‘Site of contact genotoxicity’ assessment for implants - Potential use of single cell gel electrophoresis in biocompatibility testing of medical devices

Toxicological risk assessment of medical devices requires genotoxicity assessment as per ISO 10993, Part 3, which is designed to address gene mutations, clastogenicity and/or aneugenicity endpoints. ‘Site of contact genotoxicity’ is a potential genotoxic risk especially for medical implants, that is currently not addressed in biocompatibility standards. We therefore performed initial validation study on the use of alkaline single cell gel electrophoresis (comet assay) for detecting ‘site of contact genotoxicity’ of medical devices, using test items made of acrylic implants impregnated with ethyl methanesulphonate (EMS). Comet assay detected increased DNA migration at the site of implantation, but not in the liver. The same implants also failed to show any genotoxicity potentials, when tested on the standard test battery using Salmonella/microsome and chromosome aberration assays. The study suggested that some medical implants can cause ‘site of contact genotoxicity’, without producing systemic genotoxicity. In conclusion, comet assay will add new dimension to safety assessment of medical devices, and this assay can be added to the battery of genetic toxicology tests for evaluating biocompatibility of medical implants

Equity and coverage in the continuum of reproductive, maternal, newborn and child health services in Nepal-projecting the estimates on death averted using the LiST tool.

INTRODUCTION: The third Sustainable Development Goal, focused on health, includes two targets related to the reduction in maternal, newborn and under-five childhood mortality. We found it imperative to examine the equity and coverage of reproductive, maternal, newborn and child health (RMNCH) interventions from 2001 to 2016 in Nepal; and the death aversion that will take place during the SDG period. METHODS: We used the datasets from the Nepal Demographic Health Surveys (NDHS) 2001, 2006, 2011 and 2016. We calculated the coverage and equity for RMNCH interventions and the composite coverage index (CCI). Based on the Annualized Rate of Change (ARC) in the coverage for selected RMNCH indicators, we projected the trend for the RMNCH interventions by 2030. We used the Lives Saved Tools (LiST) tool to estimate the maternal, newborn, under-five childhood deaths and stillbirths averted. We categorised the interventions into four different patterns based on coverage and inequity gap. RESULTS: Between 2001 and 2016, a significant improvement is seen in the overall RMNCH intervention coverage-CCI increasing from 46 to 75%. The ARC was highest for skilled attendance at birth (11.7%) followed by care seeking for pneumonia (8.2%) between the same period. In 2016, the highest inequity existed for utilization of the skilled birth attendance services (51%), followed by antenatal care (18%). The inequity gap for basic immunization services reduced significantly from 27.4% in 2001 to 5% in 2016. If the current ARC continues, then an additional 3783 maternal deaths, 36,443 neonatal deaths, 66,883 under-five childhood deaths and 24,024 stillbirths is expected to be averted by the year 2030. CONCLUSION: Nepal has experienced an improvement in the coverage and equity in RMNCH interventions. Reducing inequities will improve coverage for skilled birth attendants and antenatal care. The current annual rate of change in RMNCH coverage will further reduce the maternal, neonatal, under-five childhood deaths and stillbirths

Analysis of maternal and newborn training curricula and approaches to inform future trainings for routine care, basic and comprehensive emergency obstetric and newborn care in the low- and middle-income countries: Lessons from Ethiopia and Nepal

Program managers routinely design and implement specialised maternal and newborn health trainings for health workers in low- and middle-income countries to provide better-coordinated care across the continuum of care. However, in these countries details on the availability of different training packages, skills covered in those training packages and the gaps in their implementation are patchy. This paper presents an assessment of maternal and newborn health training packages to describe differences in training contents and implementation approaches used for a range of training packages in Ethiopia and Nepal. We conducted a mixed-methods study. The quantitative assessment was conducted using a comprehensive assessment questionnaire based on validated WHO guidelines and developed jointly with global maternal and newborn health experts. The qualitative assessment was conducted through key informant interviews with national stakeholders involved in implementing these training packages and working with the Ministries of Health in both countries. Our quantitative analysis revealed several key gaps in the technical content of maternal and newborn health training packages in both countries. Our qualitative results from key informant interviews provided additional insights by highlighting several issues with trainings related to quality, skill retention, logistics, and management. Taken together, our findings suggest four key areas of improvement: first, training materials should be updated based on the content gaps identified and should be aligned with each other. Second, trainings should address actual health worker performance gaps using a variety of innovative approaches such as blended and self-directed learning. Third, post-training supervision and ongoing mentoring need to be strengthened. Lastly, functional training information systems are required to support planning efforts in both countries

Trends for neonatal deaths in Nepal (2001-2016) to project progress towards the SDG target in 2030, and risk factor analyses to focus action

