Utilizing linkage disequilibrium information from Indian genome variation database for mapping mutations: SCA₁₂ case study

Stratification in heterogeneous populations poses an enormous challenge in linkage disequilibrium (LD) based identification of causal loci using surrogate markers. In this study, we demonstrate the enormous potential of endogamous Indian populations for mapping mutations in candidate genes using minimal SNPs, mainly due to larger regions of LD. We show this by a case study of the PPP2R2B gene (∼400 kb) that harbours a CAG repeat, expansion of which has been implicated in spinocerebellar ataxia type 12 (SCA12). Using LD information derived from Indian Genome Variation database (IGVdb) on populations which share similar ethnic and linguistic backgrounds as the SCA12 study population, we could map the causal loci using a minimal set of three SNPs, without the generation of additional basal data from the ethnically matched population. We could also demonstrate transferability of tagSNPs from a related HapMap population for mapping the mutation

Lack of Association of Rare Functional Variants in TSC1/TSC2 Genes with Autism Spectrum Disorder

Background: Autism spectrum disorder (ASD) is reported in 30 to 60% of patients with tuberous sclerosis complex (TSC) but shared genetic mechanisms that exist between TSC-associated ASD and idiopathic ASD have yet to be determined. Through the small G-protein Rheb, the TSC proteins, hamartin and tuberin, negatively regulate mammalian target of rapamycin complex 1 (mTORC1) signaling. It is well established that mTORC1 plays a pivotal role in neuronal translation and connectivity, so dysregulation of mTORC1 signaling could be a common feature in many ASDs. Pam, an E3 ubiquitin ligase, binds to TSC proteins and regulates mTORC1 signaling in the CNS, and the FBXO45-Pam ubiquitin ligase complex plays an essential role in neurodevelopment by regulating synapse formation and growth. Since mounting evidence has established autism as a disorder of the synapses, we tested whether rare genetic variants in TSC1, TSC2, MYCBP2, RHEB and FBXO45, genes that regulate mTORC1 signaling and/or play a role in synapse development and function, contribute to the pathogenesis of idiopathic ASD. Methods: Exons and splice junctions of TSC1, TSC2, MYCBP2, RHEB and FBXO45 were resequenced for 300 ASD trios from the Simons Simplex Collection (SSC) using a pooled PCR amplification and next-generation sequencing strategy, targeted to the discovery of deleterious coding variation. These detected, potentially functional, variants were confirmed by Sanger sequencing of the individual samples comprising the pools in which they were identified. Results: We identified a total of 23 missense variants in MYCBP2, TSC1 and TSC2. These variants exhibited a near equal distribution between the proband and parental pools, with no statistical excess in ASD cases (P > 0.05). All proband variants were inherited. No putative deleterious variants were confirmed in RHEB and FBXO45. Three intronic variants, identified as potential splice defects in MYCBP2 did not show aberrant splicing upon RNA assay. Overall, we did not find an over-representation of ASD causal variants in the genes studied to support them as contributors to autism susceptibility. Conclusions: We did not observe an enrichment of rare functional variants in TSC1 and TSC2 genes in our sample set of 300 trios

Simplified antibiotic regimens for young infants with possible serious bacterial infection when the referral is not feasible in the Democratic Republic of the Congo

