Dynamic HIV transmission models can provide evidence-based guidance on optimal combination implementation strategies to treat and prevent HIV/AIDS. However, these models can be extremely data intensive, and the availability of good-quality data characterizing regional microepidemics varies substantially within and across countries. We aim to provide a comprehensive and transparent description of an evidence synthesis process and reporting framework employed to populate and calibrate a dynamic, compartmental HIV transmission model for six US cities.a priori and sought out databases for primary analysis to augment our evidence synthesis. We ranked the quality of each parameter using context- and domain-specific criteria and verified sources and assumptions with our scientific advisory committee.We executed a mixed-method evidence synthesis strategy to populate model parameters in six categories: (i) initial HIV-negative and HIV-infected populations; (ii) parameters used to calculate the probability of HIV transmission; (iii) screening, diagnosis, treatment and HIV disease progression; (iv) HIV prevention programs; (v) the costs of medical care; and (vi) health utility weights for each stage of HIV disease progression. We identified parameters that required city-specific data and stratification by gender, risk group and race/ethnicity To inform the 1,667 parameters needed to populate our model, we synthesized evidence from 59 peer-reviewed publications and 24 public health and surveillance reports and executed primary analyses using 11 data sets. Of these 1,667 parameters, 1,517 (91%) were city-specific and 150 (9%) were common for all cities. Notably, 1,074 (64%), 201 (12%) and 312 (19%) parameters corresponded to categories (i), (ii) and (iii), respectively. Parameters ranked as best- to moderate-quality evidence comprised 39% of the common parameters and ranged from 56%-60% across cities for the city-specific parameters. We identified variation in parameter values across cities as well as within cities across risk and race/ethnic groups.Better integration of modelling in decision making can be achieved by systematically reporting on the evidence synthesis process that is used to populate models, and by explicitly assessing the quality of data entered into the model. The effective communication of this process can help prioritize data collection of the most informative components of local HIV prevention and care services in order to reduce decision uncertainty and strengthen model conclusions. In the United States, more than 1.1 million people were estimated to be living with HIV in 2015, including 162,500 (15%) people who had not been diagnosed . FurtherIncreasingly, mathematical models are being used to help set priorities to address HIV microepidemics internationally –13. DynaComprehensively reporting the evidence synthesis process and sources of data used in a model can help readers assess its validity and the credibility of its inferences. In addition, calibrating a model to match a jurisdiction’s microepidemic over a stated period is a necessary condition for ensuring a model’s external validity . DespiteWe aim to provide a comprehensive description of an evidence synthesis process and reporting framework that can be used to populate and calibrate a dynamic, compartmental HIV transmission model for six US cities. We hope to maximize the transparency of our model so that interested parties can review and evaluate its structure and equations, as well as the generating process and assumptions for all parameters (25), in order to promote the use of modeling recommendations in decision making to address city-level HIV microepidemics.We adapted a previously published dynamic, compartmental HIV transmission model –30 to siIndividuals within each of these 42 strata  progress through the model according to the health states outlined in We organized the data needed for the model into six model parameter categories: (i) initial HIV-negative and HIV-infected population estimates; (ii) parameters used to calculate the probability of HIV transmission; (iii) screening, diagnosis, treatment and HIV disease progression; (iv) HIV prevention programs, including syringe service programs (SSP), OAT, and PrEP; (v) the costs of medical care for HIV-negative and HIV-infected individuals; and (vi) health utility weights for each stage of HIV disease progression.Each parameter in the model required a point estimate and range to facilitate model calibration and probabilistic sensitivity analysis according to best practice guidelines in model-based cost-effectiveness analysis , 35.In addition to evidence informing model parameters, we required annual city-specific data for at least two time points to be used as calibration and validation targets for comparison of model projections , 37. We We first identified parameter estimates that we determined to be common across cities and generalizable across city-level microepidemics. The remaining parameters required context-specific data to adequately characterize the population mix, HIV risk behaviors and health care utilization patterns for a given city. We divided our search strategy into two parts: (i) identifying a rank order of a priori potential data sources for each model parameter category; and (ii) selecting the best data to use, given additional factors and constraints .The best possible data source for each parameter depended on factors unique to each parameter category. For example, the most accurate and reliable source for total population numbers was city-level census data, while the best source for ART effectiveness estimates came from randomized controlled trials. For each non-city-specific (common) parameter, we selected source data based on study quality, how well a study matched the ideal study type for a given model parameter, and recency of the evidence. For city-specific parameters, we selected source data based on geographic representativeness and stratification level relative to our model requirements and recency of the evidence. We assessed recency according to evidence type as we required more up-to-date surveillance data for initial populations and calibration targets in comparison to other non-city-specific evidence such as efficacy data from RCTs or untreated HIV disease progression. When necessary, parameter estimates and ranges were derived from triangulation, defined as using numbers from multiple sources and/or from the same source but requiring additional assumptions to match our model’s level of stratification.We used several search methods to identify evidence sources for the disparate data types, including searches in bibliographic databases (PubMed searches for (ii) parameters used to calculate the probability of HIV transmission conducted for all articles published prior to May 31, 2017; searches for (iii) Screening, diagnosis, treatment and HIV disease progression conducted for all articles published prior to February 8, 2018; searches for (iv) HIV Prevention Programs conducted for all articles published prior to October 26, 2018; and searches for (vi) Health utility weights conducted for all articles published prior to August 30, 2017), non-database searches, “snowballing” (such as searching references from key sources to identify further sources)  Parameters used to calculate the probability of HIV transmission conducted for all articles published prior to May 31, 2017), and local surveillance reports , 24, 38.The quality of each parameter was determined using context- and category-specific criteria, incorporating an adapted version of the Oxford Centre for Evidence-based Medicine–Levels of Evidence scale for common parameters  39]. We. We39]. For city-specific model parameters, we ranked the inputs according to how closely the evidence mapped onto the model stratification. Best quality indicated that the evidence data mapped onto the model parameter inputs by city perfectly , moderate quality indicated that the evidence was stratified by city or region, with some level of population stratification or other triangulation, and lowest quality indicated that the evidence was at the national level, aggregated across population strata, or derived from expert opinion/assumption .All quality rankings were independently assessed by at least two team members and discrepancies were resolved through discussion and consensus among team members. Finally, missing city-level parameter values were assigned using a standardized algorithm to prioritize best-available data in surveillance and peer-reviewed literature at the (i) state, (ii) regional, or (iii) national level.Where the available data was less than ideal in at least two ways , we posed explicit questions to our scientific advisory committee, a collection of city-specific experts, to confirm use of the best-available data or gain access to data otherwise unavailable publicly . We prepared a web-based survey specific to each of the six cities. For each parameter in question, we provided the specific definition of the parameter and the best publicly available data to populate it. Scientific advisory committee members were asked to (i) identify additional sources that we had overlooked or that were not in the public domain but could be made available to the study team, (ii) rate their confidence in proposed triangulation methods to estimate parameter values, (iii) explain their rated responses, and (iv) where possible, share the survey with other knowledgeable public health experts in their professional networks .We identified 1,667 parameters needed to populate our dynamic, compartmental HIV transmission model . Of thesTo inform each parameter’s point estimate and range, we synthesized evidence from 59 peer-reviewed publications and 24 public health and surveillance reports  and execThe city-specific surveys that were sent to our scientific advisory committee contained questions about four of the six model parameter categories, including questions regarding population size estimates for HIV risk groups, parameters used to calculate the probability of HIV transmission, ART dropout rates and HIV prevention programs . Each ciKey results of our evidence synthesis are highlighted by model parameter category in this section. A detailed description of the derivation of each individual parameter is provided in the supplementary material , and desA majority of the model’s parameters  were for population estimates and population dynamics. We derived the necessary evidence from 13 public health and surveillance reports –98 and 9We synthesized evidence from 29 peer-reviewed publications , 112–117Screening, diagnosis, treatment and HIV disease progression parameters represented 18% (n = 312) of all model parameters and were derived from 5 peer-reviewed publications , 121–123Parameters for HIV prevention programs (n = 23) were derived by combining evidence from 10 local, state and national sources , 126–134To quantify health resource use cost parameters for infected (n = 24) and HIV-negative (n = 2) individuals, we included evidence from 4 public health and surveillance reports –143 and We used common health utility weights across all six cities to calculate quality adjusted life years (QALYs) parameters (n = 30), synthesizing evidence from 4 peer-reviewed articles . EstimatWe identified 3 sets of calibration targets , including stratified indicators of the annual number of new HIV diagnoses per year, the total number of diagnosed PLHIV and the annual number of all-cause deaths among PLHIV . These wWe have provided a comprehensive description of an extensive evidence synthesis process that is required to populate a dynamic, compartmental HIV transmission model for six US cities. We identified differences across cities in the quality and representativeness of evidence available to inform our model. However, we identified consistency in the lack of availability of best-quality local administrative data that are critical to assess health system performance, particularly in relation to population-level rates of HIV testing and ART engagement. Nonetheless, our findings, which used the best-available evidence, highlight fundamental differences across settings related to rates of health system engagement and access to HIV prevention programs. The modeling of targeted, locally-oriented combination implementation strategies is necessary to determine how scarce resources should be allocated to interventions that can provide the greatest value for money in a given microepidemic. Our findings emphasize the need for increased public health efforts to measure and monitor the most informative components of local HIV prevention and care services, including the delivery, uptake and effect of localized HIV programs.Reviews of health economic models in specific disease areas typically focus on differences in model structures and projected outcomes, with limited discussion of how the differences in the quality of input data can function as an explanation for variations across outputs –152. FaiThe sustainability of an effective and efficient HIV response is critical to the control of local microepidemics –157. ForSystematically conducting one-way sensitivity analyses and probabilistic sensitivity analysis to quantify the uncertainty in model recommendations resulting from parameters derived from evidence of poorer quality or representativeness is critical for further information gathering . Value oThis comprehensive evidence synthesis process had several potential limitations. First, the search for evidence sources was not systematic; however, we used a systematic structured identification strategy . FurtherBetter integration of modelling in decision making can be achieved by systematically reporting on the evidence synthesis process that is used to populate models and by explicitly assessing the quality of data. The effective communication of this process can help prioritize data collection of the most informative components of local HIV prevention and care services in order to reduce decision uncertainty and strengthen model conclusions.S1 SupplementSupporting information includes descriptions of city boundaries (Supplement A), search strategy for model inputs (Supplement B), derivation of all model parameters (Supplement C), description of data sets used for primary analysis (Supplement D), derivation of model calibration/validation targets and PSA probability distributions (Supplement E), and the data verification survey/results from our scientific advisory committee (SAC) (Supplement F).(PDF)Click here for additional data file.S2 SupplementSupplement Tables Supporting information includes (i) excel file of values, ranges and PSA distributions for all model parameters, (ii) excel file of values and ranges for calibration/validation targets for all cities, and (iii) pdf of full survey given to SAC members for data verification.(ZIP)Click here for additional data file.


