Currently about 1 in 5 people with opioid use disorders receive any kind of treatment; if treatment coverage were doubled to 40%, Marks and colleagues’ model suggests that the number of initiations into injection drug use could fall significantly. This is an underappreciated benefit of opioid agonist treatment and underscores its potential public health impact, extending beyond its benefit to the individual. To assist with prevention and treatment efforts, Jesse Yedinak and colleagues aggregated data from 2015–2016 state and national data sources to estimate the proportions of Rhode Island residents in various states: at risk of, in treatment for, and in recovery from opioid use disorders. The authors’ cross-sectional approach requires assumptions about exchange ability in the transition probabilities of individuals at each stage and the absence of biases due to selective mortality, but their addition of the “recovery” stage is a novel modification to the existing framework. This body of work echoes the familiar “voltage drops” analogy pioneered by John Eisenberg and Elaine Power, who used this model to illustrate how the potential for high quality care is lost at various stages of access, enrollment, and treatment. So-called treatment cascade models have been used to identify gaps in the access and treatment continuum for a wide range of health conditions, including HIV treatment, prevention of mother-to-child transmission of HIV, depression, and,hemp drying racks most recently, opioid use disorders. Finally, for people with opioid use disorders who either cannot or do not choose to achieve sustained remission, alternative approaches might be considered to reduce the harms associated with ongoing use.
Stephanie Lake and colleagues analyzed 2014–2017 data from Vancouver, Canada, on people who use drugs and who experience chronic persisting pain and found that daily cannabis use was associated with significant reductions in high-frequency non-medical opioid use. This finding echoes previously published studies showing that expansions in access to marijuana in the US have been associated with reductions in opioid overdose mortality. Among those for whom opioids remain the drugs of choice, use of supervised consumption facilities can reduce the risk of overdose mortality, and the potential for either individual-level adverse health effects or neighborhood-level adverse social effects appears to be minimal. Mary Clare Kennedy and colleagues contribute to this literature by showing that, among clients of the first supervised consumption facility in North America , frequent utilization was associated with a reduction in all-cause mortality over 2006–2017. Although “deaths of despair” ranked highly among the causes of death observed in this study, other non-accidental causes of death were also prominent. In the US, only 1 supervised injection facility currently exists, although 13 cities have sought approval to support their implementation. Ongoing misalignment between state and federal laws governing use of recreational marijuana and availability of supervised injection facilities seriously undermines harm-reduction efforts in the US. These and other interventions across multiple sectors involving healthcare, economic, and social welfare systems need to be scaled up, dramatically and immediately, in order to substantively reduce the number of opioid overdose deaths.
However, as discussed by Alexander Tsai and colleagues, the single most all-consuming force that restrains an effective policy and programmatic response to the opioid overdose crisis—through multilevel pathways that have nimbly adapted to the contours of the crisis over time—is the stigma attached to opioid use. Women whose children are affected by neonatal abstinence syndrome carry a stigma for the rest of their lives. Current media attention devoted to the “mommy drinking” myth is driven by the stigma resulting from the intersecting levels of scrutiny targeted toward women who parent and toward those who consume alcohol. Moreover, the disparate geospatial burden of opioid-related incidents, such as those studied by Zehang Li and colleagues, generates a stigma that attaches to entire neighborhoods. Indeed, as a class, harm-reduction interventions have been tainted by stigma, leading to their chronic under funding and under utilization. These and other forms of stigma must be eliminated before the overdose crisis can be successfully overcome. This issue of PLOS Medicine is notable for several gaps. First, the majority of contributions to the Special Issue concern the North American opioid overdose crisis, but the global burden of disease attributable to alcohol use disorders greatly exceeds that attributable to opioid use disorders. Touching on harms owing to alcohol use, McKetta and Keyes used data from the 2006–2018 US National Health Interview Survey to examine national trends in binge drinking and heavy drinking. Consistent with concurrently published findings from the NSDUH, they found that heavy drinking has declined or stabilized for most age/sex subgroups but that binge drinking has increased, particularly among women and older men.
A second evidence gap has to do with the global reach of the evidence. Although PLOS Medicine publishes research findings of general interest to the medical and public health communities, we received manuscript submissions describing research conducted in only a limited number of countries. In this Special Issue, the sole paper representing research conducted outside the US, Canada, and the UK is the report by Samantha Harris and colleagues, who analyzed Swedish register data from 1984–2016 to show that both refugee and non-refugee migrants had lower rates of substance use disorders compared with Swedish-born individuals but that over time, the rates among migrants converged to that of Swedish-born individuals. The issue regrettably features no articles from Africa, Asia, or South America, and no articles focused on indigenous populations or on racial, ethnic, or sexual minority groups. A third evidence gap has to do with the portfolio of methods underlying the evidence base. Causal methods have an important role to play in characterizing the relationships between exposures and outcomes when experimental data are difficult to come by . Among the articles included in this Special Issue, only Kennedy and colleagues used the “E-value” to estimate the minimum strength of association on the risk ratio scale that an unobserved variable would need to have with both the exposure and outcome to fully explain away their observed association. More studies using causal mediation analysis, instrumental variables, marginal structural models, natural experiments, regression discontinuity designs, and synthetic control methods are needed. This Special Issue also lacks articles based on qualitative data. Qualitative methods can be used to study complex phenomena like substance use disorders in greater depth, probe for mechanistic pathways linking the phenomena of interest, and generate new insights that can be tested in future studies. Collectively, the articles published in this issue highlight the scope of discovery and implementation needed to reduce the global burden of disease attributable to substance use, misuse, and dependence. Challenges—some related to science, others related to politics—are apparent. Multiple lines of evidence have already charted a road map that can be followed with respect to immediate policy making and program deployment. But there is a yawning chasm between what we know works to reduce the burden of disease from substance use disorders and what, at a societal level, is actually done about this burden. Eliminating this gap is not beyond our reach,industrial rolling racks given the available scientific evidence and substantial burden of ill health and suffering calling for prompt action, making it a public health imperative.The impact of the COVID-19 pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 was foreshadowed by earlier epidemics of new or re-emerging diseases such as SARS , influenza , Middle East Respiratory Syndrome , Ebola , and Zika affecting localized regions . These events showed that novel and well-known viral diseases alike can pose a threat to global health.
