Since its peak in early 2016, the incidence of Zika virus (ZIKV) cases has declined to such low levels that Phase 3 field efficacy trials may be infeasible. While great progress was made to rapidly advance several vaccine candidates into Phase 1 and 2 clinical trials, in the absence of sustained viral transmission it may be difficult to evaluate the effectiveness of ZIKV vaccine candidates by conducting traditional clinical disease endpoint efficacy studies. However, ZIKV is still circulating at low levels in some areas and is likely to re-emerge in naïve populations or in sites of prior epidemics once population immunity wanes. Therefore, the public health need for a ZIKV vaccine remains. To facilitate continued ZIKV vaccine development efforts, the World Health Organization's Initiative for Vaccine Research and the National Institutes of Health’s National Institute of Allergy and Infectious Diseases co-hosted a meeting of experts in March 2018 to identify strategies to demonstrate vaccine effectiveness in view of waning ZIKV disease incidence. This paper outlines points for consideration for developers, regulators, and other stakeholders working towards a licensed ZIKV vaccine. These deliberations may also be applicable to development of vaccines for other emerging infections where the size, unpredictability, and ephemeral nature of outbreaks makes clinical disease endpoint efficacy trials to demonstrate vaccine effectiveness infeasible. Just one month later, external experts to WHO advised prioritizing the development of a ZIKV vaccine, acknowledging that such development of medical countermeasures remains imperative for a potential further future outbreak While the peak of the epidemic occurred in the first quarter of 2016 when efforts to develop ZIKV vaccines were ramped up, the number of cases in South America, the Caribbean, and Central America dropped over the course of 2016, with very low transmission remaining in 2018 . Most rein utero ZIKV infection, or both Despite the decline in cases, the development and licensure of a ZIKV vaccine remains a critical global public health need. The U.S. Centers for Disease Control and Prevention recently estimated approximately one in seven infants born to mothers with laboratory evidence of ZIKV infection in pregnancy were diagnosed with a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with Pre-licensure clinical evaluation of vaccines typically follows a stepwise progression starting with early-stage clinical trials  to obtain preliminary safety and immunogenicity data and information on dose and regimen of the vaccine candidate. One or more pivotal Phase 3 trials is normally used to demonstrate safety and efficacy To continue to facilitate ZIKV vaccine development efforts, the WHO Initiative for Vaccine Research and the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) co-hosted a meeting in March 2018 to discuss strategies to demonstrate effectiveness of ZIKV vaccine candidates in the face of waning and unpredictable disease burden. While recognizing the importance of safety considerations, discussions at the meeting were limited to approaches that could be used to demonstrate ZIKV vaccine effectiveness outside of traditional field efficacy trials. WHO and NIH share the goal of bringing one or more vaccine candidates through late-stage clinical development and licensure so that a safe and effective product is ready for use when needed. This paper outlines points for consideration for developers, regulators, and other stakeholders working towards a licensed ZIKV vaccine (Box 1).2There are several challenges to ZIKV vaccine development that influence evaluation strategies for ZIKV vaccines. These include the need for well-characterized animal models relevant to human disease; the potential role of pre-existing flavivirus immunity impacting vaccine safety, immunogenicity, and/or clinical efficacy; incomplete understanding of immune responses that would be necessary to prevent fetal infection; the theoretical risk that vaccine immune responses could induce Guillain–Barré syndrome (GBS); and challenges associated with vaccination of pregnant women, potentially with a live vaccine or technologies based on platforms not previously utilized in licensed human vaccines. Current evidence suggests that even asymptomatic maternal infections with presumably low levels of viremia could result in CZS The ZIKV vaccine landscape has included more than 40 candidates. Among them, nine are in early clinical development using proven technologies like attenuation and inactivation, as well as newer platforms for which no human vaccine has yet been licensed, such as DNA and modified mRNA 3Phase 1 and Phase 2 clinical studies will be needed to establish initial safety and immunogenicity in a sufficient number of study participants before proceeding with the demonstration of vaccine efficacy in support of licensure. In the case of vaccine candidates for which traditional Phase 3 efficacy trials cannot be conducted pre-licensure, alternative approaches need to be explored. It is considered likely that a data package that supports licensure will include immunogenicity in animals and humans as well as animal challenge studies. Developers are encouraged to meet early with regulators to discuss the proposed data package and appropriate regulatory pathways.The approach to demonstrating vaccine efficacy differs depending on the regulatory pathway to licensure. In addition, available regulatory pathways to licensure vary by country and regulatory authority. For example, in the United States, a ZIKV vaccine could be licensed by the US Food and Drug Administration (FDA) by one of three available pathways: traditional approval, accelerated approval, or the animal rule. A description of these pathways with considerations specific to Zika has been published Similarly, the European Medicines Agency (EMA) has regulatory tools and options to allow the licensure of a vaccine based on non-traditional approaches when adequately justified. Approval under exceptional circumstances and conditional marketing authorization are among the regulatory pathways that could accommodate for such scenarios. These pathways allow for flexibility in terms of the overall evidence that would be required to support the efficacy of the vaccine candidate and might include efficacy from human challenge models or extrapolation of protection to humans from adequate animal challenge models in which animals from a relevant animal species recapitulating key aspects of human disease are protected after passive transfer of human antibodies and/or after vaccination.in vitro assay. Assays that might be able to predict a reasonable likelihood of clinical benefit could be based on ZIKV challenge studies in mice that received passively transferred human immune serum (harvested post-vaccination). Immune markers associated with protection in animal studies and/or field efficacy studies (should incidence permit) could also be considered. The extent to which an immune marker associated with protection for a given vaccine candidate could predict efficacy of other vaccine candidates, particularly those employing differing vaccine platforms, is unknown at present. For some vaccines where the mechanism of protection is well understood, the immune marker that predicts protection is platform-independent , and inactivated vaccines) Regulatory pathways are available across national regulatory agencies to advance vaccine candidates without the need for a traditional clinical disease endpoint efficacy trial to demonstrate vaccine efficacy and without the existence of a scientifically well-established marker that predicts protection. In general, these pathways have in common initial licensure of a vaccine based on data that include a non-clinical endpoint in human studies and a requirement for post-licensure studies to further define or confirm benefit. For example, the US FDA Accelerated Approval regulation permits use of a surrogate marker  or an intermediate clinical endpoint to demonstrate vaccine efficacy in support of licensure. For vaccines, this surrogate marker is usually an immunological endpoint measured in an in utero infection in an animal pregnancy model (or in a combination of models) or demonstration of sterilizing immunity  may also be useful endpoints, as they indicate more direct benefit even though they may be more difficult to attain. Feasibility of individual endpoints may also depend on the timing of challenge relative to vaccination: sterilizing immunity may be achievable four weeks after vaccination but may be more difficult to attain 12 months after vaccination.There are also different options for an appropriate clinical marker or intermediate endpoint that could be used as an endpoint in animal challenge studies and extrapolated to humans. One endpoint to be considered is protection against ZIKV viremia post-challenge. However, prevention of 4From a regulatory perspective, it will be useful to identify an immune marker that is reasonably likely to predict clinical benefit in vitro neutralizing antibodies of similar titers induced by two related DNA vaccine candidates were associated with different levels of protection against viremia in animal challenge studies [unpublished data]. This finding suggests that other characteristics of the neutralizing antibody (besides the titer) may need to be identified in order to predict protection across vaccine candidates. Systems vaccinology approaches have been successful in characterizing complex immune functions associated with vaccine protection for other viruses, e.g., HIV, and may have applicability to ZIKV However, while promising data exist, there are information gaps regarding potential use of neutralizing antibodies to predict clinical benefit of ZIKV vaccines. While relatively low titers are accepted as predictive of protection for vaccines against several other flaviviruses, the titer needed to protect against ZIKV may be different from other flaviviruses. Furthermore, it is unknown whether the titer required to protect against clinical disease in the vaccinee is the same as that required to protect against fetal infection. Preliminary data from NIH found that Finally, concerns have been raised about using neutralization assays to measure ZIKV vaccine immunogenicity in individuals who have been previously exposed to other flaviviruses, either through natural infection or vaccination, due to potential cross-reactivity The assay used to measure neutralizing antibody will affect the reported numerical titer, and careful interpretation in view of the cell type used for assay, virus strain, and assay type is needed. Primary assays being used for ZIKV vaccine candidates include the traditional PRNT, microneutralization test (MN), and reporter virus particle assays. These three assays differ with respect to how viral infection is enumerated in the presence