Antenatal care service delivery and factors affecting effective tetanus vaccine coverage in low- and middle-income countries: Results of the Maternal Immunisation and Antenatal Care Situational analysis (MIACSA) project.

OBJECTIVES: To map the integration of existing maternal tetanus immunization programmes within antenatal care (ANC) services for pregnant women in low- and middle-income countries (LMICs) and to identify and understand the challenges, barriers and facilitators associated with high performance maternal vaccine service delivery. DESIGN: A mixed methods, cross sectional study with four data collection phases including a desk review, online survey, telephone and face-to-face interviews and in country visits was undertaken between 2016 and 2018. Associations of different service delivery process components with protection at birth (PAB) and with country groups were established. PAB was defined as the proportion of neonates protected at birth against neonatal tetanus. Regression analysis and structural equation modelling was used to assess associations of different variables with maternal tetanus immunization coverage. Latent class analysis (LCA), was used to group country performance for maternal immunization, and to address the problem of multicollinearity. SETTING: LMICs. RESULTS: The majority of LMICs had a policy on recommended number of ANC visits, however most were yet to implement the WHO guidelines recommending eight ANC contacts. Countries that recommended > 4 ANC contacts were more likely to have high PAB > 90%. Passive disease surveillance was the most common form of disease surveillance performed but the maternal and neonatal morbidity and mortality indicators recorded differed between countries. The presence of user fees for antenatal care and maternal immunization was significantly associated with lower PAB (<90%). CONCLUSIONS: Recommendations include implementing the current WHO ANC guideline to facilitate increased opportunities for vaccination during each pregnancy. Improved utilisation of ANC services by increasing the demand side by increasing the quality of services, reducing any associated costs and supporting user fee exemptions, or the supply side can also enhance utilisation of ANC services which are positioned as an ideal platform for delivery of maternal vaccines.

Pharmacological properties of revefenacin (TD-4208), a novel, nebulized long-acting, and lung selective muscarinic antagonist, at human recombinant muscarinic receptors and in rat, guinea pig, and human isolated airway tissues.

Revefenacin (TD-4208) is a novel, long-acting, and lung-selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pKI = 8.2-9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4-10.9) at the five human recombinant mAChRs. Kinetic studies demonstrated that revefenacin dissociated significantly slower from the hM3 (t1/2 = 82 minutes) compared to the hM 2 (t1/2 = 6.9 minutes) mAChR at 37°C, thereby making it kinetically selective for the former subtype. Similarly, in functional studies, revefenacin-mediated antagonism of acetylcholine (ACh)-evoked calcium mobilization responses were reversed less rapidly at hM3 compared to the hM2 mAChR. In isolated tracheal tissues from rat and guinea pig and isolated bronchial tissues from humans, revefenacin potently antagonized mAChR-mediated contractile responses. Furthermore, the antagonistic effects of revefenacin in rat, guinea pig, and human airway tissues were slowly reversible (t1/2 of 13.3, >16, and >10 hours, respectively). These data demonstrate that revefenacin is a potent, high affinity, and selective functional mAChR antagonist with kinetic selectivity for the hM3 receptor and produces potent and long-lasting antagonism of mAChR-mediated contractile responses in rat, guinea pig, and human airway tissue. These data suggest that revefenacin has the potential to be a potent once-daily dosed inhaled bronchodilator in COPD patients.

Implementing the WHO Safe Childbirth Checklist: lessons from a global collaboration.

The WHO Safe Childbirth Checklist (SCC) was developed to ensure the delivery of essential maternal and perinatal care practices around the time of childbirth. A research collaboration was subsequently established to explore factors that influence use of the Checklist in a range of settings around the world. This analysis article presents an overview of the WHO SCC Collaboration and the lessons garnered from implementing the Checklist across a diverse range of settings. Project leads from each collaboration site were asked to distribute two surveys. The first was given to end users, and the second to implementation teams to describe their respective experiences using the Checklist. A total of 134 end users and 38 implementation teams responded to the surveys, from 19 countries across all levels of income. End users were willing to adopt the SCC and found it easy to use. Training and the provision of supervision while using the Checklist, alongside leadership engagement and local ownership, were important factors which helped facilitate initial implementation and successful uptake of the Checklist. Teams identified several challenges, but more importantly successfully implemented the WHO SCC. A critical step in all settings was the adaptation of the Checklist to reflect local context and national protocols and standards. These findings were invaluable in developing the final version of the WHO SCC and its associated implementation guide. Our experience will provide useful insights for any institution wishing to implement the Checklist.

