One-year continuation of postpartum intrauterine contraceptive device: Findings from a prospective cohort study in India.

OBJECTIVE(S): To estimate continuation rates for postpartum intrauterine contraceptive device (PPIUD) at 6 weeks, 6 months and 1-year within existing programs in an under-resourced setting, and to identify determinants of discontinuation, removal and expulsion. STUDY DESIGN: We used a prospective cohort design and enrolled recent PPIUD adopter women across 100 public healthcare facilities in Odisha and Chhattisgarh, India. We collected their socio-demographic information and followed them up telephonically at 6 weeks, 6 months and 1 year for complications and continuation status. We assessed PPIUD continuation rates and factors associated with PPIUD discontinuation, removal, and expulsion using Cox proportional hazards modelling. RESULTS: We enrolled 916 participants (579 (63.2%) from Odisha and 337 (36.8%) from Chhattisgarh). The continuation rate of PPIUD was 88.7% at 6 weeks, 74.8% at 6 months 60.1% at one year. Once discontinued, chances of not opting for any family planning method was high (up to 81.2%). Participants with education of 6th to 12th class and those experiencing complications (pain abdomen, bleeding and discharge per vaginum) were more likely to remove the IUD with adjusted hazard ratio of 1.82 (95% CI: 1.18-2.79) and 4.39 (95% CI: 3.25-5.93) respectively. For expulsion, we did not find any factor that was statistically significant. CONCLUSION(S): PPIUD continuation rates declined considerably after the initial 6 weeks. Counselling and follow-up services for managing complications must be strengthened, especially in the first 6 weeks of PPIUD insertion, to enhance and sustain programmatic impact. IMPLICATIONS: Our findings emphasize on the need to strengthen client counseling and follow-up for management of complications, especially in the first 6 weeks of insertion of PPIUDs. Ongoing programs need to address comprehensive capacity building efforts in this regard.

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.

Inborn Errors of Ketogenesis: Novel Variants, Clinical Presentation, and Follow-Up in a Series of Four Patients.

Inborn errors of ketogenesis are rare disorders that result in acute and fulminant decompensation during lipolytic stress, particularly in infants and children. These include mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS) deficiency and HMG-CoA lyase (HMGCL) deficiency. In this series, we describe the clinical, biochemical, and molecular profiles of four patients along with dietary interventions and their outcomes on a long-term follow-up. Two patients each of HMGCS and HMGCL deficiency were evaluated with clinical history, biochemical investigations, including tandem mass spectrometry (TMS) and urine gas chromatography-mass spectrometry (GCMS). Molecular analysis was performed by whole-exome sequencing, as well as exon array validated by long-range polymerase chain reaction. All individuals were diagnosed with acute metabolic decompensation in the early infancy period except one with HMGCL deficiency who had the first presentation at 5 years of age. Central nervous system manifestations, severe metabolic acidosis, hyperammonemia, hypoglycemia with a normal lactate, and absence of urinary ketones were observed in all the affected individuals. The disorder was life-threatening in three individuals and one succumbed to the illness. TMS was nonspecific and urine GCMS revealed dicarboxylic aciduria in HMGCS deficiency. Both the patients with HMGCL deficiency demonstrated elevated 3 hydroxyisovaleryl carnitine levels in TMS and metabolites of leucine degradation in urine GCMS. We identified five novel variants that included a large deletion involving exon 2 in HMGCL gene. There was no evidence of long-term neurological sequelae in the living individuals. Diet with moderation of fat intake was followed in two individuals with HMGCS deficiency. Low leucine and protein diet with moderation of fat intake was followed in the individual with HMGCL deficiency. All affected individuals are thriving well with no further major metabolic decompensation.

Alternative classification rules for two inverse gaussian populations with a common mean and order restricted scale-like parameters.

