Evidence-based antenatal interventions to reduce the incidence of small vulnerable newborns and their associated poor outcomes.

A package of care for all pregnant women within eight scheduled antenatal care contacts is recommended by WHO. Some interventions for reducing and managing the outcomes for small vulnerable newborns (SVNs) exist within the WHO package and need to be more fully implemented, but additional effective measures are needed. We summarise evidence-based antenatal and intrapartum interventions (up to and including clamping the umbilical cord) to prevent vulnerable births or improve outcomes, informed by systematic reviews. We estimate, using the Lives Saved Tool, that eight proven preventive interventions (multiple micronutrient supplementation, balanced protein and energy supplementation, low-dose aspirin, progesterone provided vaginally, education for smoking cessation, malaria prevention, treatment of asymptomatic bacteriuria, and treatment of syphilis), if fully implemented in 81 low-income and middle-income countries, could prevent 5·202 million SVN births (sensitivity bounds 2·398-7·903) and 0·566 million stillbirths (0·208-0·754) per year. These interventions, along with two that can reduce the complications of preterm (<37 weeks' gestation) births (antenatal corticosteroids and delayed cord clamping), could avert 0·476 million neonatal deaths (0·181-0·676) per year. If further research substantiates the preventive effect of three additional interventions (supplementation with omega-3 fatty acids, calcium, and zinc) on SVN births, about 8·369 million SVN births (2·398-13·857) and 0·652 million neonatal deaths (0·181-0·917) could be avoided per year. Scaling up the eight proven interventions and two intrapartum interventions would cost about US$1·1 billion in 2030 and the potential interventions would cost an additional $3·0 billion. Implementation of antenatal care recommendations is urgent and should include all interventions that have proven effects on SVN babies, within the context of access to family planning services and addressing social determinants of health. Attaining high effective coverage with these interventions will be necessary to achieve global targets for the reduction of low birthweight births and neonatal mortality, and long-term benefits on growth and human capital.

Bootstrap tests for simultaneous monotone ordering of effects in a two-way ANOVA.

In a two-way additive analysis of variance (ANOVA) model, we consider the problem of testing for homogeneity of both row and column effects against their simultaneous ordering. The error variances are assumed to be heterogeneous with unbalanced samples in each cell. Two simultaneous test procedures are developed-the first one using the likelihood ratio test (LRT) statistics of two independent hypotheses and another based on the consecutive pairwise differences of estimators of effects. The parametric bootstrap (PB) approach is used to find critical points of both the tests and the asymptotic accuracy of the bootstrap is established. An extensive simulation study shows that the proposed tests achieve the nominal size and have very good power performance. The robustness of the tests is also analyzed under deviation from normality. An "R" package is developed and shared on "GitHub" for ease of implementation of users. The proposed tests are illustrated using a real data set on the mortality due to alcoholic liver disease and it is shown that age and gender have a significant impact on the increasing incidence of mortality.

Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.

BACKGROUND: C-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding CNP, cause milder phenotypes. In contrast, no variants in cGKII, encoded by the protein kinase cGMP-dependent type II gene (PRKG2), have been reported in humans to date, although its role in longitudinal growth has been clearly demonstrated in several animal models. METHODS: Exome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants. RESULTS: Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain, alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2. They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9. CONCLUSION: In conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).

Implementing a quality improvement initiative for private healthcare facilities to achieve accreditation: experience from India.

BACKGROUND: The Manyata program is a quality improvement initiative for private healthcare facilities in India which provided maternity care services. Under this initiative, technical assistance was provided to selected facilities in the states of Uttar Pradesh, Jharkhand and Maharashtra which were interested in obtaining 'entry level certification' under the National Accreditation Board for Hospitals and Healthcare Providers (NABH) for provision of quality services. This paper describes the change in quality at those Manyata-supported facilities when assessed by the NABH standards of care. METHODS: Twenty-eight private-sector facilities underwent NABH assessments in the three states from August 2017 to February 2019. Baseline assessment (by program staff) and NABH assessment (by NABH assessors) findings were compared to assess the change in quality of care as per NABH standards of care. The reported performance gaps from NABH assessments were then also classified by thematic areas and suggested corrective actions based on program implementation experience. RESULTS: The overall adherence to NABH standards of care improved from 9% in the baseline assessment to 80% in the NABH assessment. A total of 831 performance gaps were identified by the NABH assessments, of which documentation issues accounted for a majority (70%), followed by training (19%). Most performance gaps could be corrected either by revising existing documentation or creating new documentation (62%), or by orienting facility staff on various protocols (35%). CONCLUSION: While the adherence of facilities to the NABH standards of care improved considerably, certain performance gaps remained, which were primarily related to documentation of facility policies and protocols and training of staff, and required corrective actions for the facilities to achieve NABH entry level certification.