or absence of antibody, adaptability to multiple cellular substrates, and requirement for viral replication. Standardized, validated neutralization assays could help facilitate vaccine development. Several efforts are underway to support assay validation.The National Institute for Biological Standards and Control (NIBSC) is currently in the process of validating a serology standard and a PCR standard that will be reviewed by the WHO Expert Committee on Biologicals Standardization (ECBS). WHO international standards and reference materials for designating the activity of vaccines and other biologicals can serve as a basis for evaluation of the quality, safety and efficacy of these products for the purpose of licensure as well as post-licensure. These standards can support WHO prequalification and they also allow comparability of data worldwide NIH, through its contracting partners, is working to produce and characterize master and working ZIKV stocks, generate critical reagents, and develop and standardize assays. Assay development and optimization, and ultimately qualification, is underway or planned for the plaque assay, RT-qPCR, Reporter viral particles-flow neutralization (RVP-FN) assay, MN assay, and PRNT. Standardized protocols and qualified assays for human clinical trials, bridged to use in NHP challenge studies, will be made available to developers.5Animal models are an important element supporting licensure of vaccines in case human efficacy studies are not feasible. Mouse challenge models to evaluate efficacy can be useful tools for comparing different candidates and to study vaccine modes of action. NHP challenge models may more closely predict human outcomes and are suitable to explore efficacy against various disease endpoints, potentially including protection against CZS, transplacental infection, GBS, and viral persistence. Passive transfer studies in which human immune sera (generated in response to infection or vaccination) is transferred into animals, which are subsequently challenged with ZIKV, may be the closest currently feasible approximation in animal studies to demonstrate the protective value of human antibodies and to infer clinical benefit in humans.Several animal models for ZIKV infection and disease are currently being used. Murine models include immunocompetent adult, immunocompromised adult, and immunocompetent neonatal mice. NHP challenge models have been developed using rhesus macaques, cynomolgus macaques, and pigtail macaques. Guinea pig Vaccine data from animal challenge studies have been promising. The endpoint in most animal vaccine challenge studies is protection against viremia, measured as a lack of anamnestic response post challenge and/or lack of viremia post-challenge. Several vaccine candidates have demonstrated apparent sterilizing immunity when challenged one month following vaccination. Candidates have been successfully evaluated in NHPs with challenge one year post-vaccination 6Controlled Human Infection Model (CHIM) studies have been developed for several diseases, including influenza, malaria, cholera, and dengue CHIMs have been utilized to enhance vaccine development in several ways: (1) to assist with down-selecting vaccine candidates; (2) to study disease pathogenesis; (3) to directly evaluate vaccine efficacy and duration of protection, and (4) to identify immune markers that can predict protection. Based on these considerations, the role of a ZIKV CHIM for vaccine development has been discussed A December 2016 NIAID and the Walter Reed Army Institute of Research (WRAIR)-cosponsored expert consultation discussed conditions under which use of a ZIKV CHIM could be ethically justified. Participants raised concern that a CHIM may not be justified if traditional field efficacy trials were considered feasible, and that a ZIKV CHIM study may present risks to non-participants (third parties) if the challenge strain spread to individuals not enrolled in the study Fifteen months later, the calculus has changed. Traditional efficacy trials may be very difficult, if not infeasible, to conduct and the ability to directly demonstrate efficacy in a CHIM could provide the data needed for licensure. Data suggest that from ZIKV-infected individuals with low levels of viremia, ZIKV is only transmissible for 30 days Thus, it is perceived that the situation with respect to consideration of ZIKV CHIM has changed substantially since the time of the ethics consultation in 2016, with greater appreciation for societal value and also better or improved understanding of how risks might be mitigated. Meeting participants, including representatives of regulatory agencies US FDA and EMA, agreed that CHIM may represent a useful tool for evaluating ZIKV vaccine candidates. Scientific issues for CHIMs, including the challenge strain, route of administration, dose, and timing of challenge post-vaccination will need to be addressed before CHIMs are used to evaluate vaccine efficacy.7Regardless of the regulatory pathway used to demonstrate vaccine effectiveness for the purposes of regulatory approval, post-marketing studies will be needed for approved ZIKV vaccines. Depending on the licensure pathway, post-licensure studies may be required as confirmatory effectiveness and expanded safety studies, but even if not required by applicable regulation, it will be important to assess vaccine impact on the serious but rare sequelae of ZIKV infection.In addition to virologically-confirmed Zika disease, likely effectiveness outcomes of interest for post-licensure studies include vaccine effectiveness against CZS and GBS, which are too rare in occurrence to serve as clinical endpoints in pre-licensure trials. Such studies are likely to be challenging in the context of a ZIKV outbreak in affected areas. The majority of ZIKV-associated CZS occurred in areas of Brazil with limited surveillance and research infrastructure. The ability to do post-licensure studies also requires vaccine rollout on a large basis, as the utility of these studies in gaining additional information on the vaccine may be limited if small select populations are vaccinated. In order to be successful, it is critical to know the vaccination status of individuals, which (depending on study design) may require a vaccine registry, and for CZS it will be important to be able to link fetal outcomes with maternal immunization status. Such infrastructure is lacking in many parts of the world, especially for capturing adult vaccinations.Advanced preparation is therefore critical to assure the success of complex post-licensure studies. In Latin America, local ZIKV epidemics lasted at times only a few months, which is too short a time to set up a vaccination program and post-licensure study once an outbreak has emerged. Protocols should be prepared, and regulatory and ethics approvals received, in advance.Several post-licensure study designs could be considered, including cohort and test-negative case-control designs. Because CZS presents with a wide range of clinical manifestations, intermediate markers of CZS that are routinely collected for all neonates, such as head circumference, birth weight, and gestational age, will likely need to be used as part of a case definition of CZS. Heel blood samples that are collected for metabolic screening could potentially be used to test for ZIKV antibodies. Ongoing projects, such as the WHO individual participant data-meta-analysis (IPD-MA) that will combine de-identified data on individual pregnant women from different cohorts in Latin America, will help to identify the key predictors of CZS that could be used as a pragmatic endpoint in a vaccine effectiveness post-licensure study 8Box 1•Heterogeneity of incidence of ZIKV infection in time and space is one of the key challenges for ZIKV vaccine clinical trial design.•Neutralizing antibodies are likely to be an important immune marker of protection; however, a broader assessment of the immune response is encouraged.•Availability of WHO standards, standardization and validation of assays are critical for appropriate assessment of the immune response to Zika vaccine as well as for the interpretation of the results.•Passive transfer studies in animals demonstrating protection against disease, infection, and CZS with human sera may provide a useful approximation of clinical benefit in humans in the absence of traditional efficacy trials.•Traditional clinical disease endpoint efficacy studies may be challenging or even infeasible given the current epidemiology of ZIKV; thus, the societal benefit for CHIM is evident. With proper communications plans, risk mitigation in place, and ethical review, ZIKV CHIM could be valuable for moving forward with ZIKV vaccine development and licensure.•Post-licensure studies will be required for all approved ZIKV vaccines: the specific studies will depend on the regulatory pathway, the indication, and vaccine characteristics.•Many data gaps remain, and further epidemiologic research is critical to inform optimal vaccine development and use.Tremendous progress has been made in ZIKV vaccine development since the WHO declaration of PHEIC in February 2016. Data available from pre-clinical animal studies to date show that vaccine candidates are capable of protecting animals from subsequent challenge with ZIKV. There are several regulatory pathways for ZIKV vaccine candidate licensure if field clinical disease endpoint efficacy studies are no longer feasible in the context of a waning epidemic. Several regulatory authorities have the ability to approve vaccines when there is a reasonable likelihood of clinical benefit, allowing considerable regulatory flexibility. Based on experiences with other flavivirus vaccines, identifying immune markers associated with protection are likely feasible, but post-licensure studies would be needed to confirm clinical benefit. CHIM studies may now present the most direct opportunity to demonstrate ZIKV vaccine candidate efficacy. Manufacturers are encouraged to meet with regulators as early as possible to discuss options for regulatory pathways and post-licensure studies. While data packages without field efficacy trials may be sufficient for initial licensure, policy makers will also need data to inform decision-making for vaccine introduction. Post-licensure data might be required by regulators and would be relevant to inform and expedite public health decisions on vaccine use. Public health research agendas are critical to support aspects of vaccine development such as clinical trial site selection, and aspects following licensure, such as post-licensure studies and ZIKV transmission globally.JH and IK are staff of WHO. KV and AWS served as consultants to WHO. MC is an employee of EMA. HM, CC, and RE are staff of NIH/NIAID. PRK is a staff member of US FDA.The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the agencies or organizations with which the authors are affiliated.