Introduction Neonates with serious bacterial infections should be treated with injectable antibiotics after hospitalization, which may not be feasible in many low resource settings. In 2015, the World Health Organization (WHO) launched a guideline for the management of young infants (0–59 days old) with possible serious bacterial infection (PSBI) when referral for hospital treatment is not feasible. We evaluated the feasibility of the WHO guideline implementation in the Democratic Republic of the Congo (DRC) to achieve high coverage of PSBI treatment. Methods From April 2016 to March 2017, in a longitudinal, descriptive, mixed methods implementation research study, we implemented WHO PSBI guideline for sick young infants (0–59 dyas of age) in the public health programme setting in five health areas of North and South Ubangi Provinces with an overall population of about 60,000. We conducted policy dialogue with national and sub-national level government planners, decision-makers, academics and other stakeholders. We established a Technical Support Unit to provide implementation support. We built the capacity of health workers and managers and ensured the availability of necessary medicines and commodities. We followed infants with PSBI signs up to 14 days. The research team systematically collected data on adherence to treatment and outcomes. Results We identified 3050 live births and 285 (9.3%) young infants with signs of PSBI in the study area, of whom 256 were treated. Published data have reported 10% PSBI incidence rate in young infants. Therefore, the estimated coverage of treatment was 83.9% (256/305). Another 426 from outside the study catchment area were also identified with PSBI signs by the nurses of a health centre within the study area. Thus, a total of 711 young infants with PSBI were identified, 285 (40%) 7–59 days old infants had fast breathing (pneumonia), 141 (20%) 0–6 days old had fast breathing (severe pneumonia), 233 (33%) had signs of clinical severe infection (CSI), and 52 (7%) had signs of critical illness. Referral to a hospital was advised to 426 (60%) infants with CSI, critical illness or severe pneumonia. The referral was refused by 282 families who accepted simplified antibiotic treatment on an outpatient basis at the health centres. Treatment failure among those who received outpatient treatment occurred in 10/128 (8%) with severe pneumonia, 25/147 (17%) with CSI, including one death, and 2/7 (29%) young infants with a critical illness. Among 285 infants with pneumonia, 257 (90%) received oral amoxicillin treatment, and 8 (3%) failed treatment. Adherence to outpatient treatment was 98% to 100% for various PSBI sub-categories. Among 144 infants treated in a hospital, 8% (1/13) with severe pneumonia, 23% (20/86) with CSI and 40% (18/45) with critical illness died. Conclusion Implementation of the WHO PSBI guideline when a referral was not possible was feasible in our context with high coverage. Without financial and technical input to strengthen the health system at all levels, including the community and the referral level, it may not be possible to achieve and sustain the same high treatment coverage

Community health workers: A crucial role in newborn health care and survival

There is ample evidence from research and implementation to show that community health workers, when appropriately trained, supplied, supported and supervised, can identify and correctly treat most children for pneumonia, diarrhoea and malaria. Community management of childhood illness is an important contribution to the remarkable progress in reducing child mortality. Globally, the rate of under–five mortality has decreased by nearly half, from 90 deaths per 1000 live births in 1990 to 46 in 2013

Implementation of the WHO guideline on treatment of young infants with signs of possible serious bacterial infection when hospital referral is not feasible in rural Zaria, Nigeria: Challenges and solutions.

BackgroundBacterial infection is one of the leading causes of mortality in young infants globally. The standard practice to manage young infants with any sign of possible serious bacterial infection (PSBI) is in a hospital setting with parenteral antibiotics, which may not be feasible for majority of cases in most low resource settings. The World Health Organization developed a guideline on management of PSBI in young infants when referral is not feasible in 2016.MethodsWe conducted implementation research in selected communities in Zaria Local Government Areas of Kaduna State with an estimated population of 50,000 with the aim of understanding how to implement the WHO PSBI treatment guideline to achieve high coverage with low case fatality and treatment failure rates. Implementation was within the programmatic settings using existing health structure. We conducted policy dialogue with decision makers to adapt the recommendations to their social, cultural and programmatic context in Nigeria, held orientation meetings with program managers, built capacity of the health workers and supported the implementation within the health system. We supported a non-government organization to conduct community sensitization to promote care seeking and adherence to treatment advice. The research team collected data systematically on all young infants identified to have PSBI, the treatment they received and the clinical outcome.ResultsBetween April 2016 and March 2017, we identified 347 young infants up to 2 months of age with signs of PSBI who received treatment either as an outpatient or in a hospital among 2,154 births in the study population. The coverage of PSBI treatment in the study area was 95.5% assuming that 10% of all births have an episode of PSBI in the first two months of life. Most (89%) sick young infants with PSBI were identified by the community-oriented resource persons and sent to the Primary Health Care Centres (PHCs). Most families (97%) refused referral and were treated at a primary health care centre on outpatient basis. There were 12 deaths (3.5%) and 17 non-death treatment failures (4.9%) in 343 infants in whom an outcome could be ascertained. While non-death treatment failure rate was highest in 0-6-day infants with fast breathing (14.4%), case fatality was highest in those with signs of critical illness (20%).ConclusionWe have demonstrated that outpatient treatment strategy for young infants with PSBI when referral is not feasible is implementable within the programmatic settings, achieving very high population coverage and relatively low treatment failure and case fatality rates. Implementation at scale will require government's commitment to strengthen the health system with trained, motivated health care providers and necessary commodities

Management of possible serious bacterial infection in young infants where referral is not possible in the context of existing health system structure in Ibadan, South-west Nigeria.