Amplicon-Based Nanopore Sequencing of Patients Infected by the SARS-CoV-2 Omicron (B.1.1.529) Variant in India.

We report the sequencing of SARS-CoV-2 Omicron variants from 75 patients, using nanopore long-read sequencing chemistry. These data show a range of mutations in spike glycoprotein that are both unique and common to other populations.

Perspectives on Rapid Antigen Tests for Downstream Validation and Development of Theranostics.

Point-of-care SARS-CoV-2 rapid antigen tests have proven to be useful over the years and have become more apparent to the public eye during COVID-19 pandemic due to their ease of use, rapid processing and result times, and low cost. Here, we have assessed the effectiveness and accuracy of rapid antigen tests in comparison to the standard real-time polymerase chain reaction analyses of the same samples.

Inferring Recombination Events in SARS-CoV-2 Variants In Silico.

Over the last 34 months, at least 10 severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) distinct variants have evolved. Among these, some were more infectious while others were not. These variants may serve as candidates for identification of the signature sequences linked to infectivity and viral transgressions. Based on our previous hijacking and transgression hypothesis, we aimed to investigate whether SARS-CoV-2 sequences associated with infectivity and trespassing of long noncoding RNAs (lncRNAs) provide a possible recombination mechanism to drive the formation of new variants. This work involved a sequence and structure-based approach to screen SARS-CoV-2 variants in silico, taking into account effects of glycosylation and links to known lncRNAs. Taken together, the findings suggest that transgressions involving lncRNAs may be linked with changes in SARS-CoV-2-host interactions driven by glycosylation events.

Implementation of a large-scale breast cancer early detection program in a resource-constrained setting: real-world experiences from 2 large states in India.

BACKGROUND: The Breast Health Initiative (BHI) was launched to demonstrate a scalable model to improve access to early diagnosis and treatment of breast cancer. METHODS: A package of evidence-based interventions was codesigned and implemented with the stakeholders, as part of the national noncommunicable disease program, through the existing primary health care system. Data from the first 18 months of the BHI are presented. RESULTS: A total of 108,112 women received breast health education; 48% visited the health facilities for clinical breast examination (CBE), 3% had a positive CBE result, and 41% were referred to a diagnostic facility. The concordance of CBE findings between health care providers and adherence to follow-up care improved considerably, with more women visiting the diagnostic facilities and completing diagnostic evaluation within 1 month from initial screening, and with only 9% lost to follow-up. The authors observed a clinically meaningful decrease in time to complete diagnostic evaluation with biopsy, from 37 to 9 days. CONCLUSIONS: The results demonstrate the feasibility and effectiveness of implementing a large-scale, decentralized breast cancer early detection program delivered through the existing primary health care system in India.

Implementation research to accelerate scale-up of national screen and treat strategies towards the elimination of cervical cancer.

BACKGROUND: Cervical cancer is a significant public health problem, with 570,000 new cases and 300,000 deaths of women per year globally, mostly in low- and middle-income countries. In 2018 the WHO Director General made a call to action for the elimination of cervical cancer as a public health problem. MAIN BODY: New thinking on programmatic approaches to introduce emerging technologies and screening and treatment interventions of cervical precancer at scale is needed to achieve elimination goals. Implementation research (IR) is an important yet underused tool for facilitating scale-up of evidence-based screening and treatment interventions, as most research has focused on developing and evaluating new interventions. It is time for countries to define their specific IR needs to understand acceptability, feasibility, and cost-effectiveness of interventions as to design and ensure effective implementation, scale-up, and sustainability of evidence-based screening and treatment interventions. WHO convened an expert advisory group to identify priority IR questions for HPV-based screening and treatment interventions in population-based programmes. Several international organizations are supporting large scale introduction of screen-and-treat approaches in many countries, providing ideal platforms to evaluate different approaches and strategies in diverse national contexts. CONCLUSION: For reducing cervical cancer incidence and mortality, the readiness of health systems, the reach and effectiveness of new technologies and algorithms for increasing screening and treatment coverage, and the factors that support sustainability of these programmes need to be better understood. Answering these key IR questions could provide actionable guidance for countries seeking to implement the WHO Global Strategy towards cervical cancer elimination.

