Despite considerable progress in reduction of both under-five and maternal mortality in recent decades, Bangladesh is still one of the low and middle income countries with high burden of maternal and neonatal mortality. The primary objective of the current study is to measure the impact of a comprehensive package of interventions on maternal and neonatal mortality. In addition, changes in coverage, quality and utilization of maternal and newborn health (MNH) services, social capital, and cost effectiveness of the interventions will be measured.A community-based, cluster randomized controlled trial design will be adopted and implemented in 30 unions of three sub-districts of Chandpur district of Bangladesh. Every union, the lowest administrative unit of the local government with population of around 20,000–30,000, will be considered a cluster. Based on the baseline estimates, 15 clusters will be paired for random assignment as intervention and comparison clusters.The primary outcome measure is neonatal mortality, and secondary outcomes are coverage of key interventions like ANC, PNC, facility and skilled provider delivery. Baseline, midterm and endline household survey will be conducted to assess the key coverage of interventions. Health facility assessment surveys will be conducted periodically to assess facility readiness and utilization of MNH services in the participating health facilities.The current study is expected to provide essential strong evidences on the impact of a comprehensive package of interventions to the Bangladesh government, and other developmental partners. The study results may help in prioritizing, planning, and scaling-up of Safe Motherhood Promotional interventions in other geographical areas of Bangladesh as well as to inform other developing countries of similar settings.NCT03032276. An estimated 3.1 million neonatal deaths take place worldwide, representing two-thirds of all infant deaths . Almost Bangladesh has shown considerable progress in the reduction of child and maternal mortality in recent decades , 12. FroIn Bangladesh, successive governments have continued to prioritize health, and take alternative measures to create awareness in communities . ReasonsEvaluation of SMPP revealed positive changes after implementation of interventions: improvement in United Nation process indicators on EmOC including met needs (increase from 31% to 55%), case fatality rate (< 0.1%), and skilled birth attendance (decline from 18% to 25%). Substantial increases from baseline were observed in: any ANC (55% vs. 73%) / PNC (14% vs. 23%) rates in the model unions, institutional deliveries (14% vs. 21%), women’s birth planning knowledge (44% vs. 93%), at least three danger signs during pregnancy (3% vs. 38%), and linkages between service providers and users. Qualitative findings showed that the service providers’ behaviour had improved and become more client oriented, and that mothers had increased satisfaction and trust in the public service providers. Some of the identified bottlenecks were a shortage of human resources, frequent transfers of trained personnel, insufficient budget, and lack of supportive supervision. SMPP was recognized as a model MNH initiative and called the “Narsingdi Model” at the 2010 Bangladesh Development Forum and 2010 G8 summit .Despite successes depicted by the evaluation of SMPP, the results were inconclusive due to the unavailability of concurrent comparison areas. Therefore, this current project will conduct a rigorous evaluation of the newly designed programme titled ‘Safe Motherhood Promotion and Newborn Survival (SMPNS)’ using a cluster Randomized Controlled Trial (cRCT) design. The objective is to assess and measure the effect of an intervention package, when implemented at scale, in improving maternal and neonatal health. It is important to: (i) monitor and evaluate performance and impact of the approach; (ii) document the implementation process, identify barriers and facilitators of the implementation of SMPNS components for suggesting probable solution(s); (iii) describe non-health impacts of SMPNS; (iv) address these barriers and utilize the facilitators; and (v) conduct cost- effectiveness analysis. The intervention package is expected to raise awareness, increase social mobility and interactions, and contribute to a more stable social safety net. Consequently, the proposed approach should have a potential to increase social capital in a community, thereby reduce harmful health outcomes. Though social capital has received some research focus since the 1990s, it still remains under-theorized. This will be an important avenue to explore and contribute to as part of this project. We expect that the results will provide essential and policy-relevant findings on programme strategies to be implemented at scale, to improve maternal and newborn health in the rural areas of Bangladesh. The findings will help the Ministry of Health and Family Welfare (MOHFW) of the BG and development partners in prioritizing, planning, and further scaling-up of SMPP in other areas of Bangladesh but will also help inform other developing countries in similar settings.A.Health facility interventionsThe intervention package consists of three components: facility, community and linkages between the community and health facilities. Facility based interventions will serve both the comparison and intervention arms. Community based interventions related to promotion of community linkage will serve as comparison. Specific interventions and approaches will be implemented within the MOHFW service delivery system to improve MNH practices in families and communities and to increase the use of MNH services from appropriate facilities/providers. The intervention package Table  has beenAdequate efforts will be made to improve the provision and quality of MNH services in the targeted health facilities. The possible increase in demand for services, as a result of the intensive community mobilization activities, and improved quality of care in the facilities, will also be addressed. The facility interventions Table  will be Health facility assessment and planning.Resource support for improving infrastructure and equipment.Capacity building.Anti Natal Care, Post Natal Care campaign.Strengthening monitoring and supportive supervision.Service facilitation through welcoming person.Maternal and neonatal death review.Emergency obstetric care team meeting.B.Linkage between facilities and communityIt is expected that through the facilitated implementation of facility and community interventions, the demand for services and responsiveness of service providers will be improved. Development of a functional partnership between facilities and communities will lead to sustainable improvements from the interventions; activities for improving partnership will include:Union and Upazila Development Coordination Committee meetings.CSG and health providers’ meetings.Strengthen referral linkages.Observe relevant days.C.Community interventionsCommunity diagnosis and resource mapping exerciseLocal level advocacy and planning meetingEstablish Community Support Group (CSG)Capacity building of CSG members, key community gate keepers and Union Parishad representatives for implementingPromoting birth planning, ANC, PNC and ENC counselling sessions through engaging selective CSG members, community volunteers, MOH&FW and NGO workersMaternal and perinatal death audit at community levelCreating an enabling environment for women and children through relevant community stakeholdersCommunity interventions will enhance MNH-related knowledge of families and communities, and improve their MNH-related practices, by increased service utilisation. Effective community activities (ref) include:A community-based, cRCT design will be used for the evaluation. The union, the smallest administrative unit in Bangladesh, will be considered as a cluster, i.e., the unit of randomisation. Both quantitative and qualitative approaches will be adopted to address general and specific objectives.We proposed to conduct the study in Chandpur district. The basic geography and demography of Chandpur district are provided in Table n = 15) arm.While the GoB has implemented interventions models across Bangladesh, none have been implemented in Chandpur. Though the district level maternal and child health indicators of Chandpur are comparable with national estimates, the sub-districts significantly lack behind. Three upazilas have been selected for intervention implementation, namely Chandpur Sadar, Faridganj, and Kachua as their estimates are below the national estimates. Based on baseline estimates, pairing will be done among selected 30 unions. During pairing, the availability of health facilities and services, demographic and socioeconomic indicators, contextual factors (presence of other significant programmes/initiatives), and population size will be taken into account. Unions from each pair will be randomly allocated to either intervention (n = 15) or comparison (Number of Community Skilled Birth Attendants (CSBA)Ongoing or planned maternal and child health services / programmes by BG or NGO. This information will be obtained from relevant government programme managers, upazila managers and NGO managersNumber of functional community clinicsTerrain , accessibility . This information will be obtained from facility service providers attending UHC monthly meetings.Number of active NGOs and type of NGO activitiesStep 1 - selection of eligible unions: Contextual information for all unions of the three selected upazilas will be collected to include:If a union has a total population of less than 12,000  and pairing: A PCA score, for each union, will be developed using the following indicators.Fifteen pairs will be constructed based on the PCA scores (closest match).Step 3 – Randomisation: From each of the 15 union pairs, one union will be randomly allocated to the intervention arm, and the other to the comparison arm.The intervention (15) and comparison (15) union areas will cover approximately a total population of 375,000, in 90,000 households.Sample size was estimated using standard pair randomized controlled trial sample size calculation formula (ref). Using the Chandpur specific neonatal mortality estimate (20 per 1000 live births) , it has Live birth within two months of survey: 35.Live births at least one danger sign during the neonatal period within two months of survey: 30.Recently delivered women within 12 months of survey: 525.Recently delivered