The opioid crisis has reached epidemic proportions in the United States with rising overdose death rates. Identifying the underlying factors that contribute to addiction vulnerability may lead to more effective prevention strategies. Supply side environmental factors are a major contributing component. Psychosocial factors such as stress, trauma, and adverse childhood experiences have been linked to emotional pain leading to self-medication. Genetic and epigenetic factors associated with brain reward pathways and impulsivity are known predictors of addiction vulnerability. This review attempts to present a biopsychosocial approach that connects various social and biological theories related to the addiction crisis. The emerging role of nutrition therapy with an emphasis on gastrointestinal health in the treatment of opioid use disorder is presented. The biopsychosocial model integrates concepts from several disciplines, emphasizing multicausality rather than a reductionist approach. Potential solutions at multiple levels are presented, considering individual as well as population health. This single cohesive framework is based on the interdependency of the entire system, identifying risk and protective factors that may influence substance-seeking behavior. Nutrition should be included as one facet of a multidisciplinary approach toward improved recovery outcomes. Cross-disciplinary collaborative efforts, new ideas, and fiscal resources will be critical to address the epidemic. The opioid crisis in the US has received extensive coverage in the media leading to increased awareness of this “public health emergency.” Between 2000 and 2014, nearly a half million people in the US died from a drug overdose . AccordiGiven the current crisis and the alarming rates of overdose and death associated with prescription opioids, illicit synthetic versions , and street heroin , 9, reseIn 2001 The Joint Commission identified self-reported pain as a fifth “vital sign” for healthcare providers to consider, which led to the liberal use of pain-relieving medications. It has been suggested that the opioid crisis may be seen as a dual epidemic: one of abuse, and the other as the right to control poorly defined pain . While tThe Comprehensive Addiction and Recovery Act (CARA) signed by President Obama in July 2016 expanded funding for the availability of medication assisted treatment (MAT) for OUD. MAT consists of pharmacotherapy, ideally in conjunction with behavioral health intervention. Medications such as methadone and buprenorphine (Subutex) have proven effective in mitigating the negative side effects associated with OUD . More reThe biopsychosocial (BPS) framework was originally proposed in 1980 by Dr. George Engel stemming from his dissatisfaction with the biomedical model of illness . BPS draThis comprehensive review examines the opioid crisis using a biopsychosocial framework see  with parMany researchers and health care professionals believe that the opioid epidemic is mostly a consequence of “supply side” abundance, resulting from aggressive marketing by the pharmaceutical industry as well as physicians who have over-prescribed. A recent public opinion poll identified physicians as being responsible for the crisis . Given tSupply-reduction efforts have had some success . HoweverCan the issue of opioid misuse be tackled on the supply side alone? History suggests not. Legislative efforts at the State level to close “pill mills” have had little discernable impact in reducing opioid use . Other rThe environment in which one resides is a known predictor of consumption behavior , thus ben = 1,205) higher education and income were protective against opioid-related deaths but the data suggests that no group is immune and there is dire need for public health interventions at all SES levels , a majority of overdose patients had private insurance  which isDespite these inconsistencies in the opioid literature, in public health SES should always be considered when examining health outcomes and building interventions. The BPS Perspective considers how socioeconomic disadvantage can be deleterious , path B,Efforts to reduce supply alone are unlikely to resolve the opioid abuse problem in the US. It is possible that some of the pain associated with opioid dependence is psychological. In other words, opioid misuse may be a coping mechanism for unresolved emotional pain that cannot be easily addressed in other ways. Allostasis describes the body's adaptations to predictable or unpredictable changes in the environment. McEwen's concept of allostatic load  is an eaPost-traumatic stress disorder (PTSD) causes changes in fear and stress-related biology including hyperarousal, trauma cue-dependent recall, avoidance, and extinction memory deficits, among others . AccordiNeuroimaging studies have shown that trauma has a measurable, enduring effect on the functional dynamics of the brain, even in the absence of clinically diagnosable PTSD . In a laDeficits in reward functioning may be a mechanism underlying anhedonia (lack of pleasure) associated with PTSD . The traA considerable amount of research has connected adverse childhood experiences (ACEs) to a dose-dependent increase in risk for drug abuse , 71. StrThe “brain disease model of addiction” has been challenged by some authors who advocate for an addiction disease model that includes the presence of a pre-existing disorders such as anxiety or depression . Rodent The PTSD susceptibility model suggests that OUD can lead to increased psychosocial vulnerability via negative experiences associated with drug using  . HoweverConsumption of substances activate mesolimbic reward pathways (path H). Despite some disagreement , most auAnimals models have demonstrated impaired incentive learning in early opioid withdrawal resulting in maladaptive reward seeking  which inTaken together, neurobiological drivers of OUD should be considered in the context of the current epidemic, and potential solutions ought to look beyond pharmacology alone. It is unknown how a nutrition intervention might modify reward pathways over extended periods of time . Given the emerging data on food addiction , 100, itGenetic research has identified polymorphisms in dopaminergic genes and other neurotransmitter variants which may put individuals at an increased risk of impulsive behavior and addiction . The herNeuroeconomics is behavioral economics plus neuroscience  and has Interest in the biological imprint of trauma has been growing. The biological correlates of complex trauma have been described across various brain regions , throughout the autonomic nervous system , in various neurobiochemical measures , and across genetic as well as epigenetic factors  (path C)In utero stress exposure has been associated with DNA methylation changes leading to long term alterations in gene expression pression  includinpression . Animal pression , 122. Gipression , it is bResearch on the gut microbiome has increased exponentially in the past decade. A state of equilibrium  serves health, whereas a compromised state  promotes dysbiosis, inflammation, and susceptibility to disease . Many auThe role of the gut-brain axis in determining food reward  has led The question is: how is the microbiome linked to AUD or SUD? This emerging topic considers neuroendocrine pathways that are involved in addiction, where gut microbiota may play a causal role . In regaThere is a paucity of high-quality evidence regarding the role of nutrition in OUD recovery. Nutrition does not easily lend itself to randomized controlled trials given the amount of time needed for measurable outcomes, and the presence of confounders introduced during this period. Therefore, nutrition research has been constrained to reductionistic approaches, such as looking at single nutrients or single outcome measures such as changes in weight. Conducting research on SUD populations creates additional challenges, as there are often high attrition rates . BiopsycA high preference for sugar and sweetened foods has been consistently described during early abstinence from opioids –149. NotVitamin and mineral deficiencies associated with opioid addiction have been well-described –165. HowOUD has been associated with bowel dysfunction including but not limited to constipation while using and diarrhea during detoxification . While lActivation of mu-opioid receptors in the gut wall inhibits pathways within the enteric nervous system, which in turn reduce motility, delay gastric emptying, and slow intestinal transit . ConstipE. faecalis) increased 100-fold compared to placebo . It has been proposed that gut bacteria can influence neurobehavior including host appetite for food , 182, soEfforts to address the opioid epidemic are being led by pharmaceutical companies promoting new medications (MAT) as the solution. One major shortcoming is that it does not address individuals' underlying psychological and emotional issues that contribute to addiction susceptibility. It examines the “macro” but not the “micro” environment, and one could argue that psychosocial factors require increased public health attention.The psychosocial theory of addiction vulnerability is focused on the individual but is highly dependent upon social and environmental factors (path B). Disparities in population health are known to differ on the basis of social rather than biological factors . IndividThe biological theory of the opioid crisis may help inform future pharmacological interventions targeting key neurohormonal and/or microbial systems. An in-depth understanding of the neuroscience of addiction can also improve behavioral interventions targeting the cognitive aspects of relapse and recovery. Given our limited understanding of the biological underpinnings of OUD, one could assume that if society increased its levels of stress and depression, the epidemic could worsen due to more triggers for relapse . The bioWhile no one single policy intervention on opioid addiction has proven to be highly effective, several promising proposals have been made. Institutional level strategies  such as updated prescription guidelines for emergency rooms have decreased number of patients discharging with a prescription opioid by nearly 40% and sustained 2.5 years after the intervention . If the A trauma-focused treatment model typically involves empathy, curiosity, and trust . The curEpidemiological research suggests that nutrient imbalance is a strong predictor of substance use and may be partially mediated by depression . Some auThe Life Course Perspective (LCP) is not new to public health . The LCPThe LCP considers multiple pathways contributing to disease, at the biological level (genetic/epigenetic) but also emphasizing how social ties influence health behavior and how these accumulate throughout the life course . MeanwhiThe BPS Perspective incorporates all of the factors and levels discussed in this paper and recognizes environmental, psychosocial, biological, as well as their mediating factors. This single cohesive framework considers the interdependency of the entire system, drawing its conceptual roots from socio-ecological models , 189 incIt will be important to identify aspects of an individual's neurochemistry which are modifiable by epigenetic and microbial mechanisms. With such strong evidence of overlapping pathways between drugs of abuse and food , it is sA multifactorial problem that requires effective collaboration across multiple disciplines at multiple levels has been described. The future of multidisciplinary BPS work will necessitate an understanding of health as a dynamic and integrated system. It has been emphasized that the potential for nutrition to be utilized as one facet of a BPS approach may improve recovery outcomes. At a minimum, we should consider nutritional screening at intake in OUD treatment programs. Going forward, we need policies that address access to opioids and pain management. The overdose epidemic should be viewed through the lens of community impact. Paramount are the social determinants of health, particularly given associations between social disadvantage and the lifetime accumulation of stress and trauma, as well as how social factors impact opioid use , 225 andNo datasets were generated or analyzed for this study.The author confirms being the sole contributor of this work and has approved it for publication.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.


