The inadvertent transmission of long incubating, untreatable and fatal neurodegenerative prionopathies, notably iatrogenic Creutzfeldt–Jakob disease, following transplantation of cadaver-derived corneas, pituitary growth, hormones and dura mater, constitutes a historical precedent which has underpinned the application of precautionary principles to modern day advanced cell therapies. To date these have been reflected by geographic or medical history risk-based deferral of tissue donors. Emergent understanding of other prion-like proteinopathies, their potential independence from prions as a transmissible agent and the variable capability of scalably manufacturable stem cells and derivatives to take up and clear or to propagate prions, substantiate further commitment to qualifying neurodegenerative proteinopathy transmission risks. This is especially so for those involving direct or facilitated access to a recipient’s brain or connected visual or nervous system such as for the treatment of stroke, retinal and adult onset neurodegenerative diseases, treatments for which have already commenced. In this review, we assess the prospective global dissemination of advanced cell therapies founded on transplantation or exposure to allogeneic human cells, recap lessons learned from the historical precedents of CJD transmission and review recent advances and current limits in understanding of prion and other neurodegenerative disease prion-like susceptibility and transmission. From these we propose grounds for a reassessment of the risks of emergent advanced cell therapies to transmit neuroproteinopathies and suggestions to ACT developers and regulators for risk mitigation and extension of criteria for deferrals.The online version of this article (10.1007/s00401-018-1941-9) contains supplementary material, which is available to authorized users. Over the past 20 years, scientific and medical research communities have made significant preclinical and clinical progress in the development of new “advanced cell therapy “ (ACT) paradigms aspiring to replace, reconstitute, or regenerate diseased or injured tissues, or modulate host-immune responses. Contrary to canonical allogeneic or autologous transplantation of primary or minimally processed tissues such as bone marrow and corneas or pituitary extracts as a source of growth hormone, these new paradigms have entailed more extensive processing of renewable cell sources. This has augmented scope for dissemination and thus potential risk of harm to recipients and the general population. The provenance of cell source material for these encompasses the spectrum of cell developmental ontogeny from early pre-implantation embryos, to fetal, neonatal, and extra-embryonic and adult organ-specific tissues . Each places different constraints and requirements on the design and attributes of the intended ACT. These include the prospective quantity, purity, proliferative capacity, lineage potency, and cellularity of source material and derivative therapeutic products; the necessity for co-administration with bio-compatible materials or augmentation of function by genetic manipulation; the extent to which mechanism of action is understood or defined; and the methods, reagents and assays used in production or quality control.Concern for ACT biosafety has centered on qualifying the risk of adverse events arising from (1) uncontrolled or unexpected cell growth, behavior or neoplastic transformation, normally qualified through transplantation into animal models; and (2) adventitious pathogen transmission. The greatest concern for the latter is normally diseases for which there are no validated tests available to identify pathogen presence in the absence of visible symptoms of disease, or technology to remove infectivity if detected. Prion diseases of human or animal origin such as genetic, iatrogenic, sporadic or variant Creutzfeldt–Jacobs disease (g/i/s/vCJD), bovine spongiform encephalopathy (BSE), ovine scrapie and chronic wasting disease (CWD) in deer, which result in long incubating, invariably fatal and untreatable neurodegenerative prionopathies, have epitomized concern for such pathogens. Safeguards against these have been addressed on the basis of risk-based donor deferral founded on medical history and geographical likelihood of exposure. Unfortunately, this approach is increasingly challenged by the expanding recognition and global prevalence of prion diseases of one form or another and the increasing mobility of populations. In principle the efficacy of risk-based deferrals is determined by accuracy and sufficiency of information on which donor selection criteria is based. Rising awareness and improved understanding of prion susceptibility and propagation in ex vivo cultivated stem and derivative cells, and latterly evidence of prion-like transmission observed with other neurodegenerative disease-associated proteinopathies, now substantiate a reassessment of the risks that emergent ACT pose to transmit neuroproteinopathies to both recipients and the general population through secondary transmission. The latter is facilitated by the ageing and longer living demographic which recipients represent. In this review, we begin by summarising the current state of allogeneic ACT market authorisations and estimating their global dissemination to date via clinical trial evaluations. For the latter we assess prospective patient participation in trials of therapeutic products derived from distinctive sources differing in source material growth, lineage potency and properties impacting on the design of their use and target indication. We then recap the historical precedents of CJD transmission and review recent advances in understanding of prion and other neurodegenerative disease prion-like susceptibility and transmission. Collectively, we propose these substantiate grounds for renewed assessment of risks of transmitting neurodegenerative disease causing proteinopathies . We suggest measures to mitigate such risks through research, product testing and extension of criteria for deferrals.In principle ACT founded on a strategy of one allogeneic cell source for many recipients carries a greater risk for adventitious pathogen transmission to recipients and secondary infection to the general population, than one to one or autologous transplants. The extent of this may vary in accordance with: (1) how greatly cell source material can be renewed and expanded for dissemination; (2) the nature of the contaminant and the point in the process at which it occurs. The risk of transmitting a neuroproteinopathy will be greater where products are transplanted directly into the brain or central nervous system (CNS) or may have facilitated access to these by virtue of the site of their transplantation  vs transplantation to a peripheral organ. However, injury or inflammation compromising the blood–brain barrier at the time of a transplant or subsequently could in principle elevate the risk of transmission. Further, risks of secondary transmission to the general population, such as via recipient donated blood would either be equal or greater following a peripheral transplant owing to facilitated exposure to the recipient’s circulatory system depending first on the transmission potential of the proteinopathy and infected tissue. The likelihood of transmission to the general population would of course also depend on the eligibility of the recipient to make a tissue donation post-treatment, whether owing to health or precautionary deferral.Allogeneic ACTs currently under evaluation in clinical studies can be conceptually distinguished on the basis of cell growth and lineage potency, in order of greatest to least: human embryo or induced pluripotent stem cells (hESC/hiPSC), multipotent mesenchymal stromal/stem cells (hMSC) or lineage committed progenitors and differentiated lineage or immortalized cell lines , 80, 82.To estimate the current relative preponderance of clinical evaluations of conceptually distinct ACT globally we interrogated the international clinical trials registry  for alloThe transmissibility of CJD presents a series of public health risks, including the risk of secondary transmission through medical or surgical intervention resulting in iatrogenic CJD (iCJD). Historically routes of transmission have included corneal transplantation and neurosurgical instruments, but the largest numbers of cases of iCJD worldwide have been through the use of cadaveric pituitary-derived hormones and human growth hormone-associated CJD (hGH-iCJD) in France, the UK and the USA and dura mater grafting   should,In experimental rodent prion disease models, prions delivered to brain spread to the eye, and those administered intraocularly spread along the retinotectal pathway to the brain  would have either a sporadic, genetic or acquired etiology. Each of these formal possibilities merits further comment here and we suggest further research in order to quantify and minimize the risk of inadvertent transmission of neuroproteinopathies by ACT.PRNP. Despite the more restricted tissue distribution of infectivity in sCJD and gCJD, recent reports indicate that fibroblast, fibroblast-derived hiPSC lines and neuronal derivatives taken from patients with sCJD and gCJD show signs of prion infection [Recently, the public perception of the risks associated with CJD has been largely driven by the outbreak of BSE  and resunfection , 90. Thenfection , that anThe possibility that exogenous prion contamination could occur during human cell processing  also warrants consideration. A priori, culture additives of human or bovine origin or other reagents exposed to reagents of human or bovine origin in their preparation would seem to present the highest potential risks. All animal reservoirs of prion infectivity should be considered including those whose risk of transmission to humans remains relatively unexplored such as dromedary camels and deer , 87. As We have previously shown that hESC take up and then rapidly clear abnormal prion protein in BSE, vCJD and sCJD brain homogenates experimentally inoculated into the culture medium  homeostasis can facilitate prion replication [CJD associated with de novo lication  and chroThere is no obvious reason to presume that the physical introduction of ACT products to patients bears greater risks of infection through the use of contaminated surgical instruments than other comparable surgical interventions. Nevertheless, it is important to recognize that neurosurgery, ocular surgery in the form of corneal transplantation, transfusion and intramuscular inoculation are all recognized routes of iCJD transmission Table  and careThe hypothesis that CJD and other transmissible spongiform encephalopathies result from self-propagating conformational variants of the prion protein yielding a transmissible amyloidosis (the prion hypothesis) has in the past decade gone through a dramatic expansion. This owes to observations of prion-like behaviors of other proteins, such as beta amyloid (Aβ), tau, α-synuclein and TDP-43 that are proposed to underlie neurodegenerative diseases as diverse as Alzheimer’s disease, Parkinson’s disease, multiple systems atrophy, frontotemporal dementia and motor neuron disease, respectively. The case for reframing these diverse neurodegenerative disorders explicitly as prion diseases has been made , 68. TheThe possibility of actual disease transmission (acquired Alzheimer’s disease for example) between individuals is more controversial and currently lacking an epidemiological evidence base (see for example ); nevertThe development of methods to screen for prions in donated blood has been fraught with difficulties . This isPRNP from a prospective ACT product at the time of derivation would offer the best protection from prion disease transmission, since cellular prion protein expression is a precondition for prion propagation and neurotoxicity . This w by Ref.  and woul by Ref. , 57), soIn summation, the available evidence substantiates the perspective that the risk of transmitting prion or prion-like proteinopathies with modern day ACT for neurological or other diseases is still likely to be remote. However, historical precedent and developments in the field in recent years does justify reassessment of precautionary measures, as outlined. Such effort would be consistent with the long-standing commitment of ACT developers, regulators and public and private investors to assure the future safety and efficacy of emerging therapeutic interventions for debilitating diseases yet to be effectively treated or cured by other approaches.References used herein were identified by searches of PubMed on the 15th of June 2018 or previously known to the authors. The search terms “Cell Therapy”, “Prion”, “Prion-like”, “Prionopathy” and “Proteinopathy” were used. Cell therapies currently under clinical evaluation (Phase I–IV) were identified on the same date by searching the US international registry of clinical trials ; The finSupplementary material 1 (DOCX 19 kb)Below is the link to the electronic supplementary material.