women with at least one danger sign during pregnancy within 12 months of survey: 40.An estimated sample of 1050 live births will be required for each union, to measure a 15% decrease of neonatal deaths from 20 to 15 per 1000 live births between baseline and endline. In order to measure the knowledge, practice, and health seeking behaviour of the community to MNH issues, the following numbers of respondents from each cluster is required to be interviewed to detect the desired effect size with 80% power:Data collection will include household surveys at baseline, two midlines and endline, to measure the impact of interventions on neonatal and maternal mortalities. Two midline surveys will be conducted on a sub set population. Health facility assessments surveys will be conducted to assess the availability and quality of MNH services in the participating health facilities. Relevant data from routine Health Management Information System (HMIS) will be regularly collected and extracted from hospital records to monitor the utilization trend in the health facilities. An ongoing investigating system will be in place at the health facilities, to identify and document maternal near miss cases. Qualitative data will be collected for process documentation, and in depth exploration of implementation challenges and contextual factors. Both quantitative and qualitative methods will be employed to measure social capital. Qualitative data collection methods will include stakeholders’ meeting, focus group discussions, periodic in-depth assessments, social mapping, and other participatory exercises. These standard methods will be employed to document effects of the intervention on women’s empowerment, as measured by decision-making and mobility, within the intervention communities. Table Before participant recruitment, the data collection team will be trained by the central team on all aspects of data collection, including consent, data collection methods, questioning techniques, and cultural considerations. Refresher training will be conducted as required. Data collectors will be supervised by Field Research Assistants who will monitor data collection quality, and provide on-site feedback. A field manager will be responsible for overall project coordination. There will be separate data collection teams for household listing, household survey, health facility assessment, qualitative data collection, and social capital measurement.We started collecting baseline data for randomisation and selection of intervention and comparison clusters. We anticipate that selection of non-government organization to facilitate the interventions will commence in January 2018. Randomisation will be completed by March 2018 and intervention will be started to roll out in April 2018. Details implementation timeline including implementation of intervention in comparison clusters are illustrated in Table Trial outcomes and measurements are summarized in Table Primary outcomes are improved survival of neonates and improved MNH in the community.Secondary outcomes include improved MNH related knowledge, practices and care seeking behaviour of community people, increased and sustained utilization of facilities for neonatal and maternal cases, improved quality of health care, social capital of the community people, and measured costs.Other measurements include health care seeking behaviour during maternal and neonatal emergencies and household coverage of MNH interventions with knowledge regarding MNH issues and utilization of relevant services.All data obtained from the field will be entered in databases using Microsoft SQL Server 2005 with Visual Basic 6.0 for the user interface. This will be a Relational Database Management System (RDMS) where all data tables will be linked with unique primary and secondary keys. Range and consistency checks will be in-built to prevent errors during data entry. The learning platform will use MIS data from the health facilities, using information from the ongoing household surveillance, to measure maternal severe morbidity (near miss) and case-fatality rate for EmOC.Data will be analysed by investigators under the guidance of the expert panel, to maintain accuracy and validity. Descriptive statistics will be utilized as appropriate to describe the baseline and socioeconomic characteristics of the respondents, and facility level management. The household surveys will provide a period-specific rate for the various indicators, and information on severe maternal complications, care seeking behaviour, and neonatal and maternal deaths. Socio-demographic information collected within the survey will be used for equity analysis. Bi-variate and multivariate analysis will be used to assess the determinants of the various primary and secondary outcomes from both household and facility level surveys. Potential explanatory variables estimating relative effects after adjusting for confounder will be included. Equity analysis will be conducted for all indicators. For equity analysis, we created one absolute indicator of inequality , and two relative inequality indicators . The cost-effectiveness analysis will consider costs per Disability-Adjusted Life Years (DALYs) averted, per life-year gained, costs for delivery by skilled attendance, essential newborn care, and out of pocket payment for care seeking for maternal and newborn complications. Intervention costs will be estimated based on WHO-CHIOICE ingredients approach, and include programme and patient costs . ProgramInterviews, focused discussions, and field notes from all qualitative data collection methods, will be recorded and transcribed verbatim. Upon preparing the transcriptions, data will be coded by the researchers. To establish inter-coder reliability, each researcher will code a minimum set of interviews. After which, a master code-list will be generated, based on which the rest of the transcripts will be coded. Future additions and changes to the code-list will be duly communicated to all the researchers. The next step in analysis will be to generate summaries of codes and analyse based on a theoretical phenomenological orientation. The social capital will be measured in structural and cognitive dimensions. We hypothesize that the interventions will connect people and strengthen contacts, thereby increase knowledge of available resources, improve ability to access health services, and adopt beneficial health-related practices. Cognitive social capital, measures the degree to which people perceive they have support from others in the network, can trust others, and seek their help in times of need. We assume that the interventions will create and sustain relationships of trust and support, and this in turn will result in improvements in health. Measurement instruments will be adapted from the World Bank’s Social Capital Assessment Tools developed to assess social capital in the developing nations , to be cAn Implementation Committee (IC) will be formed to oversee project implementation and procurements required related to the study. A Steering Committee (SC), chaired by a representative from Ministry of Health and Family Welfare, BG, will be formed to meet every semester, to monitor project progression, and guide activities in adherence to objectives and goals.For conducting research related activities, six teams comprising young and mid-level researchers, will be formed. The teams will meet weekly to update the project director and project co-ordinator of progress. The teams will be employed for the following thematic areas of assessment: i) baseline, midline and endline survey; ii) facility; iii) social capital; iv) cost-effectiveness; v) Qualitative data collection; and vi) process documentation;At the completion of the endline survey, a dissemination workshop will be held to inform the local and national relevant stakeholders. In the event of positive outcomes, a policy brief will be prepared to guide policy makers to move forward with the intervention package. All findings will be presented in international scientific conferences, and submitted for peer-reviewed publication.The current study is expected to provide essential strong evidences on the impact of a comprehensive package of interventions to the Bangladesh government, and other developmental partners. The Government of Bangladesh will lead the study collaborative partners which include icddr,b, University of Tokyo, and implementing partner NGO. To maintain proper communication among the partners and execute the decision on time might be proven to be a challenge for this study. To mitigate this obstacle, a monthly call will be arranged among the partners and the minutes would be documented accordingly. One of the noteworthy strengths of the current study is the measurement of social capital which is comparatively less explored area in the context of Bangladesh. The social capital assessment in this SMPNS study would inform the scientific world a novel information regarding its association with care seeking behaviour, utilization of public health facility and ultimately with mortality indicators. Another interesting component of the study is community engagement. The study involves the community actively through CG and CSG which is one of the core essences of the community based interventions. This community based interventions may bring forth revolutionary changes for sustainable improvement in MNH sector. The study will also evaluate the impact of interventions for linkage between facility and community that may reduce the delays and ultimately affect the mortality rates. It is noteworthy to mention again that the facility based interventions will be implied on both comparison and intervention unions which would help to improve quality of care provided in the public health facilities and also will deal with the ethical issues, if there is any. This approach would help to understand the relationship between quality of care and care seeking behaviour of the community people. Moreover, the impact of improved quality on mortality rates can also be estimated from the current study. We expect to perform rigorous evaluation of the intervention maintaining utmost quality all through the project starting from data collection through final data analysis and dissemination of results. The study results may help in prioritizing, planning, and scaling-up of Safe Motherhood Promotional interventions in other geographical areas of Bangladesh as well as to inform other developing countries of similar settings.