Although the increased incidence of type 2 diabetes since the 1950s is thought to be primarily due to coincident alterations in lifestyle factors, another potential contributing factor in industrialized countries is exposure of the population to environmental pollutants and industrial chemicals. Exposure levels of many environmental toxicants have risen in the same time-frame as the disease incidence. Of particular interest in this regard is the metal lead. Although overall lead exposure levels have diminished in recent decades, there is an under-recognized but persistent occurrence of lead exposure in poor underserved urban populations. Although the neural developmental pathologies induced by lead exposures have been well documented, very little is known about the effect of lead exposure on the incidence of chronic metabolic diseases such as type 2 diabetes. Although our understanding of the metabolic health effects of lead exposure is incomplete, there are studies in model systems and a small amount of epidemiological data that together suggest a deleterious effect of environmental lead exposure on metabolic health. This article reviews the human, animal and in vitro studies that have examined the effects of lead exposure on the development of diabetes and related metabolic conditions. The well-documented dramatic increase in the incidence of type 2 diabetes that has occurred since the 1950s is thought to be primarily due to coincident alterations in general lifestyle factors in affected populations. Chief among these are increased caloric intake, altered nutrient quality, and a general reduction in physical activity. Another potential contributing factor in industrialized countries is exposure of the population to environmental pollutants and industrial chemicals. Exposure levels of many environmental toxicants have risen in the same time-frame as the disease incidence. In addition, some of these widely distributed chemicals have been shown to interact with biological systems and to result in deleterious metabolic and/or endocrine effects. There is increasing evidence that exposure to certain of these endocrine disrupting chemicals (EDCs) alters diabetes risk [One such EDC is the synthetic organic compound bisphenol A (BPA), which has been used in plastics manufacturing since the 1950s. BPA has been shown to interact directly with members of the estrogen receptor family, and importantly has been detected in the urine of greater than 95% of the US population . AlthougAn important class of environmental chemicals that pose a human health risk are the metals with no known role in normal human physiology. Although many metals are required for normal biological functioning , a subset of metals have no role in animal physiology and can be considered xenobiotic—e.g., lead, mercury, cadmium and the metalloid arsenic. These elements have negative effects on physiology and in some cases human exposure levels have been associated with the incidence of diabetes and related metabolic syndromes ,9,10,11.Of particular interest in this regard is lead. Although overall lead exposure levels have diminished in recent decades, there is an under-recognized but persistent occurrence of lead exposure in certain sectors of the population. In particular, individuals living in poor urban communities with older housing stock are at significant risk for childhood lead contamination. In addition, the recent incident in Flint Michigan, where a large portion of the population was exposed to elevated lead in the municipal drinking water system , has raiBetween childhood exposures from ingestion of lead-based paint and sporadic exposure of adults through contaminated drinking water, there probably remains a significant segment of the population exposed to low levels of lead. Although the neural developmental pathologies induced by lead exposures have been well documented ,14,15, vThe question of whether low levels of lead exposure can increase susceptibility to diabetes must be considered in light of the fact that the most exposed populations are often encumbered with additional metabolic, nutritional and environmental stressors. For example, underserved urban populations have higher rates of obesity and are generally exposed to higher levels of socio-economic and environmental stress than the general population . If leadAlthough our understanding of the metabolic health effects of lead exposure is incomplete, there are studies in model systems and a relatively small amount of epidemiological data that together suggest a negative effect of environmental lead exposure on metabolic health. In this article we will review the animal and in vitro studies that pertain to this issue as well as studies on the epigenetic effects of lead exposure that address the issue of how pediatric exposure to lead might have long-term influences on general health later in life.In the US population lead exposure, as measured by blood lead levels, has been declining for several decades. This is due in large part to the removal of lead from gasoline in the 1980s, which is regarded by many as one of the major public health triumphs of the 20th century. This change did indeed have a rapid effect on the overall level of lead exposure in children, which saw a drop in the mean blood lead concentration from 13.7 µg/dL to 3.2 µg/dL between 1976 and 1994. This trend has continued, and the CDC estimated the average blood lead level in 2005 had diminished to 1.5 µg/dL . It is eThere are several important observations however, that run counter to the view that lead toxicity is no longer a health issue. First, examination of the rates of childhood blood lead exposures between 1997 and 2015  reveals An important characteristic of the current landscape of lead exposure in the US is its non-uniform distribution. Exposure levels are higher in poor, under-served populations mainly in urban industrial areas. Since the removal of leaded gasoline, most recognized lead-exposures occur in one of two scenarios: ingestion of lead-based house paint (in the form of lead-contaminated household dust) by toddlers, and the consumption of lead-contaminated drinking water. The former occurs in urban areas where the housing stock has not been modernized since the discontinued use of lead paint in the 1970s , and theAlthough the circumstances leading to pockets of elevated lead exposure occur throughout the country, typical examples can be found in the state of Michigan. In the city of Detroit there are neighborhoods where nearly half of children tested had blood lead levels above 5 µg/dL as recently as 2006 . These eIn conclusion, while there have been dramatic reductions in the severity of lead exposure in the general populations there is still a significant level of exposure in many segments of the population.Although there is substantial epidemiological evidence that exposure to low levels of various environmental chemicals can influence the development of chronic metabolic diseases including diabetes , there aAs mentioned above, only a small number of studies have directly examined the correlation between blood lead levels and diabetes incidence. Kolachi et al. found that blood hair and urine lead was higher in diabetic compared to non-diabetic females. However, both cadmium and arsenic were higher in the diabetes group, making it difficult to assign a specific role to lead . In an eNumerous studies have examined the effects of metal exposures on the function of the endocrine pancreas . AlthougFatty liver, especially the form not associated with excessive alcohol consumption—known as NAFLD  co-exists with type 2 diabetes. In some populations up to 70% of diabetic patients also have NAFLD ,24, whicIn a recent study of the population living in the Yangtze river delta in China, Zhai et al. found that elevated blood lead levels were associated with an increased risk of NAFLD in both men and women, although the association was significantly stronger in women . ConsistAlthough, as discussed above, there are few studies that have specifically examined the effect of lead exposure on diabetes rates in the human population, several studies have looked for correlations between lead exposure and other metabolic and endocrine parameters that are potentially related to diabetes.Many of these studies examined industrial lead workers who had substantially higher levels of exposure than typically seen today (see above). Although this may reduce the direct relevance of these studies to general human exposure situation, they highlight potential physiological effects of lead that may be minor when exposure levels are low, but that still may pose a long-term health threat as the exposed population ages. Studies examining lead industry workers identified a mild correlation of blood lead levels with systolic blood pressure  and kidnThe findings from highly exposed individual are consistent with observations from non-industrial worker cohorts where correlations between lead levels and kidney function were observed even at much lower levels of