Hemp Growing

The association between marijuana use and mental health also seems to vary by gender, although the evidence is inconsistent. We do however know that women move from initiation of cannabis use to problematic use much faster than men do. This is referred to as a telescoping effect . This may suggest differences in both reasons for use and patterns of use . In addition to rapid progression to problematic use, it appears as though marijuana has a stronger mental health impact for women than men . Women, but not men, previously diagnosed with depressive disorders and who use marijuana regularly had poorer SF-12 mental health scores compared to women who did not use marijuana . And, in a study by Lev-Ran looking at the association between mental health and quality of life in the general population, those who used marijuana had poorer mental health than those who did not, and reported experiencing lower levels of vitality and accomplishing less due to emotional problems. These differences were greater among women than men . These findings highlight the importance of considering gender in the study of motives of marijuana use and mental health, as motives might provide additional insight into what drives gender differences in the association between marijuana use and mental health outcomes. Frequency of use. Heavy marijuana use, operationalized as near daily use, has been demonstrated to be detrimental to the transition to adulthood as it has been associated with poorer educational and occupational outcomes . Compared to young adults who do not use marijuana or to those who use infrequently, heavy users are the least likely to have transitioned to an adult role by the age of 28 . Frequency of use also seems to play a role in the relationship between marijuana use in adolescence and adverse young adult outcomes,vertical growing system including depression and anxiety . However, Green and Ritter found no association between frequency of marijuana use and depression in young adult men.

Furthermore, data from the Australian National Survey of Mental Health and Well-Being indicates a positive association between marijuana use and the occurrence of affective disorders, in addition to the fact that those who used marijuana more often reported greater levels of psychological distress, greater limitations in their everyday lives due to emotional distress, and lower life satisfaction . LevRan et al. reported that for those with anxiety disorders, regular, weekly use of marijuana was associated with a decrease in mental health quality of life compared to participants who did not use. This association was not present for participants who reported less than weekly use . Daily use of marijuana in young adult women has been associated with a fivefold increase in the odds of depression and anxiety . Here too, findings highlight the importance of considering frequency of use in the study of marijuana use and mental health outcomes, as frequency of use seem to influence the relationship between marijuana use and mental health outcomes. Given that an association between marijuana use and depressive symptoms, and marijuana use and anxiety symptoms have at times been demonstrated, it is crucial to understand under which circumstances such associations are present. Motives of marijuana use may be key to do so. Better understanding the nature of these associations is especially significant for young adults given their mental health vulnerability, the rising rates of affective disorders and of marijuana use, and that individuals suffering from comorbid substance use and symptoms of depression and anxiety have a worsened clinical course and outcomes and are at higher risk of suicide, impairments, and disability . Alcohol Motives. As previously mentioned, foundational work on motives of use comes from the alcohol literature. Thus, the four most common motives discussed in the literature are borrowed from the alcohol literature. These are social motives, conformity motives, coping motives, and enhancement motives. Social motives are defined as externally generated positive reinforcement motives to obtain positive social rewards . An example of a social motive is celebration. Conformity motives are also externally generated negative reinforcement motives to avoid social censure or rejection .

An individual’s use will be driven by a conformity motive either to fit in with a group or due to peer pressure because everyone else is using. Coping motives are conceptualized as internally generated negative reinforcement motives to reduce or regulate negative emotions . As an example, an individual’s use will be driven by a coping motive if he uses because he has had a bad day, or is frustrated. Enhancement motives are internally generated positive reinforcement motives to enhance positive mood or well being . Examples of enhancement motives are enjoyment and altered perceptions. In work done by Cooper, there was a positive, significant association between enhancement, coping and social motives with quantity and frequency of drinking . There was a negative, significant association between conformity motives and quantity of drinking . Furthermore, coping, enhancement, and conformity motives were predictors of drinking problems, but social motives were not . It is likely that social motives were not predictors of drinking problems as for this given motive, drinking is occasional and only occurs in social, celebratory situations. Marijuana Motives. Although there is an overlap in motives of alcohol and marijuana use, some motives are specific to marijuana use . For the purposes of this dissertation, marijuana motives of use are: 1) motives that promote positive experiences, which are motives of celebration, altered perceptions, experimentation, enjoyment, alcohol, relative low risk, and availability; 2) motives for avoidance of negative experiences, which are motives of coping, conformity, sleep, boredom; and social anxiety; and 3) medical motives, which are motives of attention, substitution, natural remedy, pain, and nausea. Figure 2.2 details the reasons for use an individual might endorse for each of these motives. Previous research has demonstrated that motives of use are associated with differing patterns of use and risk for marijuana use problems .

Differential associations between motives of use and problematic use outcomes have been consistently documented . With regards to problematic use outcomes, enhancement, expansion, coping and social motives of marijuana use have been uniquely associated with greater frequency of marijuana use in the past 30 days . When examining whether there were differences between severity of use and motives endorsed, BonnMiller & Zvolensky demonstrated that individuals with marijuana dependence endorsed motives of expansion and enhancement more frequently than those who used marijuana only occasionally or regularly. Individuals with cannabis dependence endorsed more social motives than those who used occasionally, those who used regularly, and those who abused marijuana. Individuals with dependence to marijuana also endorsed more conformity motives than those who abused marijuana. With regards to coping motives, those with dependence endorsed more coping motives than those suffering from abuse or reporting regular, occasional use. These findings demonstrate that those with marijuana dependence are more likely to use marijuana to adjust their affective states and rely on marijuana to cope with life stressors. However, with regards to mental health as an outcome, the differential association between motives of use with both diagnoses and symptoms of depression and anxiety as outcomes has yielded inconsistent findings. For a given motive and associated outcome, findings have differed across studies. One consistency however,plant growing rack is the association of coping related motives of use with poor or worse outcomes. For instance, Green & Ritter found that individuals between the ages of 30 and 40 who endorsed coping related motives reported more symptoms of depression than those who endorsed non-coping related motives of use. With regards to anxiety symptoms, Bonn-Miller, Zvolensky & Bernstein found that anxiety sensitivity was incrementally associated with coping and conformity motives, whereas enhancement was negatively associated with it. However, Moitra, Christopher & Stein found that only coping motives, and not conformity motives, were significantly associated with negative affect. When considered as a moderator, only those who reported using to cope showed poorer mental health, increased symptoms of psychopathology, more psychosocial distress, and more life events than those who did not use . Focusing on symptoms of depression and symptoms of anxiety, which are precursors to diagnoses is not trivial. Subclinical symptoms of depression and anxiety have been associated with an increased likelihood of full blown disorders in adulthood . Most of the research reviewed has focused on clinically diagnosed depression and anxiety. It is not clear however, if these findings generalize to less severe symptoms. The generalizability is important because clinical disorders may be contraindicated with marijuana use, whereas less several symptoms may not. Gender. Gender differences have also been observed in the association between motives of marijuana use and mental health outcomes. These differences may be due to differences in motives of use endorsed as well as ensuing patterns of use. With regards to gender, expectancies for marijuana use mediated the association between coping motivated use and anxiety in women, but not men . In work done by Buckner, Zvolensky & Schmidt social anxiety was associated with marijuana related problems, coping, and conformity motives.

In women, social anxiety was related to social motives but not marijuana use related problems . However, existing work has seldom considered potential gender differences in endorsed motives for use and in the association between motives of use and symptoms of depression, symptoms of anxiety, and overall psychological distress. For this dissertation, gender is included as a moderator in Cooper’s Motivational Model of Alcohol Use as motives of use endorsed, patterns of use, and ensuing outcomes are likely to differ by gender. Thus, it is important to understand the role of gender in the association between motives of use and mental health to develop successful, gender specific prevention and intervention programs, should need be. Although work has been done to understand marijuana motives of use and associated outcomes, there are some gaps particularly relevant to a context with legal access to marijuana, that this dissertation seeks to address. There is however much that remains to be understood about the associations between motives of marijuana use and mental health outcomes in young adults who use marijuana, particularly in a context of facilitated access to marijuana. First, samples used in research thus far have mostly been identified as individuals who use marijuana for medical reasons only or as individuals who use marijuana for recreational reasons only, thus reporting an illegal behavior in this latter group. Until now, work has yet to be done that considers motives of marijuana use and associated mental health outcomes in a sample of young adults comprised of individuals who use marijuana exclusively for medical reasons, exclusively for recreational reasons or for both medical and recreational reasons, in a context with a longstanding history of legalized medical marijuana. Second, current instruments used to operationalize motives of marijuana use have been validated using college samples which are not representative of the marijuana using population at large. Furthermore, these instruments do not include motives specific to medical marijuana use when it has been demonstrated that medical and recreational marijuana use overlap significantly . There is a need for an instrument that operationalizes marijuana motives of use, to include both recreational as well as medical motives of use given the significant overlap in use . Furthermore, this instrument needs to be validated in a diverse sample of young adults who use marijuana for recreational and/or medical reasons. The sample to be used in this dissertation addresses this shortcoming. Third, in the limited literature that presents research done on motives of marijuana use and mental health outcomes, the focus is often on diagnoses of depression and/or anxiety. A better understanding of the association between motives of use and symptoms of depression and motives of use and symptoms of anxiety is a primordial precursor not only to detangling the association between marijuana use and diagnoses of depression and anxiety, but also, because symptoms are an avenue ripe for intervention. This is particularly salient for young adults as we want to be able to intervene early, should need be, to maximize the likelihood of a successful transition into adulthood. Fourth, even less is known about potential gender differences in the association between motives of marijuana use and symptoms of depression, symptoms of anxiety, and overall psychological distress.

Considering the monthly reapplication interval, this still may not be a cost-effective product for large-scale application. The new US EPA-approved long-lasting formulation, FourStar Microbial Briquets , is potentially effective for up to 6 months , and preliminary data suggest that it is effective in malaria mosquito control [GZ, unpublished data]. Field-testing is needed to determine the efficacy and cost-effectiveness of this long-lasting larvicide. The central objective of this study is to determine the effectiveness and cost-effectiveness of long-lasting microbial larviciding on the incidence of clinical malaria and the reduction of transmission intensity. The hypothesis is that adding LLML to ongoing ITN and IRS programs will lead to significant reductions in both indoor and outdoor malaria transmission and malaria incidence as well as cost savings. This paper describes a protocol for evaluating the impact of LLML in reducing malaria vector populations and clinical malaria incidence.We will conduct our study in 28 randomly selected clusters in the highland localities of Kakamega and Vihiga counties, western Kenya . A cluster typically consists of an area of approximately 4 km2 in size and comprises 400–700 households and about 2000–3000 residents. The catchment population of the study area, including intervention clusters, control clusters, and buffer zones, is estimated as 250,000 according to 2010 census data. Local residents are predominantly farmers and depend upon farming, cattle and goat herding for subsistence. Malaria transmission is seasonal, with two peaks in vector abundance reflecting the bimodal rainfall pattern: a major peak between April and June and a minor peak between October and November. Most malaria is caused by Plasmodium falciparum. The main malaria vectors in the area are An. gambiae s.s., An. arabiensis, and An. funestus s.l.. Malaria vector density was high in the early 2000s,weed growing systems decreased substantially during 2006–2008 after the first round of mass distribution of ITNs in 2006, and has gradually increased since 2008.

Pyrethrum spray collections of indoor-resting Anopheles were about 1.0 females/house/ night in 2014 compared to 0.1 females/house/night in 2007. Cross-sectional community-level surveys in May 2011 indicated that parasite prevalence averaged 11.8 % in the general population but varied between localities from 3.3 % to 25.4 %. In school children aged 6–13 years, surveys in 2012 found an average parasite prevalence of 27.2 %, which varied from 18.8 to 35.4 % among villages. Active case surveillance through bi-weekly home visits in May 2011 indicated an average annual clinical malaria incidence rate of 31.4 cases per 1000 people in the general population, varying from 28.9 to 36.2 between villages. Ownership of ITNs ranged from 78.3 to 84.2 % in 2013. There have been several attempts in the past 10 years to control malaria vectors in the study area using conventional formulations of Bti/Bs and IRS. The last community-wide mass distribution of ITNs was undertaken by the Division of Malaria Control of Kenya in 2014. Currently there is no mass distribution of ITNs or IRS and no larviciding in the proposed study area.For purposes of planning and conducting an evaluation of the intervention, we will subdivide the field area into villages , which is the smallest administrative unit in Kenya. Using villages as clusters has advantages over random sampling. First, the clinical records in health centers or hospitals in Kenya generally include the name of the village and sub-location ; therefore, clinical malaria cases can be traced back to the village level. Second, villages have been conveniently used as intervention/ control clusters in previous trials. Our field team will conduct the demographic surveys before the start of the intervention. Each team will be provided with a printed overview map and a handheld Google Nexus 7 tablet.