Transcutaneous Vagus Nerve Stimulation (tVNS) on the auricular branch of the vagus nerve has been receiving attention due to its therapeutic potential for neuropsychiatric disorders. Although the mechanism of tVNS is not yet completely understood, studies have demonstrated the potential role of vagal afferent nerve stimulation in the regulation of mood and visceral state associated with social communication. In addition, a growing body of evidence shows that tVNS can activate the brain regions associated with Autism Spectrum Disorder (ASD), trigger neuroimmune modulation and produce treatment effects for comorbid disorders of ASD such as epilepsy and depression. We thus hypothesize that tVNS may be a promising treatment for ASD, not only for comorbid epilepsy and depression, but also for the core symptoms of ASD. The goal of this manuscript is to summarize the findings and rationales for applying tVNS to treat ASD and propose potential parameters for tVNS treatment of ASD. Autism Spectrum Disorders (ASD) refers to a group of lifelong neurodevelopmental disorders, characterized by persistent deficits in social communication and restricted, repetitive behavior  on the ear as a promising method for treatment of ASD. The vagus nerve consists of a complex network that regulates one's neuro-endocrine-immune axis mood, pain, and memory  has been used for more than 20 years as an non-pharmacological treatment epilepsy depression  Impaired social-emotional communication skills and repetitive behavior are two core symptoms in ASD from very early childhood to adulthood. The vagus nerve is a key component in regulating the autonomic nervous system, social-emotional function, and adaptive behavior. Investigators found that VNS may have positive social-emotional effects independent of seizure control in patients with intractable epilepsy and ASD Porges, . (2) StuBased on the above evidence, we propose that tVNS should be included as a treatment option for ASD Figure . The aimVagus nerve activity can modulate emotional social interactions and repetitive behavior of children Porges, . AccordiClinical observation and studies have shown that children with ASD often present characteristics of low vagal activity, such as flat facial expressions and intonation,  between the default mode network and anterior insula and parahippocampus decreased; the rsFC between the default mode network and precuneus and orbital prefrontal cortex increased compared with sham tVNS  in many brain regions with the exception of the insular cortex (positive blood oxygenation level dependent changes in both conditions)  and China Scholarship (201506385026), JK was supported by R01AT006364, R01AT008563, R21AT008707, R61AT009310, and P01 AT006663 from NIH/CCIH.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Great gains were achieved with the introduction of the United Nations' Millennium Development Goals, including improved child survival. Transition to the Sustainable Development Goals (SDGs) focused on surviving, thriving, and transforming, representing an important shift to a broader public health goal, the achievement of which holds the promise of longer-term individual and societal benefits. A similar shift is needed with respect to outcomes for infants born to women living with HIV (WLHIV). Programming to prevent vertical HIV transmission has been successful in increasingly achieving a goal of HIV-free survival for infants born to WLHIV. Unfortunately, HIV-exposed uninfected (HEU) children are not achieving comparable health and developmental outcomes compared with children born to HIV-uninfected women under similar socioeconomic circumstances. The 3rd HEU Child Workshop, held as a satellite session of the International AIDS Society's 9th IAS Conference in Paris in July 2017, provided a venue to discuss HEU child health and development disparities. A summary of the Workshop proceedings follows, providing current scientific findings, emphasizing the gap in systems for long-term monitoring, and highlighting the public health need to establish a strategic plan to better quantify the short and longer-term health and developmental outcomes of HEU children. Scale up of antiretroviral treatment (ART) to pregnant and breastfeeding women living with HIV (WLHIV) has had a remarkable impact on reducing infant acquisition of HIV, yielding a 47% reduction between 2010 to 2016 . With thFollowing on the first two HEU Child Workshops that explored differences in immune development, infectious morbidity risks, neurodevelopment, and optimizing research methods for HEU research, the 3rd HEU Workshop considered the benefits and risks of maternal ART for the HEU child and how to establish long-term evaluation of these . The 3rdin utero or postnatally to antiretroviral drugs (ARVs). Cumulatively, as of 2016 approximately 18 million children under 15 years of age have been HIV-exposed in utero but are HIV-uninfected, about 50% of whom also have in utero and/or postnatal ARV exposure. While the benefits of treating maternal HIV disease are undeniable, in an HEU child population of this size it is essential to continuously and objectively evaluate the benefits and potential risks of early life exposure to both ARVs and HIV in order to identify the safest ARVs and to elucidate mechanisms for observed disparities for which potential interventions can be introduced.Provisional 2017 UNAIDS Spectrum estimates of the size of the HEU child population were shared for the first time by Dr. Mary Mahy (UNAIDS). Spectrum estimates indicate that globally in 2016 there were approximately 1.4 million infants born to WLHIV, 1.25 million of whom remained HIV-uninfected and more than 1 million exposed Dr. Renaud Becquet (Bordeaux University) presented results from a collaborative individual patient meta-analysis with the objective to assess mortality risk in HEU children as well as to estimate the contribution of identified risk factors in mediating poor HEU child outcomes. More than 19,000 HEU children were included in this analysis that pooled data from 21 clinical trials and observational studies in Africa and Asia . SeventyDr. Lena Serghides , shared findings from Canadian and Ugandan cohorts of pregnant WLHIV, as well as laboratory models illustrating hormonal dysregulation associated with ARV use during pregnancy. In Canadian WLHIV, use of protease inhibitor (PI)-based regimens in pregnancy was associated with decreased progesterone and increased estradiol levels . In a UgDr. Hélène Côté (University of British Columbia) presented findings from the pan-Canadian “Children and Women: Antiretrovirals and Markers of Aging” (CARMA) cohort and on behalf of the CARMA study team. She started with a focus on autism spectrum disorder (ASD). The Canadian population prevalence of ASD averages 1.5%, yet a Canadian cohort of HEU children was found to have an ASD prevalence of 5.7%. Dr. Côté and colleagues compared plasma mitochondrial DNA (mtDNA) levels between HEU children enrolled in CARMA and matched HUU children. HEU children diagnosed with ASD had the highest mtDNA content, followed by HEU children without ASD, HUU children with ASD, and HUU children without ASD. Higher mtDNA content was significantly associated with both HEU status and ASD status . In thisin utero exposure to triple ARV regimens may have a lower risk of adverse neurodevelopmental outcomes, a trend requiring validation in larger cohorts and in high HIV burden settings.Dr. Côté also shared a CARMA study of neurodevelopmental outcomes, comparing results from HEU and matched (1:3) HUU children born between 1990 and 2012 . In multin utero ARV exposure for HEU children. However, as in the examples presented at the Workshop, laboratory studies and small cohort studies have raised concerns about potential long-term implications of ARV and HIV exposure. These concerns and risks are still not well-defined and will remain so without investment in systems for long-term evaluation of HEU child outcomes.The benefits of maternal ART undeniably outweigh the potential risks of The Workshop audience heard presentations from Dr. Ellen Chadwick (Northwestern University) providing an overview of the highly-resourced United States (US)-based Surveillance Monitoring of ART Toxicities (SMARTT) cohort study structure and from Dr. Mary Mahy (UNAIDS) on challenges of and opportunities for establishing national and global HEU child monitoring.in utero exposures to specific ARV drugs and adverse events, after controlling for social, maternal, and infant characteristics (The SMARTT cohort includes over 3,000 HEU infants, children, and adolescents in active follow-up, along with their caregivers, from 22 sites in the United States, including Puerto Rico. The novel trigger-based design employed by the SMARTT study provides an efficient way to identify associations between eristics . Under tWhile monitoring of the HEU child population is warranted, Dr. Mahy identified national and global challenges to this. Ideally designed monitoring systems measure progress toward targets over time or while implementing interventions expected to change outcomes. Monitoring systems for children living with HIV have matured over time. However, similar systems do not yet exist for HEU children. Some, but not all national programs, have sufficiently robust health systems with child health and/or immunization visit data that could be disaggregated, including by maternal HIV status, maternal ARV use in pregnancy and during breastfeeding, and child HIV exposure and infection status, facilitating monitoring of HEU child outcomes. However, even where health systems could support disaggregation of data to facilitate HEU child health outcome monitoring, longer term monitoring through health information systems is challenging as children get older and are no longer in regular contact with the healthcare system. Additionally, child well-being measures change over time and while it will be essential to compare HEU to HUU child outcomes, this will require integration of HEU child outcome monitoring within the broader child health monitoring systems. In the current era of universal ART, if maternal ART, maternal survival, and breastfeeding represent the major protective factors against HEU child mortality, we would expect to see HEU child mortality declining over the coming years as universal ART and uptake of safer breastfeeding continue to expand in countries experiencing generalized HIV epidemics. Monitoring of HEU child mortality trends at a national level in selected high HIV burden countries can provide evidence of whether maternal ART and safer breastfeeding are sufficient to ameliorate excess mortality risk in HEU children at a population level.in utero exposure to HIV and ARVs is precluded, a point of tension that was raised again during the panel discussion. From the individual perspective, WLHIV expressed the critical need to engage with communities in a process of learning together how to track long