exposure. Using data from the normative aging study Tsaih et al. observed a correlation between specific parameters of kidney function and lead levels in blood and bone , and thaWhile these findings do not directly address the question of whether lead-exposure in the human population promotes the development of diabetes, they do demonstrate that lead has deleterious effects on physiological systems that are crucial for the maintenance of normal metabolic balance.Although there have been more studies in animal models than in humans, there is still a relatively small literature on the effect of lead exposure on metabolism in animal models. Several early studies in the 1970s and 80s suggested that lead exposure could induce hepatic insulin resistance in rats. Singhal et al.  reportedWhile these findings strongly suggest that lead exposure induces hepatic glucose production and thereby contribute to elevated blood glucose levels, they were somewhat limited in technical scope and do not provide much information about potential mechanisms by which lead has these effects in the liver.The pro-diabetic effects of lead exposure on the liver were observed in recent studies that examined the effect of lead on hepatic metabolism in normal rats. When rats were exposed to lead acetate in drinking water, increased enzymatic activity of hepatic PEPCK and G6Pase were observed together with a mild increase in fasting glucose and glucose intolerance . InteresAs described above, a common route of lead exposure in humans occurs early in childhood by ingestion of lead-contaminated household dust . This exA substantial literature exists related to how early in life conditions influence later in life health; essentially the DOHaD or Developmental Origins of Health and Disease hypothesis . There aThere is clear evidence that lead exposure induces changes in DNA methylation at specific loci in humans. Sen et al. examined umbilical cord blood from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study participants . When coAn interesting aspect of epigenetic imprinting is the potential for inheritance of imprints across multiple generations. With regard to lead exposure, Sen et al. found that moms with high blood lead had children as well as grandchildren with exposure-specific epigenetic DNA methylation patterns . If DNA The possibility that early life lead exposure induces later in life health problems is supported by multiple studies in rodents. When mice were perinatally exposed to levels of lead similar to those commonly seen in humans, they exhibited neurological deficits in adult mice and late-onset obesity . In anotIf lead exposure does promote the development of diabetes as suggested by the above animal studies, what might be the molecular basis for this effect? One possible mechanism is based on the well-known effect of lead to induce oxidative stress in biological systems . This is++ does not change its valence state and cannot generate ROS by the Fenton reaction. However, it is clear that Pb++ increases oxidative pressure in living organisms [++ changes the lipid composition of membranes, resulting in a decrease in phosphatidyl choline and an increase in arachidonic acid [++) [Unlike redox active metals such as iron and copper, Pbrganisms ,51,52, anic acid ,54. The cid [++) ,54.++ stimulates superoxide formation by binding to oxyhemoglobin [++ ions. Lead has a direct effect on ALAD via active-site inhibition. Specifically, Pb++ binding displaces an essential Zn++ ion at the catalytic site and therefore inhibits ALAD activity [++ decreases super oxide dismutase (SOD) and glutathione peroxidase (GPx) antioxidant activities by binding to sulfhydryl groups or selenocysteine, which are required for their antioxidant activities [Second, Pbmoglobin ,56,57. Tactivity ,59. Consactivity ,61,62. Etivities ,64,65.Oxidative stress is thought to promote the diabetic state by direct effects on cellular signaling pathways that influence insulin signaling. One proposed mechanism is that ROS activate intracellular signaling through JNK/SAPK, p38 MAPK and NF-κB. JNK activation results in serine phosphorylation and inhibition of IRS (Insulin Receptor Substrate) 1 and 2. IRS1 and IRS2 are required for downstream signaling through additional serine/threonine kinases and their phosphorylation by JNK results in decreased insulin signaling and insulin resistance ,66.Pancreatic beta-cells appear to be exquisitely sensitive to reactive oxygen species (ROS) . The hei++ and Ca++ have very similar electron orbitals. Most of the effects of toxicity are a result of this similarity in their molecular features. Thus Pb++ can interfere with a variety of intracellular processes where normally Ca++ would have been involved. For example, Pb++ interferes with calcium homeostasis and cellular uptake by binding at the same binding sites as Ca++ on different Ca++-binding channel pore proteins and transporters. At pM concentrations, Pb++ increases resting intracellular Ca++ concentration from approximately 100 nM to 200 nM [++-dependent increase in intracellular Ca++ concentration has not been well studied, it undoubtedly exerts a significant effect on modulating calmodulin (CaM)-dependent events, e.g., activation of calcineurin. Because oxidants are effective calcineurin inhibitors only when the enzyme is active [++ concentration could produce a sustained oxidative inactivation of calcineurin.Pbo 200 nM . Althougs active , a persi++ on calcineurin in the low nM range it is likely that lead has a direct effect on calcineurin action and thereby could influence calcineurin-dependent cellular activities in for example, insulin-producing pancreatic β-cells [++.With effects of Pb β-cells . Kern an β-cells  have sho++ by CaM does not contribute to the toxic effects of Pb++ in intact cells [++ binding to CaM to the same degree as occurs with Ca++, the intracellular Pb++ concentration never reaches the high nM range required to activate CaM-dependent enzymes in vitro [indirect effect of Pb++ on CaM-dependent signaling. There are potentially two mutually reinforcing mechanisms by which CaM binding to reservoir proteins such as neuromodulin and neurogranin, and other targets might be modified by Pb++. First, because CaM reservoir proteins are phosphorylated by Pb++ stimulated PKC [++ concentration, the affinity of reservoir proteins for CaM is decreased and CaM redistributes away from reservoir locations [Most findings reported in the literature indicate that direct binding of Pbct cells ,77,78. Ein vitro ,77,78,79ated PKC ,81,82, Cocations ,84,85,86++ activates PKC in adrenal chromaffin cells [++ concentrations. Inhibition of PKC by Pb++ at micromolar concentrations has been associated with effects on neurotransmitter and c-Fos activity in PC12 cells [++ at pM concentrations have not been defined in any cell type. The chronic nature of Pb++ exposure makes any effect mediated through PKC more complex because PKC responds to stimulation by downregulating activity [Lead activates PKC at low concentrations and inhibits it at higher concentrations . At pM cin cells  and wholin cells ,90. In vin cells , results12 cells . Howeveractivity ,94. TherRecent studies indicate that components of the circadian clock machinery regulate expression of metabolic genes, including PEPCK, G6Pase and PGC1-α . This evIt is tempting to view the coincidence of the relatively high levels of lead exposure of the last century with the rise in diabetes rates that have occurred in this century, even if there is little epidemiological evidence to support this. Although relatively limited in scope and conducted at higher levels of blood lead than typically seen in human exposures (14–74 µg/dL ,34 compaThe possibility that early in life lead exposure might have later in life physiological effects is supported by the observations in humans and mice that lead exposure leads to specific epigenetic imprints in the genome that persist throughout life and even across generations. Although it is not yet possible to directly link specific patterns of epigenetic imprinting to specific physiological or pathophysiological parameters, it is likely that such links exist. This may ultimately provide a clear mechanistic pathway for how a limited exposure to lead might have long-lasting health effects.Although the solution to the public health problem is clear-—if lead is removed from the built environment the risk of exposure falls-—it is clearly still worthwhile to understand the mechanisms by which lead affects biological systems, and to determine the exact contribution that lead exposures play in determining diabetes risk. For one thing, it is unlikely that the risk of exposure to environmental lead will be removed in the near future. Human exposures, even if at a low level are likely to continue into the foreseeable future. In addition, understanding how xenobiotics affect cellular and organismal physiology can provide valuable clues to how normal physiological systems function and how changes in those systems can lead to diseases like diabetes.