Conservation of large carnivores, such as the African lion, requires preservation of extensive core habitat areas, linkages between them, and mitigation of human-wildlife conflict. However, there are few rigorous examples of efforts that prioritized conservation actions for all three of these critical components. We used an empirically optimized resistance surface to calculate resistant kernel and factorial least cost path predictions of population connectivity and conflict risk for lions across the Kavango-Zambezi Transfrontier Conservation Area (KAZA) and surrounding landscape. We mapped and ranked the relative importance of (1) lion dispersal areas outside National Parks, (2) corridors between the key areas, and (3) areas of highest human-lion conflict risk. Spatial prioritization of conservation actions is critical given extensive land use redesignations that are reducing the extent and increasing the fragmentation of lion populations. While our example focuses on lions in southern Africa, it provides a general approach for rigorous, empirically based comprehensive conservation planning based on spatial prioritization. Africa’s human population is expected to increase threefold by the end of this century , with hiPanthera leo), human-wildlife conflict and habitat loss are the primary drivers of recent declines, with lion populations within protected areas becoming increasingly isolated [In the case of the African Lion (isolated . Bjorkluisolated  found thisolated ) and somisolated  and incrisolated . Many exisolated  and inbrisolated ,9. In reisolated , 12, 13.2), in southern Africa is of immense conservation importance for lions as it contains 13 ‘Lion Conservation Units’ [The Kavango-Zambezi Transfrontier Conservation Area, KAZA  are based on predicting movement from a set of source points that reflect the distribution and density of the underlying population. Source points were established by intersecting the protected area extent with a map of estimated site carrying capacity for lions based on climatic correlates of prey biomass . SpecifiThe resistance map provides resistance values for all locations in the study extent, in the form of the cost of crossing each pixel relative to the least-cost condition . We usedThe factorial least cost path analysis calculates the least cost paths among all combinations of source points and sums them to create a path density map reflecting the relative strength of linkage across the network. The resistant kernel model calculates the expected movement of dispersing lions in each pixel, given the dispersal ability of the species and the resistance of the landscape , 22. Theth percentile of the cumulative kernel surface. These reflect areas of moderate to high predicted movement rates. Our goal was to evaluate the importance of key lion areas  that were outside National Parks and Game Reserves, so we selected the cumulative kernel surface values outside of these strictly protected areas for analysis of the number and relative importance of these dispersal areas. Likewise, we selected linkage corridors that were greater than the 25th percentile of the distribution of values in the factorial least cost path surface, and outside the network of National Parks/Game Reserves and dispersal areas, as identified above.We defined key dispersal areas as contiguous patches of cumulative resistant kernel values greater than the 25th percentile for further analysis. Essentially, this index calculates the spatial variation in local cumulative kernel value, identifying areas with high change that we would expect to represent areas with high relative conflict risk.We reasoned that areas with rapid change in cumulative kernel value  are potential hotspots where high lion movement intersects high conflict risk. We predicted conflict risk zones by calculating the standard deviation of the cumulative kernel surface within a 10km focal radius for all areas outside of National Parks/Game Reserves, and selected values above the 25We used several criteria to evaluate the importance of predicted dispersal areas, linkage corridors, and conflict hotspots. For dispersal areas, we identified three main characteristics that contribute to their importance to regional lion populations: (1) The size of the area, since lion populations require large areas; (2) The summed kernel value, reflecting the total predicted movement of dispersing lions in that region of the landscape; (3) The degree to which a key dispersal area was connected to other areas, because dispersal areas that are nodes connecting the regional populations are likely more important than peripheral populations . We thersensu [We used two measures to evaluate the importance of predicted linkage corridors . (1) We sensu ) in termFinally, we produced two measures of the importance of predicted conflict hotspots : (1) We We identified nine key dispersal areas, which differed dramatically in predicted strength Figs  and 4. BWe predicted 27 linkage corridors between the nine key dispersal areas , which dThe highest ranked predicted conflict hotspot area runs along the northern edge of the central dispersal area from Mudumu National Park in the west to Zambezi National Park in the east, with an area of particularly intense predicted conflict within the Chobe Enclave north of Chobe National Park Figs  and 3C. Habitat loss and fragmentation, coupled with severe human-wildlife conflict, have reduced lion populations to less than 10% of their historic range. It is widely recognized that conservation of lions, and other large carnivores, requires a combined strategy incorporating the preservation of extensive core habitat areas, linkages between them, and mitigation of human-wildlife conflict. However, there have been few rigorous examples of efforts that have spatially prioritized conservation actions for all three of these critical components. As human populations continue to grow . It is tWe identified nine key dispersal areas, 27 linkage corridors and 27 potential human-lion conflict hotspots outside National Parks in the KAZA Transfrontier Conservation Area and its surrounding landscape. Our results suggest that it is critical to ensure that Dispersal Areas 1, 2 and 3 continue to be managed for wildlife in their entirety. With four strategically placed corridors  protect the most important core areas, (2) establish movement across the most important corridors, and protect them from development and conflict risk, and (3) implement conflict mitigation measures and strategic fencing to reduce mortality risk to lions in the identified conflict hot spots. In some cases, it may no longer be possible to functionally restore some of the movement corridors identified in our analyses. In such cases, a potential alternative would be to mimic the outcomes that would result if the corridors were functional, such as translocations of individual lions reciprocally across the gap . TransloIt is important for conservation proposals to include consideration of risks, hidden risks, opportunity costs and cost implementation. The prioritization presented here is based exclusively on ranking locations for conservation based on biological criteria only, and does not include discussion of societal, political, or economic considerations. As such, it should not be considered to be a recommendation for specific action, but rather a step in the process of decision-making. We believe these results will be useful to managers and decision-makers in their efforts to identify solutions that meet conservation and social objectives simultaneously in a cost-effective manner. Future research, combining sociology, economics and ecology, should work on formalizing that process of balancing the conservation and social objectives surrounding lion conservation in southern Africa.This example, while for lions in southern Africa, provides a general approach for rigorous, empirically based comprehensive conservation planning based on spatial prioritization. We propose a method to quantitatively develop a comprehensive strategy for population-level carnivore conservation based on combining validated empirical connectivity models with spatial prioritization of core areas, corridors and conflict risk hotspots. By spatially mapping and ranking the relative importance of these areas our approach allows managers to identify the highest priority areas for directed and immediate conservation.S1 File(RSG)Click here for additional data file.S2 File(XY)Click here for additional data file.S3 File(ADDEDPATHS)Click here for additional data file.S4 File(ADDEDPATHS)Click here for additional data file.