The practice and perception of precautionary allergen labelling by the Australasian food manufacturing industry.

BACKGROUND: The precautionary allergen labelling (PAL) and Voluntary Incidental Trace Allergen Labelling (VITAL® ) tools were designed by industry to assist consumers with selecting safe foods for consumption. However, a sizeable proportion of food products bear no label, and it is unclear whether these products are free from allergens and therefore safe to consume or have simply not undergone a risk assessment and therefore remain unlabelled for that reason. OBJECTIVE: To assess the prevalence of unlabelled products that have undergone a risk assessment process and to examine the factors influencing industry's uptake of the VITAL® process. METHODS: A web-based questionnaire was distributed to Australasian food and grocery manufacturers. RESULTS: One hundred and thirty-seven Australasian manufacturers were contacted, and 59 questionnaires were returned (response rate: 43%). The respondents represented 454 different manufacturing sites. Manufacturers reported that 23% (95% CI 19-28) of products (n=102/434) that had been through the VITAL® risk assessment process had no PAL statement on the label. 34% (95% CI 30-38), (n=204/600) of products that had undergone another (non-VITAL® ) risk assessment process had no PAL statement. In examining the factors that influenced industry's uptake of the VITAL® process, 25 manufacturers reported on factors that influenced the uptake of the VITAL® process, 76% (CI 95% 55-91) reported that VITAL® was an effective tool because it was based on science; 52% (CI 95% 31-72) reported that it was too time-consuming and 36% (CI 95% 18-57) identified a concern with it not being endorsed by the government. CONCLUSION AND CLINICAL RELEVANCE: Currently, we estimate that at least 30% of products may have been through a risk assessment process and yet bear no PAL statement on the label. Permissive labelling could be incorporated onto these products if they have been assessed to be safe for consumption.

Does place and attendance at birth improve early neonatal mortality? Secondary analysis of nine Demographic and Health Surveys.

OBJECTIVES: To determine the relation between place and skilled birth attendance at birth and early neonatal mortality. DESIGN: Retrospective analysis using data from Demographic and Health Surveys on obstetric complications. SETTING: Nine low and middle income countries between 2006 and 2013. POPULATION: 71 758 women aged 15-49 years. METHODS: A secondary analysis was carried out to investigate the occurrence and effect of obstetric complications on early neonatal mortality and association with place and attendance at birth. Obstetric complications studied were prolonged labour, puerperal infection and eclampsia. MAIN OUTCOME MEASURES: Association between early neonatal mortality and place and attendance at birth, unadjusted and adjusted for presence of severe obstetric complications. RESULTS: Thirty-five percent of all births were at home: 70% of these were without skilled attendamts. Obstetric complications were reported in 17 079 women: 82% of these women gave birth in health facilities. Overall, no association was observed between place of birth or attendance at birth and early neonatal mortality. When adjusted for obstetric complications, the odds of early neonatal deaths for births at home without a skilled attendant were 1.3 (95% CI 1.1-1.5) compared with 1.2 (95% CI 1.0-1.5) with a skilled attendant and births in health facilities. CONCLUSIONS: When adjusted for obstetric complications, births in health facilities were associated with reduced early neonatal mortality. However, reporting and referral bias account for at least part of the association. TWEETABLE ABSTRACT: Births in health facilities are linked with fewer early newborn deaths when adjusted for obstetric complications.

Sustainable use of silver warehou (Seriollela punctata): effects of storage, processing conditions and simulated gastrointestinal digestion on selected in-vitro bioactivities.

Australian underutilised fish species may serve as a potential source of valuable proteins and potent bioactive peptides. This novel research is the first to investigate the effects of storage-processing conditions and an in-vitro simulated gastrointestinal digestion (pepsin-pancreatin) on bioactive peptides' release during storage of fish fillet, derived from Australian silver warehou (Seriolella punctata). In-vitro bioactivities including angiotensin-converting enzyme and trypsin inhibitory and antioxidant activities were analysed. The antioxidant power was evaluated by DPPH free radical scavenging activity, Cu2+ chelating and Fe3+ reducing abilities. Fillets were stored at chilled (4 and 6 °C) and freezing (-18 °C) temperatures for 7 and 28 days, respectively. Results indicated that during postmortem storage, endogenous enzymes released from fillets an array of polypeptides during storage. The demonstrated physiological activities were further increased during simulated digestion. Bioactivities were greater at 4 °C, increasing over 7 days as compared to at 6 and -18 °C. An increase by 2 °C for chilled temperature was enough to cause significant changes in activities. The crude extracts obtained by pancreatin treatment demonstrated the highest metal chelating activities at 4 °C (86.3 ± 0.1 % on day 7). Physiological potency, especially metal chelating activity, of fillets obtained from silver warehou may be manipulated by storage conditions that would consequently be further enhanced during simulated digestion.