Improving quality of intrapartum and immediate postpartum care in public facilities: experiences and lessons learned from Rajasthan state, India.

BACKGROUND: In spite of considerable improvement in maternal and neonatal outcomes over the past decade in India, the current maternal mortality ratio and neonatal mortality rate are far from the Sustainable Development Goal targets due to suboptimal quality of maternity care. A package of interventions for improving quality of intrapartum and immediate postpartum care was co-designed with the Ministry of Health as the Dakshata program and implemented in public sector health facilities in selected districts in the state of Rajasthan of India since June 2015. This article describes the key strategies, interventions, results and challenges from four years of Dakshata program implementation. METHODS: We have conducted secondary analysis of program data (government data) collected from 202 public facilities across 20 districts of Rajasthan state. The data collected between June-August 2015 (baseline) and the data collected between May-August 2019 (latest) were analyzed. The data sources included: facility assessments, service statistics, monthly progress reports. RESULTS: During the period of program implementation, there were 17,94,249 deliveries accounting for 70% of institutional deliveries in intervention districts. As a result of the intervention, there was a notable increase in competency of health care providers, availability of essential resources, achievement of labour room standards and adherence to evidence-based clinical standards. We also observed reductions in the proportion of referrals for pre-eclampsia/eclampsia, postpartum hemorrhage and neonatal asphyxia by 11, 8 and 3 percentage points respectively. Similarly, data revealed a reduction in stillbirth rates in Dakshata intervention facilities (19.3 vs 15.3) compared to non-Dakshata facilities (21.8 vs 18). CONCLUSIONS: Our experience and findings indicate that the quality of intrapartum and immediate postpartum care can be improved in low- and middle-income countries with the approach presented in this paper.

Designing a Pro-Equity HPV Vaccine Delivery Program for Girls Who Have Dropped Out of School: Community Perspectives From Uttar Pradesh, India.

India experiences a substantial burden of cervical cancer and accounts for nearly one third of cervical cancer deaths worldwide. While human papillomavirus (HPV) vaccines have been introduced subnationally in some states, HPV has not yet been rolled out nationally. Given the target age group, schools are the most common delivery channel for HPV vaccines, but this fails to account for local girls who never attended or no longer attend school. We conducted a qualitative, design-informed, community-based study conducted in Uttar Pradesh, India. We assessed facilitators and barriers among out-of-school girls and proposed program characteristics to inform the design of pro-equity HPV vaccine delivery programs for out-of-school girls. Programs should improve parental knowledge of the risk of cervical cancer, engage vaccinated girls as vaccine champions, utilize varied media options for low-literacy populations, and ensure that HPV vaccine services are accessible and flexible to accommodate out-of-school girls. In areas with poor or irregular school attendance among adolescent girls, HPV vaccine coverage will remain suboptimal until programs can effectively address their needs and reach this priority population. Our findings present a meaningful opportunity for program planners to purposefully design HPV vaccination programs according to these parameters, rather than modifying existing programs to include HPV vaccine. Adolescent girls, their parents, and other community members should be involved in program design to ensure that the program can effectively meet the needs of adolescent girls who are not in school.

Achieving equity in cervical cancer screening in low- and middle-income countries (LMICs): Strengthening health systems using a systems thinking approach.

The World Health Organization (WHO) is leading a call to action to eliminate cervical cancer by the end of the century through global implementation of two effective evidence-based preventive interventions: HPV vaccination and cervical screening and management (CSM). Models estimate that without intervention, over the next 50 years 12.2 million new cases of cervical cancer will occur, nearly 60% of which are preventable only through CSM. Given that more than 80% of the cervical cancer occurs in low- and middle-income countries (LMICs), scaling up sustainable CSM programs in these countries is a top priority for achieving the global elimination goals. Multiple technologies have been developed and validated to meet this need. Now it is critical to identify strategies to implement these technologies into complex, adaptive health care delivery systems. As part of the coordinated cervical cancer elimination effort, we applied a systems thinking lens to reflect on our experiences with implementation of HPV-based CSM programs using the WHO health systems framework. While many common health system barriers were identified, the effectiveness of implementation strategies to address them was context dependent; often reflecting differences in stakeholder's belief in the quality of the evidence supporting a CSM algorithm, the appropriateness of the evidence and algorithm to context, and the 'implementability' of the algorithm under realistic assessments of resource availability and constraints. A structured planning process, with early and broad stakeholder engagement, will ensure that shared-decisions in CSM implementation are appropriately aligned with the culture, values, and resource realities of the setting.