term HEU child outcomes, using an approach that affords confidentiality, prevents stigma, and ensures children enjoy their childhood. Parents considering disclosure of HEU status to their adolescent children require time to prepare both themselves and their children for the process. The issue of “stigma by association” for HEU children was expressed by panel members, who highlighted the importance of “mainstreaming” any programs to optimize and track HEU child outcomes into health programming for all children.The SMARTT cohort study team has found that some WLHIV are hesitant to disclose their HIV status to their HEU child/adolescent. To address this, the study's caregiver and young adult Community Advisory Board, in collaboration with SMARTT investigators, developed disclosure materials specifically designed for use by caregivers, with separate materials for study staff. These tools assess caregiver readiness for disclosure and provide caregiver support for disclosure. Without disclosure to the HEU adolescent, long-term follow-up of adult health and survival consequences following The scale up of ART to pregnant and breastfeeding women living with HIV is one of the most remarkable public health achievements of the past decade, resulting in substantial reductions globally in infant perinatal and breastfeeding acquisition of HIV. This effort was driven, in part, by the impetus of the Global Plan toward the elimination of new HIV infections among children by 2015 and keeping their mothers alive . This prThere is clearly a need to achieve consensus and develop a strategic plan for a new set of long-term cohort evaluation systems to identify subtle but possibly significant effects of HIV and ARV exposure on HEU children that individual studies are not able to identify or evaluate confidently. With the current emphasis on SDG number 17.18, calling for enhanced capacity building in developing countries to increase the availability of high-quality, timely, and reliable data disaggregated by characteristics relevant in national contexts, an opportunity exists to upgrade routine monitoring in child health and incorporate HEU children into the existing child health and SDG monitoring agenda in HIV high burden countries.AS and KP jointly prepared the initial manuscript with RB, EC, HC, SE, RH, VL, MarM, MauM, JW, LO, NR, MP, GS, LS, and MV all critically reviewing the manuscript and providing important intellectual edits.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The best therapeutic approach of bulbar urethral stenosis is debatable, with several challenging options. In this issue of Int Braz J Urol, we present an editorial (page 868) defending the excision of the stenotic area and the primary anastomotic urethroplasty, authored by Drs. Siegel and Morey, from Dallas, with low complication rates and satisfactory long term results in comparison with the internal urethrotomies or substitutive techniques.In Difference of Opinion Drs. Da Costa and Guimarães, from AC Camargo Cancer Center, São Paulo Brazil, explain that there are enough scientific evidence favoring the indication of radical prostatectomy in patients with oligometastatic prostate cancer; On the other hand, Drs. Tistau and Smaldone from the Fox Chase Cancer Center, Philadelphia, point that there is no sufficient evidence to metastatic patients be submitted to this surgery, except in clinical trials. To be updated in both these points of view is fundamental to urology community in order to understand the next steps in the therapy of advanced prostatic cancer, which have suffered successive radical transformations in the last years.A Belgian group reported the results of low dose brachytherapy with I-125, in 274 patients followed by almost 8 years (page 906). The specific survival and biochemical disease control was satisfactory for low and intermediate risk patients, and they found few significant rectal and urinary toxicities. Faimegos et al., from Athens (page 925) reported that high serum levels of free testosterone and bioavailable testosterone were associated in univariate analysis to the diagnostic of prostate cancer in 40 men submitted to a second biopsy, after the first negative biopsy; these data should be tested in large populations in the future.A binational study from Itajaí, Brazil and Milano, Italy, performed an external validation of the EORTC risk score for recurrence of non-muscle invasive bladder cancer after transurethral resection of the bladder tumor in 205 Brazilian patients (page 932). We must remember that in the Itajaí region (Santa Catarina State), the majority of the population are composed by European descents, with few Afro-Brazilian or Brazilian indigenous; perhaps they present genetics similarities with the European patients. Obesity is known as a risk factor for kidney cancer, but obese patients in some studies do not present unfavorable oncological outcomes after nephrectomy. Focusing possible associations of obesity and renal cell carcinoma, a Turkish group investigate a new concept, the VAI Visceral adipose index, which was associated with higher grades and large size renal tumors (page 955).Moving to lithiasis, a group from Guangzhou, China, described Its results with minimally invasive percutaneous nephrolithotomy, using ultrasound assisted punctures, in patients with severe spinal cord deformities, without abdominal organs injury (page 960). Researchers from Almeria, Spain proposed the measure in Hounsfield units of the density of the renal papilla in patients with urinary stones, using tomography without contrast. Patients with higher density present high odds to be a stone former patient.In page 986, we can find quality of life evaluations  of women submitted to correction of urinary incontinence surgery (from Austria) and a survey about sexual function of male partners of women with stress urinary incontinence (page 999).A Canadian group reported the rates of unilateral vas deferens absence in a population of more than 23,000 men submitted to vasectomy and discuss how to conduct these difficult cases (page 1010).You can also find experimental studies, and surgical videos, case reports, etc.


Improving access and quality of obstetric service has the potential to avert preventable maternal, neonatal and stillborn deaths, yet little is known about the quality of care received. This study sought to assess obstetric service availability, readiness and coverage within and between 17 low- and middle-income countries.We linked health facility data from the Service Provision Assessments and Service Availability and Readiness Assessments, with corresponding household survey data obtained from the Demographic and Health Surveys and Multiple Indicator Cluster Surveys. Based on performance of obstetric signal functions, we defined four levels of facility emergency obstetric care (EmOC) functionality: comprehensive (CEmOC), basic (BEmOC), BEmOC-2, and low/substandard. Facility readiness was evaluated based on the direct observation of 23 essential items; facilities “ready to provide obstetric services” had ≥20 of 23 items available. Across countries, we used medians to characterize service availability and readiness, overall and by urban-rural location; analyses also adjusted for care-seeking patterns to estimate population-level coverage of obstetric services.Of the 111 500 health facilities surveyed, 7545 offered obstetric services and were included in the analysis. The median percentages of facilities offering EmOC and “ready to provide obstetric services” were 19% and 10%, respectively. There were considerable urban-rural differences, with absolute differences of 19% and 29% in the availability of facilities offering EmOC and “ready to provide obstetric services”, respectively. Adjusting for care-seeking patterns, results from the linking approach indicated that among women delivering in a facility, a median of 40% delivered in facilities offering EmOC, and 28% delivered in facilities “ready to provide obstetric services”. Relatively higher coverage of facility deliveries (≥65%) and coverage of deliveries in facilities “ready to provide obstetric services” (≥30% of facility deliveries) were only found in three countries.The low levels of availability, readiness and coverage of obstetric services documented represent substantial missed opportunities within health systems. Global and national efforts need to prioritize upgrading EmOC functionality and improving readiness to deliver obstetric service, particularly in rural areas. The approach of linking health facility and household surveys described here could facilitate the tracking of progress towards quality obstetric care. During the Millennium Development Goal (MDGs) era, maternal health programs in low- and middle-income countries (LMICs) prioritized increasing coverage of antenatal care and skilled birth attendant at delivery, and indeed, considerable progress was made in this regard. Between 1990 and 2014, coverage of skilled birth attendance at delivery rose from 57% to 70%, and coverage of four or more antenatal visits from 35% to 52% . High-quIn light of the ambitious Sustainable Development Goals (SDGs) to end preventable maternal, neonatal and child deaths , accelerThis study aimed to gain insight into obstetric service availability, readiness and coverage in LMICs, and identify the gaps therein. Results will guide global and national efforts to improve maternal health by complementing data on coverage of facility deliveries.Our analysis was limited to 17 countries with an available, nationally representative health facility survey conducted between 2007 and 2015, and a corresponding household survey within (+/−) two years of the facility survey. We used health facility data from the Service Provision Assessments  and Service Availability and Readiness Assessments , and household survey data from the Demographic and Health Surveys  and Multiple Indicator Cluster Surveys . SPAs and SARAs provide comprehensive data on the state of health systems in LMICs, with a focus on service provision. These assessments evaluate general service readiness in the dimensions: basic amenities and equipment, standard precautions, laboratory testing capacity, and essential medicines, as well as availability of specific services including obstetric care ,22. Our For estimation of population-level coverage in each country, the health facility survey (SPA or SARA) was linked to a corresponding nationally representative household survey (MICS or DHS). Both the MICS and DHS employ a two-stage cluster sampling approach, and collect information from nationally representative samples of women of reproductive age on the place of delivery for recent live births, specifically, the health facility type , and managing authority (which we simplified to public and non-public) ,22. To rTo assess the availability of obstetric services in health facilities, four levels of functionality were defined based on reported performance