IntroductionNeonatal infections contribute substantially to infant mortality in Nigeria and globally. Management requires hospitalization, which is not accessible to many in low resource settings. World Health Organization developed a guideline to manage possible serious bacterial infection (PSBI) in young infants up to two months of age when a referral is not feasible. We evaluated the feasibility of implementing this guideline to achieve high coverage of treatment.MethodsThis implementation research was conducted in out-patient settings of eight primary health care centres (PHC) in Lagelu Local Government Area (LGA) of Ibadan, Oyo State, Nigeria. We conducted policy dialogue with the Federal and State officials to adopt the WHO guideline within the existing programme setting and held orientation and sensitization meetings with communities. We established a Technical Support Unit (TSU), built the capacity of health care providers, supervised and mentored them, monitored the quality of services and collected data for management and outcomes of sick young infants with PSBI signs. The Primary Health Care Directorate of the state ministry and the local government led the implementation and provided technical support. The enablers and barriers to implementation were documented.ResultsFrom 1 April 2016 to 31 July 2017 we identified 5278 live births and of these, 1214 had a sign of PSBI. Assuming 30% of births were missed due to temporary migration to maternal homes for delivery care and approximately 45% cases came from outside the catchment area due to free availability of medicines, the treatment coverage was 97.3% (668 cases/6861 expected births) with an expected 10% PSBI prevalence within the first 2 months of life. Of 1214 infants with PSBI, 392 (32%) infants 7-59 days had only fast breathing (pneumonia), 338 (27.8%) infants 0-6 days had only fast breathing (severe pneumonia), 462 (38%) presented with signs of clinical severe infection (CSI) and 22 (1.8%) with signs of critical illness. All but two, 7-59 days old infants with pneumonia were treated with oral amoxicillin without a referral; 80% (312/390) adhered to full treatment; 97.7% (381/390) were cured, and no deaths were reported. Referral to the hospital was not accepted by 87.7% (721/822) families of infants presenting with signs of PSBI needing hospitalization (critical illness 5/22; clinical severe infection; 399/462 and severe pneumonia 317/338). They were treated on an outpatient basis with two days of injectable gentamicin and seven days of oral amoxicillin. Among these 81% (584/721) completed treatment; 97% (700/721) were cured, and three deaths were reported (two with critical illness and one with clinical severe infection). We identified health system gaps including lack of staff motivation and work strikes, medicines stockouts, sub-optimal home visits that affected implementation.ConclusionsWhen a referral is not feasible, outpatient treatment for young infants with signs of PSBI is possible within existing programme structures in Nigeria with high coverage and low case fatality. To scale up this intervention successfully, government commitment is needed to strengthen the health system, motivate and train health workers, provide necessary commodities, establish technical support for implementation and strengthen linkages with communities.RegistrationTrial is registered on Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617001373369

Small vulnerable newborns—big potential for impact

Despite major achievements in child survival, the burden of neonatal mortality has remained high and even increased in some countries since 1990. Currently, most neonatal deaths are attributable to being born preterm, small for gestational age (SGA), or with low birthweight (LBW). Besides neonatal mortality, these conditions are associated with stillbirth and multiple morbidities, with short-term and long-term adverse consequences for the newborn, their families, and society, resulting in a major loss of human capital. Prevention of preterm birth, SGA, and LBW is thus critical for global child health and broader societal development. Progress has, however, been slow, largely because of the global community’s failure to agree on the definition and magnitude of newborn vulnerability and best ways to address it, to frame the problem attractively, and to build a broad coalition of actors and a suitable governance structure to implement a change. We propose a new definition and a conceptual framework, bringing preterm birth, SGA, and LBW together under a broader umbrella term of the small vulnerable newborn (SVN). Adoption of the framework and the unified definition can facilitate improved problem definition and improved programming for SVN prevention. Interventions aiming at SVN prevention would result in a healthier start for live-born infants, while also reducing the number of stillbirths, improving maternal health, and contributing to a positive economic and social development in the society

Management of possible serious bacterial infection in young infants closer to home when referral is not feasible: Lessons from implementation research in Himachal Pradesh, India.