A surveillance team, comprising a field technician, a reporter, and a local guide, will visit every compound to explain the study procedures, tally inhabitants, and collect information on house characteristics. If the head of the compound agrees to participate, we will record the geographical coordinates of the main house of the compound and compound codes will be written in permanent marker on the front wall next to the door. We will record the genders and ages of all compound members on questionnaire forms using the on-site Google Nexus , which will update the database in real time together with the GPS coordinates of the surveyed compound. We will map the locations of all compounds using ArcGIS. Demographic surveillance will be done in year 1, 6–12 months prior to intervention . We will draw village boundaries based on the demographic surveys and confirm it with the field teams and the database manager. If a village is too small , we will combine the village with a neighboring village to form one cluster. Total and age- and gender-specific populations will be aggregated at the cluster level.Clinical malaria records will be collected from 8 to 12 months prior to intervention, to calculate baseline incidence rate at each cluster for cluster randomization, through to 8 to 12 months after all interventions . We will collect information on clinical malaria cases retrospectively from all government-run hospitals, health care centers, and clinics located either within the study area itself or within catchment areas overlapping the study area. We will obtain clinical data from the treatment centers through the malaria control office of Kakamega and Vihiga counties, Kenya. We will also collect patient- and treatment-related information, including age, gender, date of diagnosis, parasite species, village of patient , and prescriptions given. All personal identifiers will be excluded from this study. A clinical malaria case is defined as an individual with fever and other related symptoms such as chills, severe malaise, headache, or vomiting in the presence of a Plasmodium-positive blood smear.

The clinical malaria incidence rate is calculated as the number of clinical malaria episodes divided by the total person time at risk based on demographic surveys. We will also collect the aggregated monthly diarrhea data at each site along with clinical malaria records from local health clinics and hospitals. We will not conduct prospective passive surveillance, active home visits, or cross-sectional blood surveys. We will calculate the clinical malaria incidence rate separately for each cluster, different study period and different age group . We will include all clinical malaria cases in our study, including cases diagnosed during the four study periods : preintervention period: baseline clinical malaria records started at least 8–12 months prior to the application of long-lasting microbial larvicides till intervention, intervention period: all clinical records during the intervention period, the 8-month wash-out period, and post intervention period: clinical malaria records till 8–12 months after the last round of larvicide application.Permission to use microbial larvicides for malaria vector control has been obtained from the Pest Control Products Board of Kenya. Ethical clearance has been approved by the Scientific and Ethical Unit of the Kenya Medical Research Institute . As described, aggregated clinical data will be obtained from the treatment centers through the malaria control offices of Kakamega and Vihiga counties, Kenya. According to US Department of Health and Human Services Code of Federal Regulations 45 CFR 46.101 part 4 , these data are in the category of exempt human subjects research, which involves the study of existing data, documents, or records, with no collection of subject-level information. Informed consent will be obtained from each participant. All investigative team members in the United States, Kenya, and Australia have no financial conflict of interest with the larvicide manufacturer, Central Life Sciences.We will conduct baseline malaria vector surveillance at least 4 months prior to any application of LLMLs . We will conduct malaria vector population surveillance on a monthly basis continuously till at least 8 months after the last round of larvicide application . We will monitor both indoor- and outdoor-biting mosquito abundance using CO2-baited Centers for Disease Control light traps equipped with collection bottle rotators . The collection bottle rotator,indoor farming systems which has eight separate plastic collection bottles, will be programmed to collect active mosquitoes at 2-h intervals between 16:00–08:00. We will place two traps within each sampling compound: one inside the living room, the other outside the house 5 m away. We will conduct a total of 64 trap-nights of vector sampling per cluster per month. This will provide an estimation precision of 0.2 mosquitoes using the previously determined standard deviation. Species of collected mosquitoes will be identified and blood-feeding status will be recorded. We will test for P. falciparum sporozoite infection and blood meal source using an enzyme-linked immunosorbent assay on all specimens. For each house where the vector population was sampled, we will record the number of sleeping persons at each house on the same day as the vector survey. We will calculate sporozoite rate and EIR for each cluster. EIRs will be calculated as × × , and standardized to a monthly basis.

The trapping method will allow for comparison of indoor- and outdoor-biting mosquito abundance and determination of nightly biting activity patterns. We will calculate indoor and outdoor transmission intensities separately assuming that all mosquitoes collected from a compound had their blood meal from the same household. We will calculate EIR for the four study periods as describe above: preintervention period: baseline vector surveillance started at least 6 months prior to the application of long-lasting microbial larvicides till intervention, intervention period, the 8-month washout period, and post intervention period: vector surveillance continued till 8 months after the last round of larvicide application. To determine whether new malaria vector species are present in the study sites, we will sequence the ribosomal second internal transcribed spacer and mitochondrial CO1 gene in anopheline specimens that are not amplified by the recombinant deoxyribonucleic acid polymerase chain reaction method, and we will conduct phylogenetic analysis to determine whether the new species found by Stevenson et al. are also present in the study sites.We will conduct the intervention using a two-step approach. First, we will conduct a small-scale four-cluster trial to optimize the time, duration, and quantity of LLML application. Second, we will conduct a clusterrandomized trial to test the effectiveness and cost effectiveness of LLML. The design has two parallel arms, i.e., control and intervention, and allows for baseline survey without intervention and crossover .We will select four clusters, two in each county, for an entomological evaluation of the optimal larvicide application scheme . We will randomly select two clusters, one in each county, treated with larvicides and the other two sites will serve as controls . We will treat temporary habitats with FourStar controlled release granule formulation, which maintains effectiveness through wet and dry periods for up to 1 month. We will treat semipermanent habitats with FourStar 90-day briquettes and permanent habitats with FourStar 180-day briquettes. Application dosage will follow the recommendation of the manufacturer, Central Life Sciences: 10 lbs per acre of water surface for the granule formulation, and one briquette per 100 ft2 of water surface for the briquette formulations, regardless of water depth. We will re-treat the habitats every 4 to 5 months. On a weekly basis in the treatment and control sites, we will use aerial samplers to determine habitat pupal productivity, and use standard dippers to determine larval abundance. This will allow for determination of habitat productivity with a tolerable error of 0.5 mosquitoes, based on the standard deviation identified in previous studies. We will monitor indoor and outdoor vector abundance using 64 trapnights per cluster per month. This sample size will allow detection of a difference in average vector abundance of 0.12 mosquitoes with 80 % statistical power and 0.05 type-I error. We will use ELISA methods to determine Anopheles mosquitoes’ sporozoite infection and blood feeding host preference. We will analyze the data immediately after the small scale trial using analysis of variance with repeated measures and appropriate transformation to determine the effects of habitat larviciding on mosquito abundance and transmission intensity. We will assign fourteen clusters each in the two counties to intervention or no intervention by a block randomization method on the basis of clinical malaria incidence, vector density, and human population size per site. Year 1 will focus on preparing the study sites and working with clinics and hospitals to help them improve their routine malaria surveillance . In year 2, we will conduct preliminary surveys on all 28 sites to determine clinical malaria incidence, vector density, geographic information system coordinates of larval habitats, and human population size.

The European Medicines Agency has established initiatives for the provision of accelerated development support and evaluation procedures for COVID-19 treatments and vaccines. These initiatives generally follow the EMA Emergent Health Threats Plan published at the end of 2018 . Similar to FDA’s CTAP, EMA’s COVID-19 Pandemic Emergency Task Force aims to coordinate and enable fast regulatory action during the development, authorization, and safety monitoring of products or procedures intended for the treatment and prevention of COVID-19 . Collectively, this task force and its accessory committees are empowered to rapidly address emergency use requests . Although perhaps not as dramatic as the aspirational time reductions established by the FDA’s CTAP, the EMA’s refocusing of resources and shorter response times to accelerate the development and approval of emergency use products are nevertheless laudable. In the United Kingdom, the MHRA6 has also revised customary regulatory procedures to conform with COVID-19 emergency requirements by creating flexible regulations spanning early consultation, accelerated clinical development and review, and alternatives to facility inspection.During a public health emergency, one can envision the preferential utilization of existing indoor manufacturing capacity, at least in the near term. Processes making use of indoor cultivation and conventional purification can be scrutinized more quickly by regulatory agencies due to their familiarity, resulting in shorter time-to-clinic and time-to-deployment periods. Although many, perhaps most, process operations will be familiar to regulators, there are some peculiarities of plant-based systems that differentiate them from conventional processes and, hence, require the satisfaction of additional criteria. Meeting these criteria is in no way insurmountable,grow trays 4×4 as evidenced by the rapid planning and implementation of PMP programs for SARS-CoV-2/COVID-19 by PMP companies such as Medicago, iBio, and Kentucky Bioprocessing.

During emergency situations when speed is critical, transient expression systems are more likely to be used than stable transgenic hosts, unless GM lines were developed in advance and can be activated on the basis of demand . The vectors used for transient expression in plants are non-pathogenic in mammalian hosts and environmentally containable if applied indoors, and by now they are well known to the regulatory agencies. Accordingly, transient expression systems have been deployed rapidly for the development of COVID-19 interventions. The vaccine space has shown great innovation and the World Health Organization has maintained a database of COVID-19 vaccines in development,including current efforts involving PMPs. For example, Medicago announced the development of its VLP-based vaccine against COVID-19 in March 2020, within 20 days of receiving the virus genome sequence, and initiated a Phase I safety and immunogenicity study in July.If successful, the company expects to commence Phase II/III pivotal trials by late 2020. Medicago is also developing therapeutic antibodies for patients infected with SARS-CoV-2, and this program is currently in preclinical development. Furthermore, iBio has announced the preclinical development of two SARS-CoV-2 vaccine candidates, one VLP and one subunit vaccine.Kentucky Bioprocessing has announced the production and preclinical evaluation of a conjugate TMV-based vaccine and has requested regulatory authorization for a first in-human clinical study.These efforts required only a few months to reach these stages of development and are a testament to the rapid expression, prototyping, and production advantages offered by transient expression.The PMP vaccine candidates described above are all being developed by companies in North America. The rapid translation of PMPs from bench to clinic reflects the conformance of chemistry, manufacturing, and control procedures on one hand, and environmental safety and containment practices on the other, with existing regulatory statutes.

This legislative system has distinct advantages over the European model, by offering a more flexible platform for discovery, optimization, and manufacturing. New products are not evaluated for compliance with GM legislation as they are in the EU and the United States but are judged on their own merits. In contrast, development programs in the EU face additional hurdles even when using 8 WHO 2020. DRAFT landscape of COVID-19 candidate vaccines. Process validation in manufacturing is a necessary but resource intensive measure required for marketing authorization. Following the publication of the Guidance for Industry “Process Validation: General Principles and Practices,” and the EU’s revision of Annex 15 to Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use, validation became a life-cycle process with three principal stages: process design, process qualification, and continuous process verification . During emergency situations, the regulatory agencies have authorized the concurrent validation of manufacturing processes, including design qualification , installation qualification , operational qualification , and performance qualification . Although new facility construction or repurposing/ re-qualification may not immediately help with the current pandemic, given that only existing and qualified facilities will be used in the near term, it will position the industry for the rapid scale-up of countermeasures that may be applied over the next several years. An example is the April 2020 announcement by the Bill & Melinda Gates Foundation of its intention to fund “at-risk” development of vaccine manufacturing facilities to accommodate pandemic-relevant volumes of vaccines, before knowing which vaccines will succeed in clinical trials. Manufacturing at-risk with existing facilities is also being implemented on a global scale.

The Serum Institute of India, the world’s largest vaccine manufacturer, is producing at-risk hundreds of millions of doses of the Oxford University COVID-19 vaccine, while the product is still undergoing clinical studies.Operation Warp Speed 13 in the United States is also an at-risk multi-agency program that aims to expand resources to deliver 300 million doses of safe and effective but “yet-to be-identified” vaccines for COVID-19 by January 2021, as part of a broader strategy to accelerate the development, manufacturing, and distribution of COVID-19 countermeasures, including vaccines, therapeutics, and diagnostics. The program had access to US$10 billion initially and can be readily expanded. As of August 2020, OWS had invested more than US$8 billion in various companies to accelerate manufacturing, clinical evaluation, and enhanced distribution channels for critical products.For example, over a period of approximately 6 months, OWS helped to accelerate development, clinical evaluation , and at-risk manufacturing of two mRNA based COVID-19 vaccines, with at least three more vaccines heading into advanced clinical development and large-scale manufacturing by September/October 2020.Once manufactured, PMP products must pass quality criteria meeting a defined specification before they reach the clinic. These criteria apply to properties such as identity, uniformity, batch-to-batch consistency, potency, purity, stability , residual DNA, absence of vector, low levels of plant metabolites such as pyridine alkaloids, and other criteria as specified in guidance documents . Host and process-related impurities in PMPs, such as residual HCP, residual vector, pyridine alkaloids from solanaceous hosts , phenolics, heavy metals , and other impurities that could introduce a health risk to consumers, have been successfully managed by upstream process controls and/or state-of-the-art purification methods and have not impeded the development of PMP products . The theoretical risk posed by non-mammalian glycans, once seen as the Achilles heel of PMPs, has not materialized in practice. Plant-derived vaccine antigens carrying plant-type glycans have not induced adverse events in clinical studies, where immune responses were directed primarily to the polypeptide portion of glycoproteins . One solution for products intended for systemic administration, where glycan differences could introduce a pharmacokinetic and/or safety risk , is the engineering of plant hosts to express glycoproteins with mammalian-compatible glycan structures . For example, ZMapp was manufactured using the transgenic N. benthamiana line ΔXT/FT, expressing RNA interference constructs to knock down the expression of the enzymes XylT and FucT responsible for plant-specific glycans,horticulture products as a chassis for transient expression of the mAbs . In addition to meeting molecular identity and physicochemical quality attributes, PMP products must also be safe for use at the doses intended and efficacious in model systems in vitro, in vivo, and ex vivo, following the guidance documents listed above. Once proven efficacious and safe in clinical studies, successful biologic candidates can be approved via a BLA in the United States and a new marketing authorization in the EU.In emergency situations, diagnostic reagents, vaccine antigens, and prophylactic and therapeutic proteins may be deployed prior to normal marketing authorization via fast-track procedures such as the FDA’s emergency use authorization .This applies to products approved for marketing in other indications that may be effective in a new emergency indication , and new products that may have preclinical data but little or no clinical safety and efficacy data. Such pathways enable controlled emergency administration of a novel product to patients simultaneously with traditional regulatory procedures required for subsequent marketing approval.