Craniofacial bone defect anomalies affect both soft and hard tissues and can be caused by trauma, bone recessions from tumors and cysts, or even from congenital disorders. On this note, cleft/lip palate is the most prevalent congenital craniofacial defect caused by disturbed embryonic development of soft and hard tissues around the oral cavity and face area, resulting in most cases, of severe limitations with chewing, swallowing, and talking as well as problems of insufficient space for teeth, proper breathing, and self-esteem problems as a consequence of facial appearance. Spectacular advances in regenerative medicine have arrived, giving new hope to patients that can benefit from new tissue engineering therapies based on the supportive action of 3D biomaterials together with the synergic action of osteo-inductive molecules and recruited stem cells that can be driven to the process of bone regeneration. However, few studies have focused on the application of tissue engineering to the regeneration of the cleft/lip and only a few have reported significant advances to offer real clinical solutions. This review provides an updated and deep analysis of the studies that have reported on the use of advanced biomaterials and cell therapies for the regeneration of cleft lip and palate regeneration. Craniofacial defects generally cause significant negative impacts on the quality of life and self-esteem of those individuals with musculoskeletal dysfunctionalities. Cleft lip, with or without cleft palate (CL/P), is the most prevalent congenital craniofacial defect caused by disturbed embryonic development of soft and hard tissues around the oral cavity and face area . CurrentCleft palate (CL/P) malformation occurs as a result of the non-fusion of the primary palate during the fourth and 12th weeks of gestation . During Environmental factors or maternal metabolic imbalances and infections during embryogenesis ultimately contribute to the etiology of musculoskeletal dysfunctionalities being maternal folic acid deficiency during the periconceptional period or exposure to alcohol and teratogenic medications, i.e., retinoids, corticosteroids, and the anticonvulsant phenytoin and valproic acid, which is the main cause of cleft disorders .Orofacial cleft conditions have been estimated to have a global annual prevalence of 7.94 cases per 10,000 live births with high variances of treated patients across regions and countries  11]. In. In11]. CL/P is considered as an anatomical defect of profound aesthetic and functional impact that leads to other future alterations, and therefore may negatively impact health-related quality of life, and/or speech . IndividThe management of patients with CL/P pathology is complex and requires a multidisciplinary approach that includes plastic surgeons, maxillofacial surgeons (cleft surgeons), otolaryngologists, speech/language pathologists, audiologists, dentists, orthodontists, psychologists, geneticists, and social workers. Different tissues including bone, dental organs, and soft tissue from the respiratory system are largely affected during the CL/P reconstruction , therefoRegarding the reconstruction of alveolar cleft defects, the most accepted approach consists of the secondary alveolar cleft osteoplasty in the mixed dentition phase . The goaNowadays, the use of autogenous bone is the most widely used type of grafting in bone regeneration defects ,19. HoweThe current bioartificial tissues designed for cleft palate reconstruction have been mostly based on inserted granules isolated with a single tissue layer ,21. HoweSome authors have also evaluated in vivo genetically induced CL/P models in rats. It was described that due to a sevoflurane-induced gene deletion, an incomplete development of the palate and alveolus was achieved. However, in many cases, the gene defect led to other pathologies and perinatal lethality, therefore, this methodology has been considered as not suitable to evaluate new bone grafts ,24.Adult stem cells are considered fundamental for cell therapy because of their unique ability to self-renew and differentiate into various phenotypes, in addition to being obtained from different tissues and have been used for craniofacial defect regeneration in tissue engineering. Adipocyte stem cells (ADSCs) are particularly desirable candidates for musculoskeletal tissue engineering applications such as cleft lip and palate . In thisComplementary to ADSCs, another source of adult mesenchymal stem cells can be isolated from bone marrow (BMSC) and dental pulp (HDPSC). There have been multiple examples of maxillofacial bone regeneration using these sources of cells. Korn et al. demonstrated that BMSCs could be used to promote bone formation in a maxillary defect through their osteogenic differentiation mediated by BMP-4  24], an, an24], PRF is a platelet concentrate, as a source of growth factors basically used to enhance soft and hard tissue healing and has been used in plastic and maxillofacial surgery, in addition to many tissue engineering models ,26,27,28This is why PRFs have been present as a strong alternative and presumably cost-effective biomaterial for maxillofacial tissue repair and CL/P regeneration .Biomaterials play a key role in the tissue engineering strategy for the restoration of missing tissue and its functionality. In particular, the advances in bone regeneration using biomimetic 3D scaffolds made of bioceramics, polymers, and composites, using different manufacturing methods , have permitted the exploration of new options for the repair of tissues in CL/P treatment.Bioceramics such as hydroxyapatite (HA), α-tricalciumphosphates (αTCP) and β-tricalciumphosphates (βTCP), demineralized bone matrices, calcium carbonates, calcium sulfates, bioactive glasses, and composite materials in combination with bioactive inorganic materials  constitute an important group of biomaterials used to manufacture adequate scaffolds in relation to novel treatments for CL/P due to their desired biological properties in terms of osteoconduction, biocompatibility, chemical similarity with natural bone and facilitate proliferation and osteoblast differentiation ,31. JansRecent advances in macromolecular sciences and tissue engineering methods have made it possible to efficiently generate several human artificial tissues including the oral mucosa and maxillofacial bone such as cleft palate . SeveralA new generation of advanced 3D polymeric scaffolds has resulted in very promising results. Hoshi et al. developed an implant-type tissue-engineered cartilage using a PLA based scaffold and evaluated it clinically by inserting it into subcutaneous areas of nasal dorsum in three patients to correct cleft lip–nose deformity. Subsequently, one year after implantation, the maintenance of the morphology in the dorsum and apex of the nose of the patients was confirmed . SimilarSome of the most challenging difficulties for craniofacial defect regeneration are derived from the variety of tissue-specific requirements and the complexity of anatomical structures in that region ,44. ThusMaternal folic acid during the periconceptional period is considered to be one of the main causes of clefting disorders. A recent review published by Fernandez Villa et al.  highligh2+ ions with low or the absence of secondary pharmacological effects. In this regard, Rojo et al. developed a carrier for Sr based on folic acid with a remarkable capacity of enhancing bone tissue formation and synergic benefits on cell replication and differentiation processes. In agreement with these authors, Martín-del-Campo et al. demonstrated that the incorporation of strontium folate within 3D porous bio-hybrid scaffolds provided an excellent system for the regeneration of bone tissue into the craniofacial area (The therapy based on Sr seems promising due to its proven action in improving preosteoblast replication, osteoblast differentiation, synthesis of collagen type I, and mineralization of the bone matrix. Nonetheless, any formulation should provide an effective and consistent way to deliver Srial area  39]. Th. Th2+ ioThe success of synthetic bone grafts is based on their capacity to promote osteoconductivity and osteoinductivity during the formation of new bone growth. In addition, the use of low molecular weight compounds such as those derived from folic acid and bioactive cations constitutes a promising alternative to the use of protein-based growth factors and morphogens, for the preparation of resorbable scaffolds in the maxillary defect model to allow osteoconduction and osteoinduction in the defects. In this regard, the use of bioceramics such as calcium phosphate in combination with biomimetic polymer scaffolds, folic acid derivatives, morphogens, and stem cells are currently considered as the most promising alternative for CL/P regeneration. In addition, emerging bioprinting technologies in combination with advanced manufacturing techniques such electrospinning or cryogelation processes have permitted the development of new tissue substitutes with a precise control of sizes and shapes to recreate the complex physiological, biomechanical, and hierarchical microstructure of biological tissues that are necessary for the regeneration of malformations such as CL/P.