Designing a resource-stratified, phased implementation strategy for breast health care services in India.

BACKGROUND: Breast cancer is the most common cancer among women in India. Jhpiego, a not-for-profit health organization, is providing technical assistance for developing an evidence-based model of breast health care in the states of Uttar Pradesh and Jharkhand in India. METHODS: A situational assessment of breast health care services using validated tools was conducted in the 2 states. RESULTS: Findings of the assessment were presented to the Breast Health Technical Advisory Committee comprised of subject experts and government functionaries. The committee, guided by Breast Health Global Initiative resource-stratified guidelines, developed a conceptual framework for integration of breast health services into the existing health system. This conceptual framework was presented to the Technical Advisory Groups (TAGs) of the respective state governments. Each TAG then developed an operationally feasible, contextually appropriate implementation plan in alignment with the national guidelines for noncommunicable diseases. This implementation plan guided the rollout of the breast health care program in the Lucknow (Uttar Pradesh) and Ranchi (Jharkhand) districts. CONCLUSIONS: Early results from the implementation suggest that it is feasible to integrate the breast health care pathway with the ongoing National Cancer Control Program of India.

Health system strengthening: Integration of breast cancer care for improved outcomes.

The adoption of the goal of universal health coverage and the growing burden of cancer in low- and middle-income countries makes it important to consider how to provide cancer care. Specific interventions can strengthen health systems while providing cancer care within a resource-stratified perspective (similar to the World Health Organization-tiered approach). Four specific topics are discussed: essential medicines/essential diagnostics lists; national cancer plans; provision of affordable essential public services (either at no cost to users or through national health insurance); and finally, how a nascent breast cancer program can build on existing programs. A case study of Zambia (a country with a core level of resources for cancer care, using the Breast Health Global Initiative typology) shows how a breast cancer program was built on a cervical cancer program, which in turn had evolved from the HIV/AIDS program. A case study of Brazil (which has enhanced resources for cancer care) describes how access to breast cancer care evolved as universal health coverage expanded. A case study of Uruguay shows how breast cancer outcomes improved as the country shifted from a largely private system to a single-payer national health insurance system in the transition to becoming a country with maximal resources for cancer care. The final case study describes an exciting initiative, the City Cancer Challenge, and how that may lead to improved cancer services.

A novel approach for extracting DNA from formalin-fixed paraffin-embedded tissue using microwave.

BACKGROUND: Formalin-fixed paraffin-embedded (FFPE) tissue is the gold standard procedure for tissue preservation. However, the extraction of DNA is a cumbersome procedure as the extracted DNA is fragmented because of the cross-linking effect of formalin. Hence, the aim of the present study is to extract DNA from FFPE tissues using different techniques with a specific objective of comparing the extracted DNA, both quantitatively and qualitatively. METHOD: Ten samples of FFPE tissues were retrieved from the archives of the Department of Oral Pathology. Total genomic DNA was extracted by different methods which included QIAamp DNA FFPE Tissue Kit, Norgen DNA FFPE Tissue Kit, phenol-chloroform method, mineral oil-based extraction, M/10 NaOH solution method, and microwave method. A 280-base pair sequence was selected for evaluation of downstream amplification. RESULTS: The statistical analysis was performed using unpaired student's t-test to compare the DNA yields and quality obtained by microwave methods with other methods using SPSS software. Total genomic DNA retrieved by the microwave method was superior to other methods both qualitatively and quantitatively. CONCLUSION: DNA extraction from FFPE tissues is an onerous task as irreversible bonds form between the nucleic acid during fixation which are difficult to break during DNA retrieval. Hence, the microwave method provides good total genomic DNA which gives better downstream results when compared with other methods.

Harmonizing scientific rigor with political urgency: policy learnings for identifying accelerators for scale-up from the safe childbirth checklist programme in Rajasthan, India.