In the United States, the FDA has granted EUAs for several diagnostic devices, personal protective devices, and certain other medical devices, and continuously monitors EUAs for drugs. For example, the EUA for chloroquine and hydroxychloroquine to treat COVID-19 patients was short-lived, whereas remdesivir remains under EUA evaluation for severe COVID-19 cases. The mRNA-based SARS-CoV-2 vaccines currently undergoing Phase III clinical evaluation by Pfizer/BioNTech and Moderna/ NIAID, and other vaccines reaching advanced stages of development, are prime candidates for rapid deployment via the EUA process. No PMPs have yet been granted EUA, but plant-made antibodies and other prophylactic and therapeutic APIs may be evaluated and deployed via this route. One example of such a PMP candidate is griffithsin, a broad-spectrum antiviral lectin that could be administered as a prophylactic and/or therapeutic for viral infections, as discussed later. The FDA’s EUA is a temporary authorization subject to constant review and can be rescinded or extended at any time based on empirical results and the overall emergency environment. Similarly, the EU has granted conditional marketing authorisation to rapidly deploy drugs such as remdesivir for COVID-19 in parallel with the standard marketing approval process for the new indication.The regulations commonly known as the animal rule 17 allow for the approval of drugs and licensure of biologic products when human efficacy studies are not ethical and field trials to study the effectiveness of drugs or biologic products are not feasible. The animal rule is intended for drugs and biologics developed to reduce or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substances. Under the animal rule, efficacy is established based on adequate and well-controlled studies in animal models of the human disease or condition of interest, and safety is evaluated under the pre-existing requirements for drugs and biologic products.As an example, the plant-derived mAb cocktail ZMapp for Ebola virus disease, manufactured by Kentucky Bioprocessing for Mapp Biopharmaceutical 18 and other partners, and deployed during the Ebola outbreak in West Africa in 2014, was evaluated only in primates infected with the Congolese variant of the virus , with no randomized controlled clinical trial before administration to infected patients under a compassionate use protocol . Although the fast-track and streamlined review and authorization procedures described above can reduce time-to-deployment and time-to-approval for new or repurposed products, current clinical studies to demonstrate safety and efficacy generally follow traditional sequential designs. Products are licensed or approved for marketing based on statistically significant performance differences compared to controls, including placebo or standards of care, typically generated in large Phase III pivotal trials. One controversial proposal, described in a draft WHO report , is to accelerate the assessment of safety and efficacy for emergency vaccines by administering the medical intervention with deliberate exposure of subjects to the threat agent in a challenge study. Although the focus of the WHO draft report was on vaccines, the concept could conceivably be extended to non-vaccine prophylactics and therapeutics. Results could be generated quickly as the proportion of treated and control subjects would be known, as would the times of infection and challenge. Challenge studies in humans, also known as controlled human infection models or controlled human infection studies , are fraught with ethical challenges but have already been used to assess vaccines for cholera, malaria, and typhoid . The dilemma for a pathogen like SARS-CoV-2 is that there is no rescue medication yet available for those who might contract the disease during the challenge, as there was for the other diseases, putting either study participants or emergency staff at risk .In the EU, the current regulatory environment is a substantial barrier to the rapid expansion of PMP resources to accelerate the approval and deployment of products and reagents at relevant scales in emergency situations.

The item read: “Marijuana is also called pot, weed, and grass. Are you planning to stop using marijuana?” . Participants were categorized as marijuana users if they indicated recent use on the staging item. All others were categorized as non-marijuana users. The following outcomes were assessed at 3, 6, and 12 months: 1) seven-day point prevalence abstinence, 2) smoking reduction, 3) presence of a quit attempt since the last assessment, and 4) stage of change for quitting smoking. Self-reported point prevalence abstinence and reduction were assessed with the item, “How many cigarettes have you smoked in the past 7 days?”. To measure point prevalence abstinence, responses were coded into abstinent in the past seven days or smoking . Reduction was calculated using baseline cigarettes per day, and coded into reduced or not reduced by at least 50% since baseline. Quit attempts were measured with, “Have you tried to quit smoking for at least 24 hours since your last Tobacco Status Project survey?” . Stage of change was measured using the Stages of Change Questionnaire , recoded into precontemplation, contemplation, preparation, or action/maintenance. Those in action/maintenance indicated that they had quit smoking. All outcomes were measured at each time point. Participants in the intervention group reported their perceptions of the intervention at treatment end by rating their agreement with 7 items. Items addressed whether the intervention was easy to understand, gave sound advice, gave participants something to think about, and helped them to be healthier, as well as whether they used the information, thought about the information,indoor grow rack and would recommend the intervention . Responses were coded as disagreement or agreement .

Engagement was measured by the number of Facebook comments an individual posted during the 90-day intervention, including comments on posts and during live counseling sessions . First, marijuana users and non-users at baseline were compared on baseline demographic and smoking characteristics. Second, differences in reported smoking outcomes between users and non-users during the follow-up period were analyzed using a series of generalized estimated equations with binary distributions and logit link functions for dichotomous variables and a multinomial distribution with a logit link function for the ordinal variable . Longitudinal analyses controlled for intervention group and adjusted for baseline stage of change , baseline average cigarettes per day, sex, alcohol use, and age participants began smoking regularly. The first two covariates were determined a priori and the latter were selected based on the observed baseline differences between marijuana users and non-marijuana users. Because all participants were smokers at baseline, longitudinal analyses only included data from the three follow-up points . Largely due to attrition, there were 493 missing data points across all three time points on the abstinence variable, 498 on the reduction variable, 489 on the quit attempts variable, and 502 on the readiness to quit variable. GEE analyses are relatively robust to missingness, and a participant’s data could still be included in the analyses if they were missing one or more time points. Third, chi-square tests for independence were used to compare marijuana users’ and non-marijuana users’ perceptions of the intervention. An independent-samples t-test was used to compare treatment engagement between marijuana users and non-marijuana users in the treatment group. Baseline participant characteristics are displayed in Table 1. Marijuana users were more likely to be male, more likely to drink alcohol, smoked fewer cigarettes per day, and began smoking cigarettes regularly at an older age than non-users. Associations between smoking variables and marijuana use at each follow-up time point are displayed in Table 2. Use of marijuana by young adult smokers was associated with a lower likelihood of reduced smoking and a lower likelihood of abstaining from smoking in the past seven days, as assessed over 12 months of follow-up.

Marijuana users and non-marijuana users did not significantly differ in likelihood of having made a quit attempt or readiness to quit smoking . Moreover, users and non-users did not significantly differ in their perceptions of the intervention or treatment engagement . This study showed longitudinal patterns of marijuana use, point-prevalence abstinence from smoking, and reduction in smoking among young adults participating in a digital smoking cessation intervention trial. Most importantly, results showed that young adult smokers who coused marijuana were less likely to reduce their cigarette smoking or to have been abstinent from smoking than were those who did not use marijuana; however, they did not differ in readiness to quit smoking or likelihood of having made a quit attempt. Although smoking marijuana in addition to cigarettes increases young adults’ likelihood of negative physical effects , smoking marijuana may make quitting cigarettes more difficult in part by perpetuating the habit of smoking. Quitting smoking requires breaking associations or cues between the behavior of smoking and other contextual factors . Young adults commonly use marijuana in conjunction with cigarettes . Thus, continuing to use marijuana may hamper cigarette smokers’ efforts to change their behavior. Indeed, results showed that marijuana users were less likely to have recently abstained from smoking or reduced their smoking over a 12-month period. On the other hand, marijuana use status was consistently unrelated to readiness to quit smoking at baseline and during the followup period. Moreover, users and non-users did not significantly differ in the likelihood of making a quit attempt over 12 months. Results are consistent with research showing that young adult marijuana users do generally view quitting smoking as important , but have less ability to follow through with a complete abstinence goal despite a desire to quit smoking . Overall, our finding that marijuana users are less likely to report recent abstinence or reduction in smoking is consistent with extant literature suggesting that marijuana users are less likely to be successful at quitting smoking .

Encouragingly, marijuana users and non-marijuana users participating in the digital smoking cessation arm of the intervention did not differ in their perceptions of the intervention or their engagement in it. This suggests that young adults who use marijuana were receptive to the content and digital platform of the smoking cessation intervention. Future intervention content could highlight the negative effects continued marijuana use may have on quitting smoking, and could serve as a resource for young adults who want to quit using one or both substances. The variables most strongly and consistently associated with smoking outcomes over time were baseline stage of change for quitting smoking and marijuana use. Both should be assessed to inform treatment efforts with young adult smokers. Strengths of this study include multiple smoking-related outcomes, a 12-month longitudinal design, and a focus on young adults . This study had a few notable limitations. First, outcomes were self-reported. Our group has previously demonstrated the reliability and validity of young adults’ online self-reported tobacco and marijuana use , as well as the accuracy and limited bias of self-reported point prevalence abstinence in the present sample . Therefore, we opted to use self-reported abstinence,indoor farming equipment which had a much higher response rate. Second, current marijuana use was categorized into use versus non-use. It is possible that the relationship between marijuana use and smoking outcomes differs by heaviness of marijuana use, which our survey item did not assess. Although past research has shown that readiness to avoid marijuana use is significantly correlated with past 30 day marijuana use , future research should include a more detailed measure of marijuana use. The measure of alcohol use was similarly nonspecific, and a more detailed measure may yield different results. Moreover, up to twice as many of the participants indicated being abstinent for 7 days at each follow-up than identified as being in action/maintenance for having quit smoking. This was especially true of participants who were not using marijuana concurrently, as reflected in the significant difference in point prevalence abstinence and reduction between marijuana users and non-marijuana users. This finding may be due to the sample including non-daily smokers, and/or the young adult age of the participants. Based on self-report, 5-10% of the sample refrained from smoking for at least one week, yet were not committing to quitting. Future research could include more nuanced measure of marijuana use and measures of smoking specific to non-daily cigarette smokers. For the first time in several decades—and concomitant with the rise in opioid use, misuse, and dependence—life expectancy has declined in the United States, and life expectancy gains have stalled in Canada. Consistent with these global estimates, in an accompanying paper for the Special Issue, Astrid Guttmann and colleagues analyzed 2002–2016 national data from the United Kingdom and Canada to identify women who likely used opioids during pregnancy and demonstrated markedly elevated mortality rates over up to 10 years of follow-up. The elevated rates were particularly striking for mortality due to avoidable causes like unintentional and intentional injuries. Using 1998–2014 data from a large sample of primary care practices in the UK, John MacLeod and colleagues show that coprescription with benzodiazepines was highly prevalent among patients receiving opioid agonist and partial agonist treatment and that coprescription was strongly associated with drug-related poisonings. This study adds to the relatively thin evidence base about the potential hazards of benzodiazepine coprescription in the setting of opioid agonist treatment. Although opioid agonist treatment should not be with held from patients concurrently taking benzodiazepines or other central nervous system depressants, these studies suggest a need for vigilance by healthcare professionals providing care for such patients to minimize the risk of overdose or death.