American Journal of Tropical Medicine and Hygiene, the article by Burton et al.1 documents factors associated with declines in malaria incidence in El Salvador over the past four decades and compares these trends with slower declines in El Salvador’s direct neighbors. At a time of flattening global funding for malaria elimination, sharing lessons learned from strong national programs is especially critical. Burton et al. describe three important areas that contributed to El Salvador’s success: 1) an early commitment to data-driven decision-making based on progressive stratification, 2) decentralization and community-based decision-making and provision of services, and 3) strong national leadership and sustained domestic financing.In this month’s 2 El Salvador introduced an electronic malaria information system in 1990, which provided a basis to target intervention packages to specific geographies and populations. User-friendly electronic information systems and mobile technologies are increasingly available to malaria elimination programs to support rapid reporting of case data, incorporate data collected from case and foci investigations, and use these data for visualization and stratification.3 In addition, advances in geostatistical modeling have allowed for the incorporation of incidence, prevalence, and related data into high-resolution maps of risk that can supplement health system data.4 Mathematical modeling can further support programs by informing selection of the optimal intervention mixes within each stratum.First, as in El Salvador, progressively focused, data-driven surveillance and response have long been the hallmark of successful malaria elimination programs. The recently updated World Health Organization framework for malaria elimination emphasizes the importance of programs adopting this approach as early as is feasible, by conducting progressive stratification exercises for operational planning.5 Community-based surveillance in addition increases the spatial and temporal fidelity of data that can then be used for more refined decision-making and resource targeting.6 The article highlights the combination of interventions El Salvador applied at very local levels based on these data, including integrated vector control and aggressive drug-based approaches targeted to the highest risk populations. Decentralized decision-making can introduce its own challenges, so it is important that accountability structures and oversight from higher levels of the health system are in place.7 Importantly, in El Salvador, the volunteer collaborators have been integrated into the broader infectious disease control program as malaria transmission has declined, which should help to ensure sustainability and motivation.Second, decentralization and expansion of community-based case management through a network of volunteer collaborators were likely essential to El Salvador’s success. In this setting, program decentralization increased local capacity of community health structures and facilitated rapid, data-driven decision-making by local authorities. Expanding access to early diagnosis and treatment within communities has been shown to reduce malaria transmission in other epidemiological settings.Finally, El Salvador consistently committed relatively larger amounts of domestic funding to malaria over the past thirty years compared with its neighbors. This stable funding environment provided the foundation for programmatic success, and results in El Salvador highlight the importance of national leadership and sustained political commitment to maintaining gains in control through to elimination.7 Large declines in malaria incidence in China and Indonesia over the past decade have resulted from similar commitments to aggressive surveillance and response and decentralized decision-making.8As the authors point out, El Salvador likely benefitted from its relatively small size and high degree of urbanization, but the fundamental principles underlying the El Salvador interventions and strategies have proven successful when applied in other settings.9 and ensure that lessons learned from El Salvador’s success are replicated. It is critical that platforms such as these are supported to provide a mechanism for maintaining regional momentum following national successes.Challenges remain that could threaten progress toward malaria elimination in El Salvador and other countries in the region, including political instability, high rates of population movement, waning financial support, and loss of programmatic expertise over time. In addition to efforts by national programs, regionally coordinated efforts will be needed to mitigate these threats. The Initiative for Elimination in Mesoamerica and Hispaniola is an initiative that presents an opportunity to address cross-border issues and other regional challenges


The complexity and delicacy of human brain make it challenging to recapitulate its development, function and disorders. Brain organoids derived from human pluripotent stem cells (PSCs) provide a new tool to model both normal and pathological human brain, and greatly enhance our ability to study brain biology and diseases. Currently, human brain organoids are increasingly used in modeling neurological disorders and relative therapeutic discovery. This review article focuses on recent advances in human brain organoid system and its application in disease modeling. It also discusses the limitations and future perspective of human brain organoids in modeling neurological diseases. Since the invention of method to generate induced pluripotent stem cells (iPSCs) from somatic cells, tremendous progress has been made in developing protocols for differentiating human iPSCs into various cell types, including neural cells. The iPSCs derived from patients are now widely used in disease modeling  usually are of complex and diverse etiologies, and could be further complicated by variable genetic, epigenetic and environmental factors that differ among individuals. One of the major limitations in the study of these diseases is the lack of an The three-dimensional (3D) culture models are more physiologically relevant concerning the spatial organization of tissues, cell-cell and cell-matrix connections. It is now possible to differentiate pluripotent stem cells (PSCs), including both embryonic stem cells (ESCs) and iPSCs, into 3D organ-like tissues named organoids —like aggregates with quick re-aggregation  acquires more neural properties, and differentiates into neuroepithelium, which later is the source of neural progenitors. One key development here is to combine the floating 3D aggregate approach with Matrigel, the components of extracellular matrix (ECM), by embedding the growing EBs into Matrigel , the inner subventricular zone (iSVZ) and outer SVZ (oSVZ), resembling the multi-layer progenitor zone organization of human brain , which might reduce the population of neural progenitor cells during brain development -protein kinase B (PKB/AKT) cascade regulates human cortical formation  are a group of neurodevelopmental and psychiatric conditions characterized by language deficits, social communication difficulties and repetitive behaviors, which are present in patients at their childhood , a causal gene of ASDs, encodes a member of the CHD family of ATP-dependent chromatin-remodeling factors  were not only consistent with many of those found in the analysis in neural progenitor cells and neuronal cultures, but also significantly overlapped with the DEGs previously identified in idiopathic ASDs  are known to be associated with major psychiatric disorders, such as schizophrenia, autism, bipolar disorder, and depression  gene, which encodes a multifunctional epigenetic regulator  is an X-linked early-onset neurodevelopmental disorder that is predominantly caused by mutations of theMiller-Dieker syndrome (MDS), a congenital form of lissencephaly, is caused by a heterozygous deletion of chromosome 17p13.3 leading to malformations during cortical development  which results in the loss of beta-hexosaminidase activity and subsequent lysosomal accumulation of its substrate, GM2 ganglioside  is a pathogen causing congenital microcephaly and neurological disorders. With its outbreak of in the Americas, human brain organoids are becoming a powerful tool for studying the effects of ZIKV on brain development, helping to establish the causal relationship between ZIKV infection and the selectively targeted destruction of neural progenitor cells , the most common type of dementia, which is mainly characterized by extracellular deposition of misfolded amyloid-β (Aβ) containing plaques and intracellular neurofibrillary tangles  from human PSCs or more fate-restricted neural stem cells suggests that human brain organoids may ultimately be valuable for modeling age-related neurological diseases like Parkinson disease  and investigate drug transport through BBB. Importantly, vascularized organoids, which more precisely mimic in vivo brain anatomy and physiology, may facilitate brain disease modeling and also present an ideal platform for drug testing (Kelava and Lancaster, The absence of vascularization restricts the supply of oxygen and nutrients within organoids. Brain development, especially at the late stages, highly depends on the vascularization of SVZ, as being close to blood vessels is necessary for differentiation of neural progenitor cells and neuronal survival and maturation (Kelava and Lancaster, It seems that most of current organoid protocols or medium formulations favor progenitor cells and might not well support the formation of dendritic spines and mature synapses for neurons in brain organoids. Although neurons in brain organoids make functional synapses, much more need to be done to find out the conditions most suitable for the establishment of neural circuitry and neurophysiological activity (Kelava and Lancaster, Encouragingly, biomaterials and bioengineering are providing valuable tools for brain organoid research by introducing molecular, cellular and structural features that normally exist in human brain Wan, . The orgFurther improvement of the organoid protocols with the development of technologies, will help to investigate more complicated interactions in brain, such as neuron–glia interactions and neural circuitry. Importantly, it will allow for modeling a larger range of neurological disorders, including disorders of the developing, adult and aging brain, and even phenotypic profiling or therapeutic screening at high-throughput levels (Kelava and Lancaster, The failures of potential neurotherapeutics to translate from animal models to patients highlights the need for better predictive preclinical models (Bradshaw and Porteous, HW conceived, wrote and revised the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Sarah L Dalglish and colleaguesCurrent global child health strategies have reduced wealth based inequities in care seeking for childhood illness, but we need much greater emphasis on equity in strategy design and implementation, say  Equity oriented child health policies are cost effective, improve coverage faster, and result in greater gains in child health Global strategies have contributed to reducing inequities in child health over the past 20 yearsGreater emphasis on equity in strategies’ design and implementation could have led to greater improvementsFuture strategies must emphasise intersectoral action to tackle