The problem of classification into two inverse Gaussian populations with a common mean and ordered scale-like parameters is considered. Surprisingly, the maximum likelihood estimators (MLEs) of the associated model parameters have not been utilized for classification purposes. Note that the MLEs of the model parameters, including the MLE of the common mean, do not have closed-form expressions. In this paper, several classification rules are proposed that use the MLEs and some plug-in type estimators under order restricted scale-like parameters. In the sequel, the risk values of all the proposed estimators are compared numerically, which shows that the proposed plug-in type restricted MLE performs better than others, including the Graybill-Deal type estimator of the common mean. Further, the proposed classification rules are compared in terms of the expected probability of correct classification (EPC) numerically. It is seen that some of our proposed rules have better performance than the existing ones in most of the parameter space. Two real-life examples are considered for application purposes.

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.

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.

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.

What more can be done? Prioritizing the most promising antenatal interventions to improve birth weight.

BACKGROUND: Low birth weight (LBW) is associated with neonatal mortality and sequelae of lifelong health problems; prioritizing the most promising antenatal interventions may guide resource allocation and improve health outcomes. OBJECTIVE: We sought to identify the most promising interventions that are not yet included in the policy recommendations of the World Health Organization (WHO) but could complement antenatal care and reduce the prevalence of LBW and related adverse birth outcomes in low- and middle-income settings. METHODS: We utilized an adapted Child Health and Nutrition Research Initiative (CHNRI) prioritization method. RESULTS: In addition to procedures already recommended by WHO for the prevention of LBW, we identified six promising antenatal interventions that are not currently recommended by WHO with an indication for LBW prevention, namely: (1) provision of multiple micronutrients; (2) low-dose aspirin; (3) high-dose calcium; (4) prophylactic cervical cerclage; (5) psychosocial support for smoking cessation; and (6) other psychosocial support for targeted populations and settings. We also identified seven interventions for further implementation research and six interventions for efficacy research. CONCLUSION: These promising interventions, coupled with increasing coverage of currently recommended antenatal care, could accelerate progress toward the global target of a 30% reduction in the number of LBW infants born in 2025 compared to 2006-10.

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.

Anastrozole-mediated modulation of mitochondrial activity by inhibition of mitochondrial permeability transition pore opening: an initial perspective.

The mitochondrial permeability transition pore (mtPTP) plays a vital role in altering the structure and function of mitochondria. Cyclophilin D (CypD) is a mitochondrial protein that regulates mtPTP function and a known drug target for therapeutic studies involving mitochondria. While the effect of aromatase inhibition on the mtPTP has been studied previously, the effect of anastrozole on the mtPTP has not been completely elucidated. The role of anastrozole in modulating the mtPTP was evaluated by docking, molecular dynamics and network-guided studies using human CypD data. The peripheral blood mononuclear cells (PBMCs) of patients with mitochondrial disorders and healthy controls were treated with anastrozole and evaluated for mitochondrial permeability transition pore (mtPTP) function and apoptosis using a flow cytometer. Spectrophotometry was employed for estimating total ATP levels. The anastrozole-CypD complex is more stable than cyclosporin A (CsA)-CypD. Anastrozole performed better than cyclosporine in inhibiting mtPTP. Additional effects included inducing mitochondrial membrane depolarization and a reduction in mitochondrial swelling and superoxide generation, intrinsic caspase-3 activity and cellular apoptosis, along with an increase in ATP levels. Anastrozole may serve as a potential therapeutic agent for mitochondrial disorders and ameliorate the clinical phenotype by regulating the activity of mtPTP. However, further studies are required to substantiate our preliminary findings.Communicated by Ramaswamy H. Sarma.

"Is it time for personalised medicine for Ameloblastoma?": A hypothesis.

Ameloblastoma is a benign odontogenic tumor that is locally destructive. The most common treatment option is surgery, which often results in disfigurement of the face. BRAFV600E is the common gene mutation associated with its pathogenesis. Therefore, this paper hypothesizes the use of targeted drug therapy against this mutated gene.

Global Preconception and Contraception Care: Using a Life-Course Approach to Improve Health Outcomes in Lower-Resource Settings.