In the western United States, this virus may have been mediated via migrating infected birds from southern South America, where it reemerged most recently in 2002. Flavivirus) in the Americas. Historically, SLEV caused encephalitis outbreaks in the United States; however, it was not considered a public health concern in the rest of the Americas. After the introduction of West Nile virus in 1999, activity of SLEV decreased considerably in the United States. During 2014–2015, SLEV caused a human outbreak in Arizona and caused isolated human cases in California in 2016 and 2017. Phylogenetic analyses indicate that the emerging SLEV in the western United States is related to the epidemic strains isolated during a human encephalitis outbreak in Córdoba, Argentina, in 2005. Ecoepidemiologic studies suggest that the emergence of SLEV in Argentina was caused by the introduction of a more pathogenic strain and increasing populations of the eared dove (amplifying host).We summarize and analyze historical and current data regarding the reemergence of St. Louis encephalitis virus (SLEV; genus  Culex and is amplified by passerine and columbiform avian species  is caused by St. Louis encephalitis virus (SLEV), identified as the causative agent of a mosquitoborne viral epidemic in St. Louis, Missouri, USA, during the summer of 1933  in a single gonotrophic cycle, thus making them capable of viral transmission during their second blood meal  mosquitoes, species that oviposit in the permanent aquatic habitats provided by storm drains, sewage treatment facilities, and wastewater retention ponds. Rural SLE epidemics usually involve floodwater species, such as Cx. tarsalis and Cx. nigripalpus mosquitoes  experimentally infected with WNV developed neutralizing immunity that prevented infection after rechallenge with WNV or SLEV , Columbidae , Corvidae  and Icteridae  are frequently exposed to SLEV (Passer domesticus) and blue jays are highly infectious to mosquitoes; in contrast, mourning doves were found to be 1 of the least competent WNV hosts of 25 bird species examined experimentally (Haemorhous purpureus]); song sparrow (Melospiza melodia); western scrub jay ; and white-crowned sparrow (Zonotrichia leucophrys) are considered major amplifying hosts of WNV and SLEV (Corvus brachyrhynchos), and western scrub jays were found to be amplifying hosts capable of developing viremias above the threshold for infection of Cx. tarsalis, the principal vector of WNV and SLEV throughout much of California , proving it to be the most lethal strain compared in the study . That evidence supports the hypothesis that a more virulent SLEV strain was introduced into Córdoba City in early 2005 from Santa Fe (Argentina) or São Paulo (Brazil) (Zenaida auriculata) and picui ground-dove (Columbina picui) produce high levels of viremia compared with other avian species tested  illness and death compared with sympatric nonepidemic SLEV strains isolated previously in Córdoba and Santa Fe Province, Argentina ((Brazil) . Serologhttp://www.paho.org/hq/dmdocuments/2010/alert_epi_2010_31_marz_encefalitis_san_luis.pdf). Unfortunately, no ecologic studies focused on these outbreaks. Phylogenetic analysis of SLEV genomes associated with human cases in Buenos Aires confirmed the presence of SLEV genotype III , Buenos Aires (2010), and San Juan (2011)  comparing genomes of different SLEV strains, which we carried out for this review, indicates that the SLEV strains from Brazil are closely related to SLEV genotype V. This finding indicates that genotype V SLEV strains are also pathogenic for humans, as shown in previous studies in murine models , WNV (emerged in 1999), chikungunya (2013), and Zika viruses (2015), have emerged as public health threats in the Western Hemisphere. SLEV is maintained in a bird–mosquito transmission network involving multiple species in a broad range of ecosystems encompassing a wide geographic distribution that ranges from southern Canada to southern Argentina. Biotic factors, including vector and host abundance and population age structure, as well as abiotic factors, including rainfall and drought dynamics and elevated summer temperatures, combine to produce conditions favorable for transmission of SLEV. A better understanding of how SLEV circulates between enzootic transmission cycles in nature and epidemic transmission in human populations is needed to more accurately predict where and when human SLEV epidemics will emerge.The reemergence of SLEV in central Argentina is associated with several factors, including the recent introduction of a more virulent strain of SLEV into a naive bird community and increased populations of eared doves, a highly susceptible amplification species in Argentina. Argentina has experienced intense land use changes primarily because of the expansion of agricultural and urbanized habitats. More research is needed to define the effects of environmental change on avian reservoir and vector populations to clarify the dynamics of SLEV transmission, introduction, reintroduction, and reemergence in susceptible habitats throughout the Western Hemisphere.The reemergence of SLEV in California and Arizona resulted from introduction of a South American strain of SLEV. The genetic diversity of SLEV in the Americas is spatially influenced, with wide genetic variation across the space, but some SLEV strains from North and South America show high genetic similarity, indicating long-range dispersal. Similar to WNV, long-range SLEV dispersal is likely mediated by migrating SLEV-infected birds. A better understanding of SLEV in wild birds and avian host migration patterns is necessary to predict the spread of SLEV.


With most interest we read the contribution made by Fauconnier on phage therapy regulation  and wishThe European Medicines Agency (EMA) engages in constructive dialogue with the phage scientific community through workshops, symposia and via contributions to the scientific literature, as to determine such an appropriate EU-wide framework, allowing licensing and timely use of bacteriophages in specified conditions ,8. In th


Project Lazarus (PL) is a seven-strategy, community-coalition-based intervention designed to reduce opioid overdose and dependence. The seven strategies include: community education, provider education, hospital emergency department policy change, diversion control, support programs for patients with pain, naloxone policies, and addiction treatment expansion. PL was originally developed in Wilkes County, NC. It was made available to all counties in North Carolina starting in March 2013 with funding of up to $34,400 per county per year. We examined the association between PL implementation and 1) overall dispensing rate of opioid analgesics, and 2) utilization of buprenorphine. Buprenorphine is often used in connection with medication assisted treatment (MAT) for opioid dependence.n = 7200 county-months) in North Carolina. The intervention period was March 2013–December 2014. 74 of 100 counties implemented the intervention. Exposure data sources comprised process surveys, training records, Prescription Drug Monitoring Program (PDMP) data, and methadone treatment program quality data. Outcomes were PDMP-derived counts of opioid prescriptions and buprenorphine patients. Incidence Rate Ratios were estimated with adjusted GEE Poisson regression models of all seven PL strategies.Observational interrupted time series analysis of 100 counties over 2009–2014 . None of the other PL strategies were associated with reduced prescribing of opioid analgesics. Support programs for patients with pain were associated with a non-significant decrease in buprenorphine utilization , but addiction treatment expansion efforts were associated with no change in buprenorphine utilization .Implementation of PL strategies did not appreciably reduce opioid dispensing and did not increase buprenorphine utilization. These results are consistent with previous findings of limited impact of PL strategies on overdose morbidity and mortality. Future studies should analyze the uptake of MAT using a more expansive view of institutional barriers, treating community coalition activity around MAT as an effect modifier. Deaths from opioid overdose began increasing in North Carolina (NC) in the late 1990s (Web-based Injury Statistics Query and Reporting System (WISQARS), Among demand reduction strategies, medication assisted treatment (MAT), particularly with the partial opioid agonist buprenorphine, has been widely embraced. MAT is supported by substantial evidence-based modalities of substance abuse treatment  is a comprehensive, community-based series of seven interventions designed to reduce demand, supply and harms related to prescription OA; improve treatment of chronic pain; and promote and improve access to MAT. PL was first piloted in one NC county between 2007 and 2010, and was implemented statewide in early 2013  Diversion control was designed to remove unused medications and train law enforcement on OA diversion. (3) Support programs for patients with pain provided support groups, case management and pain clinic vetting and referrals. (4) Provider education focused on educating medical professionals in chronic pain treatment, including group trainings and in-office ‘academic detailing,’ or tailored instruction. The North Carolina Medical Board’s published guidelines for pain management were referenced in trainings  policies revised hospital practices to limit ED OA prescribing and require checking the state’s Prescription Drug Monitoring Program (PDMP) before prescribing. (6) Addiction treatment expansions increased the number of providers in a community able to prescribe buprenorphine-based MAT for opioid dependence, and the number of beds available in inpatient detoxification and treatment facilities. (7) Naloxone policies promoted liberal distribution of the opioid antagonist naloxone to opioid users and their close contacts, first responders including EMS and police, and caregivers. Strategies 1–3 were focused on community entities external to the health care system, whereas strategies 4–7 were focused on health care providers  overall prescribing rate of opioid analgesics and (2) utilization of buprenorphine. The 7 PL strategies are as follows. (1) s Trado, . (5) Hos overall The statewide implementation of PL in NC has significance as one of the earliest and largest coordinated efforts to address the overdose epidemic using community-based approaches. We hypothesized that the seven PL strategies would have varying effects on opioid overdose morbidity and mortality, opioid prescribing, and utilization of buprenorphine Table . This paNC is a large state in the southeastern US (population 9.9 million in 2014) that had overdose rates comparable to the US average during the 2009–2014 study period. We used an interrupted time series design to examine the relationship between strategies implemented as a part of PL and both prescription OA dispensing and buprenorphine utilization rates.The general analytic approach has been described previously  and