social determinants, targeted coverage of interventions, and sustainable financing to support poor families Top-down leadership and bottom-up demand are needed to drive policy changes that benefit marginalised populationsOver the past two decades, the world has made considerable progress in reducing under 5 mortality, but not all children have benefitted, and stark inequities in coverage of interventions persist in nearly all countries.Box 1Integrated Management of Childhood Illness (IMCI)—introduced by WHO and Unicef in the mid-1990s, aims to reduce death, illness, and disability and to promote improved growth and development among children under 5. IMCI includes both preventive and curative elements that are implemented by families and communities as well as by health facilities. The strategy includes three main components: improving case management skills of healthcare staff; strengthening health systems; and improving family and community health practices.Integrated Community Case Management (iCCM)—introduced by Unicef and WHO in 2012 as an equity focused strategy to complement and extend the reach of public health services by providing timely and effective treatment of common illnesses to populations with limited access to facility based healthcare providers and especially to children under 5. Under iCCM, frontline workers in the community are trained, supplied, and supervised to diagnose and treat malaria, pneumonia, and diarrhoea in children with an integrated approach using artemisinin based combination therapies, oral antibiotics, oral rehydration salts, and zinc.The 2016 strategic review of IMCI and iCCM assessed the past two decades of implementation and drew lessons for meeting future child health goals, including those related to equitable outcomes, under the UN’s sustainable development goals and the Global Strategy for Women’s, Children’s and Adolescents’ Health (2016-30).Inequities in health are unjust, socially produced disparities in health resources or outcomes due to differences in characteristics such as socioeconomic status, level of education, place of residence, sex, age, and ethnicity.We tested the association between implementation of these strategies and reduction in wealth based inequities in care seeking for children with pneumonia or with any disease, using repeated panel analyses of DHS data (1993-2014) and IMCI and iCCM implementation data from a 2016 global survey from WHO and Unicef.iCCM is a more recent strategy, implemented widely in sub-Saharan Africa beginning around 2010 and aiming to extend case management to underserved populations. Its effect on equity has been mixed : countriBoth IMCI and iCCM seem to facilitate reductions in wealth based inequities in care seeking for childhood illness, but we think that emphasis on equity in strategy design and implementation could have led to greater improvements. We identified several blind spots in the design and implementation of these strategies that should be tackled to ensure maximal impact on inequities.Intersectoral interventions are those undertaken by sectors such as education, environment, or finance, with or without the active collaboration of the health sector, to improve health outcomes. Over the past two decades, countries using intersectoral interventions to tackle the social determinants of child health were most successful compared with all other countries in reducing inequities and reducing child mortality rates overall.However, the strategic review found that, globally, countries rarely used IMCI or iCCM to tackle social determinants of health, and their designs did not emphasise intersectoral approaches. Both strategies were conceived primarily as medical interventions targeting childhood illness, with less focus on the child’s overall wellbeing or the social determinants of health. Although IMCI provides room for intersectoral activities under its third component , this component was implemented to a lesser extent, owing in part to a lack of guidance, leadership, and financing from global partners. Of 94 countries that responded to the IMCI global implementation survey, 78 (83%) had conducted activities related to C-IMCI, whereas 92 (98%) had implemented the first component . Country assessments indicated that C-IMCI activities were often scattershot, with no long term gains in programming. When iCCM was introduced, in part to bolster the ailing community component, it also focused on case management, not social determinants, reflecting a preference for medicalised solutions to population health problems.22Global policy makers should prioritise intersectoral interventions, provide support for implementation, and articulate to national decision makers how these are complementary to IMCI and iCCM. WHO’s Health in All Policies framework, based on the notion that action in all sectors is required to improve the health of the poorest, is relevant but requires strong government ownership of child health goals and systematic coordination between sectors.Many health systems were underdeveloped when IMCI was introduced, and many countries selected districts for implementation based on feasibility rather than need. IMCI was implemented to a lesser extent in poorer or more remote districts in Peru and Tanzania, for example, often owing to poorer health systems in those areas. In Brazil, IMCI was less implemented in municipalities with low per capita income and small populations or those that were far from the state capital.Coverage of child health services is often incongruent with population needs. Stakeholders in Ethiopia, Nepal, and Yemen said that planning for IMCI implementation was not explicitly equity focused, resulting in a failure to target areas where mortality was higher and intervention coverage was lower. Many countries failed to coordinate activities between governmental and non-governmental actors and to target resources to areas of need. Maps of under 5 mortality in Ethiopia show regions in clear need of intervention, but health extension workers are not necessarily more numerous in these areas . EthiopiProgrammatic tools are available to support the rational, equitable distribution of health services by geographic area, which policy-makers may find preferable to targeting by wealth quintile.Insufficient funding of child health programming is a cause of substandard public services, with the resulting burden of inferior care and out of pocket expenses falling disproportionately on poor families. The largest equity gaps affect interventions that require 24 hour access to health facilities.Problems with sustainable financing are caused by more than just a lack of available funds. For the past two decades, the failure of partners to coordinate efforts globally and within countries was, in the words of one interviewed stakeholder, “inexcusable,” resulting in lopsided implementation, with some policy components and geographic areas receiving disproportionate resources and others going without. The Global Financing Facility—a World Bank initiative to coordinate resources from grants, governments, and private sources, bringing complementarity to partners’ support for maternal and child health—should be closely monitored for its effect on equity.Lack of coordinated funding by global partners was compounded by insufficient allocation of funds. In the IMCI global survey, 60% of countries (55/85) cited the lack of a dedicated budget line in the health sector plan as a major barrier to implementation. “Cost of the programme” and “budget for training” were also cited as barriers at the regional level in 55% of countries (50/91) and 82% of countries (75/91), respectively. Meanwhile, only a minority of countries report plans to increase the proportion of funding for iCCM from domestic resources,http://www.equist.info/en/dashboard), INNOV8 (http://www.who.int/life-course/partners/innov8/innov8-approach/en/), and the Health Equity Assessment Toolkit . These efforts could double as much needed evaluations establishing the tools’ differential applications or complementarity. Policy makers should also consider promoting health insurance to provide financial protection for families and reducing out of pocket spending by supporting transport costs through facilitated referral. Transferring money directly to beneficiaries has also been associated with better health outcomes for poor families,Solutions are available to ensure adequate financing and improve the equitable distribution of resources for child health. National policy makers should understand and agree that policies targeted at equity, although more costly to implement, result in faster rises in coverage and sharper decreases in child mortality than non-targeted approaches and are cost effective in terms of cost per life saved.Equity oriented policies focus on the disproportionate burden of ill health among disadvantaged groups; on geographic, financial, and psychosocial barriers to access to services; and on remedial measures both inside and outside the health system.To support such policies, countries need more resources. This will require government ownership and political will, to be spurred as necessary by well funded advocacy efforts. In our research, some countries reported advocacy or lobbying activities aimed at government, civil society, and industry , but we Box 2Intersectoral interventions—follow-up of children in schools (Niger); intersectoral commission on early childhood development led by presidency (Colombia); Communication for Development approaches (multiple countries)Outreach to underserved populations—Roving Caregivers Programme (Grenada); strengthening of outreach clinics ; outreach to children in remote communities (Guyana); Lady Health Worker Programme (Pakistan); mobile health teams in remote areas (Yemen)Social protection—community based insurance (many countries); universal child health allowance (Argentina); integral health insurance (Bolivia); conditional cash transfers (Mexico)Rights based approaches—incorporation of a rights based approach with consideration of cultural appropriateness Financing innovations—removal of user fees (many countries); mobilisation of resources with the oil sector (Republic of the Congo); providing dedicated funding under the Health Development Fund (Zimbabwe); implementing results based funding (multiple countries); inclusion of a child health plan in the government’s national budget (Dominican Republic)Advocacy—political lobbying to scale up IMCI (Mauritania); involving paediatric associations and civil society in promoting child health Source: IMCI implementation surveyThe underlying drivers of these changes must come from top-down leadership on equity and bottom-up demand for high quality services from children’s families and communities. National stakeholders in all countries have identified increased political commitment for IMCI as a priority, and reviews of iCCM have found that scaling up will require understanding and harnessing political accountability.Equity oriented child health policies fulfil a basic human right; they are also cost effective, improve coverage faster, and result in greater gains in child health indicators. In the upcoming WHO and UNICEF initiative to redesign child health guidance and in implementing child health strategies worldwide, stakeholders should focus on ensuring equitable delivery of sustainably financed intersectoral services—with leadership and accountability to make it happen.


