Embedding rapid reviews in health policy and systems decision-making: Impacts and lessons learned from four low- and middle-income countries.

BACKGROUND: Demand for rapid evidence-based syntheses to inform health policy and systems decision-making has increased worldwide, including in low- and middle-income countries (LMICs). To promote use of rapid syntheses in LMICs, the WHO's Alliance for Health Policy and Systems Research (AHPSR) created the Embedding Rapid Reviews in Health Systems Decision-Making (ERA) Initiative. Following a call for proposals, four LMICs were selected (Georgia, India, Malaysia and Zimbabwe) and supported for 1 year to embed rapid response platforms within a public institution with a health policy or systems decision-making mandate. METHODS: While the selected platforms had experience in health policy and systems research and evidence syntheses, platforms were less confident conducting rapid evidence syntheses. A technical assistance centre (TAC) was created from the outset to develop and lead a capacity-strengthening program for rapid syntheses, tailored to the platforms based on their original proposals and needs as assessed in a baseline questionnaire. The program included training in rapid synthesis methods, as well as generating synthesis demand, engaging knowledge users and ensuring knowledge uptake. Modalities included live training webinars, in-country workshops and support through phone, email and an online platform. LMICs provided regular updates on policy-makers' requests and the rapid products provided, as well as barriers, facilitators and impacts. Post-initiative, platforms were surveyed. RESULTS: Platforms provided rapid syntheses across a range of AHPSR themes, and successfully engaged national- and state-level policy-makers. Examples of substantial policy impact were observed, including for COVID-19. Although the post-initiative survey response rate was low, three quarters of those responding felt confident in their ability to conduct a rapid evidence synthesis. Lessons learned coalesced around three themes - the importance of context-specific expertise in conducting reviews, facilitating cross-platform learning, and planning for platform sustainability. CONCLUSIONS: The ERA initiative successfully established rapid response platforms in four LMICs. The short timeframe limited the number of rapid products produced, but there were examples of substantial impact and growing demand. We emphasize that LMICs can and should be involved not only in identifying and articulating needs but as co-designers in their own capacity-strengthening programs. More time is required to assess whether these platforms will be sustained for the long-term.

PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions.

Through tightly controlled multilayer mechanisms, vascular endothelial growth factor receptor-2 (VEGFR-2) activation and its downstream signal transduction govern vasculogenesis and pathological angiogenesis, such as tumor angiogenesis. Therefore, it is critical to understand the molecular mechanisms governing VEGFR-2 signal transduction. We report that protein arginine methyltransferase 4 (PRMT4) via its highly conserved EVH1 and PH domain-like N-terminal domain binds to VEGFR-2 and mediates methylation of the juxtamembrane arginine 817 (R817) on VEGFR-2. Methylation of R817 selectively increases phosphorylation of tyrosine 820 (Y820). Phosphorylation of Y820 facilitates the c-Src binding with VEGFR-2 via Src homology domain 2 (SH2). Interfering with the methylation of R817 or phosphorylation of Y820 inhibits VEGFR-2-induced filopodia protrusions, a process that is critical for the core angiogenic responses of VEGFR-2. Methylation of R817 is an important previously unrecognized mechanism of the angiogenic signaling of VEGFR-2, with implications for the development of novel-targeted VEGFR-2 inhibitors.

Avoiding the Road to Nowhere: Policy Insights on Scaling up and Sustaining Digital Health.

Digital health solutions offer tremendous potential to enhance the reach and quality of health services and population-level outcomes in low- and middle-income countries (LMICs). While the number of programs reaching scale increases yearly, the long-term sustainability for most remains uncertain. In this article, as researchers and implementors, we draw on experiences of designing, implementing and evaluating digital health solutions at scale in Africa and Asia, and provide examples from India and South Africa to illustrate ten considerations to support scale and sustainability of digital health solutions in LMICs. Given the investments being made in digital health solutions and the urgent concurrent needs to strengthen health systems to ensure their responsiveness to marginalized populations in LMICs, we cannot afford to go down roads that 'lead to nowhere'. These ten considerations focus on drivers of equity and innovation, the foundations for a digital health ecosystem, and the elements for systems integration. We urge technology enthusiasts to consider these issues before and during the roll-out of large-scale digital health initiatives to navigate the complexities of achieving scale and enabling sustainability.

Consensus and development of document for management of stabilized acute decompensated heart failure with reduced ejection fraction in India.