MAHEC, with technical support from the community-based organization Project Lazarus. Coalitions that applied received annual grants of between $6500 and $34,400, from a network of funding sources. Thus, a coalition that received the maximal funding  may have been able to provide a full-time salary for a community health worker paid at the average weekly wage in North Carolina. Given that additional coordinators and non-personnel costs would be needed to successfully implement the seven strategies, it is reasonable to assume that no county received funding sufficient to fully implement PL without the need for additional investment by the county or community. Our evaluation included a pre-intervention period (January 2009–February 2013) and an intervention period (March 2013–December 2014). CCNC also funded Medicaid regional coordinators who provided technical assistance to community coalitions, directed provider education, and advocated for changes in hospital policies related to opioid prescribing.We used measures of coalition activities and ongoing surveys of key community coalition leaders to capture the implementation of the 7 PL strategies in each county in each month. We coded implementation of PL strategies using dichotomous variables that captured the implementation of each strategy, with ‘0’ representing no implementation of a strategy in a county to-date, and ‘1’ representing any ongoing or prior implementation or policy change specific to each strategy.Community-based coalitions were identified at the time they were funded by CCNC. Coalition activities were captured through structured surveys that three of the authors  administered via web survey every 6 months to coalition leaders and the CCNC regional coordinators. Surveys included details on naloxone policy adoption, ED policy changes, creation of support programs for patients with pain, and the location and date of provider and community education events.For the diversion control strategy, details of the time and location of local law enforcement trainings on diversion control were obtained from the NC State Bureau of Investigation (SBI).For the addiction treatment strategy and the evaluation of PL association with opioid dispensing, we combined survey data on MAT expansions with measures of incident buprenorphine and methadone utilization. This measure was constructed with data from the NC Controlled Substance Reporting System (CSRS), the state PDMP, and the NC Treatment Outcomes and Program Performance System (NC-TOPPS), a quality monitoring system sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA). Overall counts of new methadone treatment program patients were abstracted from intake interviews, and added to measures of incident MAT. Buprenorphine treatment episodes were considered incident after a 90-day washout period since the last buprenorphine script dispensed. The evaluation of PL's association with buprenorphine utilization only used the former survey data on MAT expansions and policy change.Data from the CSRS were used to construct county-month counts of patients and prescriptions for opioid analgesics. PDMPs such as the CSRS are state government-run electronic databases that can be queried at the point of care by clinicians to review a patient’s history of receiving controlled substances. Selected law enforcement officers and medical examiners are allowed access to the database when they are investigating specific cases. The CSRS began collecting data in January 2009, and data were provided by the NC Division of Mental Health, Developmental Disabilities, and Substance Abuse Services (DMHDDSAS). The data are generated when prescriptions for controlled substances are dispensed at regulated pharmacies in North Carolina. The data captured comprise each field of information legally required to be included in a North Carolina prescription for a controlled substance. The data are stored locally at the pharmacy and transmitted periodically to a central database. Data elements include unique identifiers for prescribers, dispensers, and patients and their locations; quantity, dose, days supply, and National Drug Code of the prescription; and age and sex of the patient.The raw data were tabulated by active pharmaceutical ingredient (API) and dosage form  for opioid analgesics. Opioid analgesics were defined as solid oral, transbuccal, or transdermal formulations containing codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone and oxymorphone. Prescriptions with APIs comprising the top 99.9% of all prescription records were retained; data cleaning removed non-controlled substances and appended metadata on drug class. Patients were assigned a unique identification number provided by the database vendor , which takes name, date of birth, and residential ZIP code into account, and was provided as a one-way hash algorithm and was continuous over data-years.Data from the CSRS were used to create county-month counts for the two outcome measures of interest, opioid prescribing and buprenorphine utilization. For opioid prescribing, counts of dispensed full mu-opioid receptor (MOR) agonist analgesics and their prodrugs, including solid oral, transdermal, nasal spray, and transbuccal formulations, were extracted by county and month from the CSRS. For buprenorphine utilization, counts of unique monthly buprenorphine patients, created using prescription data from the CSRS, were used to identify all patients receiving pharmacy-dispensed formulations of buprenorphine with indications for addiction treatment .In order to control for fundamental differences in health status between counties  and over time, a construct from the Robert Wood Johnson Foundation (RWJF) County Health Rankings was used  to quantify the association between the each of the seven PL strategies and our two outcomes, and used Poisson regression to model the IRRs. Models were fit using generalized estimating equations (GEE) to account for clustering at the county level, with a population offset for each county-month  variables that designate the presence or absence of the seven intervention strategies for any given month and county. Each strategy was represented as dichotomous variable with no implementation as the referent (coded 0), and implementation (coded 1).X8 was the county-month rate of outpatient prescriptions dispensed for opioid analgesics in units of 1000, with total resident population as the denominator. This measure was only used as a covariate in models of buprenorphine utilization.X9 is the county health status variable of linearly interpolated annual z-scores of Health Factors from RWJF County Health Rankings. This variable was used as a marker for general community health status and was included to control for potential confounding by changes to general community health status over time and between counties.X10 was a variable for calendar year included to remove linear trends over time (“secular trend”).X11, X12, and X13 were indicator variables for seasonality, implemented with indicator coding for spring, summer and fall, with winter as the referent. These variables are included to de-trend for seasonal effects on overdose and related outcomes, which were observed in preliminary data analysis. For opioid overdoses in 2010, a Walter and Elwood analysis of seasonality using the exact method test suggested the presence of seasonality  with a peak in March.Xe denominator of the rates, defined as the resident population of the county. Annual population was obtained from the National Center for Health Statistics and linearly interpolated by month.The offset term ln(n) was the logGoodness-of-fit was assessed using Akaike and Bayesian Information Criterion (AIC and BIC), with smaller values indicating better fit relative to an intercept-only model. We assessed over-dispersion using Deviance and Pearson’s chi-square divided by its degrees of freedom. Initially, univariate models were used to examine each of the individual strategies, without any adjustment for trends by year and season, county health status, or other strategies. Multivariable adjusted models examined the associations for each of the seven strategies while controlling for the other six strategies, with additional adjustment for year and season, and county health factors. Adjusted models of buprenorphine utilization also included adjustment for each county’s population-based rate of OA prescribing.A total of 74 out of 100 NC counties implemented any strategy of PL by the end of the intervention period, covering 70% of the state population. Non-implementing counties were either ineligible due to a lack of resources or did not submit a funding application.Over the 2009–2014 study period, unique annual OA patients decreased by 6.9%, from 23.0% of all state residents in 2009 to 21.4% in 2014 , we found weak associations between the adoption of PL strategies and the rate of OA prescription dispensing Table . MAT expIn fully-adjusted multivariable models accounting for implementation of all seven strategies, year and season, and county health status, these associations were attenuated. A statistically significant association between Diversion Control strategies and increased prescribing persisted . No other strategy was associated with a 5% or higher increase or decrease in opioid prescribing. Notably, the strategy of Provider Education was not associated with any change in OA dispensing .decrease in buprenorphine .In univariate models (no adjustment), each PL strategy was associated with a 54–82% increase in the rate of buprenorphine utilization Table . After aIn fully-adjusted multivariable models including all seven PL strategies, only support programs for patients with pain were associated with a change of 5% or greater in buprenorphine use , and no strategy was associated with a statistically significant change. The addiction treatment strategy hypothesized to have a direct impact on this outcome was associated with a 2% reduction in buprenorphine use . An additional model of only the addiction treatment strategy  found no association .Project Lazarus was implemented statewide in NC as a community-based program with multi-agency support. Its goals were to address opioid supply, demand, and harm reduction. PL sought to improve access to MAT and reduce opioid prescribing, while maintaining legitimate access to opioids for patients with chronic pain. The results of this analysis, together with our previous analysis of the association between PL and overdose morbidity and mortality, indicate that implementation of the PL strategies neither appreciably reduced opioid dispensing nor increased buprenorphine utilization  sharing between friends and family as reported by national data (Lipari & Hughes, A previous study in Massachusetts demonstrated a significant decline in opioid prescribing and unique opioid patients after a comprehensive opioid and pain policy was adopted by a large statewide private insurer (Garcia et al., a priori contingency plans. One potential tool that state or federal agencies could use to identify motivated communities