The Typhoid Surveillance in Africa Program (TSAP) and the Severe Typhoid Fever in Africa (SETA) program have refined our understanding of age and geographic distribution of typhoid fever and other invasive salmonelloses in Africa and will help inform future typhoid control strategies, namely, introduction of typhoid conjugate vaccines. Salmonella in Africa was not well described. A 2004 review of global enteric fever epidemiology data showed that only 2 countries in Africa (South Africa and Egypt) conducted systematic population-based enteric fever surveillance between 1954 and 2000 [Until relatively recently, the burden of enteric fever caused by and 2000 . Subsequand 2000 . In addiThe Severe Typhoid Fever in Africa (SETA) study was initiated in 2016 to generate additional data on the clinical and economic burden of severe typhoid disease and associated sequelae and to describe antimicrobial resistance (AMR) patterns. SETA is currently enrolling in six countries . Similar efforts are ongoing in Asia as part of the Surveillance for Enteric Fever in Asia Project (SEAP), another prospective, population-based surveillance study, which is generating incidence rates and cost-of-illness data, and characterizing the burden of sequelae associated with severe enteric fever in Bangladesh, Nepal, and Pakistan . RecentlData from these and other recent studies from Asia and Africa informed the WHO’s Strategic Advisory Group of Experts’ recent recommendation for use of TCV for primary vaccination of infants and children from 6 months of age, with an option for catch-up campaigns in children up to 15 years of age in areas of high endemicity . Gavi, tSalmonella enterica serovar Typhi. Additional large-scale vaccine studies will launch in 2020 in two African countries, Ghana and the DRC, under the coordination of the University of Cambridge and International Vaccine Institute, with funding from the European and Developing Countries Clinical Trials Partnership and the Bill & Melinda Gates Foundation. Importantly, there is a strong pipeline of new TCV candidates, with three additional manufacturers conducting late-stage clinical trials, which will contribute to increased supply security and price competition [The high disease burden observed, coupled with the availability of a WHO Prequalified TCV and Gavi support, mean that there is massive potential impact of TCV introduction. Important TCV performance data are being generated by the Typhoid Vaccine Acceleration Consortium (TyVAC), which is conducting large-scale efficacy studies in Nepal, Malawi, and Bangladesh . Additiopetition .Salmonella infections at a mixture of urban and rural sites in Burkina Faso, the DRC, Ethiopia, Ghana, Madagascar, and Nigeria. Using standardized inclusion criteria, patients with suspected typhoid fever are enrolled at study facilities, where blood and stool samples are collected to identify causal agents, characterize AMR, and detect acute carriage [Streptococcus carriage. In cases where suspected intestinal perforations require surgical intervention, blood and tissue samples are also being collected when possible for testing using culture, polymerase chain reaction, and/or histopathological and cytological methods. Enrolled subjects with blood culture–confirmed invasive Salmonella infection are followed for 1 year to answer questions about long-term sequelae, host immunity, and chronic carriage. Postmortem surveys are also being conducted in selected study sites to assess potential mortality attributable to invasive Salmonella infection. Healthcare utilization surveys are being conducted to estimate the proportion of the catchment population seeking care at study facilities, as well as to collect information on socioeconomic status and other potential risk factors. Data are also being collected on cost of illness in selected study sites that will ultimately support cost-effectiveness analyses for different TCV introduction strategies [This supplement introduces the methodology of the ongoing SETA program, which was designed to focus on the impact of severe invasive carriage . In addirategies . Having The authors summarize key published data through three systematic reviews—one on published typhoid fever data from Africa since 1950, one on spatial and temporal patterns of typhoid and paratyphoid fever outbreaks globally between 1990 and 2016, and one on frequency of complications associated with severe disease. The first reports that 42 of 57 African countries have reported at least 1 typhoid fever case during this time period, with the total number of reports increasing over time . The secStaphylococcus aureus (59.5%) and Salmonella enterica (28.4%) as the most commonly isolated bacterial species [The authors in this supplement also highlight some site-specific data from TSAP and SETA. Teferi et al describe the etiology of acute febrile illness in children <15 years of age at Butajira Hospital in south-central Ethiopia, where 13.5% of febrile pediatric patients were malaria positive, and only 1.5% had blood culture–confirmed typhoid fever . The aut species . These d species .Importantly, Toy et al summarize the prevalence of extended-spectrum β-lactamase (ESBL)–producing gram-negative bacterial isolates from 12 TSAP sites collected between 2010 and 2014 . AnalysiWith additional burden data, the availability of vaccines, and supportive funding in hand, the global community is uniquely positioned to achieve extraordinary progress toward short-term typhoid control. Ideally, sustained investment in water and sanitation infrastructure and maintenance would also be incorporated to amplify the effect of TCVs on typhoid control. Still, important questions remain for African countries considering introduction of TCVs on typhoid control, particularly those countries where even the minimal passive, sentinel, blood culture surveillance has not been established. These countries must rely on other sources of data, including but not limited to modeled data, presence of known risk factors , or the presence of laboratory-confirmed typhoid in neighboring countries.In addition to furnishing important data to countries included in the studies and providing additional data points to strengthen modeled estimates, multisite surveillance studies such as SETA provide an important platform to validate new, low-cost surveillance methods, including environmental surveillance and serological markers of infection, against the current gold standard of blood culture surveillance. Assessment of such methods in the context of established blood culture surveillance can yield important data about sensitivity, specificity, and even acceptability of these new surveillance methods for decision making. Such methods will likely be important to countries that are unable to establish sentinel blood culture surveillance but are still interested in assessing local incidence of enteric fever in service of decision making around TCV use.Even with convincing burden data, decision-makers in country still must engage in a tradeoff exercise when considering introducing a new vaccine. Vaccine financing, particularly for Gavi graduating countries, and the strain that a new vaccine introduction can place on an already stressed immunization system must be weighed against the economic and health impact of a new program. Additional information about prevalence of severe disease and AMR, cost of illness, and mortality data are critically important to providing a fuller picture of the value of a vaccination program. SETA is generating such data on enteric fever in Africa, including better estimates of typhoid fever–associated mortality , which wS. Typhi from Hyderabad to Karachi. SEAP is also generating cost-of-illness estimates for the XDR typhoid strain in Pakistan, which has resulted in significantly longer hospital stays and can only be treated by one readily available oral antimicrobial [Leveraging platforms established by studies like SETA and SEAP to conduct ongoing AMR surveillance is of vital importance to understanding global disease epidemiology and informing national decision making. Established blood culture surveillance conducted by Aga Khan University, Pakistan facilitated the rapid detection of the spread of the XDR outbreak of icrobial . IdentifThe SETA sites will also provide a critical platform to demonstrate the value of the immunization program for ministries of health and Gavi, through TCV impact assessments and other evaluations. Established blood culture surveillance and associated laboratory infrastructure, trained personnel, and a well-defined catchment area will facilitate the conduct of future TCV impact assessments. This will also provide an important opportunity for countries to evaluate different vaccination strategies, looking at the impact of routine immunization plus catch-up campaigns in different areas of countries, or targeting different age groups.Salmonella (iNTS) cases [Salmonella enterica serovar Paratyphi A in Asian sites. These data will help inform future directions for broadly protective Salmonella vaccine prioritization and development.Finally, SETA is generating important information about the burden of other invasive salmonelloses in Africa. TSAP showed significant numbers of invasive nontyphoidal S) cases , and iNTSalmonella vaccine development efforts. Now, it is the responsibility of national governments and their advisory bodies to prioritize the implementation of TCVs for short-term control of the disease and reduction of transmission of the pathogen in vulnerable communities. These established surveillance sites will provide platforms for demonstrating the health impact of TCV programs.Systematic surveillance studies such as TSAP/SETA, SEAP, and others have done more than just broaden the global community’s understanding of age and geographic distribution of enteric fever. Preliminary data from such studies have informed key global policy decisions and will continue to guide optimal TCV use and future broadly protective