The WHO application of ICD-10 to deaths during the perinatal period (ICD-PM): results from pilot database testing in South Africa and United Kingdom.

OBJECTIVE: To apply the World Health Organization (WHO) Application of the International Classification of Diseases, tenth revision (ICD-10) to deaths during the perinatal period: ICD-Perinatal Mortality (ICD-PM) to existing perinatal death databases. DESIGN: Retrospective application of ICD-PM. SETTING: South Africa, UK. POPULATION: Perinatal death databases. METHODS: Deaths were grouped according to timing of death and then by the ICD-PM cause of death. The main maternal condition at the time of perinatal death was assigned to each case. MAIN OUTCOME MEASURES: Causes of perinatal mortality, associated maternal conditions. RESULTS: In South Africa 344/689 (50%) deaths occurred antepartum, 11% (n = 74) intrapartum and 39% (n = 271) in the early neonatal period. In the UK 4377/9067 (48.3%) deaths occurred antepartum, with 457 (5%) intrapartum and 4233 (46.7%) in the neonatal period. Antepartum deaths were due to unspecified causes (59%), chromosomal abnormalities (21%) or problems related to fetal growth (14%). Intrapartum deaths followed acute intrapartum events (69%); neonatal deaths followed consequences of low birthweight/ prematurity (31%), chromosomal abnormalities (26%), or unspecified causes in healthy mothers (25%). Mothers were often healthy; 53%, 38% and 45% in the antepartum, intrapartum and neonatal death groups, respectively. Where there was a maternal condition, it was most often maternal medical conditions, and complications of placenta, cord and membranes. CONCLUSIONS: The ICD-PM can be a globally applicable perinatal death classification system that emphasises the need for a focus on the mother-baby dyad as we move beyond 2015. TWEETABLE ABSTRACT: ICD-PM is a global system that classifies perinatal deaths and links them to maternal conditions.

Application of ICD-PM to preterm-related neonatal deaths in South Africa and United Kingdom.

OBJECTIVE: We explore preterm-related neonatal deaths using the WHO application of the International Classification of Disease (ICD-10) to deaths during the perinatal period: ICD-PM as an informative case study, where ICD-PM can improve data use to guide clinical practice and programmatic decision-making. DESIGN: Retrospective application of ICD-PM. SETTING: South Africa, and the UK. POPULATION: Perinatal death databases. METHODS: Descriptive analysis of neonatal deaths and maternal conditions present. MAIN OUTCOME MEASURES: Causes of preterm neonatal mortality and associated maternal conditions. RESULTS: We included 98 term and 173 preterm early neonatal deaths from South Africa, and 956 term and 3248 preterm neonatal deaths from the UK. In the South African data set, the main causes of death were respiratory/cardiovascular disorders (34.7%), low birthweight/prematurity (29.2%), and disorders of cerebral status (25.5%). Amongst preterm deaths, low birthweight/prematurity (43.9%) and respiratory/cardiovascular disorders (32.4%) were the leading causes. In the data set from the UK, the leading causes of death were low birthweight/prematurity (31.6%), congenital abnormalities (27.4%), and deaths of unspecified cause (26.1%). In the preterm deaths, the leading causes were low birthweight/prematurity (40.9%) and deaths of unspecified cause (29.6%). In South Africa, 61% of preterm deaths resulted from the maternal condition of preterm spontaneous labour. Among the preterm deaths in the data set from the UK, no maternal condition was present in 36%, followed by complications of placenta, cord, and membranes (23%), and other complications of labour and delivery (22%). CONCLUSIONS: ICD-PM can be used to appraise the maternal and newborn conditions contributing to preterm deaths, and can inform practice. TWEETABLE ABSTRACT: ICD-PM can be used to appraise maternal and newborn contributors to preterm deaths to improve quality of care.

Optimising the International Classification of Diseases to identify the maternal condition in the case of perinatal death.