Despite the importance of local ecological knowledge of forage plants, there has been little discussion on how local agro-pastoralists perceive forage species diversity, abundance trends, habitat distributions and ecological drivers influencing changing abundance trends over time in rural West Africa’s savannas. In estimating, assessing and investigating the ecological variables, we performed elaborate ethnobotanical surveys in seven villages in northern Ghana and nine villages in southern-central Burkina Faso. Data were analyzed using descriptive statistics, bivariate correlation analysis and cognitive salience index calculations to disentangle the dynamics of local responses to ecological variables considered in this study. Our results revealed that agro-pastoralists exhibited extensive knowledge on forage species diversity, habitat types, abundance trends and ecological drivers. According to agro-pastoralists interviewed, about 82 percent of all forage species known to them were commonly available in local landscapes, while a majority of our interviewees indicated that available forage resources have shown a gradually increasing trend over the past few years. Rainfall variability, tree cutting and drought were the topmost perceived threats causing changes in the trends of forage species abundance. Given our findings, local perceptions of agro-pastoralists could have substantial practical implications in favor of forage-related biodiversity conservation and sustainable livestock production. Hence, tropical West Africa, in particular, has been experiencing a significant increase in such challenging anthropogenic and natural incidences5 and human population growth6. This results in severe changes in the vegetation composition and species cover in West African savanna ecosystems7. Smallholder farmers in this region and other developing countries are thus considered as disproportionately vulnerable to climate change owing to its direct effect on their crop and animal productivity, as well as negative consequences on their food security, income and general well-being8. Being able to make use of a diverse portfolio of management strategies, and to have diversified sources of income, may therefore greatly increase (agro)pastoralists’ livelihood security, particularly in a highly variable environment10. Climate change and variability, especially scarcity of water, might lead to reduced supply of essential ecosystem services including forage provision for livestock production while increasing demand for these ecosystem services from the vegetation.A plethora of literature abounds with evidence that future projections and scenarios of global climatic conditions point to increasing incidences of unpredictable precipitation patterns, drought spells, overgrazing, severe mean annual temperature rises, intermittent floods and land degradation particularly in global drylands11. For instance, overgrazing is a commonly observed land use challenge in communal rangelands caused by domestic livestock reared among smallholder farmers, as it was reported by Bahru et al.12 in semi-arid localities in Ethiopia. However, many local smallholder farmers in West African savannas largely engage in rain-fed agricultural practices as their main source of employment, food and income13. While dryland rangelands do support approximately 50 percent of global livestock production14, continued forage availability for livestock production is highly crucial since about 45 percent of rural households heavily rely upon sources of livestock-related income in typical West African settings15. The delivery of these forage services from dryland rangelands is mainly dependent on rangelands’ floristic composition17.Apart from climate change and variability, smallholder farmers are also faced with non-climatic stressors18. Studies have shown that land users’ local ecological knowledge (LEK) on forage plants is of critical importance for their adaptive rangeland management20. Research has also shown that agro-pastoralists’ LEK of forage resources is an essential component of management decisions21, and plays a crucial role in agro-pastoralists’ adaptation to climate change22. Identifying crucial aspects of an adaptive natural resource management appears a promising approach for developing mitigation strategies for negative consequences of projected climate change in West Africa.To ensure effective sustainability and biodiversity conservation efforts in natural resources management, understanding social-ecological systems (SES) is vitally critical23, we expect local agro-pastoralists’ perspectives on the above-referenced ecological variables to be different. This ethnobotanical study is not intended to investigate causalities of such ecological variables with respect to plant citations provided by local agro-pastoralists in the research region. The main research question we address in this paper is: ‘what are the important ecological variables from the perspectives of local ago-pastoralists for sustainable livestock production in West Africa?’ We set the following specific research objectives, which include:Estimation of forage species diversity based on local agro-pastoralists’ LEK.Assessment of abundance and trends of forage resources based on perceptions of local agro-pastoralists.Investigation of perceived local ecological drivers responsible for changes in abundance and trends of forage plants and local conservation measures.Despite the importance of LEK on forage plants, very little research has been done on how local agro-pastoralists perceive forage species diversity, abundance trends, habitat distributions and ecological drivers influencing their changing numbers over time in rural West Africa’s savannas. As local knowledge tends to be unevenly distributed among local resource users and better understood in a particular context23. The species composition is made of various kinds of tree and grass species. The sparse tree layer is composed of economic trees/shrubs as well as other woody species which serve as good source of valuable feed for cattle, goats and sheep24. Common herbaceous species in both Ghana and Burkina Faso include Loudetia togoensis, Dactyloctenium aegyptium, Digitaria horizontalis, Andropogon spp, Rottboellia cochinchinensis (Lour.) W. D. Clayton, Sida acuta Burm. F. As members of predominantly farming-oriented communities, the local agro-pastoralists involve in subsistence agriculture, including traditional crops like millet, sorghum, maize and cowpea being the main crop plants.The climate of the study areas is seasonal in nature. The climatic conditions in the villages of Burkina Faso are largely semi-arid, while the study sites in Ghana vary from dry sub-humid to humid in the Northern Region and show semi-arid conditions in the Upper East Region Fig. . Regardi25. Local farmers in the study areas are agro-pastoralists: they don’t only engage in crop farming but also rear various kinds of livestock in their homes such as cattle, sheep, goats and poultry  on both sides of the border, and the Dagbani ethnic group predominantly living in northern Ghana  is classified as agro-pastoral farming systemry Table . Among tana Fig. .Table 1B28. However, this study tries to overcome this limitation by covering a broad spectrum of these varied social groups. For age-based stratification, we used age class definitions  from a previous study in West Africa’s Sudanian savannas29. Field research was undertaken between October and December 2012 and from July to October 2013. In sum, we interviewed over 500 local agro-pastoralists in 16 rural communities situated within northern Ghana and southern-central Burkina Faso  between Germany and ten West African countries (Phase One from 2012 to 2016). We administered structured ethnobotanical questionnaires to local agro-pastoralists by applying a stratified random sampling design  to collect representative data on considered ecological variables in the selected sixteen study sites  many (common), (ii) few (not common) or (iii) rare (very difficult to find). Regarding the changing trends of abundance of these forage species, the local agro-pastoralists were asked to provide information on whether the forage plant communities have changed over the past years or not. We specifically asked the local agro-pastoralists to indicate whether the trends of changes in the abundance of forage plants have increased rapidly, increased gradually, remained stable, decreased gradually or decreased rapidly.With respect to the abundance of the cited forage species, we asked local agro-pastoralists to indicate whether the cited forage species were many, few or rare within their vicinity at the time of the interviews. It has been reported by other researchers that local pastoral farmers commonly use terms like increasing, decreasing or not changing in assessment of species trendsTo extract more information, we also asked the local people to provide possible reasons why they thought that their forage resources were perceived to be either increasing, decreasing or remain stable over the years. This was done to better understand local ecological drivers to changing quantity and/or quality of forage resources experienced by these local agro-pastoralists in the face of global environmental change. Finally, they were asked to describe their own solutions or management strategies with regards to the current abundance trends situation of their forage resources. To ensure the independence of individual views expressed by local agro-pastoralists during the fieldwork, we separately interviewed them to avoid exchange of ideas and answers of questions asked in each village visited. This was done by performing interviews with only one person at a time. We then informed them not to share questions and answers with yet-to-be-interviewed participants and this was strictly followed throughout the interview process. All questions were translated from English into local dialects of various ethnic groups  and answers provided by local agro-pastoralists in vernacular were directly translated and written down in English on the structured questionnaires Table . Transcret al.7. Thus, S = N, where N = number of species per village. With respective to species evenness (E), it is the ratio of the Shannon Wiener index to the natural log of S. Thus, E = H’/In (S). This reflects the balance in the distribution of individual forage species cited by local agro-pastoralists in the context of this study, which is independent of the frequency of species occurring in interviews in a village. When E is close to zero, a forage species is very similar while a value of one indicates a rather different forage species composition7. Regarding Shannon Wiener’s diversity Index (H’) estimation, it is also known as alpha diversity and defined as follows: H’ = −Sum (Pi*In(Pi)), where Pi is the proportion of individuals belonging to the ith forage species (relative abundance of forage species) per village. As for Simpson’s diversity index (SDI), is also known as the Beta diversity index, whereby it is mathematically represented as: SDI = Sum (Pi2). It is important to note that, species which could not be identified scientifically but were only known by their vernacular names, representing six percent were excluded from further analysis. As investigating the causalities of the ecological variables is not a focus of this study, we conducted bivariate correlation analysis to determine relationships between the diversity metrics of these forage species reported by the local agro-pastoralists in West Africa’s savannas. Given the lack of normality in some of the variables and coupled with the relatively small sample size used in this correlation analysis, we employed Kendall’s tau, a non-parametric correlation which is a better estimate of the correlation in the sampling population instead of the popularly used Spearman’s rho statistic32. We additionally conducted bootstrapping to obtain robust confidence intervals (CIs). The significance level for correlation coefficients was assessed at P < 0.05.We estimated the diversity of scientifically identified forage species in the studied communities using four diversity indices: species richness (S), species evenness (E), Shannon-Wiener diversity index (H’) and Simpson’s diversity index (SDI). For S, it represents the number of forage species via the ethnobotanical interviews in a village irrespective of whether a species is abundant or not, as also done