AIM: Ensuring adherence to guideline-directed medical therapy (GDMT) is an effective strategy to reduce mortality and readmission rates for heart failure (HF). Use of a checklist is one of the best tools to ensure GDMT. The aim was to develop a consensus document with a robust checklist for stabilized acute decompensated HF patients with reduced ejection fraction. While there are multiple checklists available, an India-specific checklist that is easy to fill and validated by regional and national subject matter experts (SMEs) is required. METHODOLOGY: A total of 25 Cardiology SMEs who consented to participate from India discussed data from literature, current evidence, international guidelines and practical experiences in two national and four regional meetings. RESULTS: Recommendations included HF management, treatment optimization, and patient education. The checklist should be filled at four time points- (a) transition from intensive care unit to ward, (b) at discharge, (c) 1st follow-up and (d) subsequent follow-up. The checklist is the responsibility of the consultant or the treating physician which can be delegated to a junior resident or a trained HF nurse. CONCLUSION: This checklist will ensure GDMT, simplify transition of care and can be used by all doctors across India. Institutions, associations, and societies should recommend this checklist for adaptability in public and private hospital. Hospital administrations should roll out policy for adoption of checklist by ensuring patient files have the checklist at the time of discharge and encourage practice of filling it diligently during follow-up visits.

What makes primary healthcare facilities functional, and increases the utilization? Learnings from 12 case studies.

BACKGROUND: The last few decades have witnessed a number of innovative approaches and initiatives to deliver primary healthcare (PHC) services in different parts of India. The lessons from these initiatives can be useful as India aims to strengthen the PHC system through Health and Wellness Centers (HWCs) component under Ayushman Bharat Program, launched in early 2018. MATERIALS AND METHODS: Comparative case study method was adopted to systematically document a few identified initiatives/models delivering the PHC services in India. Desk review was followed by field visits and key informant interviews. Twelve PHC case studies from 14 Indian states, with a focus on equity and "potentially replicable designs" were included from the government as well as the "not-for-profit" sector. The cases studies comprised of initiatives/models having the provision of PHC services, whether exclusively or as part of broader hospital services. The data was collected from May 2016 to March 2017. RESULTS: The "political will" for government facilities and "leadership and motivation" for "not-for-profit" facilities adjudged to contribute towards improved functioning. A comprehensive package of services, functional 'continuity of care' across levels, efforts to meet one or more type of quality standards and limited "intention to availability" gap (or assured provision of promised services) were considered to be associated with increased utilization. A total of 10 lessons and learnings derived from the analysis of these case studies have been summarised. CONCLUSIONS: The case studies in this article highlights the components which makes PHC facilities functional and have potential for increased utilization. The article underscores the need for institutional mechanisms for health system research and innovation hubs at both national and state level in India, for the rapid scale of comprehensive primary healthcare. Lessons can be applied to other low- and middle-income countries intending to deliver comprehensive PHC services to advance towards universal health coverage.

Evaluation of a comprehensive diabetic foot ulcer care quality model.

AIMS: Diabetes-related amputations are typically preceded by a diabetic foot ulcer (DFU) but models to assess the quality of care are lacking. We investigated a model to measure inpatient and outpatient quality. METHODS: Cohort study among adults hospitalized with a DFU to a safety-net hospital during 2016. We measured adherence to DFU-related quality metrics based on guidelines during and 12 months following hospitalization. Inpatient metrics included ankle-brachial index measurement during or 6 months prior to hospitalization, receiving diabetes education and a wound offloading device prior to discharge. Outpatient metrics included wound care ≤30 days of discharge, in addition to hemoglobin A1c (HbA1c) ≤8%, tobacco cessation, and retention in care (≥2 clinic visits ≥90 days apart) 12 months following discharge. RESULTS: 323 patients were included. Regarding inpatient metrics, 8% had an ankle brachial index measurement, 37% received diabetes education, and 20% received offloading prior to discharge. Regarding outpatient metrics, 33% received wound care ≤30 days of discharge. Twelve months following discharge, 34% achieved a HbA1c ≤8%, 13% quit tobacco, and 52% were retained in care. Twelve-month amputation-free survival was 71%. CONCLUSIONS: Our model demonstrated large gaps in DFU guideline-adherent care. Implementing measures to close these gaps could prevent amputations.