Coprescription of alprazolam may warrant particularly heightened scrutiny, however, given that it is the short-acting benzodiazepine most frequently involved in drug overdose deaths.The elevated mortality risks facing people with opioid use disorders are attributable to a complex web of interrelated structural and psychological causes. The concept of the “risk environment” may be useful to reference here, given its focus on the interplay between various structural factors that increase vulnerability to morbidity and mortality. The study by Zehang Li and colleagues provides an example of the use of spatiotemporal data to characterize one aspect of the risk environment. Applying a Bayesian space–time model to emergency medical services dispatch data on suspected heroin-related overdose incidents from Cincinnati in 2015–2019, the investigators identified significant spatial heterogeneity in the distribution of these calls, with strong associations with features of the built environment and temporal spikes corresponding to local media reporting. Analyzing 2005–2016 claims data, Yu-Jung Wei and colleagues identified more than 200,000 adults with new claims related to opioid use disorder or overdose. They found that, by the end of the study period, nearly one-half had filled no opioid prescriptions in the 12 months prior to an incident opioid use disorder diagnosis or overdose. Among those who had filled opioid prescriptions, nearly three-quarters were prescribed a mean daily dose lower than the threshold needed to trigger most risk stratification algorithms. Also noteworthy is the analysis of 2015–2016 data from the US National Survey on Drug Use and Health by Joel Hudgins and colleagues. These authors found that approximately 1 in 20 adolescents and young adults reported either past-year opioid use disorder or past-year non-medical use of prescription opioids and that three-quarters of those reporting non-medical use of prescription opioids had obtained them from outside the healthcare system. These estimates are generally consistent with trends identified in similar, previously published analyses of NSDUH data. Thus, although opioid prescribing patterns undoubtedly played a significant role in how opioid use disorders came to be so highly prevalent and asymmetrically distributed in the US, a public health response that focuses solely on prescribing behavior is likely to be ineffective in reducing the number of fatal and nonfatal opioid overdoses.For people with existing opioid use disorders, opioid agonist treatment is known to reduce mortality. Monica Malta and colleagues add to this evidence base with a systematic review showing a wide range of health and prosocial benefits of opioid agonist treatment for people with opioid use disorders who are incarcerated or have recently been released. Opioid agonist treatment may have important collateral health effects as well. Analyzing data from a 3-country cohort of people who inject drugs, Charles Marks and colleagues found that people who inject drugs and who receive opioid agonist treatment are approximately half as likely to assist others in initiating injection drug use. They then developed a deterministic, dynamic transmission model of initiation into injection drug use, ongoing drug use, and cessation of drug use.

A greater presence of marijuana co-marketing in neighborhoods with a higher proportion of school-age youth and lower median household income raises concerns about how industry marketing tactics may contribute to disparities in LCC use. The study results also suggest that $1 buys significantly more cigarillos in California school neighborhoods with lower median household income. Policies to establish minimum pack sizes and prices could reduce the widespread availability of cheap cigar products and address disparities in disadvantaged areas. After Boston’s 2012 cigar regulation, the mean price for a grape-flavored cigar was $1.35 higher than in comparison communities. The industry circumvented sales restrictions in some cities by marketing even larger packs of cigarillos at the same low price, and the industry’s tipping point on supersized cigarillo packs for less than $1 is not yet known. The retail availability of 5- and 6-packs of LCCs for less than $1 observed near California schools underscores policy recommendations to establish minimum prices for multi-packs .A novel measure of marijuana co-marketing and a representative sample of retailers near schools are strengths of the current study. A limitation is that the study assessed the presence of marijuana co-marketing, but not the quantity. The protocol likely underestimates the prevalence of marijuana co-marketing near schools because we lacked a comprehensive list of LCC brands and flavor varieties. Indeed, state and local tobacco control policy research and enforcement would be greatly enhanced by access to a comprehensive list of tobacco products from the US Food and Drug Administration, including product name, category, identification number and flavor. Both a routinely updated list and product repository would be useful for tobacco control research,bud drying rack particularly for further identifying how packaging and product design reference marijuana use.

This first assessment of marijuana co-marketing focused on brand and flavor names because of their appeal to youth. However, the narrow focus is a limitation that also likely underestimates the prevalence of marijuana co-marketing. Other elements of packaging and product design should be considered in future assessments. Examples are pack imagery that refers to blunt making, such as the zipper on Splitarillos, as well as re-sealable packaging for cigarillos and blunt wraps, which is convenient for tobacco users who want to store marijuana. Coding for brands that are perforated to facilitate blunt making and marketing that refers to “EZ roll” should also be considered. Future research could assess marijuana co-marketing across a larger scope of tobacco/nicotine products. The same devices can be used for vaping both nicotine and marijuana. Advertising for vaping products also features compatibility with “herbs” and otherwise associates nicotine with words or images that refer to marijuana . Conducted before California legalized recreational marijuana use, the current study represents a baseline for understanding how retail marketing responds to a policy environment where restrictions on marijuana and tobacco are changing, albeit in opposite directions.20 The prevalence of marijuana co-marketing near schools makes it imperative to understand how tobacco marketing capitalizes on the appeal of marijuana to youth and other priority populations. How marijuana co-marketing contributes to dual and concurrent use of marijuana and tobacco warrants study, particularly for youth and young adults. In previous research, the prevalence of adult marijuana use in 50 California cities was positively correlated with the retail availability of blunts.

Whether this is correlated with blunt use by adolescents is not yet known. Consumer perception studies are necessary to assess whether marijuana co-marketing increases the appeal of cigar smoking or contributes to false beliefs about product ingredients. Research is also needed to understand how the tobacco industry exploits opportunities for marijuana co-marketing in response to policies that restrict sales of flavored tobacco products and to policies that legalize recreational marijuana use. Such assessments are essential to understand young people’s use patterns and to inform current policy concerns about how expanding retail environments for recreational marijuana will impact tobacco marketing and use.Patients with obstructive sleep apnea experience apneic and hypopneic events that, when untreated, have detrimental cardiovascular and neurocognitive consequences. Under normal conditions, blood pressure and heart rate decrease during non–rapid eye movement sleep and increase commensurately upon waking. This is attributed to a decrease in sympathetic nervous system activation and a subsequent increase in cardiac vagal tone during sleep . The transient episodes of hypoxemia and hypercapnia caused by apneas or hypopneas, as well as arousals, result in an increase in cardiac output and heart rate that leads to sympathetically induced peripheral vasoconstriction that causes a marked increase in blood pressure. The result of this chronic sympathetic excitation and inflammation does not resolve upon waking, and over time, together with the loss of the normal nocturnal blood pressure dip, it can lead to pathophysiologic changes such as impaired vascular function and stiffness . This impairment in the untreated patient with moderate to severe OSA has been found to increase the risk of both acute coronary syndrome and sudden cardiac death . The increased sympathetic nervous activity, inflammation, and oxidative stress seen in OSA can lead to hypertension.

The prevalence of hypertension in moderate to severe OSA ranges between 13% and 60%, and OSA is considered the most common cause of secondary hypertension . Arrhythmias can be common in patients with OSA, and the prevalence of atrial fibrillation is higher in these patients than in patients without OSA. In fact, severe sleep disordered breathing is associated with twofold to fourfold higher odds of having complex arrhythmias. In addition, untreated OSA has been associated with higher rates of failure to maintain sinus rhythm after cardioversion or ablation therapy . Inflammation, atrial fibrillation, and atherosclerosis are all associated with OSA and overlap with risk factors for cerebrovascular disease. OSA may be frequently diagnosed after stroke, and it can be difficult to determine whether the condition is causal or resultant. Evidence suggests that OSA is associated with an increased risk of stroke in elderly patients, and untreated OSA after stroke increases mortality risk during 10-year follow-up . Another disease state affected by sleep apnea is heart failure. Both OSA and central sleep apnea are common in patients with acute and chronic systolic and diastolic heart failure. Untreated OSA in this patient population has been associated with an increased risk of death. However, screening for sleep disordered breathing can be difficult because patients with OSA and heart failure often do not report excessive daytime sleepiness. This absent symptom raises challenges in diagnosis and treatment adherence for OSA . Untreated OSA can affect many cognitive domains, including learning, memory, attention, and executive functioning. Data suggest that OSA is linked with cognitive impairment and may advance cognitive decline or dementia . In addition, intermittent hypoxemia and sleep fragmentation have been linked to structural changes in the brain that may be responsible for cognitive impairment . Given the increased prevalence of obesity and the common nature of diagnoses such as hypertension, coronary artery disease, atrial fibrillation, heart failure, and neurocognitive impairment, healthcare providers should be cognizant of the hazards of untreated OSA .Positive airway pressure therapy is highly efficacious in treating OSA, but its effectiveness relies on adherence. There is a dose–response relationship between continuous PAP usage and clinical outcomes in OSA, although the optimal adherence threshold may vary depending on the clinical outcome of interest . Consequently, recognition of barriers to use and interventions to augment adherence are pivotal to the successful management of patients with OSA. Studies have explored potential modifiable and non-modifiable predictors of PAP adherence with inconsistent results . Most adherent patients have higher baseline daytime somnolence, possibly worse OSA severity based on the apnea– hypopnea index , higher self-efficacy ,4×8 tray grow and confidence for troubleshooting as well as greater social support, including bed partner engagement. Patients who have challenges with PAP adherence tend to have lower socioeconomic status, type D personality, high expectations in treatment outcome, claustrophobia, and small nasal passages. Patient age, sex, marital status, and amount of anxiety and depression have not been shown to consistently predict PAP adherence . Therefore, an individualized patient centered approach is recommended to optimize PAP adherence in OSA. Interrogation of PAP tracking systems can reveal patterns and the duration of PAP use and may help identify potential modifiable targets to improve adherence, such as mask leak . High residual AHI can point toward suboptimally treated obstructive events or the emergence of central events. Prompt and early troubleshooting of any side effects is important, as the pattern of PAP usage is established early and has been shown to predict long-term use.

Attention to mask fitting is essential, with otolaryngologic evaluation helpful in patients with narrow nasal passages or nasal congestion that may be amenable to surgery . Given the psychological influences on PAP adherence, educational and behavioral interventions aim to address patient perceptions and promote self efficacy. Motivational counseling by psychologists during appointments with follow-up phone calls has been shown to increase adherence by 99 min/night compared with control subjects . In a meta-analysis, behavioral therapy improved average PAP usage by 1.44 h/night and increased the number of nights with >4 hours usage from 28% to 47%, although the quality of evidence was low . In addition, studies exploring educational and behavioral strategies are limited by heterogeneity, often combining various modalities and thus making generalizations difficult. Increasingly, technological innovations are being used to improve PAP management and adherence. Cloud-based platforms and wireless capabilities offer real-time monitoring and active patient engagement. In a retrospective analysis of two cloud based databases, patients who actively engaged in real-time feedback through a website connected to their PAP devices had 87% compliance compared with 70% compliance in the usual-care group , as defined by the U.S. Medicare criteria for compliance . These technologies are also being incorporated in telemedicine. In a recent trial on telemedicine education and telemonitoring on CPAP adherence, patients randomized to receive web-based education and automated message feedback through telemonitoring had a Medicare adherence rate of 73% compared with 55% in the usual-care group . Modern PAP devices are including features in an attempt to improve comfort and adherence, including ramp, automatically adjusting pressures , expiratory pressure relief technologies, lighter interfaces such as nasal pillows, and heated humidification . Although none of these have been shown to consistently improve adherence, these technological advancements reflect ongoing efforts to personalize OSA management.Chronic insomnia, characterized by difficulties falling asleep, staying asleep, or early morning awakenings, is the most prevalent sleep disorder in the United States, affecting an estimated 10–15% of Americans. Symptoms occur despite adequate opportunity to sleep and are associated with daytime impairment, including impaired attention and cognition, increased risk of industrial and motor vehicle accidents, reduced work productivity, and increased healthcare costs . Insomnia is also a risk factor for multiple chronic health conditions, including cardiovascular disease , mood disorders, and pain conditions . Despite the widespread public health impact, insomnia remains both under recognized and under treated. Nearly two-thirds of patients with insomnia are unaware of available treatment options, and ~40% self medicate with alcohol and unproven over-the-counter sleep aids . Evaluation of insomnia should include a comprehensive sleep history, including sleep/wake routines , daily behaviors that impact sleep , and screening for comorbid sleep disorders . Given the high prevalence of concurrent mood disorders and other comorbidities, a thorough medical and psychiatric history is also warranted. Prior treatments for insomnia should also be reviewed. Use of a sleep diary to capture the patient’s habitual sleep patterns, including differences between weekday and weekend sleep routines, is very helpful. Comorbid depression and anxiety as well as pain syndromes are distinct but overlapping entities and should be treated concurrently . Current guidelines recommend multi-component cognitive behavioral therapy for insomnia as first-line treatment for chronic insomnia in adults . Data suggest that compared with pharmacotherapy, the effects of CBT-I are similar but more durable and have a better safety profile . CBT-I is also effective for insomnia in adults with comorbid moodand medical conditions, including conditions in which sleep medication may be contraindicated. The key components of CBT-I include sleep hygiene, stimulus control, sleep restriction, cognitive restructuring, and relaxation techniques .

Among Vancouver participants there was an apparent downward trend in the proportion of participants reporting recent homelessness across follow-up visits.The distribution of stabilized IPTWs was narrow at each follow-up visit in both settings, ranging from 0.65 to 1.40 in Tijuana and from 0.38 to 2.75 in Vancouver, respectively. Fig. 1 plots the distribution of log-transformed stabilized weights across follow-up visits for Tijuana and Vancouver. Given that, for each site-specific IPTW distribution, the mean untransformed weight over follow-up is approximately 1 , the interquartile ranges are relatively balanced, and the minimum and maximum weight values are not too extreme, we were satisfied with the estimated weights and did not alter them further prior to analysis. Based on our inverse-probability-of-treatment-weighted estimates – which are conditional on participants’ baseline age, gender, and their origin cohort – we found that recent homelessness was associated with increased odds of having recently assisted an IDU initiation event among PWID in Tijuana and Vancouver . In Tijuana , recent homelessness was associated with 66% greater odds of having provided IDU initiation assistance over the same six-month period. In Vancouver , recent homelessness was associated with 47% greater odds of having provided IDU initiation assistance over the same six-month period. Results of our sensitivity analyses indicate that, in both Tijuana and Vancouver, the weighting and adjustment procedures applied in this study attenuated the observed effect of recent homelessness on recently assisting IDU initiation. This is the first quantitative study to assess the longitudinal relationship between recent homelessness and assisting others in initiating IDU, while accounting for potential time varying confounders through inverse-probability-of-treatment weights. Based on 2619 visits made by 703 PWID in Tijuana over three years,vertical farming equipment we found that recent homelessness was associated with 66% greater odds of having provided IDU initiation assistance over the same six-month period.