Nearly 2 billion people globally have no access to essential medicines. This means essential medicines are unavailable, unaffordable, inaccessible, unacceptable or of low quality for more than a quarter of the population worldwide. This supplement demonstrates the implications of poor medicine access and highlights recent innovations to improve access to essential medicines by presenting new research findings from low- and middle-income countries (LMICs). These studies answer key questions such as: Can performance-based financing improve availability of essential medicines? How affordable are cardiovascular treatments for children? Which countries’ legal frameworks promote universal access to medicines? How appropriately are people using medicines? Do poor-quality medicines impact equity? Answers to these questions are important as essential medicines are vital to the Sustainable Development Goals and are central to the goal of achieving Universal Health Coverage. Access to affordable, quality-assured essential medicines is crucial to reducing the financial burden of care, preventing greater pain and suffering, shortening the duration of illness, and averting needless disabilities and deaths worldwide. This supplement was organized by the Medicines in Health Systems Thematic Working Group of Health Systems Global, a membership organization dedicated to promoting health systems research and knowledge translation. The five studies in the supplement further our understanding by showcasing recent successes and challenges of improving access to quality-assured medicines through health systems in LMICs. Key MessagesNearly 2 billion people globally have no access to essential medicines.No access means medicines are unavailable, unaffordable, inaccessible, unacceptable or of low quality.We showcase successes and challenges of improving access to medicines in LMICs. Nearly 2 billion people globally have no access to essential medicines—resulting in greater pain and suffering, prolonged illness, needless disabilities and preventable deaths . EssentiAccess to medicines in health systems encompasses five dimensions of access: (1) availability, (2) affordability, (3) accessibility , (4) acceptability  and (5) quality . Based uFirst, we present a study on the use of innovative financial incentives to drive medicine availability. The second study examined the availability and affordability of cardiovascular medicines for children in Nigeria. The third study examined the role of UHC laws in making essential medicines accessible. Another study considered the acceptability of medicines based on their rational selection and proper use. Finally, we include a study that examined the impact of medicine quality on equity. In a recent meta-analysis across LMICs, 13.6% of essential medicines were found to be substandard or falsified, including 12.4% for antibiotics and 19.1% for anti-malarials  inadequate financing to pay for a basket of essential medicines through UHC, (2) affordability of essential medicines, (3) assuring the quality and safety of essential medicines, (4) inappropriate use of essential medicines, and (5) developing and supplying new types of essential medicines that target unmet disease burden or offer more effective outcomes (One of the areas this supplement does not cover is the role of pharmaceutical companies in accelerating medicine access in LMICs. The Lancet Commission reveals that the present system for developing medicines is in crisis, failing to produce needed medicines that address the needs of millions of people globally . The AccWhile access to medicines is part of the right to health as noted by the SDGs, many individuals struggle to access medicines. Despite the importance of medicines in reducing the world’s morbidity and mortality, availability of affordable quality-assured medicines continues to be poor, especially in LMICs. Ensuring access to medicines requires a complex systems approach involving diverse stakeholders and disciplines, from law and pharmacy to economics, with a global accountability mechanism (


In the past few years, there has been an unprecedented increase in the number of forcibly displaced migrants worldwide, of which a substantial proportion is refugees and asylum seekers. Refugees and asylum seekers may experience high levels of psychological distress, and show high rates of mental health conditions. It is therefore timely and particularly relevant to assess whether current evidence supports the provision of psychosocial interventions for this population. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) assessing the efficacy and acceptability of psychosocial interventions compared with control conditions  aimed at reducing mental health problems in distressed refugees and asylum seekers.We used Cochrane procedures for conducting a systematic review and meta-analysis of RCTs. We searched for published and unpublished RCTs assessing the efficacy and acceptability of psychosocial interventions in adults and children asylum seekers and refugees with psychological distress. Post-traumatic stress disorder (PTSD), depressive and anxiety symptoms at post-intervention were the primary outcomes. Secondary outcomes include: PTSD, depressive and anxiety symptoms at follow-up, functioning, quality of life and dropouts due to any reason.I2 = 83%; 95% CI 78–88; 20 studies, 1370 participants; moderate quality evidence), depression  and anxiety outcomes . This beneficial effect was maintained at 1 month or longer follow-up, which is extremely important for populations exposed to ongoing post-migration stressors. For the other secondary outcomes, we identified a non-significant trend in favour of psychosocial interventions. Most evidence supported interventions based on cognitive behavioural therapies with a trauma-focused component. Limitations of this review include the limited number of studies collected, with a relatively low total number of participants, and the limited available data for positive outcomes like functioning and quality of life.We included 26 studies with 1959 participants. Meta-analysis of RCTs revealed that psychosocial interventions have a clinically significant beneficial effect on PTSD (standardised mean difference [SMD] = −0.71; 95% confidence interval [CI] −1.01 to −0.41; Considering the epidemiological relevance of psychological distress and mental health conditions in refugees and asylum seekers, and in view of the existing data on the effectiveness of psychosocial interventions, these interventions should be routinely made available as part of the health care of distressed refugees and asylum seekers. Evidence-based guidelines and implementation packages should be developed accordingly. Over the past two decades, the population of forcibly displaced migrants has grown substantially, from 33.9 million in 1997 to 65.6 million in 2016, of which 22.5 million people were refugees and 2.8 million asylum seekers UNHCR, . Most ofRefugees are a subset of a wider population who are forcibly displaced, as the term refugee is a legal definition related to the 1951 United Nations Convention on the rights of refugees  suggest that psychosocial interventions, that is interventions with a focus on the interrelation between social circumstances and peoples’ thoughts, emotions and behaviours, may be helpful in treating some mental disorders in asylum seekers and refugees , registration number: CRD42017071523.et al., et al., The following bibliographical databases were searched up to September 2017: Cochrane Central Register of randomised trials (CENTRAL), CINAHL, EMBASE, PILOTS, PsycINFO, PubMed and Web of Science. The McMaster University algorithm to locate RCTs was used and complemented with the terms asylum seeker*, refugee*, migrant*, immigrant*, torture* AND psychother*, psychosocial, therapy, intervent*, treatment, counsel, support*, mental (both MESH terms and text words). Studies in any language were considered for inclusion. Grey literature was searched using the databases listed in the Cochrane Handbook for Systematic Reviews of Interventions  RCTs; (b) assessing the efficacy of a psychosocial intervention aimed at reducing mental health problems; (c) reporting PTSD, depressive or anxiety outcomes measured with validated rating scales; (d) comparing psychosocial interventions with: treatment as usual (TAU), or no treatment, or waiting list (WL), or psychological placebo ; (e) including participants having an asylum seeker and/or refugee status and (f) being of any age and resettled in high-income countries (HIC) or in LMICs, as classified by the World Bank criteria   independently extracted the data on participant characteristics, intervention details and outcome measures. Disagreements were resolved by discussion and consensus with a third member of the team (CB). Data extraction was performed in agreement with the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 7  using the ‘Risk of bias’ assessment tool developed by Cochrane  [Computer program]. Version 5.3., p or standard error values were reported, standard deviations were calculated according to Altman and Bland  as different measurement scales were used. A loose intention-to-treat analysis was applied, whereby all participants with at least one post-baseline measurement were represented by their last observations carried forward  v. eye movement desensitisation and reprocessing (EMDR) v. other types of intervention), age (adult v. children/adolescents/mixed), mental health condition at baseline , study setting (HICs v. LMICs), control condition , level of intervention  and degree of risk of bias .To explore heterogeneity, the following subgroup analyses were performed: type of psychosocial intervention (narrative exposure therapy (NET) et al., To investigate the impact of each study on the pooled effect, we consecutively removed each study as a possible outlier to test its impact on the combined effect, as implemented in comprehensive meta-analysis (CMA)  was calculated for primary outcomes, which indicates the number of patients that would need to be treated in order to generate one additional positive outcome . After title and abstract screening, 88 full text papers were considered for inclusion, of which 26 studies fulfilled the eligibility criteria and were included in the systematic review . Psychological placebo interventions were: supportive counselling, trauma counselling and stabilisation therapy. The mean study sample size was 75 participants (range 10–347) . EighteeThe following interventions were included: NET, a manualised short-term variant of CBT with a trauma focus (seven studies), Narrative Exposure Therapy for children (KIDNET), a form of NET adapted for children (one study), EMDR (four studies), music therapy (one study), Common Elements Treatment Approach (CETA) (one study), CBT (six studies), writing for recovery (one study), interpersonal psychotherapy (IPT) (one study), Teaching Recovery Techniques (TRT), a form of CBT (one study), Culture-Sensitive Oriented Peer (CROP) (one study), Family-Group Intervention (FGI) (one study), need-satisfaction intervention (one study). The quality of the studies varied as 16 of the 26 studies included in the primary outcome analysis were at high risk of bias in two or three items of the Cochrane risk of bias tool (online Supplementary Appendix 1).I2 = 83%; 95% CI 78–88; GRADE certainty in estimate: moderate) (p = 0.12) did not suggest publication bias (online Supplementary Appendix 1). Removing each of the studies as a possible outlier did not change the overall estimate. Removing the five studies with outlier results  with heterogeneity below 50%.The meta-analysis of PTSD outcomes  showed that psychosocial interventions were effective in decreasing PTSD symptoms relative to controls  . Visual I2 = 89%; 95% CI 82–93; GRADE certainty in estimate: moderate) and anxiety symptoms  relative to controls  and anxiety  outcomes showed that psychosocial interventions were effective in decreasing depressive symptoms , depressive outcomes  and anxiety outcomes . In terms of treatment acceptability, we found that psychosocial interventions were not associated with more participants leaving the study early than the control condition .The efficacy of psychosocial interventions was maintained at follow-up assessments for PTSD outcomes  and quality of life , psychosocial interventions were not different from control interventions . In terms of delivery modality, no differences were observed between individual and group interventions (online Supplementary Appendix 1). The type of control condition was significantly associated with overall efficacy. While psychosocial interventions were effective against WL, TAU or no treatment, no difference was found against psychological placebo (online Supplementary Appendix 1). Subgroup analysis by age revealed that most studies were conducted in adults or in mixed populations of adults and children, and so there is uncertainty on the efficacy of psychosocial interventions in children in this population. The type of mental health condition was not associated with overall efficacy, thus suggesting the efficacy of these interventions both in participants with a formal diagnosis of a mental health