of signal functions in the three months before the health facility survey. Of note, data on neonatal resuscitation were not collected as part of the two health facility surveys conducted prior to 2010 . Other newborn signal functions such as kangaroo mother care for low birthweight babies were excluded from the classification of functionality, as such data were not collected across all the health facility surveys included in this analysis . In linegeneral requirements including basic amenities, 2) staff and guidelines, 3) equipment, and 4) medicines and commodities  for assessing service readiness for basic obstetric and newborn care using the SARA [We assessed the availability of 23 items essential for obstetric and newborn care across four domains, capturing different aspects of service readiness: 1) the SARA . All 23 Descriptive analyses were conducted to assess obstetric service availability and readiness at health facilities, and the proportion of facility deliveries. We reported the percentage of health facilities in each country meeting respective indicator criteria, and the median level across all countries included in our analysis. Medians were not weighted by country-level population size or the number of facilities offering obstetric services. Results were disaggregated by urban-rural location based on country specific definitions. For each country and indicator, urban-rural inequalities were derived by calculating the absolute differences in indicator values between urban and rural areas. Information on the urban or rural location of health facilities was not available in health facility survey data sets for Kenya, Namibia, Nepal and Rwanda.We linked health facility and household survey data at the aggregate level to estimate the proportion of deliveries occurring in different service environments. We defined strata of health facilities based on facility type  and managing authority . We then estimated indicators of service availability and readiness for each stratum, using the health facility survey data. To estimate population-level coverage indicators, we estimated the proportion of recent live births occurring in a stratum from the household survey, and then multiplied these proportions by service availability and readiness indicators for that stratum. This approach assumed that all the women who delivered in a health facility assigned to a specific stratum experienced the “average” service availability and readiness for that stratum. Linking health facility and household survey data allowed us to consider gaps in population level coverage of obstetric services, overall and separately by urban and rural areas. To show coverage and quality gaps, we plotted the proportion of deliveries in facilities “ready to provide obstetric services” by coverage of facility deliveries.All analyses were conducted using STATA 14.2  and accounted for the complex survey sampling of each survey.The majority of countries meeting our eligibility criteria (14/17) were in sub-Saharan Africa, with three countries  outside the region  , injectable uterotonics  and skin disinfectants  were in good supply. Compared to the other medicines and commodities assessed, injectable magnesium sulphate had the lowest availability (median 63%), and was more variable across countries (range: 10–97%).Basic medicines and commodities (79%), followed by general requirements (68%), equipment (59%), and staff and guidelines (51%) . In contrast, across countries, the urban-rural gap was narrowest for manual removal of placenta, performed in a median of 73% of urban and 63% of rural facilities. A median of 43% of facilities in urban areas were designated as EmOC vs 14% of facilities in rural areas, an absolute difference of 29 percentage points. We also found urban-rural disparities in all four domains of facility readiness assessed . An enabling environment with functioning equipment, adequate drugs and competent staff is a prerequisite but not a guarantee of receipt of good quality care by those in need . To compOur study is not without limitations. While this study sheds light on obstetric service provision across 17 LMICs, the countries in our analysis are not representative of all LMICs, and sampled facilities assessed may not be representative of all service providers in a country. Notably, in countries actively promoting home-based models of care such as skilled birth attendance for homebirths, the results presented here may underestimate coverage of obstetric services. Sampling of all service providers rather than health facilities will allow for a complete understanding of obstetric service provision than a sample of health facilities, and provide more reliable estimates of coverage. Further research is needed to determine the validity and feasibility of this sampling approach. Lastly, the data sources and methodology used are prone to several limitations including the time difference between the household and health facility surveys and various forms of bias ,35. Of nDespite these limitations, we used the most recent and best available nationally-representative health facility and household survey data to generate population-based estimates of the coverage of obstetric services within  and between countries. Our analysis adds to the growing evidence on the coverage and quality of maternal health services in LMICs ,26,31,38


Worldwide, stroke is the second leading cause of death and a leading cause of serious long-term disability. In the United States, nearly 800,000 strokes occur each year; thus stroke is the fifth leading cause of death overall and the fourth leading cause of death among women  , including recommendations for different levels of stroke care   functions at the integration of clinical care and community-based public health. In 2001, PCNASP began funding academic principal investigators in eight states, and since 2004, has funded thirteen state health departments to improve the quality of care for acute stroke patients (https://mindyourrisks.nih.gov/).Since at least 2012, the National Institutes of Health has invested approximately $300 million annually to improve stroke prevention, treatment, and recovery (https://millionhearts.hhs.gov/), co-led by the CDC and the Centers for Medicare and Medicaid Services, focuses on a core set of strategies to prevent heart attacks and stroke. Community prevention includes tobacco control, sodium reduction, and physical activity. Clinical strategies include using aspirin when appropriate, hypertension control, cholesterol management, and smoking cessation, along with the use of health information technology to improve detection and management of patient-level risk factors for heart disease and stroke and patient and family engagement in health care decisions.The Million Hearts initiative  employing epidemiology and surveillance to identify where progress is being made and where health care delivery gaps exist and to monitor and evaluate progress toward reducing those gaps; 2) promoting health system interventions to more effectively deliver high-quality preventive services; 3) improving community-clinical linkages to enhance access to community resources that can prevent, delay, and manage chronic diseases; and 4) implementing broad environmental approaches to improve the social and physical environment, promote healthy behaviors, and make healthy choices the easier choices (


Since the late 1980s, human immunodeficiency virus (HIV) sentinel serosurveillance among pregnant women attending select antenatal clinics (ANCs) based on unlinked anonymous testing (UAT) has provided invaluable information for tracking HIV prevalence and trends and informing global and national HIV models in most countries with generalized HIV epidemics. However, increased coverage of HIV testing, prevention of mother-to-child transmission (PMTCT), and antiretroviral therapy has heightened ethical concerns about UAT. PMTCT programs now routinely collect demographic and HIV testing information from the same pregnant women as serosurveillance and therefore present an alternative to UAT-based ANC serosurveillance. This paper reports on the evolution and current direction of the global approach to HIV surveillance among pregnant women attending ANCs, including the transition away from traditional UAT-based serosurveillance and toward new guidance from the World Health Organization and the Joint United Nations Programme on HIV/AIDS on the implementation of surveillance among pregnant women attending ANCs based on routine PMTCT program data. Countries affected by the human immunodeficiency virus (HIV) epidemic require information on trends in HIV prevalence to monitor the course of their HIV epidemics, allocate HIV control resources, and plan programs for HIV prevention and control . Over thAs HIV control programs expanded in coverage and quality, routine HIV testing with return of results was increasingly available to pregnant women attending ANCs. This evolution raised questions about the appropriateness of the serosurveillance approach. From an ethical perspective, testing pregnant women for HIV without their consent or the return of results became increasingly untenable. From a sustainability perspective, the cost and effort of serosurveillance were called into question, given that the provision of HIV testing and the registering of test results were being accomplished routinely.This paper attempts to summarize the evolution of the global approach to HIV surveillance among pregnant women attending ANCs, including origins of ANC serosurveillance, program expansion and questioning of the serosurveillance approach, and movement to consensus, culminating in the 2015 World Health Organization (WHO) guidelines recommending the use of routine program data for HIV surveillance among pregnant women.In 1988, 2 years after the global program on acquired immunodeficiency syndrome (AIDS) was founded by the WHO, epidemiologists recommended the establishment of HIV sentinel surveillance systems among different health services to monitor the HIV epidemic in select populations, including pregnant women . This stInternational guidelines for HIV sentinel serosurveillance describing UAT were disseminated by WHO in 1989 and updated in 2003 . These gUAT-based ANC serosurveillance has provided valuable information about trends in HIV prevalence among pregnant women attending ANCs and served as a proxy for trends in prevalence among the general population, enabling countries to monitor the course of their HIV epidemics; advocate for support for HIV programming and resources; allocate resources for design; and measure the effectiveness of HIV control and prevention interventions ,8. BetweBelmont Report, the 1991 Council for International Organizations of Medical Sciences and WHO International Guidelines for Ethical Review of Epidemiological Studies, and the 2009 International Ethical Guidelines on Epidemiological Studies), as it failed to respect the autonomy