Based on 5617 visits made by 1551 PWID in Vancouver, we found that recent homelessness was associated with 47% greater odds of having provided IDU initiation assistance over the same six-month period. Given the concentrated intersection of homelessness and IDU in North America, this study adds insight into the potential influence of housing on IDU initiation. Prior literature has indicated that experiencing homelessness may, for injection-naïve individuals, increase the risk of initiating IDU or, for former PWID, increase the risk of reinstating IDU – taken together with our results, these findings indicate that interventions aimed broadly at addressing homelessness, such as Housing First models , have the potential to reduce IDU and related harms via multiple pathways. Our findings in Vancouver are consistent with previous research exploring the dynamics of housing and IDU in the region. The Downtown Eastside of Vancouver, in particular, is an area with a high concentration of both homelessness and public IDU . Chami et al. found that, among a cohort of street-involved youth, that those living in the Downtown Eastside were more than twice as likely to initiate IDU compared to those living elsewhere. Further, findings from DeBeck et al. indicate that, throughout Vancouver, those experiencing homelessness are almost seven times as likely to report IDU in public spaces than those not experiencing homelessness. This high visibility and the high density of PWID in the Downtown Eastside may provide injection-naïve individuals ready access to those with knowledge about IDU practices and thereby make PWID who inject in public more likely to be recipients of injection initiation assistance requests. Given the high concentration of homelessness and public injection in the Downtown Eastside , these findings add an additional dimension to our understanding of this drug using context, particularly with respect to how the endemic homelessness experienced by many of its drug-using residents may be contributing to an expansion of IDU practices across injection-naïve individuals vulnerable to drug use transitions.

The context of IDU and homelessness in Tijuana, though, is substantially different than that of Vancouver. In particular, the over-policing of PWID experiencing homelessness may play a more determinative role in shaping IDU trajectories compared to housing status. It is noteworthy that a previous pooled analysis undertaken by our group, which included data from the same cohorts as the present study, found that a higher frequency of police interactions was associated with a higher odds of assisting IDU initiation . What this study also found, though, was that in Tijuana 71% of police interactions were arrests and detainments, whereas in Vancouver only 24% were arrests and detainments with 63% described as “neutral interactions” – indicating a more severe impact of policing on PWID in Tijuana than in Vancouver. It is likely that policing also plays a differential role for PWID experiencing homelessness in each of these settings. The over-reliance on policing in Tijuana is highlighted by the Tijuana Mejora program in which, from December 2014 to March 2015, law enforcement detained approximately 1000 people, most of whom were PWID, living along the Tijuana River Channel and forced many of them into unregulated, involuntary drug treatment programs . This indicates a potential mediating pathway, in which both IDU and homelessness in Tijuana increase exposure to policing, and that this exposure to policing then results in an array of harms. It is important that future research into the phenomenon of IDU initiation assistance be designed to capture and evaluate the validity of such mediating pathways in order to better characterize the role that experiencing homelessness may play in providing IDU initiation assistance across heterogeneous geographic settings. The provision of injection initiation assistance is a highly stigmatized behavior among PWID and, as stated in prior PRIMER studies, our outcome measure is likely prone to underreporting, which may have contributed in part to the low observed frequency of injection initiation assistance in our study . Non-probability sampling methods were used in both Tijuana and Vancouver to recruit participants, meaning our findings may not be generalizable to other populations and settings. While this study leveraged the longitudinal nature of the data, we modelled contemporaneous measures of recent homelessness and recent IDU injection initiation, i.e., both reflect behaviors over the same six-month period.

Correspondingly, it is possible that the observed association may be driven, in part, by the outcome causing the exposure . Despite reverse causality as an alternative explanation for our main findings, we elected to lag the covariate measures for a given visit to ensure that potential confounder values always preceded both exposure and outcome measures; if we had lagged both exposure and covariate values instead—to alleviate concerns of reverse causality—it is possible that some covariates, now contemporaneously measured with the exposure, might be acting as mediators versus as confounders, resulting in an effect estimate closer to the null. We observed a decline in the proportion of participants reporting recent homelessness across follow-up visit for Vancouver, which may indicate that participants experiencing homelessness were more likely to be lost to follow-up over time than those not experiencing homelessness. We note as well that research indicating more severe law enforcement exposure among people experiencing homelessness in Tijuana may have resulted in challenges in recruiting and following-up with participants experiencing homelessness due to higher rates of incarceration . Given that our homelessness exposure was operationalized differently in each setting, it is not immediately clear if the findings across settings are readily comparable. Finally, while estimates indicate that 40%–61% of PWID in North America experience homelessness each year,4×4 grow tray the proportion of participants in our study who reported an experience of homelessness in the past six months was substantially lower. This is likely due to the challenges of recruiting and retaining individuals experiencing more severe homelessness. If severity of homelessness is inversely related to selection into our study and also directly related to risk of providing injection initiation assistance, then our findings likely underestimate the relationship between severe homelessness and assisting in IDU initiation events among PWID. Δ 9 -tetrahydrocannabinol , the primary cannabinoid responsible for the psychotropic and biologic activities of marijuana , mediates its effects on the immune system by interacting with cannabinoid receptor type II . Although few immunologic studies have been carried out in active MJ smokers , we have documented that alveolar macrophages recovered from the lungs of habitual MS exhibit alterations in phagocytosis, bacterial killing and cytokine production . Using a variety of in vitro models and animal exposure studies, THC has also been shown to suppress the function of lymphocytes and dendritic cells , skew their cytokine production , promote the generation of myeloid suppressor cells , and prevent effective host responses to infections and tumors . A few epidemiologic studies have identified MJ use as a potential risk factor for opportunistic infections and progression from HIV to AIDS . However, when short-term MJ use was studied prospectively in a cohort of HIV-positive subjects it had no impact on systemic viral load, cytokine production or CD4 counts . Given the potent immuno suppressive properties of cannabinoids that have been observed in model systems and the potential implications for public health, the current study was designed to assess whether habitual MJ smoking has a similar adverse effect on adaptive humoral and cellular immune responses to a viral challenge. Matched cohorts of otherwise healthy non-smokers and chronic MS, who were naive to Hepatitis B virus , were prospectively recruited to receive a standard series of three Hepatitis B vaccinations.

HBV is a serious pathogen and vaccine responses to hepatitis B surface antigen are directly dependent upon the function of DC, T cells and B cells . As such, by examining the generation of adaptive immune responses to HBsAg, the intent was to carry out a realistic assessment of the potential impact of longterm MJ smoking on human immunity and adaptive host defenses. Peripheral blood was obtained from healthy volunteers with written informed consent and procedures approved by the UCLA Institutional Review Board. Peripheral blood mononuclear cells were isolated by ficoll density centrifugation. Monocyte-derived DC were generated by culturing adherent PBMC in X-VIVO 15 medium supplemented with GM-CSF and IL-4 according to a standard protocol . THC Drug Supply Program, Bethesda, MD) was added at the initiation of DC cultures at 500 ng/ml while control DC cultures received diluent alone . After 6 days, DC were purified by negative selection as previously described and cultured overnight with/without 40 μg/ml of hepatitis B surface antigen protein . Autologous CD3+ T cells were purified by negative selection and labeled with carboxyfluorescein succinimidyl ester to monitor proliferation in response to HBsAg-loaded DC that had been exposed in vitro to THC or diluent alone . Following 5 days of co-culture, non-adherent cells were recovered and analyzed by flow cytometry . Associated culture supernatants were evaluated for pre-selected cytokines by SearchLight® immunoassay .Interested volunteers provided written informed consent and all procedures were approved by the UCLA Institutional Review Board. Both men and women, 21 to 54 years of age, were eligible if they had never received prior HBV vaccination and met the criteria for either a NS or MS. Marijuana smokers were defined by a lifetime history of >10 joint-yrs of MJ smoking and current use of at least 5 joints/wk. Subjects with a history of routine tobacco or non-MJ substance abuse at any time in the past, or any use of such substances within the past 2 yrs were excluded. Non-smokers were defined as those with no history of tobacco, cocaine, MJ or other substance abuse on a regular basis and no use at all within the last 5 years. Any subject that had abused intravenous drugs or inhaled cocaine or methamphetamine was excluded. Urine drug screening was performed in addition to a detailed drug history questionnaire. Participants were also screened to exclude chronic illnesses that might impair vaccine responses or increase risks from smoking including chronic lung disease; active cardiac or vascular disease; kidney disease; seizures or significant psychiatric disorder; collagen-vascular disease, diabetes mellitus, cancer or HIV. Use of immunosuppressive medications within the past 30 days was excluded . A screening serum HBsAb titer was performed on all subjects to exclude those with evidence of pre-existing immunity to HBV . In addition, female subjects of child-bearing age who were pregnant, lactating or not using approved contraception were not allowed to participate.

Despite the success of antiretroviral therapy, approximately 20–50% of HIV-infected individuals have HIVassociated neurocognitive disorder. HIV infection and stimulation of monocytes and lymphocytes promotes trafficking into the central nervous system, triggering a neuroinflammatory response. Within the CNS, inflammation leads to activation of microglia, the resident immune cells in the brain, which induces chemokines and cytokines that drive a chemotactic gradient along the blood -brain barrier and allows further infiltration of infected and uninfected peripheral immune cells. Chemokines and cytokines function as immunomodulatory proteins that influence HIV neuropathogenesis with both positive and negative effects that may contribute to the ongoing prevalence of HAND. The chemokine C-C motif ligand 2 , alternatively known as monocyte chemoattractant protein-1 , is a b-chemokine that is expressed during inflammation and that, upon activation of its receptor , can induce chemotaxis of monocytes to inflammatory sites generated by injury and infectious events. CCL2 is expressed by monocytes, macrophages, dendritic cells, neurons, astrocytes, microglia and endothelial cells, while CCR2 is expressed by monocytes, microglia, astrocytes, epithelial cells, activated T cells and dendritic cells. CCL2 has been identified as the most potent activator of macrophages in comparison to other monocyte chemoattractants, including RANTES, macrophage inflammatory protein-1a , MIP- 1 b, MCP-2 b and MCP-3. CCL2 levels in the brain and cerebrospinal fluid are elevated in HIV patients with encephalitis, AIDS patients with cytomegalovirus, AIDS dementia and HIV-positive patients with cerebral inflammation. Recently,pruning cannabis peripheral blood monocyte expression of CCR2 has been shown to predict HAND in combination ART – era HIV cohorts. Elevated levels of CCL2 expression have also been observed in non HIV-positive samples.

In patients with mild cognitive impairment and Alzheimer’s disease, higher levels of CSF CCL2 correlated with lower cognitive scores. The presence of elevated CCL2 in HIV-positive patients with neuroinflammation, predictive power of monocyte CCR2 for HAND and elevations of CCL2 in non HIVpositive patients with neurocognitive deficits suggests that CCL2 may have a critical role in the neuropathogenesis of HAND and other noninfectious dementing disorders. A number of studies have examined genetic variation in the CCL2 gene and identified single nucleotide polymorphisms to be associated with HIV-disease progression and neurocognitive functioning over time. Individuals with an A to G polymorphism in the CCL2 enhancer region, annotated as rs1024611 , have higher CCL2 levels in serum, plasma and CSF than individuals without the A to G polymorphism. Increased CCL2 expression from the – 2578G allele has also been investigated in pathologic conditions and was found to be associated with higher incidences of tuberculosis, breast cancer and atherosclerosis, suggesting that the SNP is involved in chronic inflammatory conditions. Among HIV-infected individuals, homozygosity for the -2578G allele was associated with accelerated disease progression, enhanced leukocyte recruitment to tissues and a 4.5-fold risk for HIV-associated dementia. In a study examining the -2578G allele in a cognitively impaired population, elderly patients with senile dementia due to Alzheimer’s disease, CCL2 serum levels were significantly higher in patients who carried at least one G allele, whereas the highest levels of CCL2 were present in patients carrying two G alleles. The -2578G allele has also been reported to be associated with diminished performance in working memory over time in HIV infected individuals. The HIV-positive group who did not carry the -2578G allele improved at a faster rate in working memory than the HIV-positive group who carried the -2578G allele, but not faster than the HIVnegative groups. However, direct associations between the CCL2 rs1024611 SNP and HIV-disease progression have not been consistent across studies , suggesting that there may be intermediate mechanisms that mediate the association between CCL2 genotype, host immune responses and neurocognitive outcomes.