is the Community Readiness scale developed by the Tri-Ethnic Center for Prevention Research (Ringwalt et al., It is also likely that the effectiveness of PL activities to limit prescribing were affected by the changing pace and form of the overdose epidemic in the US during the implementation period. When PL was initially piloted in Wilkes County, NC, through the planning of the statewide implementation, it was not anticipated that nested epidemics of heroin and fentanyl overdose would occur at the scale since documented (Ciccarone, We found no strong association between any component of PL and buprenorphine utilization in adjusted models. Unadjusted univariate models indicated consistent increases in the utilization rate, even for strategies not expected to have a direct impact on buprenorphine, which were hypothesized to be the result of secular trends in MAT over the study period.In our previous study, we found the PL addiction treatment strategy was associated with increased overdose mortality (Alexandridis et al., It is important to note that even buprenorphine MAT requires a substantial investment to reduce fatal overdose. National surveillance of buprenorphine and heroin overdose in France, where buprenorphine accounts for well over 80% of all MAT, found an 82% reduction in heroin overdose deaths between 1995 and 2003 after the introduction of community-based MAT through primary care providers and community pharmacies in 1996 (Emmanuelli & Desenclos, Recent strategy recommendations, such as the President’s Commission Report, have heavily stressed substance abuse treatment expansion, particularly maintaining access to MAT (Christie et al., Our evaluation of PL was limited by funder priorities that all North Carolina counties should implement PL, necessitating an observational interrupted time series study design. We were therefore unable to randomize communities to receive PL funding and supports, and residual or uncontrolled confounding may be present. The associations between PL strategies and our outcomes cannot be interpreted as causal. In particular, we were unable to quantify any of the selection factors associated with higher intensity of PL implementation in a given community. Multiple factors influencing coalition activity and substance use could not be obtained with the appropriate spatial and temporal resolution, including: previous collaborations among stakeholders (Kegler et al., Outcomes for both analyses in this study were derived from PDMP data, which have the typical caveats of administrative, secondary data. Our ability to identify unique buprenorphine patients is limited by the proprietary entity resolution algorithms used to link prescriptions based on name, address, and date of birth, potentially more challenging in vulnerable populations that may be more geographically mobile (Galea & Vlahov, Finally, our post-intervention period was limited to 22 months. The original pilot of PL in Wilkes County saw its greatest effect after three years of implementation (Albert et al., Despite other accomplishments, the statewide implementation of Project Lazarus in North Carolina did not meet its objectives of marked increases in the utilization of buprenorphine or reductions in opioid analgesic prescribing. Future support for community coalitions addressing the opioid crisis may need a more narrow focus and targeted coalition capacity building to ensure impacts on such outcomes as prescribing behaviors and addiction treatment.


In Greek mythology, Helen of Troy was so beautiful that her face “launched a thousand ships,” compelling King Menelaus to wage war to reclaim her from Prince Paris. Human preoccupations with beauty are enduring and now support a multibillion-dollar industry. Each day, our brains identify and catalog innumerable datapoints that bear on our impressions of beauty—those related to youth, health, adiposity, complexion, coloration, averageness, symmetry, masculinity/femininity, and personality, to name some of the best characterized  1]. Con. Con1]. Evolutionary hypotheses concerning the importance of attractiveness and its component factors in mate choice have revolved around the utility of these components in predicting the qualities of prospective mates . For exaGiven the importance of attractiveness across interpersonal contexts, studies that investigate the underlying genetics of facial attractiveness, such as the one reported by Hu and colleagues  in this CDC42EP3) affects height, which directly influences BMI. Similarly, the genetic association between female-rated male attractiveness and lipid levels observed by Hu and colleagues could be explained by the previously identified impact of candidate genes CERS2 and ANXA9 on both high- and low-density lipoprotein cholesterol levels . Indeedl levels . It is aThe results of this study point to underlying genetic architecture mediating attractiveness. In the future, careful multivariate studies testing the relative contribution of each associated locus to the component traits of attractiveness, and to attractiveness corrected for those traits, will help researchers unravel and interpret the genetic architecture of this important and complex phenotype. Of course, replication in the few other datasets possessing both genotype and attractiveness data will aid in validation and resolution of these results, and sequencing studies will help clarify the possibly functional variants at each locus and further explore their effect on attractiveness or its related components. Hu and colleagues also briefly mention signatures of selection on alleles associated with male facial attractiveness. This result is especially intriguing and brings up several avenues for future research. Do other secondary sex traits, such as vocal characteristics, show similar signatures of selection in males, indicating sexual selection among our male ancestors ? ImportaWhen contemplating how to depict Helen of Troy, the 5th century BC painter Zeuxis recognized the challenge of identifying the features that define beauty . This ch


The design and implementation of sound occupational health and safety (OHS) programmes require understanding of the main issues that need attention. This article highlights key issues regarding the (i) organisation of OHS services in southern Africa, (ii) role of the International Labour Organization (ILO) in the provision of OHS services and (iii) implementation of policies in general.Relevant peer-reviewed journal articles, ILO conventions and policies were identified and discussed.Inadequacies that exist on the organisation of OHS services in southern Africa include (i) lack of some critical categories of OHS practitioners, (ii) no emphasis on the surveillance of the work environment (iii) disregard of the worker’s right to refuse to work in unsafe work environments and (iv)non-coverage of some sectors of the economy. Further research is needed to identify additional efforts that the ILO requires to effectively discharge its OHS promotion mandate.Responsible authorities need to attend to the shortcomings of the national OSH laws and intergovernmental pacts. On February 17, 1988, the International Labour Organization’s (ILO) Convention 161 , the IntAnnals of Global Health, Moyo and colleagues [In the four regions of Africa, very few research efforts have been focused on examining existing OHS legislation in order to suggest required improvements for actioning by policy makers. However, in the lleagues  make a vlleagues  may alsoAbout two decades back, Auria  rightly 45Moyo and colleagues rightly bemoan the lack of coverage of informal workers, the civil service and domestic workers in reviewed compensation laws. The economies of developing countries appear to be driven by the informal sector, which suggests that informal workers, like their formally employed counterparts in the manufacturing and mining industries, deserve top priority with regard to OHS services provision. Similarly, in industrialised countries, the work conditions of informal workers seem not to meet the fundamentals of decent work. For instance, some studies report that informal workers: (1) do not have social security coverage , (2) req78A central theme emerging from the Moyo et al.  study isMoyo and colleagues wonderfully present the strengths of Zimbabwe’s Pneumoconiosis Act . The proMost sub-Saharan countries are predominantly agrarian  but lackMoreover, ILO seems grossly limited to the production of OHS proposals for implementation by member states, particularly, conventions and recommendations. Since ILO lacks the mandate for direct OHS lawmaking, its conventions merely serve as draft legislation ultimately requiring both ratification and subsequent enactment into locally binding national OHS law by member states. Worse still, recommendations are not designed to be legally binding but to instead provide optional guidelines concerning OHS policies, laws and practice. Therefore, beyond conventions and recommendations, further research may need to identify additional efforts that ILO requires to effectively discharge its OHS promotion mandate.On the other hand, the ILO conventions anchoring decent work concerns have several missing components, which make them less relevant in the OHS field. For example, the ILO’s Convention for Minimum Age on Child Labour lacks the much needed specific standard definition of what constitute a minimum working age. Without such a definition, member states are bound to adopt different minimum ages for working, which will make it a complicated and daunting task for ILO to effectively carry out its watchdog functions. Resultantly, member states that practice child labour may set a minimum working age as low as 13 years and still not adhere to it, thus perpetuating the employment of children, who in fact, are school age. Therefore, ILO needs to urgently rectify this loophole by setting a uniform minimum working age, say 18 years, if meaningful gains on banning chid labour are to be attained.Improvements are required for industrialised and developing countries with regard to addressing some health inequalities. For example, migrant workers and refugees’ right of access to health services seem to be unfulfilled in some industrialised countries 14, whichIn light of the explosive HIV/AIDs prevalence rate in some low- and middle-income countries, it is also important for the scientific community to examine how governments and employers have addressed the issues of workplace discrimination against workers with HIV/AIDs. Areas of focus may entail the adequacy and coverage of existing national legislative and policy measures. The existence of global anti-discrimination pacts 18 is a pTo conclude, Moyo and colleagues’ findings elegantly provide a wonderful call for governments to freshen up and attend to deficits within their OHS laws. We urge responsible authorities to rectify the limitations of the national OHS laws and of the intergovernmental pacts. We also call upon industrialised nations to attend to the health needs of refugees, migrant and informal workers.