OBJECTIVE: The WHO application of the tenth edition of the International Classification of Diseases (ICD-10) to deaths during the perinatal period (ICD Perinatal Mortality, ICD-PM) captures the essential characteristics of the mother-baby dyad that contribute to perinatal deaths. We compare the capture of maternal conditions in the existing ICD-PM with the maternal codes from the WHO application of ICD-10 to deaths during pregnancy, childbirth, and the puerperium (ICD Maternal Mortality, ICD-MM) to explore potential benefits in the quality of data received. DESIGN: Retrospective application of ICD-PM. SETTING: South Africa and the UK. POPULATION: Perinatal death databases. METHODS: The maternal conditions were classified using the ICD-PM groupings for maternal condition in perinatal death, and then mapped to the ICD-MM groupings of maternal conditions. MAIN OUTCOME MEASURES: Main maternal conditions in perinatal deaths. RESULTS: We reviewed 9661 perinatal deaths. The largest group (4766 cases, 49.3%) in both classifications captures deaths where there was no contributing maternal condition. Each of the other ICD-PM groups map to between three and six ICD-MM groups. If the cases in each ICD-PM group are re-coded using ICD-MM, each group becomes multiple, more specific groups. For example, the 712 cases in group M4 in ICD-PM become 14 different and more specific main disease categories when the ICD-MM is applied instead. CONCLUSIONS: As we move towards ICD-11, the use of the more specific, applicable, and relevant codes outlined in ICD-MM for both maternal deaths and the maternal condition at the time of a perinatal death would be preferable, and would provide important additional information about perinatal deaths. TWEETABLE ABSTRACT: Improving the capture of maternal conditions in perinatal deaths provides important actionable information.

A Review of Potential Marine-derived Hypotensive and Anti-obesity Peptides.

Bioactive peptides are food derived components, usually consisting of 3-20 amino acids, which are inactive when incorporated within their parent protein. Once liberated by enzymatic or chemical hydrolysis, during food processing and gastrointestinal transit, they can potentially provide an array of health benefits to the human body. Owing to an unprecedented increase in the worldwide incidence of obesity and hypertension, medical researchers are focusing on the hypotensive and anti-obesity properties of nutritionally derived bioactive peptides. The role of the renin-angiotensin system has long been established in the aetiology of metabolic diseases and hypertension. Targeting the renin-angiotensin system by inhibiting the activity of angiotensin-converting enzyme (ACE) and preventing the formation of angiotensin II can be a potential therapeutic approach to the treatment of hypertension and obesity. Fish-derived proteins and peptides can potentially be excellent sources of bioactive components, mainly as a source of ACE inhibitors. However, increased use of marine sources, poses an unsustainable burden on particular fish stocks, so, the underutilized fish species and by-products can be exploited for this purpose. This paper provides an overview of the techniques involved in the production, isolation, purification, and characterization of bioactive peptides from marine sources, as well as the evaluation of the ACE inhibitory (ACE-I) activity and bioavailability.

Renal effects of chronic pharmacological manipulation of CB2 receptors in rats with diet-induced obesity.

BACKGROUND AND PURPOSE: In diabetic nephropathy agonism of CB2 receptors reduces albuminuria and podocyte loss; however, the role of CB2 receptors in obesity-related nephropathy is unknown. The aim of this study was to determine the role of CB2 receptors in a model of diet-induced obesity (DIO) and characterize the hallmark signs of renal damage in response to agonism (AM1241) and antagonism (AM630) of CB2 receptors. EXPERIMENTAL APPROACH: Male Sprague Dawley rats were fed a high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks. In another cohort, after 9 weeks on a HFD, rats were injected daily with either 3 mg·kg(-1) AM1241, 0.3 mg·kg(-1) AM630 or saline for 6 weeks. KEY RESULTS: Ten weeks on a HFD significantly reduced renal expression of CB2 receptors and renal function. Treatment with AM1241 or AM630 did not reduce weight gain or food consumption in DIO. Despite this, AM1241 significantly reduced systolic BP, peri-renal adipose accumulation, plasma leptin, urinary protein, urinary albumin, urinary sodium excretion and the fibrotic markers TGF-ß1, collagen IV and VEGF in kidney lysate. Treatment with AM630 of DIO rats significantly reduced creatinine clearance and increased glomerular area and kidney weight (gross and standardized for body weight). Diastolic BP, glucose tolerance, insulin sensitivity, plasma creatinine, plasma TGF-ß1 and kidney expression of fibronectin and α-smooth muscle actin were not altered by either AM1241 or AM630 in DIO. CONCLUSIONS: This study demonstrates that while agonism of CB2 receptors with AM1241 treatment for 6 weeks does not reduce weight gain in obese rats, it leads to improvements in obesity-related renal dysfunction. LINKED ARTICLES: This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc.