BACKGROUND: Quick scaling-up of innovative and promising interventions in health systems of low and middle-income countries to rapidly achieve population level benefits is a key challenge. While there is consensus on the need for rigorous scientific evidence on effectiveness of interventions before considering scale-up, there can be significant time lag for the want of gold-standard evidence. The Safe Childbirth Checklist (SCC) programme in India, demonstrated how an innovation was robustly evaluated and scaled up nationally, within a short span of time. In this narrative review, we describe the strategies discussed in various published scale-up frameworks and map them against the strategies adopted by the SCC programme to identify accelerators which facilitated its rapid scale up. METHODS: The narrative review - done from May to June 2017 - involved keyword searches of electronic databases of PubMed, Ovid Medline and Google Scholar. It included the key words 'pilot', 'health innovations', 'scale-up', 'replication', 'expansion', 'increased coverage', 'conceptual models for scale-up', 'frame-works for scale-up', 'evidence for scale-up' in the title of publications,. This search was limited to publications in English after the year 1995. We used snowball sampling approach (by referring to bibliographies of shortlisted publications) to identify additional publications related to scale-up. We then screened the identified publications independently and relevant publications that discussed attributes for a conceptual model for scale-up of public health interventions in low and middle-income countries were shortlisted. We then mapped the strategies we used in SCC program scale up against those described in the shortlisted frameworks to identify seven accelerators which facilitated rapid scale up. RESULTS: The identified accelerators were: testing the intervention in real world, resource constrained settings; using an appropriate and time sensitive research design; testing the intervention at substantial scale and in diverse settings; using an adaptive and iterative prototyping approach for implementation; sharing data and evidence with key stakeholders on an ongoing basis; targeting bridge resources through strategic engagement of stakeholders and timely integration of scale-up plans with annual planning and budgeting cycles and systems. CONCLUSION: These accelerators will complement current frameworks and provide guidance to future scale-up initiatives in India and elsewhere.

Effectiveness of the WHO SCC on improving adherence to essential practices during childbirth, in resource constrained settings.

BACKGROUND: India accounts for 27 % of world's neonatal deaths. Although more Indian women deliver in facilities currently than a decade ago, early neonatal mortality has not declined, likely because of insufficient quality of care. The WHO Safe Childbirth Checklist (SCC) was developed to support health workers to perform essential practices known to reduce preventable maternal and new-born deaths around the time of childbirth. Despite promising early research many outstanding questions remain about effectiveness of the SCC in low-resource settings. METHODS: In collaboration with the Ministry of Health SCC was modified for Indian context and introduced in 101 intervention facilities in Rajasthan, India and 99 facilities served as comparison to study if it reduces mortality. This Quasi experimental Observational intervention-comparison was embedded in this larger program to test whether a program for introduction of SCC with simple implementation package was associated with increased adherence to 28 evidence-based practices. This study was conducted in 8 intervention and 8 comparison sites. Program interventions to promote appropriate use of the SCC included orienting providers to the checklist, modest modifications of the SCC to promote provider uptake and accountability, ensuring availability of essential supplies, and providing supportive supervision for helping providers in using the SCC. RESULTS: The SCC was used by providers in 86 % of 240 deliveries observed in the eight intervention facilities. Providers in the intervention group significantly adhered to practices included in the SCC than providers in the comparison group controlling for baseline scores and confounders. Women delivering in the intervention facilities received on an average 11.5 more of the 28 practices included compared with women in the comparison facilities. For selected practices provider performance in the intervention group increased as much as 93 % than comparison sites. CONCLUSION: Use of the SCC and provider performance of best practices increased in intervention facilities reflecting improvement in quality of facility childbirth care for women and new-born in low resource settings.

Newborn screening for G6PD deficiency: A 2-year data from North India.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common erythrocyte enzymopathy, being present in more than 400 million people worldwide that may lead to neonatal jaundice or hemolytic crisis due to drugs or infections. In our study, we aimed to study the frequency of G6PD deficiency in neonates and the proportion of deficient neonates, who developed neonatal hyperbilirubinemia in the study population. The study was an observational one, conducted at the Division of Genetics of Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, over a 2-year period from January 2011 to December 2012. A total of 6,000 newborns delivered during that period underwent newborn screening on 24-72 h of birth. Neonatal hyperbilirubinemia was presented in 13.3% of the study population. Of female neonates, 16% demonstrated G6PD deficiency. This is worth noting for an X-linked recessive trait. Thus, in view of a high gene frequency for a disorder that is manageable with just elimination of few drugs and foodstuff, we stress the need for a newborn screening program for G6PD deficiency.