of pregnant women to make informed choices about participation in surveillance and surveillance-related testing [Despite the historical contributions of UAT-based ANC serosurveillance to monitor the HIV epidemic, its use as a surveillance strategy has been questioned on ethical grounds since the early 1990s . Critics testing -18. The  testing ,22.Over the last 15 years , coverage of HIV services has increased significantly in low- and middle-income countries, including HIV testing among women attending ANCs, prevention of mother-to-child transmission (PMTCT), and antiretroviral therapy (ART). The introduction of provider-initiated HIV testing and counseling within ANC services also contributed to substantial increases in coverage of HIV testing among pregnant women attending ANCs. In 2015, an estimated 16,738,964 pregnant women in sub-Saharan Africa had an HIV test and received their results at their first ANC visit .In 2013, WHO published Consolidated Guidelines on General HIV Care and the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection, recommending immediate initiation of life-long ART (option B+) for all pregnant women diagnosed with HIV . As of AThe move to offer treatment for all sharpened ethical questions surrounding UAT, namely, (1) UAT did not obtain informed consent from pregnant women tested for HIV for surveillance purposes, provide them with their surveillance HIV test results, or refer women with HIV-positive surveillance test results to available HIV care, treatment, and prevention interventions and (2) information needed for surveillance  was largely present in routine PMTCT program records, rendering UAT-based serosurveillance redundant ,22. In aGuiding principles on ethical issues in HIV surveillance, states that UAT should be used for surveillance only when data from clinical settings and other studies cannot provide the necessary information and that surveillance programs implementing UAT must demonstrate that program data are not adequate for the purpose of public health surveillance [Consolidated guidelines on HIV testing services recommended that “HIV surveillance systems should work toward assuring that all participants in biological surveillance receive their HIV status” and specifically recommended that countries move from traditional ANC surveillance to using routine program data for surveillance among pregnant women attending ANCs [HIV testing in PEPFAR-supported survey and surveillance activities, specifying that “All PEPFAR-supported survey and surveillance activities will provide participants the opportunity to receive final HIV status information generated by the activity.”In February 2009, UNAIDS and WHO held a partner consultation in Geneva, Switzerland, to review ethical issues associated with HIV testing in the context of national population surveys and sentinel surveillance among pregnant women. This meeting recommended that WHO and UNAIDS commission formal guidance on ethical issues in HIV surveillance . The reseillance . In addiing ANCs . FinallyOver the past several years, a shared vision has emerged in the global HIV surveillance community that recognizes the advantages and desirability of transitioning to using routine program data for ANC surveillance. The urgency of this transition has been underlined by the dramatic expansion in the coverage of HIV services in ANC settings.ANC surveillance based on routine program data offers multiple potential advantages over UAT-based serosurveillance. First, this approach adheres to the WHO and UNAIDS guidelines by guaranteeing that all HIV serostatus data used for surveillance come from HIV testing that ensures—as per routine clinical practice—that pregnant women have the informed and free choice to accept or decline  testing, receive pre- and posttest counseling, receive their HIV test result, and are referred to HIV services if the test result is positive. Second, because ANC surveillance based on routine data would eliminate or substantially reduce the need for additional training, human resources, logistics, and HIV testing associated with traditional ANC serosurveillance, such a system can significantly reduce the workload and financial costs associated with monitoring the HIV epidemic. This can improve the sustainability of surveillance systems by integrating surveillance into routine activities and data systems. Third, increased use of program data for surveillance can contribute to the monitoring, use, and strengthening of routine data and routine HIV testing to benefit program implementation, program monitoring, and surveillance.In the context of increasing global consensus on the benefits of using routine program data for surveillance, in 2013 the WHO and UNAIDS HIV Global Surveillance Working Group, in collaboration with the US Centers for Disease Control and Prevention (CDC), published guidelines for countries to assess how routine PMTCT program data can be used for surveillance. The guidelines stressed that collaboration between surveillance, monitoring and evaluation, and program  is foundational to the use of routine data for surveillance. Cooperation among these entities is crucial to monitor and strengthen the quality and completeness of routine PMTCT program data, the accuracy of routine PMTCT HIV testing, and quality assurance (QA) for routine PMTCT HIV testing .In the context of the new WHO guidance, a broad contingent of countries has conducted studies examining how to use routine program data for surveillance. Since 2013, at least 22 countries examined or are currently examining how to use PMTCT program data for surveillance, including Angola, Botswana, Burkina Faso, Cameroon, Cote D’Ivoire, Democratic Republic of the Congo, Ethiopia, Ghana, Haiti, India, Kenya, Lesotho, Mozambique, Namibia, Nigeria, Rwanda, Senegal, Sierra Leone, South Africa, Swaziland, Zambia, and Zimbabwe ,32-39. AGuidelines for conducting HIV surveillance among pregnant women attending antenatal clinics based on routine programme data was developed by WHO and UNAIDS in collaboration with other international stakeholders and ministries of health and published in 2015 [In September 2013, the WHO and CDC organized a consultation of African countries that had conducted assessments of how to use routine program data for ANC surveillance. The consensus was that countries are moving toward using routine data for surveillance in the coming years, and countries in attendance requested that the WHO provide technical guidance on how to operationalize the transition and to ensure the continued quality of HIV surveillance estimates and epidemic modeling estimates such as those produced by Spectrum. To this end,  in 2015 .This WHO and UNAIDS guidance provides comprehensive direction for surveillance programs through each step of designing and implementing ANC surveillance based on routine program data, including ethical considerations, sample size calculations, data collection, data management, QA of surveillance activities, data analysis, surveillance monitoring, and results’ interpretation and dissemination.Importantly, the WHO and UNAIDS guidance includes the use of routine syphilis testing data for the surveillance of syphilis among pregnant women attending ANCs. Routine syphilis testing in pregnancy is considered an essential antenatal care intervention by WHO; testing for reactive syphilis serology using rapid diagnostic tests and providing treatment of seropositive women are highly effective and cost-efficient. Historically, HIV serosurveillance of ANC attendees frequently included surveillance for maternal syphilis. This integrated approach to surveillance is both practical and epidemiologically appropriate and is reinforced in the new guidance. Furthermore, in the same way that reliance on routine testing and data for HIV surveillance can provide information to improve routine services, surveillance of maternal syphilis based on routine data can help identify gaps, and drive improvements, in the provision of routine syphilis testing and treatment services.Important elements of the new WHO and UNAIDS guidance, which include principles of ANC surveillance, operational design approaches, monitoring and QA, and ethical issues, are discussed below:New WHO and UNAIDS guidance stresses three principles of ANC surveillance. First, epidemiologic information provided by ANC surveillance, combined with other sources of epidemiological data, allows surveillance programs to address key aspects of the “know your epidemic” approach of second-generation surveillance of HIV and provides a key input for modeling national and global HIV incidence and burden . Second,New WHO and UNAIDS guidance describes two methodological approaches to ANC surveillance. The first approach involves a census of ANC—the gathering of individual-level or aggregate data from all pregnant women attending all  ANC sites providing PMTCT services by leveraging existing above-site  data repositories such as health management information systems (HMIS) or routine reporting systems. Census is the preferred design because it is highly resource-efficient and provides complete geographical coverage of surveillance of pregnant women attending ANCs. However, census requires the availability of routine PMTCT HIV testing and high-quality routine data at all  ANC sites. The guidelines encourage countries to strengthen and expand routine testing and data systems to progress, over time, toward a census approach.A census based on individual-level data is preferable because it allows subgroup analyses that take advantage of demographic parameters  and clinical variables . The complete geographic coverage of individual-level census data could be a valuable input into global efforts to create geospatial models that estimate trends in new HIV infections at the local level. Individual-level data, as compared with aggregate counts, also enable closer monitoring of surveillance data, facilitating the identification of gaps in routine data quality. However, a census based on individual-level data is only feasible in the presence of electronic medical records (EMR) systems  to capture individual-level ANC data and the capacity to safeguard the confidentiality of, and manage, large volumes of individual-level data. Furthermore, the coverage of EMR systems is currently limited in ANC settings. Therefore, a more feasible approach to census in the short term is to use aggregate service counts reported by an HMIS or routine reporting system that has a verified high degree of accuracy, completeness, and integrity. Aggregate data systems for program monitoring are already in place, and these data have the advantages of simplicity, economy, and the absence of personally identifying information. However, aggregate data may limit the ability of surveillance to conduct subanalyses  or to monitor data quality.The second design option for ANC surveillance is a sentinel surveillance design—a convenience sample of ANC sites that are chosen