Introduction Nepal has made considerable progress on improving child survival during the Millennium Development Goal period, however, further progress will require accelerated reduction in neonatal mortality. Neonatal survival is one of the priorities for Sustainable Development Goals 2030. This paper examines the trends, equity gaps and factors associated with neonatal mortality between 2001 and 2016 to assess the likelihood of Every Newborn Action Plan (ENAP) target being reached in Nepal by 2030. Methods This study used data from the 2001, 2006, 2011 and 2016 Nepal Demographic and Health Surveys. We examined neonatal mortality rate (NMR) across the socioeconomic strata and the annual rate of reduction (ARR) between 2001 and 2016. We assessed association of socio-demographic, maternal, obstetric and neonatal factors associated with neonatal mortality. Based on the ARR among the wealth quintile between 2001 and 2016, we made projection of NMR to achieve the ENAP target. Using the Lorenz curve, we calculated the inequity distribution among the wealth quintiles between 2001 and 2016. Results In NDHS of 2001, 2006, 2011 and 2016, a total of 8400, 8600, 13,485 and 13,089 women were interviewed respectively. There were significant disparities between wealth quintiles that widened over the 15 years. The ARR for NMR declined with an average of 4.0% between 2001 and 2016. Multivariate analysis of the 2016 data showed that women who had not been vaccinated against tetanus had the highest risk of neonatal mortality (adjusted odds ratio [AOR] 3.38; 95% confidence interval [CI] 1.20–9.55), followed by women who had no education (AOR 1.87; 95% CI 1.62–2.16). Further factors significantly associated with neonatal mortality were the mother giving birth before the age of 20 (AOR 1.76; CI 95% 1.17–2.59), household air pollution (AOR 1.37; CI 95% 1.59–1.62), belonging to a poorest quintile (AOR 1.37; CI 95% 1.21–1.54), residing in a rural area (AOR 1.28; CI 95% 1.13–1.44), and having no toilet at home (AOR 1.21; CI 95% 1.06–1.40). If the trend of neonatal mortality rate of 2016 continues, it is projected that the poorest family will reach the ENAP target in 2067. Conclusions Although neonatal mortality is declining in Nepal, if the current trend continues it will take another 50 years for families in the poorest group to attain the 2030 ENAP target. There are different factors associated with neonatal mortality, reducing the disparities for maternal and neonatal care will reduce mortality among the poorest families

Exploring behaviors of stochastic differential equation models of biological systems using change of measures

Stochastic Differential Equations (SDE) are often used to model the stochastic dynamics of biological systems. Unfortunately, rare but biologically interesting behaviors (e.g., oncogenesis) can be difficult to observe in stochastic models. Consequently, the analysis of behaviors of SDE models using numerical simulations can be challenging. We introduce a method for solving the following problem: given a SDE model and a high-level behavioral specification about the dynamics of the model, algorithmically decide whether the model satisfies the specification. While there are a number of techniques for addressing this problem for discrete-state stochastic models, the analysis of SDE and other continuous-state models has received less attention. Our proposed solution uses a combination of Bayesian sequential hypothesis testing, non-identically distributed samples, and Girsanov's theorem for change of measures to examine rare behaviors. We use our algorithm to analyze two SDE models of tumor dynamics. Our use of non-identically distributed samples sampling contributes to the state of the art in statistical verification and model checking of stochastic models by providing an effective means for exposing rare events in SDEs, while retaining the ability to compute bounds on the probability that those events occur

Study design and baseline characteristics of patients on dialysis in the ASCEND-D trial

BACKGROUND: The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor (PHI) Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is non-inferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: haemoglobin efficacy and cardiovascular safety. METHODS: We report the trial design, key demographic, clinical, and laboratory findings, and baseline therapies of 2964 patients randomised in the open-label (sponsor-blinded) active-controlled, parallel-group, randomised ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large cardiovascular outcome trials (CVOTs) and in the most relevant registries. RESULTS: The median age of patients was 58 years, 43% were female; 67% were white and 16% were black. The median haemoglobin at baseline was 10.4 g/dL. Among randomised patients, 89% were receiving haemodialysis and 11% peritoneal dialysis. Among key co-morbidities, 42% reported a history of diabetes mellitus, and 45% a history of cardiovascular disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron use was noted in 64% and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries. CONCLUSION: ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anaemia with CKD G5D

The ASCEND-ND trial: Study design and participant characteristics

BACKGROUND: Anaemia is common in chronic kidney disease (CKD), and assessment of the risks and benefits of new therapies is important. METHODS: The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3-5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8-10 g/dL, or receiving ESAs with screening Hb of 8-12 g/dL. Participants were randomised to daprodustat or darbepoetin alfa (1:1) in an open- label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28 to 52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials. RESULTS: Overall, 3872 patients were randomised from 39 countries (median age 67 years, 56% female; 56% White, 27% Asian, and 10% Black). Median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and eGFR was 18 mL/min/1.73 m2. Among randomised patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin- angiotensin system blockers, 55% were taking statin and 49% oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials. CONCLUSION: ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis