Estimation of daily risk of neonatal death, including the day of birth, in 186 countries in 2013: a vital-registration and modelling-based study

Background The days immediately after birth are the most risky for human survival, yet neonatal mortality risks are generally not reported by day. Early neonatal deaths are sometimes under-reported or might be misclassifi ed by day of death or as stillbirths. We modelled daily neonatal mortality risk and estimated the proportion of deaths on the day of birth and in week 1 for 186 countries in 2013. Methods We reviewed data from vital registration (VR) and demographic and health surveys for information on the timing of neonatal deaths. For countries with high-quality VR we used the data as reported. For countries without high-quality VR data, we applied an exponential model to data from 206 surveys in 79 countries (n=50 396 deaths) to estimate the proportions of neonatal deaths per day and used bootstrap sampling to develop uncertainty estimates. Findings 57 countries (n=122 757 deaths) had high-quality VR, and modelled data were used for 129 countries. The proportion of deaths on the day of birth (day 0) and within week 1 varied little by neonatal mortality rate, income, or region. 1·00 million (36.3%) of all neonatal deaths occurred on day 0 (uncertainty range 0·94 million to 1·05 million), and 2·02 million (73.2%) in the fi rst week (uncertainty range 1·99 million to 2·05 million). Sub-Saharan Africa had the highest risk of neonatal death and, therefore, had the highest risk of death on day 0 (11·2 per 1000 livebirths); the highest number of deaths on day 0 was seen in southern Asia (n=392 300). Interpretation The risk of early neonatal death is very high across a range of countries and contexts. Cost-eff ective and feasible interventions to improve neonatal and maternity care could save many lives

Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000-2013.

OBJECTIVE: To estimate cause-of-death distributions in the early (0-6 days of age) and late (7-27 days of age) neonatal periods, for 194 countries between 2000 and 2013. METHODS: For 65 countries with high-quality vital registration, we used each country's observed early and late neonatal proportional cause distributions. For the remaining 129 countries, we used multinomial logistic models to estimate these distributions. For countries with low child mortality we used vital registration data as inputs and for countries with high child mortality we used neonatal cause-of-death distribution data from studies in similar settings. We applied cause-specific proportions to neonatal death estimates from the United Nations Inter-agency Group for Child Mortality Estimation, by country and year, to estimate cause-specific risks and numbers of deaths. FINDINGS: Over time, neonatal deaths decreased for most causes. Of the 2.8 million neonatal deaths in 2013, 0.99 million deaths (uncertainty range: 0.70-1.31) were estimated to be caused by preterm birth complications, 0.64 million (uncertainty range: 0.46-0.84) by intrapartum complications and 0.43 million (uncertainty range: 0.22-0.66) by sepsis and other severe infections. Preterm birth (40.8%) and intrapartum complications (27.0%) accounted for most early neonatal deaths while infections caused nearly half of late neonatal deaths. Preterm birth complications were the leading cause of death in all regions of the world. CONCLUSION: The neonatal cause-of-death distribution differs between the early and late periods and varies with neonatal mortality rate level. To reduce neonatal deaths, effective interventions to address these causes must be incorporated into policy decisions

Source of Variant Creutzfeldt-Jakob Disease outside United Kingdom

Bovine imports during the 1980s and the first half of the 1990s from the UK contributed substantially to the global spread of this disease

Variant Creutzfeldt-Jakob disease in the United Kingdom: a countrywide or local risk?

BACKGROUND: The aim of this study was to identify factors that may have augmented local risks for variant Creutzfeldt-Jakob disease (vCJD). METHODS: A descriptive study was conducted of local investigations of UK cases of vCJD, who had lived close together at some point since 1980. The main outcome measures were domestic, educational, occupational, healthcare associated, social and recreational links between cases; common dietary, iatrogenic and other possible routes of exposure to vCJD infection; and locally elevated vCJD risk. RESULTS: A cluster of five cases of vCJD in a rural area in North Leicestershire was investigated in 2000 (p=0.004). A further 12 investigations of geographically associated cases of vCJD have been undertaken in the UK. In nine of the 12 locations, some or all of the local cases had consumed beef purchased from the same local retail outlets or provided by a common supplier of school meals, or had some aspect of their medical-dental care in common. In only three of these locations were circumstances identified where the local risk of transmission might have been elevated. In none of the locations was there strong evidence to exclude chance as a likely explanation for the local occurrence of these vCJD cases. CONCLUSION: Although it is possible that in some parts of the UK local factors may have increased the risk of acquiring vCJD, most cases that were geographically close to each other are most likely due to the same factors that gave rise to the large majority of other vCJD cases in the UK

Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Intermittent preventive treatment of malaria in children (IPTc) is a promising new approach to the control of malaria in areas of seasonal malaria transmission but it is not known if IPTc adds to the protection provided by an insecticide-treated net (ITN). METHODS AND FINDINGS: An individually randomised, double-blind, placebo-controlled trial of seasonal IPTc was conducted in Burkina Faso in children aged 3 to 59 months who were provided with a long-lasting insecticide-treated bednet (LLIN). Three rounds of treatment with sulphadoxine pyrimethamine plus amodiaquine or placebos were given at monthly intervals during the malaria transmission season. Passive surveillance for malaria episodes was established, a cross-sectional survey was conducted at the end of the malaria transmission season, and use of ITNs was monitored during the intervention period. Incidence rates of malaria were compared using a Cox regression model and generalized linear models were fitted to examine the effect of IPTc on the prevalence of malaria infection, anaemia, and on anthropometric indicators. 3,052 children were screened and 3,014 were enrolled in the trial; 1,505 in the control arm and 1,509 in the intervention arm. Similar proportions of children in the two treatment arms were reported to sleep under an LLIN during the intervention period (93%). The incidence of malaria, defined as fever or history of fever with parasitaemia ≥ 5,000/µl, was 2.88 (95% confidence interval [CI] 2.70-3.06) per child during the intervention period in the control arm versus 0.87 (95% CI 0.78-0.97) in the intervention arm, a protective efficacy (PE) of 70% (95% CI 66%-74%) (p<0.001). There was a 69% (95% CI 6%-90%) reduction in incidence of severe malaria (p = 0.04) and a 46% (95% CI 7%-69%) (p = 0.03) reduction in the incidence of all-cause hospital admissions. IPTc reduced the prevalence of malaria infection at the end of the malaria transmission season by 73% (95% CI 68%-77%) (p<0.001) and that of moderately severe anaemia by 56% (95% CI 36%-70%) (p<0.001). IPTc reduced the risks of wasting (risk ratio [RR] = 0.79; 95% CI 0.65-1.00) (p = 0.05) and of being underweight (RR = 0.84; 95% CI 0.72-0.99) (p = 0.03). Children who received IPTc were 2.8 (95% CI 2.3-3.5) (p<0.001) times more likely to vomit than children who received placebo but no drug-related serious adverse event was recorded. CONCLUSIONS: IPT of malaria provides substantial protection against malaria in children who sleep under an ITN. There is now strong evidence to support the integration of IPTc into malaria control strategies in areas of seasonal malaria transmission. TRIAL REGISTRATION: ClinicalTrials.govNCT00738946. Please see later in the article for the Editors' Summary

Neonatal resuscitation and immediate newborn assessment and stimulation for the prevention of neonatal deaths: a systematic review, meta-analysis and Delphi estimation of mortality effect

BACKGROUND: Of 136 million babies born annually, around 10 million require assistance to breathe. Each year 814,000 neonatal deaths result from intrapartum-related events in term babies (previously "birth asphyxia") and 1.03 million from complications of prematurity. No systematic assessment of mortality reduction from tactile stimulation or resuscitation has been published. OBJECTIVE: To estimate the mortality effect of immediate newborn assessment and stimulation, and basic resuscitation on neonatal deaths due to term intrapartum-related events or preterm birth, for facility and home births. METHODS: We conducted systematic reviews for studies reporting relevant mortality or morbidity outcomes. Evidence was assessed using GRADE criteria adapted to provide a systematic approach to mortality effect estimates for the Lives Saved Tool (LiST). Meta-analysis was performed if appropriate. For interventions with low quality evidence but strong recommendation for implementation, a Delphi panel was convened to estimate effect size. RESULTS: We identified 24 studies of neonatal resuscitation reporting mortality outcomes (20 observational, 2 quasi-experimental, 2 cluster randomized controlled trials), but none of immediate newborn assessment and stimulation alone. A meta-analysis of three facility-based studies examined the effect of resuscitation training on intrapartum-related neonatal deaths (RR= 0.70, 95%CI 0.59-0.84); this estimate was used for the effect of facility-based basic neonatal resuscitation (additional to stimulation). The evidence for preterm mortality effect was low quality and thus expert opinion was sought. In community-based studies, resuscitation training was part of packages with multiple concurrent interventions, and/or studies did not distinguish term intrapartum-related from preterm deaths, hence no meta-analysis was conducted. Our Delphi panel of 18 experts estimated that immediate newborn assessment and stimulation would reduce both intrapartum-related and preterm deaths by 10%, facility-based resuscitation would prevent a further 10% of preterm deaths, and community-based resuscitation would prevent further 20% of intrapartum-related and 5% of preterm deaths. CONCLUSION: Neonatal resuscitation training in facilities reduces term intrapartum-related deaths by 30%. Yet, coverage of this intervention remains low in countries where most neonatal deaths occur and is a missed opportunity to save lives. Expert opinion supports smaller effects of neonatal resuscitation on preterm mortality in facilities and of basic resuscitation and newborn assessment and stimulation at community level. Further evaluation is required for impact, cost and implementation strategies in various contexts. FUNDING: This work was supported by the Bill & Melinda Gates Foundation through a grant to the US Fund for UNICEF, and to the Saving Newborn Lives program of Save the Children, through Save the Children US

Effectiveness of artemisinin-based combination therapy used in the context of home management of malaria: A report from three study sites in sub-Saharan Africa

BACKGROUND: The use of artemisinin-based combination therapy (ACT) at the community level has been advocated as a means to increase access to effective antimalarial medicines by high risk groups living in underserved areas, mainly in sub-Saharan Africa. This strategy has been shown to be feasible and acceptable to the community. However, the parasitological effectiveness of ACT when dispensed by community medicine distributors (CMDs) within the context of home management of malaria (HMM) and used unsupervised by caregivers at home has not been evaluated. METHODS: In a sub-set of villages participating in a large-scale study on feasibility and acceptability of ACT use in areas of high malaria transmission in Ghana, Nigeria and Uganda, thick blood smears and blood spotted filter paper were prepared from finger prick blood samples collected from febrile children between six and 59 months of age reporting to trained CMDs for microscopy and PCR analysis. Presumptive antimalarial treatment with ACT (artesunate-amodiaquine in Ghana, artemether-lumefantrine in Nigeria and Uganda) was then initiated. Repeat finger prick blood samples were obtained 28 days later for children who were parasitaemic at baseline. For children who were parasitaemic at follow-up, PCR analyses were undertaken to distinguish recrudescence from re-infection. The extent to which ACTs had been correctly administered was assessed through separate household interviews with caregivers having had a child with fever in the previous two weeks. RESULTS: Over a period of 12 months, a total of 1,740 children presenting with fever were enrolled across the study sites. Patent parasitaemia at baseline was present in 1,189 children (68.3%) and varied from 60.1% in Uganda to 71.1% in Ghana. A total of 606 children (51% of infected children) reported for a repeat test 28 days after treatment. The crude parasitological failure rate varied from 3.7% in Uganda (C.I. 1.2%-6.2%) to 41.8% in Nigeria (C.I. 35%-49%). The PCR adjusted parasitological cure rate was greater than 90% in all sites, varying from 90.9% in Nigeria (C.I. 86%-95%) to 97.2% in Uganda (C.I. 95%-99%). Reported adherence to correct treatment in terms of dose and duration varied from 81% in Uganda (C.I. 67%-95%) to 97% in Ghana (C.I. 95%-99%) with an average of 94% (C.I. 91%-97%). CONCLUSION: While follow-up rates were low, this study provides encouraging data on parasitological outcomes of children treated with ACT in the context of HMM and adds to the evidence base for HMM as a public health strategy as well as for scaling-up implementation of HMM with ACTs

