published and peer-reviewed health policy impact evaluation studies passed a set of key design checks for identifying the causal impact of policies on COVID-19 outcomes. DISCUSSION: The reviewed literature directly evaluating the impact of COVID-19 policies largely failed to meet key design criteria for inference of sufficient rigour to be actionable by policy-makers. More reliable evidence review is needed to both identify and produce policy-actionable evidence, alongside the recognition that actionable evidence is often unlikely to be feasible.

Challenges with pediatric surgical financing and universal health coverage in Guatemala: A qualitative analysis.

The financing of surgical care for children in low- and middle-income countries (LMICs) remains challenging and may restrict adherence to universal health coverage (UHC) frameworks. Our aims were to describe Guatemala's national pediatric surgical financing structure, to identify financing challenges, and to develop recommendations to improve the financing of surgical care for children. We conducted a qualitative study of the financing of surgical care for children in Guatemala's public health system with key informant interviews (n = 20) with experts in the medical, financial, and political health sectors. We used this data to generate recommendations to improve surgical care financing for children. We identified several systemic challenges to the financing of surgical care for children, including passive purchasing structures, complex political contexts, health system fragmentation, widespread use of informal fees for surgical services, and lack of earmarked funding for surgical care. Patient and provider challenges include lack of provider input in non-personnel funding decisions, and patients functioning as both financing agents and beneficiaries in the same financing stream. Key recommendations include reducing health finance system fragmentation through resource pooling, increasing earmarked funding for surgical care with quantifiable outcome measures, engagement with clinical providers in non-personnel budgetary decision-making, and use of innovative financing instruments such as resource pooling. Surgical financing for children in Guatemala requires substantial remodeling to increase access to timely, affordable, and safe surgical care and improve alignment with Guatemala's UHC scheme.

The psychological distress of parents is associated with reduced linear growth of children: Evidence from a nationwide population survey.

BACKGROUND: Stunting, an indicator of restricted linear growth, has become a primary measure of childhood undernutrition due to its persistent high prevalence globally, and importance for health and development. Although the etiology is recognized as complex, most analyses have focused on social and biomedical determinants, with limited attention on psychological factors affecting care and nurturing in the home. We assessed whether the psychological distress of parents is related to child linear growth and stunting, and documented the associated risk factors, and examined the relationship between parental distress and behavioral and other risk factors for stunting. METHODS: We used data from the Indonesia National Health Survey 2013, including 46,315 children 6-59 months of age. Multivariate linear, logistic, and multilevel multinomial logistic regression, using survey weights, were used to assess the relationship between parental distress, as assessed by the WHO Self Reporting Questionnaire (SRQ20), with height-for-age z score (HAZ), stunting, and behavioral and other risk factors for stunting. RESULTS: Maternal, paternal and parental distress (i.e. both maternal and paternal distress) were associated with reduced linear growth of the children by 0.086 (95% CI -0.17, -0.00), 0.11 (95% CI -0.24, -0.02) and 0.19 (95% CI -0.37, -0.00) HAZ-scores, respectively. Maternal and paternal distress increased the risk of mild stunting (HAZ <-1) by 33% (95% CI 1.17,1.50) and 37% (95% CI 1.18,1.60), and the risk of moderate stunting (HAZ <-2) by 25% (95% CI 1.10,1.43) and 28% (95% CI 1.08,1.51]), respectively. Parental stress increased the risk of moderate stunting by 40% (95% CI 1.06,1.85). Amongst specific groups of risk factors, the proportion of HAZ-score lost was associated with socioeconomic factors (30.3%) including, low wealth, low maternal occupational status, low maternal education, rural residence, and low paternal occupational status; physiological factors (15.5%) including low maternal height, low maternal mid-upper arm circumference, being male, low paternal height; behavioral factors (8.9%) including open garbage disposal, paternal smoking, not using iodized salt; and experiencing at least one infectious diseases episode (1.1%). CONCLUSIONS: Maternal, paternal and parental stress were associated with reduced linear growth of children. These findings highlight the complex etiology of stunting and suggest nutritional and other biomedical interventions are insufficient, and that promotion of mental and behavioral health programs for parents must be pursued as part of a comprehensive strategy to enhance child growth and development, i.e. improved caretaker capacity, integrated community development, improved parenting skills, as well as reduced gender discrimination, and domestic violence.

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for a soluble glycoprotein vaccine to prevent disease caused by Nipah or Hendra viruses.

Auro Vaccines LLC has developed a protein vaccine to prevent disease from Nipah and Hendra virus infection that employs a recombinant soluble Hendra glycoprotein (HeV-sG) adjuvanted with aluminum phosphate. This vaccine is currently under clinical evaluation in a Phase 1 study. The Benefit-Risk Assessment of VAccines by TechnolOgy Working Group (BRAVATO; ex-V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of protein vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of such a vaccine platform. The structured and standardized assessment provided by the template may also help contribute to improved public acceptance and communication of licensed protein vaccines.