Although CCL2 expression in both plasma and serum has been linked to neurocognitive impairment, the purpose of the current study was to elucidate interrelationships between CCL2 genotype at the rs1024611 SNP, CCL2 levels in CSF, expression of other neuroinflammatory markers in the CSF. In addition, we considered plasma viral load, CD4þ cell count and neurocognitive performance in our analysis of HIV-infected individuals. We hypothesized that HIV-positive carriers of the CCL2 -2578G allele would exhibit high levels of CCL2 expression in CSF, and that elevated levels of CCL2 would be associated with higher concentrations of other proinflammatory markers in CSF, higherneurocognitive deficit scores, higher HIV viral load and a lower CD4þ T-cell count in blood plasma. We also hypothesized that accounting for CSF levels of CCL2 would explicate the relationship between CCL2 genotype and cognition.The cohort that was examined consisted of 145 HIVinfected individuals enrolled in the National NeuroAIDS Tissue Consortium cohort for whom CCL2 genotyping and CSF samples were available. The NNTC is a multicentre consortium engaged in a longitudinal study of adults with HIV/AIDS. The four participating clinical centres in the United States were The National Neurological AIDS Bank located in Los Angeles, California, USA; the Texas NeuroAIDS Research Center located in Galveston, Texas, USA; the Manhattan HIV Brain Bank located in New York, New York, USA; and the California NeuroAIDS Tissue Network located in San Diego, California, USA. Participants are administered a comprehensive battery of psychometric measurements that include tests of neuropsychological function and self-report instruments that estimate past and current substance and psychiatric illness. Neurological examinations, lumbar puncture for CSF collection and laboratory tests were conducted for plasma HIV viral load and plasma CD4þ lymphocyte count. The following were the inclusion criteria in the current study: at least 18 years of age, fluent in the English language, at least sixth grade education, able to provide informed consent.

Exclusion criteria were as follows: no history of CNS opportunistic infections , no history of traumatic brain injury, no history of learning disability or other developmental disorders and no other major neurologic syndromes .In line with previous reports, the results of this study showed that carriers of the -2578G allele had significantly higher levels of CCL2 in CSF. In addition, higher CCL2 expression was correlated with neurocognitive deficit score, higher levels of other proinflammatory markers in CSF, higher plasma viral load and lower CD4þ lymphocyte counts. We did not observe a significant interaction between CCL2 genotype at rs1024611 and neurocognitive deficit score, suggesting that carrying the -2578G allele alone does not appear to effect cognition. Instead, the findings suggest that increased expression of CCL2, modulated by CCL2 genotype, influences neurocognitive test performance. As expected, there was a strong correlation between CCL2 genotype and CCL2 expression, which led to the investigation of whether CSF CCL2 expression was acting as a moderating variable to the effects of CCL2 genotype on cognition. This suggests that the -2578G genotype results in a more reactive immune response, and increased viral load results in higher concentrations of CCL2 than normal, resulting in neurocognitive dysfunction. After controlling for CCL2 expression, the association between genotype and cognition emerged, indicating that CCL2 genotype has an effect on cognition, which may be moderated by CCL2 expression. Using plasma viral load to further probe the relationship between CCL2 genotype on cognition in the context of HIV infection,drying room we found that in the presence of high viral load, the CCL2 -2578G allele was associated with greater CCL2 expression and neurocognitive deficit. Although plasma viral load was used as a surrogate for CSF viral load , these results suggest that as HIV infection persists, carrying the – 2578G allele will lead to worse cognitive outcomes . The results also suggest that carrying the CCL2 -2578G allele and thereby expressing higher levels of CCL2 may contribute to or support a pro-inflammatory state in the CNS. We found that CSF CCL2 was associated with increased sCD14, sIL-6Ra, IL-2, IL-6, BAFF and sTNFR2. However, we are unable to determine whether increased CCL2 expression is a consequence of an already established pro-inflammatory state or if induction of CCL2 drives the pro-inflammatory immune response. Interestingly, in addition to CCL2, we found that BAFF and sTNFR2 correlated with cognitive performance; however, CCL2 was the only marker that was associated with CCL2 genotype. These results suggest that BAFF and sTNFR2 may also play an important role in neuroinflammation and cognitive impairment among HIV-infected individuals. B-cell activating factor , a cytokine that is a member of the TNF superfamily, plays a critical role in mediating B-cell differentiation, activation and survival to generate efficient B-cell responses.

Within the CNS, BAFF is expressed by microglia and astrocytes, with recombinant BAFF inducing secretion ofinflammatory markers, IL-6 and TNF-a, and IL-10, highlighting BAFF’s contribution to the inflammatory response. Consistent with our results, elevated levels of BAFF in CSF from patients with inflammatory neurological diseases, including HIV, have been reported to be significantly higher than in patients with nonin- flammatory neurological diseases. These findings highlight the importance of controlled BAFF expression for an efficient B-cell response, which is a contributing factor in HIV disease progression. Increased CSF BAFF may be indicative of neuroinflammation and may be important in the persistence of HIV within the CNS. TNFR2 is a receptor for TNF-a, a key regulatory cytokine in the inflammatory response, and upon binding, induces a signalling cascade to promote cell survival. TNFR2 is expressed by lymphocytes , microglia, oligodendrocytes, astrocytes, endothelial cells, myocytes, thymocytes and mesenchymal stem cells. Soluble TNFR2 can be generated via shedding from the cell surface and may act as a scavenger in a protective capacity by sequestering TNF-a to reduce TNF mediated inflammation. TNFR2 signalling in neurologic disorders and cognitive impairment has been examined and increased levels of sTNFR2 have been reported in CSF and plasma from patients diagnosed with bipolar disorder, mild cognitive impairment and AD compared with healthy controls. Increased staining for TNFRs has also been demonstrated in brains of individuals with HIV encephalitis and other opportunistic infections, and one report has described an association of plasma sTNFR2 with HIV-associated cognitive abnormalities. These results suggest that increased sTNFR2 expression in CSF may serve as a marker of the neuroinflammatory response to HIV and may play an important role in HIV neuropathogenesis and neurocognitive impairment. Our results indicate that individuals carrying the CCL2 – 2578G allele expressed higher levels of CCL2 in CSF and correlational analyses demonstrated that increased CCL2 was associated with increased pro-inflammatory markers, including sCD14, sIL-6Ra, IL-2, IL-6, BAFF and sTNFR2, in addition to greater cognitive deficit. These results are in line with previous studies reporting that increased levels of CCL2 are associated with a faster rate of cognitive decline. Furthermore, the CCL2- CCR2 axis was recently reported to be a critical signalling pathway in HAND, with CCR2 on CD14þCD16þ monocytes serving as a peripheral biomarker for HAND . Overproduction of cytokines in the CNS may allow for HIV-infected cells to persist in the brain despite antiretroviral therapy treatment. As stated previously, CCL2 expression was also correlated with plasma viral load. This is of particular clinical importance because the failure to adequately suppress viral replication may result in repeated BBB insults that further contribute to peripheral immune cell migration into the CNS. This is an area that requires further investigation and has the potential to inform therapeutic interventions. Owing to the cross-sectional nature of the current study, we cannot determine whether the expression of CCL2 is a precursor, consequence or simply correlative to cognitive status. It is possible that elevations in CCL2 expression in CSF may signal other inflammatory processes or genetic influences that were not evaluated in the current study. For instance, HIV-1 Tat protein is produced in infected astrocytes and may be secreted and taken up by neighbouring cells, and has been identified as a potential factor in the pathophysiology of HAND. Expression of the CCL2 gene has been shown to be directly transactivated by HIV-1 Tat protein in human astrocytes. Although we cannot determine from this study whether the CCL2 gene is solely driving the CCL2 gradient or whether the presence of infected cells or HIV- 1 Tat are also contributing to CCL2 expression, the results suggest a link between CCL2 genotype and cognition that warrants further study. Overall, these results underscore the importance of examining intermediate phenotypes as modulating factors that may link host genotype to cognitive outcomes in HIV.Treatment-seeking individuals with an alcohol use disorder exhibit a range of neurocognitive and inhibitory control deficits.

Participants provided written informed consent for participation.We assessed the prevalence, severity, and duration of pain using questions from the Brief Pain Inventory .We asked participants whether they had experienced pain or taken medicine for pain in the past week. Next, we asked participants to rate their average pain over the past week on a 0–10 numeric rating scale, where 0 was ‘no pain’ and 10 was ‘pain as bad as you can imagine’. We categorized average pain ratings as no to mild , moderate , and severe pain.If individuals indicated in response to the first question that they had not experienced pain in the past week, we classified their pain as ‘zero’. We asked participants with pain how long they had experienced their pain. We categorized these answers as ‘less than 3 months’, ‘3 months to 5 years’, and ‘more than 5 years’. We categorized participants with moderate to severe pain lasting over 3 months as experiencing chronic pain.We asked participants to rate how their pain interfered with their enjoyment of life and general activity on a scale of 0 to 10 .3 We categorized these responses as mild , moderate , and severe interference . We inquired about health conditions that are prevalent in this population and likely associated with pain, including arthritis, human immunodeficiency virus , diabetes, and traumatic brain injury .To assess for HIV infection, we asked participants whether they had ever been tested and if so, for the result of the test. We asked participants whether a clinician had ever told them that they had diabetes or arthritis. To evaluate for a history of likely TBI,cannabis drying racks we asked participants whether they had ever been hit in the head, and if so, whether any of the three most severe head injuries resulted in loss of consciousness.To assess the association of chronic pain with living environment, we used participants’ self report of the places where they had stayed for the prior 6 months.

We performed a cluster analysis to create a classification of living environments.We used Ward’s linkage to minimize the sum-of-square differences within groups. We performed visual analysis of a dendrogram representing the structure of the data to select the optimum number of clusters. Using bivariate matrices, we confirmed that we could identify natural groupings. We used kmedians cluster methodology to verify cluster classifications.We performed chi-square tests of significance for differences in the independent variables representing the domains we hypothesized to be associated with chronic moderate to severe pain. These results informed a multivariate logistic regression analysis in which we included all hypothesized variables that were associated at a p<0.2 level in the bivariate analyses. Then, we used backward selection to define our final, reduced model. We performed a sensitivity analysis to evaluate missing data in our final model by assuming that missing dichotomous variables were either positive or negative and measuring their effects on the observed odds ratios and confidence intervals. We performed all analyses with SAS 9.4 . A total of 350 participants completed the enrollment interview .Two people did not provide information on pain, leaving a sample of 348. The cohort was 77.3% male, 79.6% African American, and 74.4% high school-educated . The median age was 58 years, with a range from 50–80 years. Almost half of participants first experienced homelessness after turning. Almost half of participants reported being diagnosed with arthritis. Three-quarters endorsed a personal history of abuse. Nearly a third reported symptoms consistent with PTSD and over a third reported recent anxiety. Symptoms of depression and substance use problems were common .In the overall cohort, 17.2% reported moderate pain and 39.4% reported severe pain over the past week. Approximately half of participants reported experiencing chronic moderate to severe pain. The majority of participants experiencing pain reported chronic pain . The median duration of both moderate and severe pain was 5 years .

Most individuals with pain reported that it interfered with both general activity and life enjoyment. Participants with severe pain reported the most interference . We derived four categories of participants based on their current living environments: unsheltered , cohabiters , multiple institution users , and recently homeless . Participants in the unsheltered group spent a large portion of the prior 6 months in unsheltered locations; cohabiters spent a large portion of their time staying with friends and family; multiple institution users stayed in multiple locations including shelters, transitional housing, motels, and jails ; and renters, who had recently become homeless, spent a large portion of their time in rental housing.In the bivariate analyses, compared with the no to mild pain group, participants with chronic moderate to severe pain described significantly more depressive symptoms, PTSD, recent anxiety, arthritis, histories of traumatic brain injury, and histories of abuse . We did not find an association with living environment, gender, race, or substance use. We included significant variables as well as those that met the pre-specified criterion of p<0.2 in our full multivariate model. In our reduced multivariate model, we found significant associations between PTSD , arthritis , and a history of abuse with chronic pain . Depressive symptoms were not significant in the reduced multivariate model.In a sample of adults 50 and older experiencing homelessness, almost half of the participants reported chronic moderate to severe pain. While definitions for chronic pain vary within the literature, the prevalence of chronic pain in the general population ranges from 2.0% to 40.0%.Studies of pain in community living older adults found the prevalence of any pain to range from 28%–59%.Studies of pain in nursing home residents found the prevalence of pain to range between 32%–57%, with more than half of that reported to be moderate-severe pain.Despite the younger age of our sample, we found a higher prevalence of chronic moderate-severe pain. Participants reported their pain to be longstanding: three-quarters of those with moderate or severe pain reported that their pain had lasted for 5 years or more.