India's health and wellness centres: realizing universal health coverage through comprehensive primary health care.

In common with other countries in the World Health Organization South-East Asia Region, disease patterns in India have rapidly transitioned towards an increased burden of noncommunicable diseases. This epidemiological transition has been a major driver impelling a radical rethink of the structure of health care, especially with respect to the role, quality and capacity of primary health care. In addition to the Pradhan Mantri Jan Arogya Yojana insurance scheme, covering 40% of the poorest and most vulnerable individuals in the country for secondary and tertiary care, Ayushman Bharat is based on an ambitious programme of transforming India's 150 000 public peripheral health centres into health and wellness centres (HWCs) delivering universal, free comprehensive primary health care by the end of 2022. This transformation to facilities delivering high-quality, efficient, equitable and comprehensive care will involve paradigm shifts, not least in human resources to include a new cadre of mid-level health providers. The design of HWCs and the delivery of services build on the experiences and lessons learnt from the National Health Mission, India's flagship programme for strengthening health systems. Expanding the scope of these components to address the expanded service delivery package will require reorganization of work processes, including addressing the continuum of care across facility levels; moving from episodic pregnancy and delivery, newborn and immunization services to chronic care services; instituting screening and early treatment programmes; ensuring high-quality clinical services; and using information and communications technology for better reporting, focusing on health promotion and addressing health literacy in communities. Although there are major challenges ahead to meet these ambitious goals, it is important to capitalize on the current high level of political commitment accorded to comprehensive primary health care.

Taking stock of 10 years of published research on the ASHA programme: examining India's national community health worker programme from a health systems perspective.

BACKGROUND: As India's accredited social health activist (ASHA) community health worker (CHW) programme enters its second decade, we take stock of the research undertaken and whether it examines the health systems interfaces required to sustain the programme at scale. METHODS: We systematically searched three databases for articles on ASHAs published between 2005 and 2016. Articles that met the inclusion criteria underwent analysis using an inductive CHW-health systems interface framework. RESULTS: A total of 122 academic articles were identified (56 quantitative, 29 mixed methods, 28 qualitative, and 9 commentary or synthesis); 44 articles reported on special interventions and 78 on the routine ASHA program. Findings on special interventions were overwhelmingly positive, with few negative or mixed results. In contrast, 55% of articles on the routine ASHA programme showed mixed findings and 23% negative, with few indicating overall positive findings, reflecting broader system constraints. Over half the articles had a health system perspective, including almost all those on general ASHA work, but only a third of those with a health condition focus. The most extensively researched health systems topics were ASHA performance, training and capacity-building, with very little research done on programme financing and reporting, ASHA grievance redressal or peer communication. Research tended to be descriptive, with fewer influence, explanatory or exploratory articles, and no predictive or emancipatory studies. Indian institutions and authors led and partnered on most of the research, wrote all the critical commentaries, and published more studies with negative results. CONCLUSION: Published work on ASHAs highlights a range of small-scale innovations, but also showcases the challenges faced by a programme at massive scale, situated in the broader health system. As the programme continues to evolve, critical comparative research that constructively feeds back into programme reforms is needed, particularly related to governance, intersectoral linkages, ASHA solidarity, and community capacity to provide support and oversight.

Infective Endocarditis in the Elderly: Diagnostic and Treatment Options.

Infective endocarditis (IE) is an uncommon, life-threatening systemic disorder with significant morbidity and persistently high mortality. The age of the peak incidence of IE has shifted from 45 years in the 1950s to 70 years at the present time, and elderly people have a five-fold higher risk of IE than the general adult population. Elderly IE patients demonstrate a higher prevalence of coagulase-negative staphylococci, enterococci and Streptococcus bovis, and lower rates of infection by viridans group streptococci. Methicillin resistance is more prevalent in elderly patients as a consequence of increased nosocomial acquisition. The elderly are a vulnerable group in whom diagnosis is often difficult on account of non-specific presenting features and where higher prevalence of comorbidities contributes to adverse outcomes. Treatment of older patients with IE presents specific challenges associated with prolonged antibiotic therapy, and access to surgery may be denied on account of advanced age and attendant comorbidities. This practical review covers all aspects of elderly IE, including clinical and microbiological diagnosis and appropriate diagnostic procedures, initial antibiotic selection, antibiotic prophylaxis, considerations about antibiotic therapy and surgery.