There are approximately 35,000 human deaths from rabies in Asia annually. Rabies can be prevented through timely post-exposure prophylaxis (PEP) consisting of wound washing, rabies vaccine, and in some cases, rabies immunoglobulin (RIG). However, access to rabies PEP often remains limited to urban areas and is cost-prohibitive. There is little information on procurement, distribution, monitoring, and reporting of rabies PEP.We interviewed key informants in the public sector from various levels in Bangladesh, Bhutan, Cambodia, and Sri Lanka between March 2017 and May 2018 using a descriptive assessment tool to obtain information on procurement, distribution, monitoring, and reporting of rabies PEP. These four countries in Asia were chosen to showcase a range of rabies PEP systems. National rabies focal points were interviewed in each country and focal points helped identify additional key informants at lower levels.A total of 22 key informants were interviewed at various levels  including national rabies focal points in each country. Each country has a unique system for managing rabies PEP procurement, distribution, monitoring, and reporting. There are varying levels of PEP access for those with potential rabies exposures. Rabies PEP is available in select health facilities throughout the country in Bangladesh, Bhutan, and Sri Lanka. In Cambodia, rabies PEP is limited to two urban centers. The availability of RIG in all four countries is limited. In these four countries, most aspects of the rabies PEP distribution system operate independently of systems for other vaccines. However, in Bhutan, rabies PEP and Expanded Programme on Immunization (EPI) vaccines share cold chain space in some locations at the lowest level. All countries have a monitoring system in place, but there is limited reporting of data, particularly to the central level.Systems to procure, deliver, monitor, and report on rabies PEP are variable across countries. Sharing information on practices more widely among countries can help programs to increase access to this life-saving treatment. Worldwide, rabies causes an estimated 59,000 human deaths annually with approximately 60% of cases occurring in Asia .Rabies in humans can be prevented through timely and appropriate post-exposure prophylaxis (PEP). Rabies PEP consists of wound washing, immediate rabies vaccination following the potential exposure, and in some cases, rabies immunoglobulin (RIG). Currently only cell-culture or embryonated egg-based rabies vaccines (CCEEVs) are recommended by the World Health Organization (WHO); the original nerve-tissue based vaccine (NTBV) has not been recommended since the 1980s ,4. Very WHO provides guidance for rabies PEP according to three categories of bites  3]. Rab. Rab3]. In 2015, WHO, the World Organization for Animal Health (OIE), the Food and Agriculture Organization of the United Nations (FAO) and the Global Alliance for Rabies Control (GARC) established a global goal of zero dog-mediated human rabies deaths by 2030. The AssOverview of rabies post-exposure prophylaxis access, procurement and distribution in selected countries in Asia and Africa, 2017–2018 . Bangladesh, Bhutan, Cambodia, and Sri Lanka were chosen for in-depth assessments to highlight unique aspects of delivery and distribution systems in Asia. We aimed to include countries with varying burdens of human rabies and varying levels of effort to control and eliminate rabies, as well as countries in both the Southeast Asia and Western Pacific WHO regions and countries in various categories of eligibility for support from Gavi, the Vaccine Alliance  [Knowledge on rabies PEP procurement and distribution is limited, and there is little information on monitoring and reporting of its use. This project was part of a larger global project conducted in 23 countries to better understand rabies PEP systems; results can be found in tioning) –21. This2.We interviewed key informants to obtain information on procurement, distribution, monitoring, and reporting of rabies PEP, using a descriptive assessment tool. The tool consisted of ten categories of questions on program delivery, vaccine procurement, demand, distribution, cold-chain and vaccine storage, forecasting, monitoring, utilization, and reporting. Key informants were identified at each level of the healthcare system based on the structure of the country’s healthcare and rabies PEP system  and included national rabies focal points and health facility heads. When possible, we also interviewed other key informants such as Expanded Programme on Immunization (EPI) focal points to gain a more comprehensive understanding of immunization programs in the countries. Additionally, we reviewed vaccination registers to understand the monitoring system of rabies PEP and type of information recorded on bite patients and evaluated cold chain capacity at health facilities visited. We collected data between March 2017 and May 2018. To provide background information on the rabies situation in each country, we also reviewed WHO documents and published studies on rabies relevant to the selected countries.3.A total of 22 individuals were interviewed in the four countries. In each country, the national rabies focal point was interviewed, some with over 20 years of experience in the role. Other individuals interviewed included national-level staff working on rabies (5), WHO country office rabies focal points (2), national-level EPI staff (2), WHO country office EPI staff (2), and health facility heads and health workers (7). In some countries, health facilities were not visited specifically for this assessment and thus are not included in the total number interviewed, but were visited by national rabies focal points as part of their routine work. 3.1.In Bangladesh, there are an estimated 2000 deaths due to rabies with over 166,000 animal bite victims, the majority of which are dog-bite victims, annually . Rabies Rabies PEP is offered at 66 public District Rabies Prevention and Control Centers (DRPCCs) around the country with at least one center in each of the 64 districts and at a National Rabies Prevention and Control Center (NRPCC). The NRPCC provides treatment to approximately 500 patients daily ,24. At pThe Ministry of Health (MoH) uses an open bidding system to select the vaccine provided in public facilities. The timeframe from bidding to delivery is six months to one year. Central level procurement is based on the previous years’ consumption through the Communicable Disease Control (CDC) operational plan of the Directorate General of Health Services (DGHS). Since 2014, CDC/DGHS has procured 20–30% more vaccine each year than the previous year, but PEP demand continues to exceed the supply due to increasing public awareness. CDC/DGHS strives to fulfill 100% of the demand year-round at the NRPCC, and 50–80% of the demand at DRPCCs. Rabies focal points from the DRPCCs are responsible for collecting vaccine monthly from the central medical store. Collection requires prior approval for the amount requested from CDC/DGHS and a report on the previous month’s utilization. Focal points are responsible for transporting vaccine back to treatment centers using cold boxes and ensuring storage of vaccines in a refrigerator at the DRPCCs. This system is separate from the EPI program as the EPI program transports routine vaccines from the capital to regional centers and then to the local level using their own mechanisms.CDC/DGHS provides a standardized register to track patients, record demographics, and monitor vaccine usage, as well as a standardized rabies vaccination card for patients. Patients are also given a reminder card for future appointments. The NRPCC and DRPCCs are required to report the total number of doses and the dates of administration to CDC/DGHS through the National Health Management Information System (MIS-DHIS2) on a monthly basis and reports are aggregated at the central level for planning purposes. The NRPCC and DRPCCs also submit a hard-copy report detailing patient demographic and bite-related information to CDC/DGHS for future planning purposes. There is no formal system for monitoring and reporting adverse events following rabies PEP; instead, information on adverse events is collected and reported ad hoc to CDC/DGHS. There is currently no follow-up of defaulters and individual vaccine completion rates are not checked. However, CDC/DGHS is establishing a regular mobile phone-based monitoring system to identify adverse events and to detect reasons for incompletion of the vaccination schedule.3.2.In Bhutan there were over 7900 reported dog bites and one rabies death in the country in 2016 ,27. The Bhutan’s healthcare system consists of one national, two regional-level, and 30 district hospitals, and 210 basic health units (BHU-I and II), as well as indigenous and outreach clinics throughout the country . Rabies All drugs including rabies vaccines are procured through the Medical Procurement and Supplies Division (MSPD) of the MoH while EPI vaccines are procured by Vaccine Preventable Disease Control Program (VPDP) through UNICEF. Head pharmacy technicians submit annual rabies vaccine requests based on the previous year’s consumption with a one-month buffer. Requests are submitted to the Health Care and Diagnostic Division (HCDD) using a standardized form for all drugs. The HCDD verifies the quantities of rabies vaccine requested and submits the request to the MSPD. The MSPD receives rabies vaccines and they are then distributed in a cold chain van to the hospital level. BHUs then request and collect rabies vaccine from their respective district hospitals as needed. Within some health facilities, rabies vaccines and EPI vaccines are stored together. Rabies vaccine distribution was previously integrated with EPI vaccines as an interim measure until resources were made available to separate the two systems.All health facilities that provide rabies PEP are required to maintain a vaccine inventory