Participants reported a high prevalence of pain interference, which suggests that, despite other barriers faced by homeless adults, pain plays a role in reducing self-efficacy and quality of life.Consistent with other research, we found an association between a personal history of victimization,arthritis, and PTSD symptoms with chronic pain.In contrast to other populations,we did not find an association between either substance use, number of chronic medical conditions, nor depression and chronic pain. Our study population experiences a higher burden of chronic disease, injuries, substance use, and mental health problems, than the general population. Despite a median age of 58, our participants had a higher prevalence of functional and cognitive impairments than the general population of older adults in their 70s and 80s.The high prevalence of these factors, as well as unique factors associated with homelessness may explain the high prevalence of chronic pain in our sample.Homeless adults experience harsh environmental conditions: approximately half spent almost all of their nights outdoors, without shelter. A significant minority spent many nights in group shelter situations, where individuals may sleep on floor mats or low quality mattresses. These conditions may contribute to the high prevalence of chronic pain. The lack of an association between substance use and chronic pain may be due to its overall high prevalence in our sample. We found that PTSD was more prevalent than in the general population and that it was associated with chronic pain. More than 40% of those who experienced chronic moderate to severe pain and more than 20% of those who did not, had likely PTSD, compared to approximately 8% of the general population.These prevalence ratios are similar to those found in other studies of homeless populations. PTSD is common in homeless populations, possibly due to a high prevalence of traumatic childhood experiences,pots for cannabis plants high prevalence of experiencing interpersonal violence, exposure to violence while homeless, coexisting psychiatric disorders, and poor social support.Unstable housing status may itself contribute to the development of PTSD.Existing research conceptualizes the relationships between chronic pain and PTSD to be one of mutual maintenance.Mutual maintenance asserts that mental health and substance use disorders maintain or worsen existing pain, while pain worsens these underlying conditions. The effective management of both pain and mental health problems should incorporate treatment of pain and behavioral health conditions simultaneously and longitudinally.We found a high prevalence of arthritis and a strong association between arthritis and chronic pain. In studies of primary care in the general population, older individuals are more likely than younger ones to attribute pain to arthritis. Approximately one-quarter of chronic pain in adults ≥55 years is attributed to arthritis.In a previous study of chronic pain in homeless adults of all ages, between 9% and 24% attributed their pain to arthritis.

Homeless older adults may have fewer evidence-based treatment options for arthritis pain than the general population, due to difficulties accessing regular medical care, low-impact exercise, and healthy food choices.Finally, our study found that victimization throughout the life course was associated with chronic pain. Similar associations were found in other populations.The increased recognition of the role of trauma in chronic pain and other clinical conditions has led to the development of “trauma informed care” as an approach to address patients’ experiences of trauma. Trauma informed care refers to the reorientation of systems of care to incorporate a fundamental understanding of the role that traumatic experiences play in the lives and symptoms of people seeking care. Although limited data exists as to its effectiveness, especially for the relief of somatic symptoms such as physical pain, data that do exist suggest that trauma informed care reduces PTSD and depressive symptoms.While the efficacy of opioid analgesics for the treatment of chronic non-cancer pain is questioned, their use for this condition remains widespread.While older adults may, counterintuitively, experience a lower risk of overdose than younger adults,10 the cooccurrence of substance use disorders and the chaotic conditions of homelessness limit the use of opioids in this population. While multiple consensus statements describe multidisciplinary care as the best approach for the management of chronic pain, limited data are available to support its efficacy.Most studies showed only a modest effect for a minority of participants with no or minimal benefits lasting after six months.Even if this care were efficacious, homeless individuals face numerous barriers to engaging in longitudinal care, including their need to prioritize food and housing, lack of insurance or financial resources, inadequate transportation, and inability to communicate with clinicians between visits.The health care of patients experiencing homelessness and the challenges of managing chronic pain are both foci of increasing research interest,yet chronic pain remains largely understudied among homeless adults. Homeless individuals face many barriers to research participation, and in particular, few studies focused on the emerging population of older homeless individuals. Most existing studies of homeless populations recruit either from health care facilities or homeless shelters, which may not be representative. By using population-based sampling and focusing on older homeless adults, our study provides the first estimates of chronic pain in a high-risk, but poorly understood, group of individuals. Our data demonstrate that chronic pain is not only common, but that it has detrimental effects on life enjoyment and general activity in older homeless adults. By decreasing functioning, chronic pain presents yet another hurdle for marginalized and under-resourced individuals to receive much needed health care and social services. In addition to causing physical and emotional distress, chronic pain can hamper individuals’ abilities to obtain and retain employment and stable housing, let alone to manage other health problems. This study has several limitations. The analysis is cross-sectional, so we cannot identify causality. Only 12% of the study participants are aged 65 or over, reflecting, in part, premature mortality among homeless adults. While homeless populations are considered “older” by age 50,13, 14 the study population is younger than most studies of older adults. Study participants’ poor access to health care may lead to under reporting of chronic health conditions, limiting our ability to find associations. Due to the stigma associated with victimization, participants may have under reported experiences of verbal, physical, or sexual abuse. This misclassification would limit our ability to find an association between abuse and chronic pain, so our results could be interpreted as conservative. We did not assess pain related diagnoses, such as back pain, sprains, strains, or fractures, or obtain participants’ understanding of the causes of their pain. We did not attain data on how they managed their pain or whether they had received treatment, including medication, for their pain.

Craving likely represents a more proximal determinant of alcohol use than stimulation and sedation, which are shown to indirectly influence alcohol self-administration through craving . An additional exploratory aim was to test whether a characteristic of AUD severity, withdrawal-related dysphoria, moderated ibudilast’s effects on daily alcohol-induced changes in mood and craving. Notably, we found that individuals without a reported history of withdrawal-related dysphoria who were treated with ibudilast showed attenuation of alcohol-induced changes in craving, urge, and positive mood when compared to placebo. This tempering of alcohol’s effects may reflect ibudilast’s enhancement of antiinflammatory and neurotrophic factors suspected to impact dopaminergic signaling in rewards regions, such as the nucleus accumbens, where PDE4 and PDE10 are highly expressed . However, individuals who endorsed this withdrawal-dysphoric profile did not appear to benefit from treatment via this mechanism, such that ibudilast did not significantly blunt acute rewarding and reinforcing effects of alcohol. Although intriguing, these moderation findings should be interpreted with caution given the limited sample size, particularly the subgroup of individuals reporting experiences with withdrawal-related dysphoria . Despite these findings, preliminary analyses from this two-week RCT show that withdrawal dysphoria did not moderate clinical response to ibudilast regarding rates of heavy drinking or drinks per drinking day. Notably, these subjective response results are somewhat in contrast to what might be expected for individuals with a history of withdrawal and experiencing the “dark side of addiction”,cannabis indoor grow system such that these individuals may potentially show greater dysfunction of the immune system and thus may be predicted to have better response to an anti-inflammatory treatment, such as ibudilast.

However, it is suspected that other mechanisms may be central to the maintenance of AUD among individuals with withdrawal dysphoria, beyond the enhancing effects of alcohol. Namely, these individuals may primarily drink to feel ‘normal’ and alleviate physiological or psychological distress, particularly during early abstinence , which was not the focus on the current study. The present findings also differ somewhat from our laboratory’s initial efficacy trial of ibudilast, in which individuals with higher levels of depression showed attenuation of alcohol-induced increases in positive mood and ‘wanting’ during intravenous alcohol administration . A relevant difference between these studies is that participants enrolled in the efficacy trial were likely in a state of early abstinence, as they were asked to refrain from drinking for safety reasons; yet those enrolled in the present trial were not asked to change their drinking behaviors and consumed alcohol on roughly 60% of trial days and around 6 DPDD on average. In preclinical models, withdrawal increases the expression of innate immune markers in brain regions regulating autonomic and emotional states and while speculative, may thus represent a unique condition with the potential to impact ibudilast’s therapeutic effects. For instance, ibudilast reduced opioid withdrawal symptoms among individuals with heroin dependence and another PDE4 inhibitor, rolipram, diminished withdrawal-induced behaviors indicative of negative affect in rodents . Future research evaluating the impact of withdrawal states on immune signaling in larger clinical samples is needed to advance understanding of these complex processes and immune intervention. These findings should be considered in the context of the study’s strengths and limitations. One limitation is that DDAs were reported retrospectively once daily, which is less temporally accurate than EMA designs.

As such, items on subjective response and drinking were reported by participants concurrently the morning following a drinking episode and did not capture one’s subjective response level at a specific BrAC or blood alcohol curve limb. As such, this weakens our ability to draw a causal link between the effect of subjective response on alcohol intake and may introduce recall bias. Next, participants with more non-drinking days and incomplete DDAs during the trial are suspected to have greater error variance in their data given the lower number of observations with subjective response data. The lack of daily pre-drinking data on stimulation and sedation prevented us from examiningdaily changes in these variables, such that we could not account for pre-drinking levels. The sample was comprised of non-treatment seeking individuals with moderate AUD on average and the majority did not fall in the withdrawal-related dysphoria category. Future work with ibudilast in more diverse and treatment-seeking samples with more significant experiences of withdrawal-related dysphoria is needed. This study’s strengths include a clinical AUD sample enrolled in a rigorous double-blind RCT testing a promising novel pharmacotherapy. This trial displayed strong medication adherence rates and tolerability. Further, DDAs had high completion rates and the data comprise a substantial number of drinking episodes . Morning reports are also less likely to be affected by the intoxicating effects of alcohol that may lend to reporting errors, as could be seen with EMA or nightly reports. Finally, to our knowledge, this is the first study on the effect of immune modulation on subjective alcohol response in the natural environment. In closing, this daily diary study complements findings from our previous reports of ibudilast treatment for AUD by examining medication effects on subjective response during real-world drinking episodes.

The nuanced nature of the findings, including the distinction among those with and without withdrawal-related dysphoria and within vs. between person subjective response effects, speak to the heterogeneity of AUD and dynamic mechanisms maintaining alcohol use. Ibudilast’s effects on subjective alcohol responses, such as positive mood and craving, appear to be nuanced and perhaps most salient for individuals drinking for positive reinforcement as opposed to normalizing. Treatment with ibudilast potentiated the within-person relations between stimulation/ sedation and alcohol intake in this trial, such that an individual’s quantity of consumption on a given day appears to be more tightly connected to subjective response. The ecologically valid nature of these DDA, through retrospective reports of past day drinking and subjective responses to alcohol, provide a clinically useful window into how individuals experience and recall alcohol’s effects while taking ibudilast, compared to placebo. Novel medications and novel biological targets call for careful assessment of mechanisms beyond the “usual suspects”, such as changes in mean levels of subjective response and alcohol craving. Ultimately, the combination of multiple scientific approaches, including human laboratory, DDAs, neuroimaging, and biomarker assessment, offer complementary and clinically useful findings that can inform the development of ibudilast, and immune treatments for AUD more broadly.In 2021, an estimated 66,570 women in the United States will be diagnosed with uterine cancer and 21,410 will be diagnosed with ovarian cancer.Within each of these diseases, the worst outcomes are among patients with the rarest forms: uterine carcinosarcoma and ovarian carcinosarcoma . Although only 5% of uterine cancers are UCS,this aggressive disease causes 15% of all uterine cancer deaths.Similarly, between 1% and 4% of ovarian cancers are OCS, and patients with OCS have a shorter 5-year survival than those with other ovarian cancers .In part, these poor outcomes are because these patients often present at a late stage. For example,cannabis equipment more than half of patients with UCS present with regional or distant metastases,and 5-year disease-free survival is shortest in those with the latest stage disease . Outcomes are often poor even in those diagnosed with early-stage UCS; more than 50% of such patients experience disease recurrence, leading to death.Standard treatment for patients with UCS and OCS is surgery , peritoneal washings, and retroperitoneal lymph node assessment.Developing and testing treatments for these diseases has been hampered, as historically, UCS was treated with other sarcomas. However, recent evidence indicates that the carcinomatous components dictate tumor behavior,and molecular studies demonstrated that the sarcomatous components are derived from the carcinomatous components through metaplastic transformation.Thus, in 2009, the International Federation of Gynecology and Obstetrics mandated that UCS should be staged as an endometrial carcinoma.A 2013 Cochrane review of both published and unpublished data from the large phase III trials in UCS evaluated the efficacy of adjuvant radiotherapy, paclitaxel and ifosfamide , cisplatin, ifosfamide, and mesna, or ifosfamide alone. The review concluded that patients in the PI and cisplatin, ifosfamide, and mesna arms had longer overall survival and progression-free survival than those in the radiotherapy or ifosfamide-alone arms, but those in the cisplatin, ifosfamide, and mesna arm experienced greater toxicity than those in the PI or ifosfamide-alone arms. Thus, PI was established as the evidence-driven standard for treating UCS.