Diversity and motif conservation in protein 3D structural landscape: exploration by a new multivariate simulation method.

In this paper, diversity and conservation in the 'landscape' of random variation of protein tertiary structures are explored for quantitative feature-vector models of major types of functionally important 3D structural motifs. For this, I have deployed a recently developed nonparametric regression (NPR)-based multidimensional copula method of simulation. Apart from improved accuracy of multidimensional random sample generation, the simulation provides additional insight into diversity in the protein structural landscape in terms of random variation in the feature-vector. It shows the relative importance of several features, with biological implications, in conservation of motifs. Mapping of this landscape in distance-preserving 2D eigenspace also shows consistency in demarcation of different motif classes and preservation of their characteristic patterns in this 2D space.

Association between genetic loci linked to HDL-C levels and Indian patients with CAD: a pilot study.

OBJECTIVE: To examine the association between loci linked to high-density lipoprotein cholesterol (HDL-C) levels and coronary artery disease (CAD). METHODS: A pilot study consisting of age-matched and gender-matched angiographically confirmed CAD cases (n=150) and non-CAD controls (n=150) was performed to test an association. Illumina's Human Cardio-Metabo BeadChip containing 3112 variants associated with HDL-C levels was used for genotyping. RESULTS: A preliminary analysis identified 36 variants from 16 genes that were statistically significant (p<0.05) between cases and controls. However, none of the variants remained statistically significant after correction for multiple testing. Besides, variants rs11039159 (MADD), rs749067 (MADD), rs367070 (LILRA3) and rs330921 (PPP1R3B) showed modest association with HDL-C levels. CONCLUSIONS: None of the HDL-C associated loci included in this study were found to be a significant risk factor for CAD. However, the study could replicate the findings of four variants influencing HDL-C levels.

Genetic determinants of lipid-lowering response to atorvastatin therapy in an Indian population.

WHAT IS KNOWN AND OBJECTIVE: Statins form the backbone of lipid-lowering therapy for the prevention of cardiovascular disease. However, there is large interindividual variability in clinical response to statin treatment. Several gene variants that can be aligned to either the pharmacokinetics or pharmacodynamics of statin have been proposed as potentially important determinants of statin response. We aimed to study the association of known variations in SLCO1B1, CYP3A4, ABCB1, CYP3A5, ABCG5 and CYP7A1 genes with lipid levels in response to atorvastatin therapy. METHODS: Genotypes were determined using multiplex allele-specific polymerase chain reaction in 177 Indian patients, treated with 10 mg of atorvastatin for 8 weeks. Low-density lipoprotein-cholesterol (LDL-C) levels were recorded at baseline and after 8 weeks of atorvastatin treatment. RESULTS AND DISCUSSION: A total of 177 hypercholesterolaemic patients were genotyped to study genetic determinants of atorvastatin response. The genotype distribution for all polymorphisms investigated was in Hardy-Weinberg equilibrium. In our study, patients with wild-type genotypes of CYP7A1 (rs3808607), CYP3A4 (rs2740574), SLCO1B1 (rs2306283) and variant allele-carrying genotype of ABCB1 (rs2032582, rs1045642) showed significantly greater LDL-cholesterol reductions in response to atorvastatin therapy. WHAT IS NEW AND CONCLUSION: The variable response to atorvastatin therapy in terms of LDL-cholesterol lowering due to genetic variations in CYP7A1, CYP3A4, SLCO1B1 and ABCB1 is a promising finding. Further validation in large Indian cohorts is required before it can be assessed for clinical utility.

Are all metal-on-metal hip revision operations contributing to the National Joint Registry implant survival curves? : a study comparing the London Implant Retrieval Centre and National Joint Registry datasets.

AIMS: The National Joint Registry for England, Wales and Northern Ireland (NJR) has extended its scope to report on hospital, surgeon and implant performance. Data linkage of the NJR to the London Implant Retrieval Centre (LIRC) has previously evaluated data quality for hip primary procedures, but did not assess revision records. METHODS: We analysed metal-on-metal hip revision procedures performed between 2003 and 2013. A total of 69 929 revision procedures from the NJR and 929 revised pairs of components from the LIRC were included. RESULTS: We were able to link 716 (77.1%) revision procedures on the NJR to the LIRC. This meant that 213 (22.9%) revision procedures at the LIRC could not be identified on the NJR. We found that 349 (37.6%) explants at the LIRC completed the full linkage process to both NJR primary and revision databases. Data completion was excellent (> 99.9%) for revision procedures reported to the NJR. DISCUSSION: This study has shown that only approximately one third of retrieved components at the LIRC, contributed to survival curves on the NJR. We recommend prospective registry-retrieval linkage as a tool to feedback missing and erroneous data to the NJR and improve data quality. TAKE HOME MESSAGE: Prospective Registry - retrieval linkage is a simple tool to evaluate and improve data quality on the NJR.