to represent geographical areas or populations of interest for HIV surveillance. Sentinel surveillance has the advantages of familiarity, collecting rich individual-level data, and the ability to prescreen sentinel sites  to ensure readiness to participate in surveillance. In addition, sentinel surveillance can involve either retrospective or real-time data collection, which can allow surveillance programs to provide extra support to routine PMTCT activities to ensure the quality of routine PMTCT testing and data that are used for surveillance. However, sentinel surveillance requires the safeguarding of personally identifying information present in individual-level data, necessitates fieldwork to collect routine data from ANC sites, and does not provide representative estimates of HIV prevalence among ANC attendees at national or subnational levels. A sentinel surveillance design could be an appropriate option for countries initially transitioning to using routine program data for surveillance.Just as UAT serosurveillance included robust surveillance monitoring and QA, ANC surveillance based on routine data requires similar mechanisms to ensure the reliability of surveillance methods and estimates. Because ANC surveillance based on routine program data relies on data and activities owned and managed by nonsurveillance programs , monitoring HIV surveillance among pregnant women attending ANCs is best viewed as a collaborative activity that engages these partners. Results of surveillance monitoring provide valuable information to strengthen routine activities. Surveillance monitoring can augment, reinforce, and highlight the value of routine monitoring and QA of the following: (1) the completeness of routine site-level data and data in HMIS or routine reporting systems and the appropriateness of routine data collection and reporting tools and (2) HIV rapid testing, including accuracy of testing, adherence to appropriate testing algorithms and practices, staff training, record keeping, and stock management.All HIV surveillance activities, regardless of the data source, adhere to ethical principles of biomedical research and surveillance, including respect for persons, beneficence, and justice . In the Data from ANC surveillance are a key input for modeling national, regional, and global HIV trends and burden using HIV modeling software. Continuing work is needed to evolve best methods to incorporate routine program data into HIV modeling software, calculate adjustment factors, and understand the implications of this new data source for modeled estimates .The transition to ANC surveillance based on routine data is an important milestone in HIV surveillance that enhances the efficiency, integration, sustainability, and ethical approach of surveillance. This shift represents a substantial achievement in building strong routine data systems to support HIV service delivery, program monitoring, and strategic information. Routine program data also enable surveillance estimates and UNAIDS Spectrum models to provide a more geographically granular description of subnational HIV epidemics, enabling highly targeted HIV control programs.The use of routine data for surveillance and monitoring the response to the HIV epidemic is essential to inform planning, and measure country progress, towards achieving UNAIDS 90-90-90 goals  at the national and subnational levels . The WHO


Aedes aegypti, suggest that yellow fever has the propensity to spread further internationally. The aim of this study was to estimate the disease's contemporary distribution and potential for spread into new areas to help inform optimal control and prevention strategies.Yellow fever cases are under-reported and the exact distribution of the disease is unknown. An effective vaccine is available but more information is needed about which populations within risk zones should be targeted to implement interventions. Substantial outbreaks of yellow fever in Angola, Democratic Republic of the Congo, and Brazil, coupled with the global expansion of the range of its main urban vector, We assembled 1155 geographical records of yellow fever virus infection in people from 1970 to 2016. We used a Poisson point process boosted regression tree model that explicitly incorporated environmental and biological explanatory covariates, vaccination coverage, and spatial variability in disease reporting rates to predict the relative risk of apparent yellow fever virus infection at a 5 × 5 km resolution across all risk zones (47 countries across the Americas and Africa). We also used the fitted model to predict the receptivity of areas outside at-risk zones to the introduction or reintroduction of yellow fever transmission. By use of previously published estimates of annual national case numbers, we used the model to map subnational variation in incidence of yellow fever across at-risk countries and to estimate the number of cases averted by vaccination worldwide.A aegypti, with low receptivity to yellow fever transmission in southern China, where A aegypti is known to occur.Substantial international and subnational spatial variation exists in relative risk and incidence of yellow fever as well as varied success of vaccination in reducing incidence in several high-risk regions, including Brazil, Cameroon, and Togo. Areas with the highest predicted average annual case numbers include large parts of Nigeria, the Democratic Republic of the Congo, and South Sudan, where vaccination coverage in 2016 was estimated to be substantially less than the recommended threshold to prevent outbreaks. Overall, we estimated that vaccination coverage levels achieved by 2016 avert between 94 336 and 118 500 cases of yellow fever annually within risk zones, on the basis of conservative and optimistic vaccination scenarios. The areas outside at-risk regions with predicted high receptivity to yellow fever transmission  were less extensive than the distribution of the main urban vector, Our results provide the evidence base for targeting vaccination campaigns within risk zones, as well as emphasising their high effectiveness. Our study highlights areas where public health authorities should be most vigilant for potential spread or importation events.Bill & Melinda Gates Foundation. Aedes aegypti, suggest that yellow fever has the potential to spread further internationally and increase its financial burden on health systems as well as its toll on population health.The global spread of mosquito-borne viruses such as dengue, chikungunya, West Nile virus, and Zika virus during recent decadesYellow fever is vaccine preventable, yet incomplete coverage means that the disease is still widely distributed in the tropics and subtropics of Latin America and Africa. Local transmission of yellow fever has never been reported in Asia, despite multiple opportunities for introduction and seemingly suitable ecological and climatic conditions.A aegypti, and large-scale epidemics can occur. The spectrum of human clinical disease caused by yellow fever virus is broad, ranging from asymptomatic (unapparent) infections to fatal disease.Multiple transmission cycles of yellow fever virus coexist with different mosquito genera serving as vectors in each cycle. The virus is principally maintained by a sylvatic transmission cycle involving non-human primate reservoirs, and human beings can sporadically be incidental hosts. When infected people introduce yellow fever virus into heavily populated areas with competent vector populations and insufficient vaccination, the virus is transmitted from person to person via Evidence before this studyWe searched PubMed on Dec 13, 2017, using the search terms “yellow fever” [All Fields] AND (“geograph*” [All Fields] OR “spati*” [All Fields]) without any date or language restrictions. This search returned 267 articles, of which seven contained information about the existing or potential geographical distribution of yellow fever risk. Five studies quantified yellow fever risk at national levels as well as at first or second administrative subnational units, or by ecological zone for a subset of countries; however, such results might mask considerable differences in yellow fever risk at more local levels. In 2006, Rogers and colleagues mapped yellow fever risk across both Africa and South America, as well as predicted climatic suitability for transmission outside these regions. This study analysed yellow fever data up to 2005, did not provide any estimate of spatial variation in disease incidence, or account for vaccination. An analysis of yellow fever data up to 2011 evaluated the impact of yellow fever vaccination in Africa, but the application of these findings might be limited in more recent years, and for other regions that have yellow fever epidemics . WHO has also done yellow fever risk assessments for high-risk and middle-risk African countries to identify regions most vulnerable to epidemics. To date, no study has quantified yellow fever risk or incidence across global risk zones at a high geospatial resolution, or evaluated potential for receptivity to yellow fever in areas outside current risk zones.Added value of this studyWe used 1155 records of human yellow fever virus infection from 1970 to 2016 to generate a novel model of incidence of yellow fever at a 5 × 5 km resolution for 47 countries across risk zones. We estimated potential receptivity to yellow fever transmission in all countries that are currently outside of defined risk zones. This work incorporated the most contemporary data on occurrence of yellow fever, and the chosen modelling approach allowed the inclusion of vaccination coverage rates, variation in disease reporting effort, mechanistic knowledge of suitability for vectors, distribution maps for reservoir and vector species, and a range of covariate data on land cover.Implications of all the available evidenceOur work furthers understanding of the contemporary global distribution of yellow fever, and the potential for its introduction and establishment into new regions. These results provide a current evidence base to prioritise areas for vaccination and surveillance programmes in present risk zones , and highlight areas where public health authorities should be most vigilant for potential spread or importation events .The epidemiology of yellow fever on the African continent, where most cases and epidemics are reported, involves a mix of transmission cycles. In recent decades, almost all cases of yellow fever in Latin America arose from sylvatic cycles, with inter-human transmission only reported a handful of times since the early 1940s.A aegypti is not established, and no secondary cases resulting from local transmission were detected.The outbreak that started in Luanda, Angola, in December, 2015, developed into the largest and most widespread outbreak of yellow fever reported in Africa in more than 20 years.A aegypti.Informing vaccination and other control strategies for yellow fever