stock ledger and rabies vaccine register with demographics, information on exposure, and vaccination dates. However, there is no mandatory reporting requirement or system to report rabies PEP data, nor are the data monitored at the central level . Vaccina3.3.There are an estimated 800 human rabies deaths annually in Cambodia with over 700,000 people bitten by dogs each year; dog vaccination campaigns are not conducted regularly ,30. TherThree non-private entities provide rabies PEP in Cambodia: Angkor Hospital for Children (AHC) in Siem Reap and the Institut Pasteur du Cambodge (IPC) rabies vaccination center and National Institutes of Public Health (NIPH) clinic in Phnom Penh. Children ≤16 years can receive PEP free of cost at the AHC. Patients of all ages can access rabies vaccine (US$ 12 for the full course) and RIG (US$ 37) at subsidized costs at IPC in Phnom Penh. At both AHC and IPC, RIG is only available in limited quantities and patients are prioritized based on status of dog, wound location, and age. IPC receives approximately 22,000 new patients for PEP annually and AHC receives around 3000 patients. Rabies vaccine is available at full cost (US$ 8–15 per dose depending on brand) at the NIPH clinic; RIG is not available. The NIPH clinic receives around 500 new patients each year. Rabies vaccine is administered using the ID administration route at AHC and IPC and intramuscular (IM) administration route at NIPH clinic. Additionally, rabies vaccine is widely available at a number of private clinics throughout the country, with some also offering RIG. Public health facilities outside of Phnom Penh will often refer adult patients to the private sector for treatment. However, there is limited knowledge of the availability, quality, and cost of PEP at these private clinics.All three clinics have a procurement focal point. Forecasting is done based on the previous month’s  consumption. Vaccines and RIG are purchased directly from a supplier in Phnom Penh and delivered directly to the hospital or clinic, as needed. Vaccines are stored in refrigerators either in the immunization room or in a store room and transferred to a vaccine carrier for daily use.The NIPH clinic and IPC use electronic databases for stock monitoring and reporting with standardized information collected on patients including demographics, vaccine brand, administration route, WHO bite category, status of dog, and PEP vaccination dates. AHC records similar information in a hard-copy stock ledger and patient chart. Each facility provides their own vaccination card to their patients. There are no mandatory reporting requirements of rabies PEP or patients receiving rabies PEP to the MoH. The NIPH clinic reports the numbers of people receiving rabies vaccine at the clinic to NIPH monthly. NIPH then reports the numbers to MoH. IPC reports annually to the MoH or when requested. AHC does not report to the MOH on rabies vaccination. There is limited defaulter tracking in all facilities with follow-up done ad hoc and only for those with probable rabies exposures , and no system for monitoring of adverse events.3.4.Sri Lanka has had a national rabies control program since 1975 and human rabies has been a notifiable disease since 1971 ,16,31. ERabies PEP is provided for free at the 204 rabies units located in hospitals throughout the country. Higher volume hospitals carry both vaccine and RIG; lower levels only carry rabies vaccine. Rabies units have at least one bed and one computer for electronic reporting, and are staffed with doctors and nurses trained on PEP protocols. PEP is also available in the private sector on a limited basis and at high cost.Rabies PEP is procured at the central level by the State Pharmaceutical Corporation of Sri Lanka (SPC) and arrives in three stocks annually. SPC is required to procure WHO pre-qualified vaccines. Each rabies unit prepares an annual request based on the previous year’s vaccine use. All rabies units use the same standardized form as for other drug and vaccine requests. Rabies PEP are transported from the central to the regional to the district level either by refrigerator truck or by cold box throughout the year according to a delivery plan decided by the government. Within rabies units, PEP is stored in its own refrigerator. Within emergency rooms, it is stored in ward refrigerators, along with other non-rabies biologicals. Rabies PEP arrives in the country throughout the year, but is often issued to health facilities in smaller stocks because of space shortages. Additional stocks are kept at the district or central level, and sent to facilities as needed.Each unit maintains an electronic or paper-based patient register with information on patient demographics, animal involved and status, and dates of vaccination. Some rabies units have transitioned to a real-time online data reporting system with other units expected to enhance reporting systems soon. All patients receive a printed PEP card with the dates of subsequent visits. Each unit also has a register for stock monitoring showing daily, weekly, monthly, and yearly balances. Rabies units are required to report on rabies PEP stock and the numbers of individuals receiving PEP monthly to the anti-rabies campaign at the MoH. Defaulter tracking is done for all patients that are considered high risk based on the location or severity of the wound and biting animal status. If a patient is considered high risk, follow-up is done by phone or in-person by a rabies public health inspector (one per district). Adverse events following rabies vaccination is reported through the adverse event reporting system, as with other vaccines.4.The countries described have differently structured systems for rabies vaccine procurement, distribution, monitoring, and reporting. Bangladesh, Bhutan, Cambodia, and Sri Lanka also had varying levels of access to rabies PEP for persons with potential exposure. Because of the low numbers of patients requiring rabies PEP, as compared to other types of treatments, PEP can be made accessible without being available at every level of the healthcare system or every health facility . In BangThroughout the four countries, availability of RIG is limited, and is cost-prohibitive to governments and patients. When available, its use is often prioritized for young children, patients with severe wounds or wounds at highly innervated body parts, or in exposures to probable or confirmed rabid animals. This prioritization is in line with the 2018 WHO position on rabies immunization emphasizing dose- and cost-sparing approaches [Rabies vaccine distribution systems in these four countries primarily operate independently of systems for other vaccines. Bangladesh’s distribution system requires district level facilities to collect rabies vaccines from a central location. In Sri Lanka, rabies vaccine is delivered from the central level to the lower level facilities. In Cambodia, all three non-private rabies PEP providers work directly with the supplier to have rabies vaccines delivered. Bhutan provides an example of rabies vaccines being successfully incorporated into existing EPI distribution structures while awaiting development of a rabies vaccine-specific distribution network. Even with a separate distribution network, rabies PEP is stored in refrigerators with EPI vaccines at some Bhutan health facilities. Additionally, some Bhutan EPI staff administer rabies vaccine. EPI staff receive extensive training on immunization practices and EPI’s cold storage is closely monitored which provides assurance that the cold chain for rabies PEP remains intact.There is limited collection and reporting of data on demographics of patients, bite categories, barriers to PEP access and factors affecting adherence to vaccination schedules and completion in most countries. In some cases, this information is collected at the local level. For example, in Cambodia, NIPH clinic collects detailed information on each patient through a comprehensive electronic database . HoweverRabies PEP systems in these four countries have several good practices that may be valuable to share. Exploring these systems provides an opportunity to learn and tailor country programs with the aim of increasing access to life-saving rabies prophylaxis. Additionally, rabies PEP management and delivery systems can be adapted from existing systems, such as those of the EPI program. EPI programs often include extensive trainings on administration and cold chain, and standardized guidelines on vaccine introduction, defaulter tracking, and adverse event reporting. These aspects could be leveraged to strengthen rabies PEP distribution systems. There are currently no global standardized protocols for country rabies PEP systems. While unique aspects of countries mean that it is not feasible to implement the same system everywhere, a standardized set of recommendations would help countries to develop effective systems tailored to the country context. Although this assessment focused solely on human rabies PEP, elimination of human rabies deaths cannot be done with rabies PEP alone. Achievement of elimination targets will require the collaborative efforts of the human, animal and other sectors ,12,35–39