However, this regimen has three important limitations. First, it is difficult to administer, requiring 3 days of infusion. Second, it requires the use of growth factor support. Third, it is associated with a greater risk for central neurologic toxicity than other chemotherapy regimens, especially for older patients. Paclitaxel and carboplatin has been a standard regimen for epithelial ovarian carcinoma since the late 1990s and became the standard for endometrial carcinomas with the results of GOG-209.This regimen has been evaluated in small studies of patients with both OCS and UCS. For example, among 28 patients with OCS treated with PC, 16 had a complete response and six had a partial response, and the median OS for all patients was 27 months. Thus, PC was recommended for all stages of OCS.GOG-0232 evaluated 55 patients with UCS treated with PC and found that 13% of patients had confirmed complete response and 41% had partial response. The total overall response rate was 54% , which compared favorably with earlier ifosfamide-based regimens for similar patients.Given the limitations of PI noted above, the efficacy of PC in ovarian carcinomas, and the findings of small studies evaluating PC in patients with OCS and UCS, PC could be a good alternative to PI. Here, we tested the null hypothesis that PC was inferior to PI for patients with all stages of UCS and OCS.The study accrued 637 women between August 17, 2009, and March 24, 2014, at 176 sites across the United States and Korea. As of February 18, 2019, the median follow-up time was 61 months. Ninety-eight patients deemed ineligible on central review were distributed equally across treatment arms as shown in the CONSORT diagram . Of all eligible patients enrolled, 24 were never treated and 20 withdrew consent to continuous follow-up. Of the 449 eligible patients enrolled with uterine primary disease , 21 were never treated with protocol-assigned treatment . Select patient and tumor characteristics of the patients with UCS are shown in Table 1, and additional details are given in Appendix Table A1 . For characteristics of the patients with OCS, see Appendix Table A2 . Most participants were between the age 50 and 79 years and non-Hispanic or White and had a stage I or III uterine primary disease. More than 60% of patients completed all planned treatment, and the median time on treatment was 16 weeks from random assignment. Thirteen percent of participants discontinued treatment because of progression, 9% refused some or all treatment, and 13% discontinued treatment early because of AEs or death. Similar numbers of cycles of therapy were given to eligible patients in both regimens; 69% received four-six cycles of PC, and 70% received four-six cycles of PI. Major protocol violations occurred more commonly in the PI arm than in the PC arm and were often due to the complex dosing adjustments required in response to nadir blood counts.This open-label, randomized, phase III therapeutic non-inferiority clinical trial shows that PC is not inferior to PI in terms of OS and PFS and significantly increases PFS duration for patients with UCS. Findings were similar but not statistically significant in the smaller OCS cohort. Overall, the toxicity and patient-reported quality-of-life profiles were similar for the two drug regimens. These results establish that PC should be used as a standard regimen for patients with UCS and should be considered for treating patients with OCS. These findings are important because PC is easier to administer than is PI. Moreover, patients with UCS could be considered for inclusion in clinical trials for patients with the more common epithelial sub-types of uterine cancer treated with PC. Similarly, it may be reasonable to combine OCS patients with other epithelial subtypes in ovarian cancer trials. Both UCS and OCS have significant racial and age disparities in risk and outcome. For example, UCS occurs up to three times more frequently in Black women than in White women, and this disparity appears to be increasing. In addition, carcinosarcomas are most common in older women; the mean age at diagnosis is 68 years.In part, this is because tamoxifen and previous radiation therapy are likely risk factors.

More importantly, greater reductions in discounting predict a greater likelihood of protracted abstinence among cocaine users and smokers . Thus, if a causative link between D2 /D3 receptor availability and temporal discounting is established, it may lead to the development of novel D2 /D3 -targeted interventions which could be used to more effectively treat a variety of disorders. In conclusion, the results of this study indicate that low D2 / D3 receptor availability is associated with steep temporal discounting. This link may explain why some individuals choose to continue using drugs despite knowledge of their future negative consequences, and could help to guide strategies for treating substance abuse and other psychiatric disorders.Dissociation, which involves detachment from one’s physical and emotional experiences and is associated with symptoms such as depersonalization , de-realization , and other amnesic/ fugue states, is generally understood to be a psychological defense in the face of current and past trauma . There is some evidence that dissociation is linked to genetic factors within the context of early trauma exposure . Furthermore, childhood physical and sexual abuse are associated with elevated dissociative symptoms in homeless veteran populations and younger populations including homeless teens . In fact, child abuse appears to be one of the more robust predictors of dissociation in adulthood . Adult survivors of childhood abuse are more likely to experience dissociative symptoms than individuals who are not survivors of childhood abuse in both clinical and non-clinical populations . Several studies across a variety of cultures and populations have demonstrated that survivors of childhood sexual abuse are more likely to develop dissociative symptoms than those who have experienced other types of childhood abuse . Furthermore,4×8 grow table with wheels numerous studies have noted that individuals who are victims of childhood abuse are more likely to become victims of violence in adulthood .

Given that survivors of childhood abuse are at increased risk of exposure to other traumas across the lifespan , Chu has suggested that dissociation experienced after childhood sexual abuse may mediate the influence of childhood sexual abuse on future increased risk for adult violent victimization . Although the mechanisms behind violent victimization remain varied and unclear, it is suggested that elevated dissociative symptoms may be linked to a suppressed anticipatory anxiety response, which increases the likelihood that individuals with a history of childhood abuse may put themselves in potentially dangerous situations . One study that investigated the relationship between post traumatic stress disorder and dissociative symptoms in a sample of college women found no evidence that dissociative symptoms mediated violent victimization . However, other studies have found evidence that dissociation may be associated with an increased likelihood of violent physical and sexual victimization in both clinical and non-clinical adult samples . Whether differences in results are due to different populations, different research questions, or other factors is unclear. Few investigations have directly assessed the relationship between violence and dissociation among homeless and unstably housed women and none have attempted to establish a causal or directional relationship between child abuse, dissociation, and recent adult violent victimization. The dearth of relevant research leaves a notable gap in our understanding of how childhood abuse and dissociation may lead to violent victimization, especially for particularly vulnerable populations such as homeless and unstably housed women. Our prior work among homeless and unstably housed women found extremely high levels of childhood abuse , as well as recent violent victimization . Within the same sample of homeless and unstably housed women, we have also shown that recent sexual violence is strongly associated with other subsequent negative outcomes such as the increased likelihood of stimulant use initiation .

The disproportionately common occurrence of violence against unstably housed women, and the strong influence of violence on a variety of other mental health conditions, makes these critical issues to address in this population . The current study aimed to increase our understanding of the relationships between childhood abuse, dissociation, and violent victimization in the same population of homeless and unstably housed adult women. Using the Chu model, which hypothesizes that dissociation resulting from childhood sexual abuse increases risk for future sexual violence, as a frame we asked women to report any violent victimization six months prior to an initial assessment and in the intervening six months prior to a followup assessment. Our hypothesis was that after accounting for psychiatric comorbidity and other sociocultural factors unique to homeless persons, childhood physical abuse, childhood sexual abuse and dissociation would still predict both physical and sexual violence between the initial assessment and the six-month follow-up interview. We also hypothesized that dissociation would mediate the influence of childhood physical abuse and sexual abuse on physical and sexual violence. This prospective analysis was conducted within the Shelter, Health, and Drug Outcomes among Women Study, a community-based observational cohort study designed to understand risks for poor health and victimization among homeless and unstably housed women. As we have described elsewhere , a mobile outreach team used systematic probability sampling to recruit a cohort reflective of the larger San Francisco homeless and unstably housed female population. Details regarding recruitment have been previously published . In brief, study participants were recruited from homeless shelters, free meal programs and low-income single room occupancy hotels. Eligibility was limited to biological females who were ≥ 18 years old and who had a history of housing instability .

Three-hundred homelessness or unstably housed women were enrolled in the cohort between 2008 and 2010, and followed every six months for a total of 7 time points ranging for a follow-up period of up to 3 years from recruitment date. In accordance with the aims of the parent study, HIV-positive women were over sampled so that they comprised 50% of the total cohort. The two-hundred-eighty-one participants who completed enrollment and 6- month follow-up interviews were included in the current study. Participants engaged in check-in visits with study staff between semi-annual study visits to update contact information and to ensure they remained engaged in study activities. All participants provided written informed consent. Upon enrollment, structured interviews were conducted in a private space at a community-based field site. Study questionnaires were interviewer administered. Socially sensitive questions, including those regarding violent victimization and drug use, were administered via an audio computer-assisted self-interviewing approach in which participants listened to questions through headphones and entered responses into a computer. All questionnaires and study procedures were pilot tested to ensure appropriateness for the target population. Reimbursement of $15 was given for each study interview. Study procedures were approved by the Institutional Review Board at the University of California, San Francisco.Measurement of violent victimization—Violent victimization was assessed using questions based on the Severity of Violence Against Women Scales ,grow tray stand which were tested previously in this cohort . Physical violence was defined as being hit, slapped, kicked, bitten, choked, shot, stabbed, or struck with an object. Sexual violence was defined as being forced to have sex of any kind. Physical and sexual violence occurring before age 18 were classified as childhood abuse. Adult violent victimization occurring in the preceding six months was assessed at the baseline and at the six-month follow-up. Dissociative Experiences Scale—Dissociation was assessed at the initial assessment using the Dissociative Experiences Scale , a 28 item scale where items related to dissociative experiences are rated on a 10-point scale. Items assess feelings of depersonalization they actually see themselves as if they were looking at another person. What percentage of the time do you have the experience?”, de-realization , and other dissociative experiences . The DES demonstrates excellent convergent and predictive validity in clinical and non-clinical populations . Higher scores on the DES indicate more self-reported dissociative experiences. The DES total score was computed as the sum of the 28 items. The DES does not provide a diagnosis of a dissociative disorder; however, for the purposes of this study it was defined as a score > 45 . Individual characteristics—Demographic, social, structural, and behavioral characteristics previously associated with health and violence among low-income women were used to describe the cohort.

Socioeconomic status was measured in terms of dichotomous indicators of low income , any unmet subsistence needs Gelberg, Gallagher, Andersen, & Koegel, , and homelessness . Substance use was measured by dichotomous indicators of any current cocaine use, any current methamphetamine use, any current opiate use, and current at-risk alcohol use . Mental health diagnoses were assessed at the initial assessment by the computerized Diagnostic Interview Schedule for the DSM-IV . Thirty-nine psychiatric diagnoses were assessed, including anxiety disorders , mood disorders , psychotic disorders , substance use disorders associated with alcohol, amphetamines, cocaine, opiates, and sedatives; abuse and dependence associated with hallucinogens, inhalants, marijuana, and phencyclidine; and dependence on other drugs, as well as somatization disorder, pain disorder, and dementia. All diagnoses assessed the presence versus absence of disorders. STATA Statistical Software: Release 13.1 was used to conduct all statistical analyses . Descriptive statistics were first generated for the variables described above. We then employed two separate hierarchical logistic regression models to understand the effects of four main characteristics on physical violence and sexual violence at the six-month follow up. The four main effects were childhood physical abuse, childhood sexual abuse, violent victimization during the six months prior to the initial assessment, and dissociation reported at the initial assessment. Specifically, physical violence in the six months prior to initial assessment was used to predict physical violence in the six months after initial assessment. Similarly, sexual violence in the six months prior to initial assessment was used to predict sexual violence in the six months after initial assessment. Main effects were estimated controlling for age, race, and, in accordance with our prior work regarding significant correlates of violence in this cohort , whether participants had recently experienced unmet subsistence needs. Ten theoretically and diagnostically relevant psychiatric diagnosis variables were created from the thirty-nine diagnoses assessed by the DIS. Related diagnoses were grouped into categories reflecting depressive, anxiety, bipolar, psychotic, alcohol, cannabis, amphetamine, cocaine, and opiate disorders, while uncommon diagnoses, such as dementia, were not included. We then used the Variance Inflation Factor to evaluate multicollinearity. Out of the ten psychiatric diagnoses, two highly dependent variables, any anxiety disorder; VIF = 13.02 and any bipolar disorder; VIF = 12.56 were dropped from the final list of variables that were included in the final analyses due to multicollinearity . Hierarchical modeling included four steps. The initial model included age in years, race, and dichotomous indicators of unmet subsistence needs, and violent victimization in the six months prior to initial assessment. The second step of the model included childhood physical abuse and childhood sexual abuse. The third step included mental health and substance use diagnoses. The final step included dissociation as measured by the DES total score. Interactions between dissociation and relevant covariates such as the presence of a substance use disorder were also tested because substance use is associated with symptoms similar to dissociation. Omnibus χ2 tests were used to assess model fit in predicting either physical violence or sexual violence at each step of analysis. McFadden’s R2 was used to assess proportion of model variance explained. Wald χ2 tests used to assess whether each subsequent model was incrementally more predictive of violent victimization from the previous one. Mediation analyses were based on significant relationships between childhood physical and sexual abuse, dissociation, and physical and sexual violence identified in the logistic regression analyses. Bootstrapping was used to assess whether dissociation mediated childhood abuse and violent victimization. Bootstrap estimates on 10,000 replications were obtained using a user written binary mediation ado program in conjunction with STATA’s native bootstrap code. Bootstrapping is generally recommended over other methods of testing indirect effects because it does not assume normality and has greater power while maintaining control over Type I error rates . Compared to the entire cohort , a lower proportion of study participants included in follow-up analyses were homeless at baseline ; no statistically significant differences existed between excluded and included participants according to drug use or mental health variables. Among those enrolled, 93% completed a six-month followup and were included in the current analysis . Approximately 70% of study participants included in the current analysis were women of color. The mean age was 47 years .