condition and in those with psychological distress in absence of formal assessment for mental disorder (online Supplementary Appendix 1). In terms of country income level, studies conducted in HIC and studies conducted in LMIC provided similar findings for PTSD and anxiety outcome. For depressive outcomes, the efficacy of psychosocial interventions was more evident in studies conducted in LMICs (online Supplementary Appendix 1). Subgroup analysis by study quality revealed that psychosocial interventions were effective in terms of PTSD, depressive and anxiety outcomes in the subgroup of studies at high risk of bias, while in studies at low risk of bias psychosocial interventions were effective only in terms of PTSD outcomes (online Supplementary Appendix 1). Heterogeneity remained substantial in the majority of subgroups (online Supplementary Appendix 1).For the primary outcomes, meta-analysis results were transformed into NNTs. The provision of psychosocial interventions was associated with NNTs ranging between 2 and 3 in case of very high frequency of unfavourable outcomes in those receiving control conditions (60%), between 3 and 4 in case of high frequency of unfavourable outcomes in those receiving control conditions (40%), between 6 and 7 in case of moderate frequency of unfavourable outcomes in those receiving control conditions (20%), and between 12 and 14 in case of low frequency of unfavourable outcomes in those receiving control conditions (10%) (online Supplementary Appendix 1).To our knowledge, this is the most comprehensive systematic review and meta-analysis conducted to date on the efficacy and acceptability of psychosocial interventions in asylum seekers and refugees. We found moderate quality evidence that psychosocial interventions have a beneficial effect on PTSD, depressive and anxiety symptoms, and results did not change in subgroup analyses. In addition, this beneficial effect was maintained at follow-up (measured at least one month after completion of the intervention), which is particularly relevant for populations exposed to ongoing post-migration stressors. Depending on the natural course of psychological distress in different target populations of asylum seekers and refugees, the magnitude of effect may reach a NNT between two and three in people showing low frequency of spontaneous improvement. This suggests that between two and three refugees and asylum seekers need to be treated in order for one to benefit; by contrast, in people showing high frequency of spontaneous improvement, the NNTs may be between 12 and 14. It is important to acknowledge that this variability depends on factors still largely unknown, particularly the expected improvement rate in those not receiving treatment. Another source of expected variability is related to the between-study heterogeneity observed, that likely depends on differences in populations, interventions, control conditions and contextual factors.Despite the current emphasis on general well-being in studies involving this population, functioning and quality of life were as assessed in four studies only and no difference between psychosocial interventions and control conditions emerged.et al., et al., which showed efficacy of NET for PTSD experienced by asylum seekers and refugees  , and the use of pharmacological treatment.The present review has some limitations. A first limitation is that despite refugees and asylum seekers may be vulnerable to serious mental health conditions including psychosis, only PTSD, depression and anxiety outcomes were considered. We made this choice as these are the best studied mental health outcomes in this population, while data for psychosis are still too limited to be re-analysed to generate meaningful pooled estimates. Second, a limited number of studies were included, with a relatively low total number of participants contributing to the primary analysis, and an overall moderate to low quality of the included studies. In particular, lack of blinding emerged as a major issue as it may have increased risk of performance bias. However, detection bias should not have been substantially affected by lack blinding, as studies employed masked outcome assessors. A third concern is that follow-up assessments were not very long, leaving uncertainty on the long-term effect of psychological interventions. Another limitation is that the included studies differed with respect to background origins of the included populations, time since resettlement, year and country of study publication, outcome measures, content and modalities of delivering psychosocial interventions. All these differences likely contributed to the very high level of statistical heterogeneity that was detected when all studies were pooled together. Heterogeneity was not fully explained even by subgroup analyses, however the effects were generally consistent across them. Unfortunately, it was not possible to conduct subgroup analyses to investigate the role of some important variables, such as time since resettlement, the legal condition of the included population  income category, also recognising that forms of supportive counselling  may provide some initial relief in the short term, when access to mental health services may still be limited. In fact, the feasibility and sustainability of the availability of psychosocial interventions, especially in the long-term and especially in LMICs, may be an important challenge. To facilitate availability, brief, basic, group and non-specialist-delivered versions of these evidence-based psychosocial treatments should be considered as an affordable, scalable alternative. They are currently under investigation in several countries and early results from RCTs showed efficacy (Rahman In this review psychosocial interventions have been shown to provide clinically relevant beneficial effects not only in those with a diagnosis of a mental health condition but also in those with psychological distress without a formal assessment of mental disorder. However, since studies conducted in participants with psychological distress did not systematically exclude those with a diagnosis of mental disorder, the present review cannot be used to claim a preventative effect. To claim a preventative effect, future studies should be designed to include participants with psychological distress but without a mental disorder at study entry. Research should also aim to identify important mechanisms of change for these interventions e.g. improvement in functioning, increased hope, and/or enhanced quality of life.In conclusion, this review provided evidence in support of the availability of psychological interventions with a trauma focus to refugees and asylum seekers. Specific evidence-based guidelines and implementation packages should be developed accordingly (Giacco and Priebe,


Breastfeeding has many benefits for newborns, mothers, and the wider society. The World Health Organization recommends mothers to feed newborns exclusively with breastmilk for the first 6 months after birth, but breastfeeding rates in many countries fail to align with the recommendations because of various barriers. Breastfeeding success is associated with a number of determinants, such as self-efficacy, intention to breastfeed, and attitudes toward breastfeeding. Information and communication technology (ICT) has been leveraged to support breastfeeding by means of improving knowledge or providing practical supports in different maternal stages. Previous reviews have examined and summarized the effectiveness and credibility of interventions; however, no review has been done from a human-computer interaction perspective that is concerned with novel interaction techniques and the perspective of end users.The objective of this review was to provide a comprehensive overview of existing digital interventions that support breastfeeding by investigating systems’ objective, technology design, validation process, and quality attributes, both in terms of clinical parameters as well as usability and user experience.A systematic search was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in the following libraries: PubMed, Science Direct, Association for Computing Machinery Digital Library , and Institute of Electrical and Electronics Engineers Xplore (IEEE Xplore).A total of 35 papers discussing 30 interventions were included. The main goals of these interventions were organized into 4 categories: breastfeeding education (n=12), breastfeeding promotion (n=8), communication support (n=6), and daily practical support (n=4). Of the interventions, 13 target mothers in the postnatal period. Most interventions come in forms of client communication systems (n=18), which frequently leverage Web technologies, text message, and mobile apps to provide breastfeeding support. Systems predominantly focus on mothers; validation strategies were rather heterogeneous, with 12 user studies concerning usability and user experience and 18 clinical validation studies focusing on the effects of the interventions on breastfeeding determinants; 5 papers did not report results. Generally, straightforward systems  seem to be more effective than complex interventions .Existing information and communication systems offer effective means of improving breastfeeding outcomes, but they do not address all relevant periods in parenthood  and often do not involve important stakeholders, such as partners. There is an opportunity to leverage more complex technical systems to open up avenues for the broader design of ICT to support breastfeeding; however, considering evaluation outcomes of existing support systems of higher complexity, such systems need to be designed with care. Breastfeeding has many benefits for infants, mothers, and the wider society. A meta-analysis by Victora et al  suggestsBreastfeeding success is associated with a number of barriers and facilitators. Studies ,8 have sSelf-efficacy , the perInformation and communication technology (ICT) has been leveraged for breastfeeding support, for example, to provide breastfeeding education , throughThis review aims to give an overview of the currently available digital interventions to address barriers and facilitators to breastfeeding by investigating the trend in technology design through the lens of human-computer interaction that focuses on the design, development, and evaluation of technology to solve real-world challenges that involve end users. Through this review, we reveal strengths and weaknesses in existing systems and underlying technologies, thereby identifying future opportunities for researchers in human-computer interaction, digital health, and public health, and hope to inform the work of health care professionals.Toward these goals, we seek to explore this space via the following research questions:RQ1. What type of ICT-based breastfeeding-supporting systems are available? Who are they intended for?RQ2. How did the systems integrate into health care provisions to support breastfeeding? What technology platforms were used to achieve their goals?RQ3. Were the existing systems validated in terms of the experience they provide for users and their effectiveness in clinical terms?breastfeeding and technology and their variations in Title, Abstract, and Keywords fields. Combinations of search terms in the search query were modified for every database to preserve the intent of the query.This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses  guidelinWe queried papers published before November 2018 using a search strategy specified in We included papers discussing digital interventions that satisfied all the