Together, the Hajj and Umrah rank among the leading global venues that host annual mass human migrations. The Hajj is an annual pilgrimage to the Islamic holy city of Makkah in Saudi Arabia . It is cThrough the Hajj and Umrah, it is estimated that visitors to Saudi Arabia arrive from almost every country, based on a ratio of “one pilgrim per 1,000 Muslims from that country” . CurrentThe largest numbers of Hajj immigrants are from South and Southeast Asian tropical countries where globally the largest numbers of cases of dengue, lymphatic filariasis (LF), soil-transmitted helminth infections, leprosy, and kala-azar are also endemic . SimilarPreviously reported major Hajj-associated infectious diseases included respiratory tract infections like seasonal influenza, meningococcal disease, lower respiratory infections due to pneumococcus, and tuberculosis; water-borne and blood-borne infections including hepatitis A, B, and C were discussed elsewhere , 6. In tAedes aegypti mosquitoes are found in the western Arabian Peninsula [Because eninsula , there ieninsula . It is beninsula , 7, 9. Seninsula . AltogetA. aegypti mosquito-transmitted viruses could follow during Hajj seasons. Of particular concern was the possibility of Zika virus infection emerging as a consequence of mass migrations through Jeddah in 2015–2016 [Based on the ease of introduction of dengue into Saudi Arabia, there are concerns that other 015–2016 , 12, alt015–2016 . Yet ano015–2016 , 14. Thi015–2016 , 14. AddPhlebovirus in the family Bunyaviridae) is believed to have been introduced at least twice into the MENA region from sub-Saharan Africa including entry into Egypt from Zimbabwe in the 1970s and from Kenya into Saudi Arabia near the border with Yemen in 2000 [Culex triteniorynchus and Aedes vexans arabiensis mosquitoes [Finally, Rift Valley fever  viral infection, Alkhumra hemorrhagic fever virus (AHFV), was first identified in western Saudi Arabia. Between November and December of 1995, AHFV was isolated for the first time from blood samples of six butchers who worked for a slaughterhouse in Alkhumra  [Another tick-borne (both  Makkah) . AHFV is Makkah) , 21. Acc Makkah) . ComparaBecause the 2014 Hajj season coincided with the Ebola outbreak in West Africa, the Saudi authorities suspended issuing Umrah and Hajj visas for people from Guinea, Liberia, and Sierra Leone during that year . Until tSince its discovery in 2012, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infected around 1,800 individuals with a 35% fatality rate. About 80% of the reported cases occurred in Saudi Arabia . The firLeshmania major (zoonotic species) and L. tropica (anthroponotic species), and the vector sand flies (Phlebotomus papatasi and P. sergenti) are distributed throughout Saudi Arabia, including the two holy cities (Makkah and Medina). As a result, CL could be potentially transmitted to other countries through Hajj and Umrah pilgrims leaving Saudi Arabia. In fact, different reports indicate that CL may have been introduced to Asia and Europe through Saudi Arabian visitors [Saudi Arabia is ranked among the highly endemic countries of cutaneous leishmaniasis (CL). During the last 10 years, the number of reported CL cases has dramatically dropped, with the average reported annual prevalent cases being around 2,500 , 27. Botvisitors –30. Compvisitors , 32.Anopheles mosquito vector, especially from highly endemic African Muslim–majority nations. Surveillance programs in place in Makkah help to limit local transmission [Malaria previously posed a threat to Hajj and Umrah pilgrims in western Saudi Arabia. However, decades of malaria control programs have helped to minimize these threats. For example, between 2010 and 2015, the indigenous malaria cases remained below 100 per year. This number increased to 272 cases in 2016. The total confirmed malaria cases in 2016 was 5,382 (indigenous and imported). The vast majority of these cases (95%) was due to importation, possibly through Hajj, workers and illegal migrants from South Asian and African nations and Yemen, where malaria is endemic . Therefosmission , 35.Salmonella, Shigella, and Escherichia coli accounted for the majority of the circulating enteric infections, with approximately more than one third of these bacteria harboring β-lactamases resistance genes [The Hajj gathering over a small area of land provides opportunities for the emergence of enteric bacterial infections, which include antibacterial-resistant strains. For example, during the Hajj seasons between 2011–2013, ce genes . Active ce genes . TherefoVibrio cholerae do not show symptoms and remain undetected complicates detection and surveillance efforts [Multiple cholera outbreaks occurred during the Hajj between 1877 and 1912. The largest cholera outbreak occurred in 1893 with total deaths of 32,994 at the end of the Hajj season . Cholera efforts .The government of Saudi Arabia undertakes enormous efforts for planning the Hajj and Umrah seasons each year through 24 different committees representing the different Saudi sectors. The design of the annual plan is coordinated with different international agencies, including the World Health Organization (WHO), the European Centre for Disease Prevention and Control (ECDC), and the United States Centers for Disease Control and Prevention (CDC), which provide more information about development of outbreaks and emerging diseases including NTDs. Based on these combined efforts, the Saudi Ministry of Health issues recommendations for the required vaccinations and other preventive measures.The ambitious Saudi Arabia’s Vision 2030, “@SaudiVision2030,”  includes programs that introduce major transformation to the different sectors and services within the country. A key strategic program is ensuring opportunities to expand safe Hajj and Umrah pilgrimages . To achiAs a result of the increase in the pilgrims to Saudi Arabia, the risk of NTDs is magnified. Therefore, the future plans for Umrah and Hajj expansion also include strengthening the healthcare system and constructing a national plan to deal with potential public health threats. The Saudi government’s health sector expansion also includes research and development (R&D) capacity building. For example, Saudi Arabia intends to build a national center for vaccine and biologic research and development within King Saud University (KSU) in Riyadh. KSU is a leading university in healthcare research, and in order to support establishing this center, it signed an agreement with the Texas Children’s Hospital Center for Vaccine Development, focusing on education and training and to support the transfer of technology to the Kingdom of Saudi Arabia. This collaboration will help to train Saudi scientists at various steps of vaccine development and help to establish a parallel vaccine facility in Saudi Arabia. The ultimate goal for the Saudi’s national center for vaccine and biologic research and development is to help in the research and development of vaccine candidates against local and regional infectious diseases, including major NTDs in the region. Furthermore, the Saudi Ministry of Energy, Industry, and Mineral Resources is sponsoring a new Saudi Vaccine and Biopharmaceutical Center funded by the King Abdulaziz City for Science and Technology  and operated by SaudiVax and PnuVax, applying the concept of government-owned, contractor-operated model (GOCO). The center will have the capacity to scale up cell-based vaccines up to 2,000 L under good manufacturing practice (GMP) guidelines with approval from the Saudi Food and Drug Authority (SFDA). The idea of the center is to support moving early discoveries from the bench to the market, especially those with low global market value and so week incentives for large multinationals to support. Finally, the Saudi government has formed a thinktank with representatives from the different groups mentioned above and from the policy-making side that is called the “Saudi Vaccine Alliance.” This thinktank is used to address matters related to combating new issues and to expand on the Saudi reach to the international scientific community.Similar efforts will be required to expand disease diagnostic capacity. In that context, the Saudi Ministry of Health has recently mandated the expansion of the National Health Laboratory (NHL) located north of Riyadh, with emphasis on increased capacity and scope for its reference diagnostic labs, including three core laboratories: infectious diseases, genetic diseases, and molecular biology systems. The NHL aims to support the Saudi’s strategic plans by achieving high standards in scientific research, diagnosis, and disease prevention. The NHL expansion includes the establishment of a new Center for Neglected Tropical Diseases.Indeed, during the coming years, we can continue to expect a large influx of pilgrims to Saudi Arabia, especially from countries known to be endemic for NTDs. Therefore, there is an urgent need for development of more comprehensive surveillance programs and data collection not only during the Hajj but also around the year to account for Umrah pilgrims. Such programs could monitor for any possible outbreaks for all NTDs highlighted above, with an emphasis on countries with the highest number of pilgrims coming from NTD-endemic nations. In addition, surveillance monitoring will continue to include Hajj and Umrah pilgrims leaving Saudi Arabia and traveling globally. Collectively, these data will enable the policymakers to make informed decisions to control and prevent NTDs in the Middle East and also in all of the Muslim-majority nations comprising the Organization of the Islamic Conference (OIC).In parallel, many of the NTDs highlighted above are transmitted by insects and ticks, which are now widespread in the western region of Saudi Arabia. Therefore, intensified vector management and control will represent a critical component of health sector planning for the Hajj and Umrah. Toward that goal, the Saudi Ministry of Health through the Center for NTDs will develop programs to focus on vector controls and surveillances.In summary, mass gatherings may facilitate the emerging of NTDs just as they do other diseases of epidemic or pandemic potential. Since the Hajj and Umrah represent international gatherings, collaboration at multiple levels is required, including expanded surveillance and intensified vector management and control, increased reference laboratory diagnostic testing, and R&D for both new diagnostics and vaccines. Through its strategic planning, the Ministry of Health and its research university and institute partners are committed to undertaking a multidimensional approach to disease threats in the Kingdom of Saudi Arabia, the MENA region, and across the OIC nations.