In 2014, an article published in Nature Medicine stated that the Ebola outbreak should have been “a wake-up call to the research and pharmaceutical communities, and to federal governments, of the continuing need to invest resources in the study and cure of emerging infectious diseases” . Recommendations and even new regulations have been implemented to reduce the risk of zoonotic viral infections , but the extent to which these recommendations are applied and enforced on a regional and, more importantly, local level remains unclear. Furthermore, most vaccine programs for SARS, MERS, and Zika are still awaiting the fulfillment of clinical trials, sometimes more than 5 years after their initiation, due to the lack of patients . In light of this situation, and despite the call to action, the SARS-CoV-2 pandemic has resulted in nearly 20 million infections and more than 700,000 deaths at the time of writing based on the Johns Hopkins University Hospital global database.The economic impact of the pandemic is difficult to assess, but support programs are likely to cost more than €4 trillion in the United States and EU alone. Given the immense impact at both the personal and economic levels, this review considers how the plant-based production of recombinant proteins can contribute to a global response in such an emergency scenario. Several recent publications describe in broad terms how plant-made countermeasures against SARSCoV-2 can contribute to the global COVID-19 response . This review will focus primarily on process development, manufacturing considerations, and evolving regulations to identify gaps and research needs, as well as regulatory processes and/or infrastructure investments that can help to build a more resilient pandemic response system. We first highlight the technical capabilities of plants, such as the speed of transient expression, making them attractive as a first-line response to counter pandemics, and then we discuss the regulatory pathway for plant-made pharmaceuticals in more detail. Next, we briefly present the types of plant-derived proteins that are relevant for the prevention, treatment, or diagnosis of disease. This sets the stage for our assessment of the requirements in terms of production costs and capacity to mount a coherent response to a pandemic, given currently available infrastructure and the intellectual property landscape. We conclude by comparing plant-based expression with conventional cell culture and highlight where investments are needed to adequately respond to pandemic diseases in the future. Due to the quickly evolving information about the pandemic, our statements are supported in some instances by data obtained from web sites . Accordingly, the scientific reliability has to be treated with caution in these cases.The development of a protein-based vaccine, therapeutic, or diagnostic reagent for a novel disease requires the screening of numerous expression cassettes, for example, to identify suitable regulatory elements that achieve high levels of product accumulation, a sub-cellular compartment that ensures product integrity, as well as different product candidates to identify the most active and most amenable to manufacturing in plants . A major advantage of plants in this respect is the ability to test multiple product candidates and expression cassettes in parallel by the simple injection or infiltration of leaves or leaf sections with a panel of Agrobacterium tumefaciens clones carrying each variant cassette as part of the transferred DNA in a binary transformation vector . This procedure does not require sterile conditions, transfection reagents, or skilled staff, and can, therefore, be conducted in standard bio-safety level 1 laboratories all over the world. The method can produce samples of even complex proteins such as glycosylated monoclonal antibodies for analysis ~14 days after the protein sequence is available. With product accumulation in the range of 0.1–4.0 g kg−1 biomass , larger-scale quantities can be supplied after 4–8 weeks , making this approach ideal for emergency responses to sudden disease outbreaks. Potential bottlenecks include the preparation of sufficiently large candidate libraries, ideally in an automated manner as described for conventional expression systems, and the infiltration of plants with a large number of candidates. Also, leaf-based expression can result in a coefficient of variation >20% in terms of recombinant protein accumulation, which reduces the reliability of expression data . The variability issue has been addressed to some extent by a parallelized leaf-disc assay at the cost of a further reduction in sample throughput . The reproducibility of screening was improved in 2018 by the development of plant cell pack technology, in which plant cell suspension cultures deprived of medium are used to form a plant tissue surrogate that can be infiltrated with A. tumefaciens in a 96-well microtiter plate format to produce milligram quantities of protein in an automated, high-throughput manner. The costs can be as low as €0.50 per 60-mg sample with a product accumulation of ~100 mg kg−1 and can typically result in a CV of <5% . These costs include the fermenter-based upstream production of plant cells as well as all materials and labor.