by Zerbo 33, CSI is the ratio of frequency (F) to the average position (mP) and sample size (N). The CSIs were calculated based on the unrestricted responses from local agro-pastoralists and were assumed to be “free lists” for cited ecological drivers and local conservation measures. The CSI values for the 10 most important items considered in the calculation were finally visualized using pie and bar charts. The data analyses were quantitatively analyzed using the Statistical Package for the Social Sciences (SPSS) vs. 2332 and ANTHROPAC 4.034 statistical softwares.To explore perceived ecological drivers responsible for changes in abundance trends of forage plants and local conservation measures, we performed cognitive salience index (CSI) calculations for the responses provided by the local agro-pastoralists. According to SutropPrior to the implementation of our structured questionnaires Table , the resSorghum bicolor), Maize (Zea mays) and Pearl Millet (Pennisetum glaucum) were the topmost crop species while legumes like Pigeon Pea (Cajanus cajan) and Cowpea (Vigna unguiculata) were top legumes grown in Ghana and Burkina Faso. Pennisetum pedicellatum and Rottboellia cochinchinensis were found to be the most frequently cited herbaceous forage species in both countries. Our findings also showed that local agro-pastoralists regarded leaves of Afzelia africana and Pterocarpus erinaceus as very important forage sources for livestock feeding in both countries. Acacia species such as Acacia sieberiana, Faidherbia albida and Acacia dudgeonii were found to be predominantly mentioned among local agro-pastoralists in Burkina Faso and in the Upper East region of study area within Ghana. The Acacia spp and Balanites Egyptiaca, which are morphologically thorny in nature, were commonly cited as good sources of forage resources for livestock grazing especially in central Burkina Faso (mostly inhabited by Mossi people) but were not highly considered for forage resources in northern Ghana (where mostly Dagbanis and Gurunsis dwell in). It was also observed that yams (Dioscorea cayensis) are cultivated among the Dagbanis in northern Ghana and their peels were only cited as good forage sources in this part of the study region , but not mountainous in nature. The habitat types associated with forage species cited by local agro-pastoralists were mostly uplands/highlands, lowlands or both types of landscapes. It was also recorded that some forage species, especially many trees, could exist in both lowland and upland areas. Our results indicated that most cited forage species were believed to be associated with upland/highland habitats (constituting 47 percent), as compared to 25 percent for lowland areas and 28 percent considered to be suitable for both habitat types Fig. .Figure 2S. bicolor and Z. mays), and legumes (Groundnuts-Arachis hypogaea and V. unguiculata) were regarded common by local agro-pastoralists while herbaceous and woody forage species were perceived to be less common. Ficus sycomorus was reported as one forage species which topped those considered to be fewer in number. It is important to state that local agro-pastoralists’ assessment of the abundance of forage species was quite ambiguous as some of these cited forage species included S. bicolor, A. hypogaea, R. cochinchinensis and P. pedicellatum were cited to be many, few or rare based on individual experiences  to control the presence of witchweed (Striga spp).A wide array of ecological drivers believed to be responsible for changing trends in the abundance of forage resources were provided by the local agro-pastoralists. Ecological threats negatively affect the production and availability of crop-related as well as naturally available woody and herbaceous forage resources. According to local agro-pastoralists, rainfall variability (e.g. late rains or disproportionate down pour of rains within a short period of time) is the most important driver to either a rapidly or slowly declining trend in crop production also leading to lesser quantities of crop residues for livestock grazing. Related to rainfall variability are drought spells, which local farmers experience from time to time. Drought incidences were widely reported as very serious threats particularly in Burkina Faso which lead to declining trends in the availability of forage resources. Another dominant reason mentioned by local agro-pastoralists why there are declining crop-related forage resources was soil fertility deterioration which negatively affects crop production Fig. . It was Regarding the availability of tree species used as livestock feed, deforestation (trees cutting), agricultural expansion, human population growth and bushfires were perceived by local agro-pastoralists to be highly salient ecological drivers to changes in the abundance of woody forage resources Fig. . All theAccording to local agro-pastoralists, the declining trend in the abundance of crop residues for provision of livestock feed could be arrested via several ways. On the part of rainfall variability, this is nothing that can be done by the local agro-pastoralists since that is a natural phenomenon and requires God’s intervention as they reported. However, irrigation was mentioned to be an intervening practice that could help with respect to rainfall variability, but rural communities lack the resources  to make irrigation possible. Chemical fertilizers (and compost manure) are applied to deal with the widespread decline of natural soil fertility. The local agro-pastoralists also indicated that they needed to ensure high maintenance of their farmlands via regular weeding. Proper conditions in their farms would lead to increased production of food crops as well as crop residues for domestic livestock feed Fig. .Furthermore, it was suggested by local agro-pastoralists that cutting down of trees  for charcoal production and fuel wood should be stopped, while afforestation of useful trees should be encouraged by fellow farmers to increase the frequency of rainfall incidences and increase soil fertility. Considering the dangers of indiscriminate bush burning inherent in the study region it was also suggested that bushfires should either be avoided completely, or early bush burning be done to curtail intensive destruction of available dead and living forage materials. Others even added that culprits when caught burning the environment for whatever reason should be severely punished as a deterrent to others Fig. . There set al.35. The most dominant genera of forage species cited included the Acacia, Ficus and Andropogon. This could be indicative of the predominant role local climatic conditions play in the distributional patterns of forage-related LEK among local agro-pastoralists23. In a semi-arid savanna ecosystem in South Africa, it was also found that local agro-pastoralists had extensive ecological knowledge on the grass compositions in three different regions in Botswana36.The most represented plant families Table  in the ret al.37, who found species richness and evenness to be negatively correlated in their study of meadow communities on the eastern Qinghai-Tibetan Plateau in China. The overall relationship between richness and evenness has been found to be contradictory. Existing studies suggest a positive38 or a strongly negative correlation39 between richness and evenness, or they see them as largely independent40 which is often associated with plant communities and difficult to be easily reconciled37. This may also be explained by the vegetation dynamics of the forage plants pertaining to various villages located in both Burkina Faso and Ghana  were linked to upland areas, except rice which is mostly grown in lowland areas. Especially tree species were cited to exist in both upland and lowland areas. These findings reflect how local people hold different opinions regarding where to suitably find forage plants based on their personal life experience.Responses from local agro-pastoralists on cited forage species vary with respect to habitat distributions. This was expected as LEK is unevenly distributed among its holders44 but also differs significantly from an individual to another even within the same community36.The findings of this study revealed that about 82 percent of citations were regarded by local agro-pastoralists as many in their landscapes, while the rest of them were either few or rare in number. This reflects the availability of various forage resources for feeding their livestock. There was, however, ambiguity in the assessment of abundance of forage species by local agro-pastoralists which may be attributable to their individual viewpoint. Also, competing uses of crops cultivated in the study areas for both humans and livestock consumption might have influenced how they assessed their abundance. For woody and herbaceous forage species, it may dependent upon an agro-pastoralists’ knowledge and interest in these forage species. Our findings are supported by studies which suggested that LEK is not only unique to different communitiesWith respect to the abundance trends of forage resources assessed by local agro-pastoralists, our findings reflect a positive assessment. Most local agro-pastoralists held the view that many forage species (57 percent) cited were either gradually or rapidly increasing. We also found that other cited forage species either had a gradually or rapidly decreasing trend, which is strongly linked to various drivers such as overgrazing or deforestation. For forage species which showed a stable trend, some local agro-pastoralists felt that herbaceous forage species are always available, and they are therefore neither declining nor increasing trend over the years Fig. .46. Deforestation is the second most important driver to vegetation dynamics in the study areas. People cut down trees for firewood and charcoal production. Also, with the quest to undertake agricultural expansion to meeting growing demands for more food and feed, uneconomic trees will have to be slashed and burnt. As a result, leaves of trees may not be available for feeding livestock especially during dry seasons. Bushfires and overgrazing incidences are also rampant in the surveyed communities  are of utmost importance for subsistence farming activities in the study areas. According to our findings, rainfall variability is perceived as the most important driver to changing trends of forage resources, particularly crop-related forage. This may be because surveyed local people are mainly subsistence farmers and therefore depend majorly upon rain-fed agriculture. Thus, when annual rainfall is very low, crop production becomes poor leading to unavailability of crop residues to support livestock feed. This suggests that fresh crop plants and crop residues availability is strongly modulated by rainfall variability, as good rains would lead to better yields. Also, rains enable growth of fresh and more grasses/forbs for livestock grazing. Also related to rainfall variability is the incidence of droughts, which is detrimental to farming activities. The issue of drought is more often experienced by local agro-pastoralists living close to the north of Burkina Faso as compared to northern Ghana, where rains are more reliable. The problems of rainfall variability and grazing pressure are also reported elsewhere in Africaies Fig. . Our fin48.When asked about how above-stated ecological drivers could be curbed, an array of conservation measures was given. Stoppage of deforestation and avoiding bushfires by all local farmers topped the solutions offered. It was also suggested that tree populations should be replenished via afforestation. Government and or NGOs interventions were seriously needed to overcome problems of droughts as well as for the provision of support for chemical fertilizers and irrigational facilities to improve farming Fig. . It is tStriga spp) to increase cereals production (including crop residues) by intercropping cereals with e.g. Glycine max in the study areas is more potent and environmentally-friendly than use of weedicides. Also, organic farming practices by local farmers such as use of compost manure, non-destruction of economic woody species on farms and limited clearing of farmlands support biodiversity conservation unlike establishment of plantations. Notwithstanding, these local efforts are often negatively affected by direct climate change impacts coupled with environmental degradation. Thus, Ghana government agricultural