requires an improved evidence base for identifying the most vulnerable populations. Risk mapping for yellow fever occurrence in areas at risk of transmission has previously been done at national and subnational levels,In this study, we modelled subnational variation in risk of yellow fever across all risk zones and predicted receptivity to yellow fever virus transmission outside risk areas, using a model that is based on yellow fever infection data, vaccination coverage rates, and a range of environmental and biological covariates.A aegypti following 50 years of eradication efforts,We collated and georeferenced reports of symptomatic yellow fever virus infection in people for the 47-year period from 1970 to 2016. Records before 1970 were not included because we aimed to map the contemporary spatial distribution of yellow fever, and this timepoint coincides with the re-infestation of Latin America with HealthMap system, as described elsewhere.We assembled a database of locations where at least one laboratory-confirmed symptomatic human infection of yellow fever virus had been reported in any given year. This information was extracted from various sources including online sources, peer-reviewed literature, and WHO reports. Data from online sources were collated by the automated To account for the effects of yellow fever vaccination in our temporally static model of yellow fever infection risk, we required an estimate of the average susceptible population size across the study time period. To calculate this temporal average, we used vaccination coverage estimates for every 5 years from 1970 to 2016 (for which details can be found elsewhere),Ten 5 × 5 km gridded data surfaces of a range of environmental and biological factors thought to affect transmission of yellow fever virus were used as potential explanatory covariates .20, 21, We fitted an inhomogeneous Poisson point process model to the dataset of yellow fever disease reports using a BRT model to characterise the expected number of observations per unit area. By explicitly accounting for human population density, vaccination coverage rate, and variable reporting effort, this model estimated the incidence of apparent infections in susceptible individuals , to within a constant of proportionality at each 5 × 5 km grid square across risk zones.By considering the size of the susceptible population within each 5 × 5 km grid square (based on vaccination coverage levels in 2016), and applying continental calibration factors, we estimated the average annual number of cases across risk zones (averaged over the 47-year study period). Calibration factors were calculated using the average annual number of cases (from 1990 to 2015) estimated by GBD 2015The model's predictive performance within risk zones was assessed by spatially stratified ten-fold cross-validation and by calculating the predictive deviance of the model, which is the mismatch between the predicted number of occurrence records and the number observed. Cross-validation was done for each bootstrap of the model, resulting in a bootstrapped estimate of the model's predictive capacity. Details of the validation procedures and results are provided in the We estimated the average annual number of cases of yellow fever per pixel using estimated vaccination coverage rates in 2016, based on three vaccination targeting scenarios for historical campaigns: conservative ; untargeted, unbiased; and optimistic (targeted).The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.Our model predicted substantial international and subnational spatial variation in individual infection risk for yellow fever . This riConsidered together, the maps of individual infection risk, average annual incidence, and average annual cases  highlighUsing the total average annual cases estimated by our model, we calculated that globally, between 94 336 and 118 500 cases of yellow fever are averted each year by vaccination coverage rates achieved in 2016 . These numbers represent 33% to 42% of total predicted cases if vaccination coverage was zero across risk zones. The global totals represent between 84 385 and 99 840 cases averted on the African continent  and between 9951 and 18 660 cases within Latin America .A aegypti is known to be present, for example southern China and southern USA.Outside contemporary risk zones, we predict high receptivity to yellow fever virus transmission across much of southeast Asia, where yellow fever has never been reported, including large areas of Cambodia, India, Indonesia, Laos, Malaysia, Myanmar, Papua New Guinea, the Philippines, Thailand, and Vietnam . High reThe high resolution maps of risk and incidence of yellow fever produced in this study highlight the success of vaccination in reducing incidence in high-risk regions, including Brazil, Cameroon, and Togo. The maps also identify areas with high predicted average annual case numbers, where vaccination coverage in 2016 was less than the recommended threshold to prevent outbreaks, such as large parts of Nigeria, DR Congo, and South Sudan. These maps provide an evidence base to prioritise areas for vaccination and vector control programmes in current risk zones. Receptivity to yellow fever virus transmission in areas outside risk zones was also mapped, including areas where yellow fever has been controlled, such as Central America, or has never persisted, such as southern Asia. Our findings highlight areas where public health authorities should be most vigilant for potential spread or importation events. Furthermore, the areas of high receptivity near the edge of the current risk zone on the southeast coast of Brazil  reflect a need to geographically expand the existing risk limits because locally acquired cases have recently been reported in this area.Rogers and colleaguesA aegypti and non-human primate hosts in our model, because countries where both exist are thought to be most vulnerable to the introduction and establishment of yellow fever virus.We included distributions of Yellow fever has both urban and sylvatic transmission cycles, and the spatial and temporal distribution of cases fluctuates substantially. The periodicity of yellow fever epidemic activity is driven in part by the rapid depletion and slow replenishment of susceptible hosts, as illustrated by upsurges at irregular intervals in parts of west and east Africa. Our model did not attempt to capture temporal and spatial spikes in cases of yellow fever; the focus was on predicting spatial variation in the underlying risk of infection. Our outputs represent the period from 1970 to 2016, averaged over the large fluctuations that occur. Thus, the results might smooth over important secular trends across time, and our estimated incidence for a particular location will be different from the 2016 incidence, or even a 5-year average. Indeed, the five most recently reported outbreaks of yellow fever began in areas of variable predicted risk. Additionally, since all reports of yellow fever virus infection in human beings were included in the model, irrespective of whether infection was the result of a sylvatic, intermediate, or urban transmission cycle, the model predicts apparent infection risk from any transmission cycle. The BRT model is capable of encompassing different relations in the data arising from these distinct transmission cycles, with the given covariates.A aegypti-inhabited areas of southeast Asia might be missing from our analysis. Indeed, most theories that have been used to explain the absence of yellow fever in Asia involve biological factors rather than climatic or environmental ones. These factors include cross-protection from other flaviviruses, lower competence of local populations of A aegypti, and competition between other flaviviruses within mosquito cells,A aegypti, or to further speculate on reasons for the disease's absence from Asia to date. Our work, however, highlights areas for future improvement in our understanding of yellow fever ecology.Our model predicts receptivity to yellow fever virus transmission based on the relation between locations where yellow fever has been reported from 1970 to 2016, and the values of environmental and biological covariates at those locations. For this reason, predictions of high receptivity in southeast Asia should be interpreted with caution. Potential variables that distinguish current risk zones in Africa and the Americas from Our study involved multiple stages of analysis, each containing potential sources of bias and uncertainty, much of which was difficult to account for or quantify. Each stage of the analytical process involved fitting a model to an independent, fixed dataset. Since each of these models was fitted to fixed data, not the output of previous models, it was not meaningful to propagate uncertainty through these steps. However, there were some steps where it was important to account for or report uncertainties. In fitting the model of risk for apparent yellow fever virus infection, uncertainty in the spatial locations of reported cases was propagated through the model via Monte Carlo simulation. Similarly, uncertainty in the final step of the analytical process—calibrating spatial predictions of yellow fever risk against GBD 2015 estimates of annual cases—was estimated and reflected in reported results.High-quality spatial data on yellow fever are lacking, largely because of diagnostic complexity and limitations of health-care systems in many affected countries. Our occurrence dataset included human yellow fever virus infections confirmed via both genetic and serological diagnostic methods. As a result of cross-reactivity among flaviviruses, the precision of serological diagnostic techniques is limited, particularly when considering historical records. Additionally, we assumed that estimates of vaccination coverage, combined with data on population size, were proportional to the number of people susceptible to yellow fever virus infection. Translating maps of unvaccinated individuals into maps of susceptible people is complicated by the acquisition of immunity via natural infection, which is difficult to quantify. Modelling efforts will be improved as the volume and quality of geographical data on yellow fever increases, ideally using diagnostics that distinguish past infection from vaccination, and from other flavivirus infections. For now, the work presented here provides the best available evidence base for identifying populations most vulnerable to yellow fever.To develop the most cost-effective vaccination strategies that prevent outbreaks and minimise adverse events, vaccination policy makers require a clear understanding of geographical disease risk. Within risk zones, our model improves understanding of geographical risk and comes at a time when current policies may require re-evaluation in view of the demonstrated inadequacy of emergency stocks and surge capacity of vaccine manufacture to meet the needs of the recent outbreak in Angola.