A life-course approach incorporating appropriate preconception and contraception care is key to achieving optimal maternal, neonatal, and child health outcomes. In low- and middle-income countries (LMIC), there is a large unmet need for contraception and an estimated 49% of pregnancies are unintended. In this article, we discuss preconception and contraception care in LMIC settings including key recommendations for content and service delivery. We discuss barriers and facilitators to contraceptive provision, discuss considerations for providers who may practice in LMIC settings, and highlight strategies for achieving increased contraceptive uptake including several examples of successful programs.

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.

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.

Integration of other services with human papillomavirus vaccination; lessons from earlier in the life course highlight the need for new policy and implementation evidence.

Integration of vaccination against human papillomavirus (HPV) with other essential health services for adolescents has been proposed in global strategies and tested in demonstration projects in low- and middle-income countries (LMIC). Published experiences, global guidance, and one key example, the implementation of "HPV Plus" in Tanzania, all demonstrate the need for greater operational evidence to guide future implementation and policy. Review of experiences earlier in the life course, integrating post-partum family planning with infant immunization, show lessons from 13 LMICs that can apply to provision of adolescent health information and services alongside HPV vaccination. Three distinct models of integration emerge from this review comprising: 1) multiple tasks and functions by health staff providing vaccination and other care, or 2) secondary tasks added to the main function of vaccination, or 3) co-location of matched services provided by different staff. These models, with strengths and weaknesses demonstrated in family planning and immunization experiences, apply in different ways to the three main platforms used for HPV vaccination: school, facility or community. For HPV vaccination policy and programming, an initial need is to combine the existing evidence on vaccine service delivery - including coverage, efficiency, cost, and cost-effectiveness information - with what is known on how integration works in practice; the operational detail and models employed. This synthesis may enable assessment which models best suit the different service delivery platforms. An additional need is to link this with more tailored local assessments of the adolescent burden of disease and other determinants of their well-being to develop new thinking on what can and cannot be done to integrate other services alongside HPV vaccination. New approaches placing adolescents at the center are needed to design services tailored to their preferences and needs. The potential synergies with cervical cancer screening and treatment for older generations of women, also require further exploration. Coordinated action aligning HPV vaccination with broader adolescent health and wellbeing will generate social, economic and demographic benefits, which in themselves are sufficient justification to devote more attention to integrated approaches.

Integrating HPV vaccination programs with enhanced cervical cancer screening and treatment, a systematic review.

A WHO global strategy launched in November 2020 sets out an ambitious pathway towards the worldwide elimination of cervical cancer as a public health problem within the next 100 years. Achieving this goal will require investment in innovative approaches. This review aims to describe integrated approaches that combine human papillomavirus (HPV) vaccination and cervical cancer screening in low- and middle-income countries (LMIC), and their efficacy in increasing uptake of services. A systematic review was conducted analyzing relevant papers from Embase, Medline, CINAHL and CAB Global Health databases, as well as grey literature. Narrative synthesis was performed on the included studies. Meta-analysis was not appropriate due to the heterogeneity and nature of included studies. From 5,278 titles screened, 11 uncontrolled intervention studies from four countries (from Africa and east Asia) were included, all from the past 12 years. Four distinct typologies of integration emerged that either increased awareness of HPV and/or cervical cancer screening, and/or coupled the delivery of HPV vaccination and cervical cancer screening programs. The synthesis of findings suggests that existing HPV vaccination programs can be a useful pathway for educating mothers and other female caregivers about cervical cancer screening; through in person conversations with care providers (preferred) or take-home communications products. Integrated service delivery through outreach and mobile clinics may overcome geographic and economic barriers to access for both HPV vaccination and cervical cancer screening, however these require significant program and system resources. One study promoted HPV vaccination as part of integrated service delivery, but there were no other examples found that examined use of cervical cancer screening platforms to promote or educate on HPV vaccination. This review has demonstrated gaps in published literature on attempts to integrate HPV vaccination and cervical cancer screening. The most promising practices to date seem to relate to integrated health communications for cervical cancer prevention. Future research should further explore the opportunities for integrated health communications to support the efforts towards the new global cervical cancer elimination agenda, and costs and feasibility of integrated service delivery for underserved populations.

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).