policy of planting for food and jobs should make good use of local agricultural knowledge. We therefore conclude that the findings of this study have management and policy relevance since knowledge and experiences of smallholder farmers could be harnessed to effectively address food and nutrition insecurity issues particularly in developing countries amidst global warming.In this study, ecological variables such as forage species diversity, their habitat distribution, abundance trends as well as associated ecological drivers in terms of livestock production were assessed from the viewpoints of local agro-pastoralists in rural West Africa. This study confirms an intimate interaction among humans, domestic livestock and ecosystem services (e.g. forage provisioning) from the natural environment to sustainably serve the needs of domestic livestock and their owners. It also becomes clear that the biodiversity metrics estimated from the information provided by local agro-pastoralists are diverse and widely distributed within the topography of the study areas. For instance, about 50 percent of cited forage species are perceived to be associated with upland areas as compared to low areas and both habitat types combined. Regarding the dynamics of abundance of forage plants over the past few years, most of the forage species are still believed to be increasing gradually. This reflects a positive opinion of forage plant population status as compared to other negative trends cited by local agro-pastoralists. These varying trends in changing abundance of forage species are greatly influenced by underlying ecological drivers including rainfall variability, deforestation for charcoal production and farming activities, drought and bushfires, and livestock grazing. Since local agro-pastoralists’ livelihoods are heavily dependent upon natural resource availability in their communal lands, they are well aware of the need to manage their forage resources sustainably. This is especially true with regards to their own proposed local solutions including avoidance of bushfires (or encouraging early bushfires), moderately use herbicides, application of organic manure/chemical fertilizer, crop rotational and shifting cultivation. It should be noted that local farmers often know very well which specific ecological variables are the most relevant for their livestock production and their views should be considered in land management strategies and/or policies. For instance, indigenous knowledge in biological control of witchweed (Supplementary information files


Court-mandated treatments imply a dual role for therapy providers not only of caring for, but also of having control over, involuntary clients. The impact of legal coercion on the therapeutic relationship and feelings of stigma is widely regarded as negative and detrimental for treatment outcomes. This point of view stands in contrast to advocates of the perspective that involuntary treatment can ameliorate social functioning and thus promote a better quality of life. Regarding other outcome measures, there is evidence that offender treatment is effective and leads to reduced recidivism in criminal behavior. This narrative review provides an overview of research assessing the effects of mandatory treatment on therapeutic process and outcome factors. We conclude that legal mandatory treatment does not have to necessarily result in perceived coercion and reduced satisfaction with treatment and that a caring and authoritative treatment style aids a favorable therapeutic alliance, motivation, and therapy outcomes. Correctional treatment mandated by court is aimed at reducing recidivism in offending behavior. There is some evidence that this form of legal coercion can be effective in reducing the offending outcome , while oWhile mandated therapy provides external motivation to attend treatment, voluntary clients are normally believed to be intrinsically motivated. This view is challenged by studies that demonstrated perceived coercion in voluntarily admitted service users . PerceivLiterature suggests that mandated clients are more resistant to therapy than voluntary clients , 15. ThiWithin the scope of this narrative review, a literature search was conducted in PubMed, PsycInfo, and Google Scholar using various combinations of the following search terms: “mandated therapy,” “court ordered treatment,” “perceived coercion,” “therapy outcome,” “treatment outcome,” “therapeutic process factors,” “recidivism,” and “symptom levels.” From the resulting body of literature, domains were generated  and grouped according to clinical significance and empirical relevance for general therapy outcomes and factors. Papers were referenced in the review if they included relevant and additional insight into the respective domain; studies were not integrated or reproduced in their fundamental conclusions if publications with similar conclusions had already been discussed. The resulting summary of factors constitutes a compilation for service providers who are interested in the clinical application of the results. The quality of the therapeutic relationship is described as an important process factor in psychiatry and psychotherapy . The quaExperiencing stigmatization and accompanying discrimination are a powerful negative attribute in all social relations including psychiatric treatment. Feeling stigmatized has multiple negative consequences for mentally ill persons . BesidesAccording to literature of all available client-reported outcome measures, treatment satisfaction has the greatest evidence base . ImproveThe limited systematic research on clients following coerced hospital admission and symptom change over time suggests some improvements , 47. As So what does literature suggest about the impact of mandated therapy on the addressed therapeutic process and outcome factors?n = 295) was a heterogeneous, mixed gender sample of voluntary and legally coerced drug abusers with stages of change as an outcome measured by a self-administered instrument  investigated adult male inpatients with a diagnosis of schizophrenia spectrum disorder being treated in general psychiatric wards and medium secure forensic psychiatric units via questionnaires  of consecutive admissions to acute adult wards measured perceived coercion, global functioning, and therapeutic relationship with self-reports. The examined disorders included affective and substance use disorders besides schizophrenia and others. Major limitations were the single-site design, the exclusion of a substantial proportion (about 22%) of possible participants because they were deemed too ill or too intellectually impaired, and retrospective measurements. A meta-analysis of the effectiveness of interventions of juvenile offenders  in English-speaking countries emphasized the importance of a “therapeutic” intervention philosophy as opposed to a focus on deterrence, surveillance, or discipline  and therefore the stigmatization of mentally ill persons in this vignette-based study were lower in relation to psychiatric service use than to psychiatric symptoms; i.e., being treated in a psychiatric unit at a general hospital decreased stigmatization. It was of no relevance for stigmatization if hospitalization occurred in a general or forensic psychiatric clinic. Limiting the results is the fact that it is not clear how the attitudinal measure  translates into real-world behavior.There is a lack of research investigating the effect of mandated treatment on feelings of stigma. A Swiss study investigated the impact of different psychiatric service institutions on the stigmatization of mentally ill persons through a representative population survey : The desn = 184) was limited through a possible dropout bias and possible confounding variables. There was evidence supporting the hypothesis that self-reported feelings of coercion increased experience of stigma and devaluation. Further, there was a strong correlation between the number of involuntary hospitalizations and the current perception of stigma. This finding indicates that prior experiences with coercion influence subsequent experiences of coercion. Surprisingly, the ill-effects of perceived coercion and resulting lower self-esteem did not seem to affect illness-related social functioning or symptoms. This finding is in line with results from Ref.  regarding longer-term therapy outcomes. Stated limitations include a moderate follow-up period (1 year after discharge) and completion rate of instruments, regarding engagement and functioning, which might have introduced a selection bias in these results.Outpatient voluntary and court-ordered treatment for people  with serious mental illness were examined in the US study of Link and Castille . The obsrom Ref. , which fper se but rather perceived coercion seems to be linked to feelings of devaluation in adults. Also, having a history of coercive experiences makes it more probable to reexperience discrimination. As mentioned, lower self-esteem does not necessarily result in lower functioning  observed a good overall level of satisfaction with services following voluntary and involuntary admissions  in the United States observed improvements in symptoms, resulting in better social functioning and at a trend level better quality of life  after involuntary treatment in comparison to voluntary admission to services is often the primary focus of debate. A multinational European study investigating about 3,000 adult male and female inpatients of differing legal status and their subjective feeling of coercion concluded that, following coerced hospital admission, clients show, on average, moderate improved symptom levels after 1 and 3 months . This fon = 412 male adult offenders; mean follow-up, 7.9 years; mean duration of treatment in the intervention group, 4.5 years; overall about 85% psychiatric diagnoses of participants) revealed only a trend toward a positive treatment effect in violent and sexual offenders  of mandated treatment of offenders was found to be ineffective on general recidivism, particularly in custodial settings, voluntary treatment was found to produce significant treatment effect sizes regardless of setting . A more ffenders . The sigffenders , 66 who,ffenders  stated tIn juvenile offenders  a meta-analysis (548 mostly US study samples) stated a mean reduction in recidivism of 10–13% from a control group for interventions following a therapeutic and qualitative approach . The infIn summary, literature suggests that criminal recidivism can be effectively reduced if treatment is evidence-based, supportive, and based on relational care , 69–72. Evidence suggests that perceived coercion in treatment is linked to an impaired therapeutic process and outcome compared to voluntary treatment. While correlations have repeatedly been reported between perceived coercion and involuntary legal status , 73–75, Discrimination does not seem especially associated with a forensic setting , but ratEthical considerations place a great emphasis on personal autonomy and self-determination of clients . RegardiResearch on the therapeutic process and outcome factors described above suggests that mandated treatment can also be associated with results comparable to and, in some cases, better than voluntary treatment. While perceived coercion, resistance, and lack of intrinsic motivation to change are more likely to be present at the beginning of treatment, these do not seem to be determinative of the mentioned therapeutic factors and outcomes as therapy progresses . These tr) of up to 0.29] . Therefore, the current review provides a clinical overview to summarize the most relevant results for service providers and aims to raise awareness of important issues associated with mandated therapy for future research. Another major limitation of the current review is that the present overview—due to the state of the literature—cannot make specific statements on various determinants of mandated treatment outcome . In addition, most of the reported studies were observational, cross-sectional studies, which could only report associations and no causalities.In conclusion, treatment outcomes in different domains seem to be linked to the client’s motivation to attend treatment and the feeling of being coerced into therapy, regardless of mandate . It has HH and TV wrote the initial article, and CH revised the paper critically for important intellectual content.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.