Multidetector computed tomography sizing of bioprosthetic valves: guidelines for measurement and implications for valve-in-valve therapies.

AIM: To describe a technique for bioprosthetic multidetector computed tomography (MDCT) sizing and to compare MDCT-derived values against manufacturer-provided sizing. MATERIALS AND METHODS: Fourteen bioprosthetic stented valves commonly used in the aortic valve position were evaluated using a Philips 256 MDCT system. All valves were scanned using a dedicated cardiac CT protocol with a four-channel electrocardiography (ECG) simulator. Measurements were made of major and minor axes and the area and perimeter of the internal stent using varying reconstruction kernels and window settings. Measurements derived from MDCT (MDCT ID) were compared against the stent internal diameter (Stent ID) as provided by the valve manufacturer and the True ID (Stent ID + insertion of leaflets). All data were collected and analysed using SPSS for Mac (version 21). RESULTS: The mean difference between the MDCT ID and Stent ID was 0.6±1.9 mm (r=0.649, p=0.012) and between MDCT ID and True ID 2.1±2 mm (r=0.71, p=0.005). There was no difference in the major (p=0.90), minor (p=0.87), area (p=0.92), or perimeter (p=0.92) measurements when sharp, standard, and detailed stent kernels were used. Similarly, the measurements remained consistent across differing windowing levels. CONCLUSION: Bioprosthetic stented valves may be reliably sized using MDCT in patients requiring valve-in-valve (VIV) interventions where the valve type and size are unknown. In these cases, clinicians should be aware that MDCT has a tendency to overestimate the True ID size.

Discovery of anti-malarial agents through application of in silico studies.

Among the various parasitic diseases, malaria is the deadliest one. Due to the emergence of high drug resistance to the existing drug candidates there is a global need for development of new drug candidates which will be effective against resistant strains of malaria parasite. In silico molecular modeling approaches have been playing an important role in the discovery of novel lead molecules having antimalarial activity. Present review is an effort to cover all the developments related to the application of computational techniques for the design and discovery of novel antimalarial compounds since the year 2011 onwards.

Quantitative characterization of protein tertiary motifs.

A quantitative feature-vector representation/model of tertiary structural motifs of proteins is presented. Multiclass logistic regression and a probabilistic neural network were employed to apply this representation to large data sets in order to classify them into major families of distinct motif types (including those of functional importance) with high statistical confidence. Scatter plots of random samples of these motifs were obtained through two-dimensional transformation of the feature vector by metric MDS (multidimensional scaling). The plots showed distinct clusters and shapes for different families and demonstrated the relevance and importance of the proposed quantitative feature-vector representation for characterizing protein tertiary structural motifs. The relative importance of the features was analyzed. The scope of the present work to investigate Nature's prioritization and optimization of functional motif structures is highlighted.

Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review.

INTRODUCTION: There is an urgent need to discover new antimalarial drugs due to emergence of resistance in the parasite to the existing drugs. Malarial cysteine proteases falcipin-2 (FP-2) and falcipain-3 (FP-3) are attractive targets for antimalarial chemotherapy. The structures and functions of FP-2/3, their binding domains and their interactions with small- and macro-molecules are well studied. These studies could provide important insight into rational designing of FP inhibitors as potential antimalarial drugs. AREAS COVERED: This review is focused on a selection of interesting patents published during 1999 - 2011 on peptidic and nonpeptidic chemotypes of the FP-2/FP-3 inhibitors. EXPERT OPINION: It is a known fact that malaria is a serious health problem worldwide due to the emergence of resistant strains. Hence, development of novel, potent and affordable antimalarial drugs devoid of side effects is of great significance and in great demand. FPs, the malarial cysteine proteases are potential targets for development of new antimalarial drugs. Assessing the available literature on FP-2/3 and their inhibitors it could be speculated that these inhibitors have the potential to enter the clinical stages of development for the treatment of malaria in the years to come.