Diet induced obesity in rats reduces NHE3 and Na(+) /K(+) -ATPase expression in the kidney.

The consumption of a high fat diet (HFD) is associated with proteinuria and altered sodium handling and excretion, which can lead to kidney disease. In the proximal tubule, the Na(+) /H(+) Exchanger 3 (NHE3) is responsible for normal protein reabsorption and the reabsorption of approximately 70% of the renal sodium load. It is the Na(+) /K(+) -ATPase that provides the driving force for the reabsorption of sodium and its exit across the basolateral membrane. This study investigates the effects that consumption of a HFD for 12 weeks has on NHE3 and Na(+) /K(+) -ATPase expression in the kidney. Western blot analysis identified a significant reduction in NHE3 and its modulator, phosphorylated protein kinase B, in renal lysate from obese rats. In the obese rats, a reduction in NHE3 expression in the proximal tubule may impact on the acidification of endosomes which are responsible for albumin uptake, suggesting a key role for the exchanger in protein endocytosis in obesity. Western blot analysis identified a reduction in Na(+) /K(+) -ATPase which could also potentially impact on albumin uptake and sodium reabsorption. This study demonstrates that consumption of a HFD for 12 weeks reduces renal NHE3 and Na(+) /K(+) -ATPase expression, an effect that may contribute to the albuminuria associated with obesity. Furthermore the reduction in these transporters is not likely to contribute to the reduced sodium excretion in obesity. These data highlight a potential link between NHE3 and Na(+) /K(+) -ATPase in the pathophysiological changes in renal protein handling observed in obesity.

The cannabinoid receptor 1 and its role in influencing peripheral metabolism.

Evidence from in vitro and in vivo studies has demonstrated the deleterious pathological effects of a dysregulated endocannabinoid system. Increased stimulation of the cannabinoid receptor 1 (CB1 ) and subsequent downstream cellular signalling are both causative in the deleterious pathological effects observed in a number of diseases. When the CB1 cell signalling cascade is blocked, this results in whole body weight-loss, leading to a reduction in obesity and associated co-morbidities. In the central nervous system; however, CB1 antagonism results in adverse psychological side effects. Blockade of CB1 via peripheral acting compounds that do not cross the blood-brain barrier have been determined to have beneficial effects in metabolic tissues such as the liver and skeletal muscle. These results support the notion that peripheral blockade of CB1 using pharmacological antagonists is a viable target for the treatment of the current epidemic of obesity and its associated co-morbidities.

Clinical-dosimetric relationship between lacrimal gland dose and ocular toxicity after intensity-modulated radiotherapy for sinonasal tumours.

OBJECTIVE: To characterise the relationship between lacrimal gland dose and ocular toxicity among patients treated by intensity-modulated radiotherapy (IMRT) for sinonasal tumours. METHODS: 40 patients with cancers involving the nasal cavity and paranasal sinuses were treated with IMRT to a median dose of 66.0 Gy. Toxicity was scored using the Radiation Therapy Oncology Group morbidity criteria based on conjunctivitis, corneal ulceration and keratitis. The paired lacrimal glands were contoured as organs at risk, and the mean dose, maximum dose, V10, V20 and V30 were determined. Statistical analysis was performed using logistic regression and the Akaike information criterion (AIC). RESULTS: The maximum and mean dose to the ipsilateral lacrimal gland were 19.2 Gy (range, 1.4-75.4 Gy) and 14.5 Gy (range, 11.1-67.8 Gy), respectively. The mean V10, V20 and V30 values were 50%, 25% and 17%, respectively. The incidence of acute and late Grade 3+ toxicities was 23% and 19%, respectively. Based on logistic regression and AIC, the maximum dose to the ipsilateral lacrimal gland was identified as a more significant predictor of acute toxicity (AIC, 53.89) and late toxicity (AIC, 32.94) than the mean dose (AIC, 56.13 and 33.83, respectively). The V20 was identified as the most significant predictor of late toxicity (AIC, 26.81). CONCLUSION: A dose-response relationship between maximum dose to the lacrimal gland and ocular toxicity was established. Our data suggesting a threshold relationship may be useful in establishing dosimetric guidelines for IMRT planning that may decrease the risk of acute and late lacrimal toxicities in the future. ADVANCES IN KNOWLEDGE: A threshold relationship between radiation dose to the lacrimal gland and ocular toxicity was demonstrated, which may aid in treatment planning and reducing the morbidity of radiotherapy for sinonasal tumours.