Treatment of fast breathing in neonates and young infants with oral amoxicillin compared with penicillin-gentamicin combination: study protocol for a randomized, open-label equivalence trial

Background: The World Health Organization recommends hospitalization and injectable antibiotic treatment for young infants (0–59 days old), who present with signs of possible serious bacterial infection. Fast breathing alone is not associated with a high mortality risk for young infants and has been treated with oral antibiotics in some settings. This trial was designed to examine the safety and efficacy of oral amoxicillin for young infants with fast breathing compared with that of an injectable penicillin–gentamicin combination. The study is currently being conducted in the Democratic Republic of Congo, Kenya and Nigeria Methods/Design: This is a randomized, open-label equivalence trial. All births in the community are visited at home by trained community health workers to identify sick infants who are then referred to a trial study nurse for assessment. The primary outcome is treatment failure by day 8 after enrollment, defined as clinical deterioration, development of a serious adverse event including death, persistence of fast breathing by day 4 or recurrence up to day 8. Secondary outcomes include adherence to study therapy, relapse, death between days 9 and 15 and adverse effects associated with the study drugs. Study outcomes are assessed on days 4, 8, 11 and 15 after randomization by an independent outcome assessor who is blinded to the treatment being given. Discussion: The results of this study will help inform the development of policies for the treatment of fast breathing among neonates and young infants in resource-limited settings

Simplified Regimens for Management of Neonates and Young Infants With Severe Infection When Hospital Admission Is Not Possible

Background: In resource-limited settings, most young infants with signs of severe infection do not receive the recommended inpatient treatment with intravenous broad spectrum antibiotics for 10 days or more because such treatment is not accessible, acceptable or affordable to families. This trial was initiated in the Democratic Republic of Congo, Kenya and Nigeria to assess the safety and efficacy of simplified treatment regimens for the young infants with signs of severe infection who cannot receive hospital care. Methods: This is a randomized, open-label equivalence trial in which 3600 young infants with signs of clinical severe infection will be enrolled. The primary outcome is treatment failure in 7 days after enrollment, which includes death or worsening of the clinical condition on any day, or no improvement in the clinical condition by day 4 of treatment. Secondary outcomes include compliance with study therapy, adverse effects due to the study drugs and relapse or death during the week after completion of treatment. Discussion: The results of this study, along with ongoing studies in Pakistan and Bangladesh, will inform the development of global policy for treatment of severe neonatal infections in resource-limited settings

Diallyl disulfide-induced apoptosis in a breast-cancer cell line (MCF-7) may be caused by inhibition of histone de-acetylation

The health benefits of garlic have been proven by epidemiological and experimental studies. Diallyl disulphide (DADS), the major organosulfur compound found in garlic oil, is known to lower the incidence of breast cancer both in vitro and in vivo. The studies reported here demonstrate that DADS induces apoptosis in the MCF-7 breast-cancer cell line through interfering with cell-cycle growth phases in a way that increases the sub-G0 population and substantially halts DNA synthesis. DADS also induces phosphatidylserine (PS) translocation from the inner to the outer leaflet of the plasma membrane and activates caspase-3. Further studies revealed that DADS modulates the cellular levels of Bax, Bcl-2, Bcl-xL and Bcl-w in a dose-dependent manner, suggesting the involvement of Bcl-2 family proteins in DADS induced apoptosis. Histone deacetylation inhibitors (HDACi) are known to suppress cancer growth and induce apoptosis in cancer cells. Here it is shown that DADS has HDACi properties in MCF-7 cells as it lowers the removal of an acetyl group from an acetylated substrate and induces histone-4 (H4) hyper-acetylation. The data thus indicate that the HDACi properties of DADS may be responsible for the induction of apoptosis in breast cancer cells