BackgroundGovernment of India and the World Health Organization have guidelines for outpatient management of young infants 0-59 days with signs of Possible Serious Bacterial Infection (PSBI), when referral is not feasible. Implementation research was conducted to identify facilitators and barriers to operationalizing these guidelines.MethodsHimachal Pradesh government implemented the guidelines in program settings supported by Centre for Health Research and Development, Society for Applied Studies. The strategy included community sensitization, skill enhancement of Accredited Social Health Activists (ASHA), Auxiliary Nurse Midwives (ANMs) and Medical Officers (MOs) to identify PSBI and treat when referral was not feasible. The research team collected information on facilitators and barriers. A technical support unit provided training and oversight.FindingsAmong 1997 live births from June 2017 to January 2019, we identified 160 cases of PSBI in young infants resulting in a coverage of 80%, assuming an incidence of 10%. Of these,29(18.1%) had signs of critical illness (CI), 92 (57.5%) had clinical severe infection (CSI), 5 (3.1%)had severe pneumonia (only fast breathing in young infants 0-6 days), while 34 (21%) had pneumonia (only fast breathing in young infants 7-59 days). Hospital referral was accepted by 48/160 (30%), whereas 112/160 (70%) were treated with the simplified treatment regimens at primary level facilities. Of the 29 infants with CI, 18 (62%) accepted referral; 26 (90%) recovered while 3 (10%) who had accepted referral, died. Of the 92 infants who had CSI, 86 (93%) recovered, 65 (71%) received simplified treatment and one infant who had accepted referral, died. All the five infants who had severe pneumonia, recovered; 3 (60%) had received simplified treatment. Of the 34 pneumonia cases, 33 received simplified treatment of which 5 (15%) failed treatment; two out of these 5 died. Overall, 6/160 infants died (case-fatality-rate 3.4%); 2 in the simplified treatment (case-fatality-rate 1.8%) and 4 in the hospital group (case-fatality-rate 8.3%). Delayed identification and care-seeking by families and health system weaknesses like manpower gaps and interrupted supplies were challenges in implementation.ConclusionsImplementation of the guidelines in program settings is possible and acceptable. Scaling up would require creating community awareness, early identification and appropriate care-seeking, strengthening ASHA home-visitation program, building skills and confidence of MOs and ANMs, uninterrupted supplies and a dependable referral system

Feasibility of implementation of simplified management of young infants with possible serious bacterial infection when referral is not feasible in tribal areas of Pune district, Maharashtra, India.

IntroductionNeonatal infections are a common cause of death in India, but many families cannot access appropriate hospitals for its treatment due to various reasons. We implemented the World Health Organization PSBI management guideline when referral is not feasible within the public health system in Pune, India to evaluate feasibility, barriers and facilitators for its implementation.MethodsA national-level consultative meeting between government officials and study partners resulted in a consensus on adaptation and implementation in four demonstration sites in selected states in India. At the state and district levels, similar meetings to plan the implementation strategy and roles were held between KEM Hospital Research Centre (KEMHRC) Pune and the public health system Pune, Maharashtra. The public health system was responsible for implementation of the intervention at eight tribal primary health centres (PHC) in Pune district, India, including delivering the intervention and ensuring supplies of all commodities while KEMHRC was responsible for technical support including training of health workers, assistance in PSBI identification and management, data collection and documentation of the implementation strategy.ResultsA total of 175 young infants with PSBI were identified and managed. Of these, 34 had critical illness (CI), 46 had clinical severe infection (CSI) and 10 were infants aged 0-6 days with fast breathing (FB) while 85 infants aged 7-59 days had fast breathing. Assuming a 10% incidence of PSBI among all live births, with 3071 live births recorded, the actual incidence of PSBI found in the study was 5.7%, resulting in an actual coverage was of 57%. Among the 90 infants with CI, CSI and FB in 0-6 days, who were advised referral to government tertiary care centre as per the PSBI guideline algorithm, 81 (90%) accepted referral while 9 (10%) refused and were offered treatment at primary health centres (PHC) with a seven-day course of injectable gentamicin and oral amoxicillin. All infants with FB in 7-59 days were offered treatment at PHCs as per the PSBI guideline algorithm with a seven-day course of oral amoxicillin. All except six infants who died and one with FB in 7-59 days, who was lost to follow-up, were successfully cured. Of the six who died, five had CSI and one had CI. Among the 81 infants with CI, CSI and FB in 0-6 days who accepted referral; 48(53%) were successfully referred to government tertiary facility while 33 (36.6%) preferred to visit a private tertiary health facility. The implementation strategy demonstrated a relatively high fidelity, acceptance and intervention penetration. Lack of training and confidence of the public health staff were major challenges faced, which were resolved to a large extent through supportive supervision and re-trainings.ConclusionManagement of PSBI is feasible to implement in out-patient facilities in the public health system, but technical support to the health system is required to jump-start the process. Fast breathing in 7-59 days old infants can be managed with oral amoxicillin without referral. A sustainable adoption of this intervention by the health system can lead to decrease in neonatal mortality and morbidity