following criteria: (1) full text in English, (2) targeted healthy human subjects regardless of breastfeeding role, and (3) provided direct or partial breastfeeding support.We also included publications that discussed a system from different perspectives, for example, from experience-centric and clinical aspects. Work-in-progress papers were also included if their fully implemented system was not available.We excluded papers that met any of the following criteria: (1) contained only abstract, (2) targeted subjects with special medical conditions, for example, preterm infants or severely sick mothers, and (3) reviews, books, book chapters, or reports or papers from scientific magazines.If a paper of a fully implemented system is available, the work-in-progress papers of that system will be excluded.In the full-text assessment phase, we eliminated 26 publications that did not fit our criteria see . FinallyAs a preprocessing step, papers that discussed the same systems were grouped. We defined an extraction scheme that comprised 3 corresponding perspectives.RQ1. Here, systems with similar goals were grouped to craft categories from the data. For systems that fell into multiple categories, we coded the highest priority goal. We then extracted excerpts of breastfeeding-supporting methods for each system. Finally, we coded each system by its intended audience and context of use, if made explicit by the authors.We first coded the goals and methods of breastfeeding support of each system to extract necessary data to answer RQ2), we coded the technology used in the systems and the motivation behind the choice of platform for each system. In this step, we classify the systems according to the system classification framework for digital health intervention 1.0 of WHO [To identify the technology platforms used by the systems (0 of WHO . After tRQ3). The papers were first examined to identify whether a user study or a clinical study had been conducted; a paper may be coded twice if it discusses both types of studies. In case of user studies, we coded their methods and results . For clinical studies, we extracted outcome measures, the statistical significance of results, the number of participants in the study, and possible limitations of results, if explicitly stated.The last data extraction step is to identify the validation process and the reported effectiveness of the systems , we characterized the digital interventions by their technology platform and system purpose. We structured our findings around the WHO system classification framework for digital health interventions [To answer the second research question , we coded the papers into 2 categories: user studies  and clinical validation studies. A total of 5 papers [To understand the validation process of the systems  on a CD-ROM software  and a 25Here, the heterogeneous nature of interventions and validation processes and outcome parameters limit the opportunity to conduct a meaningful comparison between interventions. On a general level, our results suggest that breastfeeding learning and training systems for health care professionals tend to succeed in improving breastfeeding knowledge among their intended users, whereas some client communication systems showed a positive effect on improving breastfeeding adherence. Other breastfeeding determinants were rarely influenced, and validation studies evaluating complex technology  suggested that such systems were ineffective in their current designs.RQ1). From a technical perspective, client communication systems were the most commonly used systems, with Web technologies, mobile apps, and SMS being the dominant platforms and only a small number of studies exploring more complex technologies, such as games (RQ2). System effectiveness was predominantly demonstrated in terms of improved breastfeeding knowledge, although improvement in behavioral outcomes might be because of systems that provided continuous proactive support. In terms of usability and user experience, results were mixed, with some systems failing to engage users (RQ3). Generally, our analysis suggests that straightforward technology fared better than complex systems, leaving room for an interesting debate. Here, we discuss these results; drawing from our findings, we further reflect on available systems through the lens of barriers and facilitators toward breastfeeding, and we outline opportunities for future research into the development of engaging technology interventions to promote breastfeeding.This review gives an overview of digital interventions to support breastfeeding. We draw from research in computer science, engineering, and medical field to provide an overview of systems with a focus on technology, users, and outcomes. Our results show that the majority of systems were designed to address mothers in the postnatal period, either promoting or educating them about breastfeeding  other than clinical effectiveness. Other systematic reviews ,30 analyThere are various attempts to leverage ICT to encourage breastfeeding, aiming to improve breastfeeding education, persuade mothers to initiate and follow through with breastfeeding, and provide practical support. Our results show that although certain groups of systems are effective, they often only target 1 domain , requiring end users to engage with a multitude of systems to achieve good coverage. In addition, the majority of interventions exclusively targeted mothers and failed to consider other relevant stakeholders, most strikingly partners. Therefore, further study is necessary to explore how innovative concepts in ICT can be fully leveraged to provide comprehensive breastfeeding support, starting in the antenatal period and extending beyond the birth of the child, while engaging both parents. Through reflection on the way that existing systems (fail to) address determinants of breastfeeding, our review provides a first step toward outlining research opportunities for future study in this space.


Globalization has increased the rate at which arthropod vectors and associated pathogens emerge and spread. A persistent challenge to the public health agencies in the United States is to identify and control emerging foreign human and animal health threats. This is especially important, given that entomological surveillance capacity in the US has declined in recent years . In thisBorrelia spp. pathogens) (Aedes (Stegomyia) albopictus (Skuse) [A. (Finlaya) japonicus japonicus  [A. (Finlaya) notoscriptus (Skuse) [Haemaphysalis longicornis)—native to East Asia—were recently found to infest sheep on a farm in New Jersey, with subsequent detections in additional states [Since 1980, many invasive (not native to the US) and emerging (newly recognized or native and expanding in range) vector-borne pathogens have been identified in the US . Some ofthogens) . Routine (Skuse) , A.  , and A.  (Skuse) . Keiransl states . As globWhat is the next emerging or invasive pathogen? Surveillance programs should seek to strengthen the global public health network by building capacity for vector and pathogen surveillance, detection, and response in foreign countries as well as on home turf. Multiple US agencies have launched significant global biosecurity initiatives that embody this goal. In particular, the Centers for Disease Control and Prevention (CDC) maintains a significant global presence in pathogen detection, outbreak investigation, and response through the multisectoral efforts of the Global Health Security Agenda to strengthen public health systems and improve pathogen detection and response capacity , as wellWhat local vector and vertebrate species might contribute to the transmission of invasive or emerging pathogens? Data on vector distributions, habitat associations, seasonal abundance, and blood feeding patterns inform models that assess and predict community risk to pathogen transmission –18. FurtHow and where will a foreign pathogen arrive? Global movement data can be used to quantitatively predict likely pathways of introduction. Vectors can invade via ship, ground, or air traffic, in some cases while attached to a host; pathogens can be introduced through vectors, contaminated products, or vertebrate hosts (including humans). Investigators have analyzed global movement data of people and animals in the context of pathogen and vector invasions for a number of different pathogen systems , 25, 26;How do we detect and respond to invasive or emerging pathogens? Effective surveillance and response will take an army of professionals to identify invasive species and pathogen introductions, support collection of long-term entomological and virus infection data, and provide local capacity to respond to future outbreak events. The devastating effect that suboptimal surveillance capabilities and public health infrastructure can have on a national and global scale was evident in West African Ebola outbreak in 2014. Without the ability to detect and respond rapidly to emerging pathogens, outbreaks can quickly overwhelm existing capacity . TrainedSuccess of these critical activities relies heavily on maintaining strong and sufficient surveillance capacity in the US. Routine vector surveillance activities for established pathogens also monitor seasonal transmission dynamics, which can guide the deployment of evidence-based intervention measures. The crisis of having alarmingly few trained medical entomologists at federal and local levels to handle these activities became evident in 2015 and 2016 during the height of the ZIKV outbreak response . To addrA. aegypti mosquitoes and revealed that at least 4—but as many as 40—introductions contributed to the outbreak in Florida and that local transmission is likely to have started several months before its initial detection. Multiplex assays that screen for multiple high-priority pathogens at once, such as screening pools of A. aegypti mosquitoes simultaneously for ZIKV, chikungunya virus (CHIKV), and dengue virus (DENV), can also make high-throughput processing more efficient [Additionally, pathogen detection strategies need testing algorithms that permit the identification of unknown agents so novel pathogens will not be missed. The traditional approach of virus isolation remains valuable today for this purpose, although it lacks the high-throughput capacity of PCR-based screening and has biosafety considerations. Next-generation sequencing (NGS) offers a powerful technology towards the identification of unknowns and the simultaneous detection of multiple circulating pathogens . Still, fficient –37.Vector-borne disease agents will continue to emerge globally and invade new places; it is not a matter of “if” but “when.” Through multiple current initiatives, international consortia are working to strengthen global health security by building partnerships and capacity to control emerging infectious diseases before they become pandemics. In addition to building pathogen detection and response capacity, proactive research agendas should assess what invasive pathogens threaten the US and by what pathways these agents would arrive to inform local and national surveillance and response infrastructure. Having diagnostic tools and targeted surveillance strategies in place for rapid roll-out is critically important once a high-priority pathogen is identified. As such, support for global health security needs to be unwavering; the ephemeral infusion of funds that are reactionary to threats are not sufficient to maintain necessary infrastructure required to identify and mitigate emerging and reemerging disease threats.S1 Table(DOCX)Click here for additional data file.