Hemp Growing

The symposium addressed the intricate relationship between epilepsy and other medical conditions. Dr Scott Mintzer kicked off the symposium with his talk “Epilepsy & Heart Disease: Tips for the Consultant.” He identified the impacts of anticonvulsants on the cardiovascular system and the interactions between antiepileptic drugs and cardiac medications. Hepatic enzyme inducing anticonvulsants are associated with worse lipid profiles and vascular risk markers and reduce the efficacy of some cardiovascular medications, such as statins.1 Older anticonvulsants, such as carbamazepine, may even be associated with increased risk of myocardial ischemia. Dr Steven Pacia presented “Syncope and Other Seizure Mimics,” where he reviewed key clinical features that distinguish seizures fromsyncope and other seizure mimics such as migraine, transient ischemic attacks, metabolic disorders, nonepileptic psychogenic seizures, transient global amnesia, and sleep disorders.Some, such as prolonged QT syndrome, should not be missed.Dr. Andres Kanner led the discussion on “Do Psychotropic and Antibiotic Drugs Cause Seizures? A Review of the Evidence.” He reviewed selection of antibiotics and psychiatric medications that would minimize seizure risk. Therapeutic doses of serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants appear to be associated with reduced seizure incidence, though overdoses of these classes of medications can be associated with increased risk of seizures.Bupropion and clomipramine were the exceptions to the rule,vertical grow system and seizure risk was increased with these medications compared to placebo. Antibiotics may increase the risk of seizures.

The mechanism by which antibiotic lower seizure threshold may be decreased GABAergic activity. Dr Page Pennell discussed the management of AEDs during pregnancy to optimize seizure control and pregnancy outcomes in her talk “Seizure Management during Pregnancy.” Her presentation reviewed the teratogenic risk of AEDs and other pregnancy outcomes including “small for gestational age” .Valproate was also associated with lower IQ in childhood and increased risk of autism. On the other hand, folate prescribed before pregnancy or at start of pregnancy was associated with higher IQ and lower risks of autism. There are changes in pharmacokinetics of AEDs during pregnancy and dose adjustments are needed to maintain seizure control. Dr Jeanne Young discussed “Anticonvulsants and the Skin Hypersensitivity”. Dr Young emphasized the diversity in hypersensitivity associated with AEDs, distinguishing drug rash based on pathophysiology and clinical characteristics, and recognizing clinical features that could alert us to severe cutaneous adverse reactions. The most common type of reaction is a morbilliform rash with erythematous papules or plaques due to immune complex deposition and cell-mediated immunity. These rashes characteristically begin 7 to 10 days after starting medication and typically resolve in 2 to 3 weeks. Patients usually feel well, though they may complain of pruritis. Interestingly, in some cases it is possible to “treat through” the rash, or re-challenge later with the same medication, with the patient under close observation by dermatology. Signs characteristic of more severe drug reactions are swelling of the face, presence of pustules, bullae, or vesicles, dusky or painful lesions, mucous membrane involvement, or signs of systemic involvement. Morbilliform skin eruptions beginning later than expected along with systemic symptoms and patient feeling ill are more concerning for progressing to Drug Rash with Eosinophilia and Systemic Symptoms syndrome.

The neurobiology of memory has long been a central issue in epilepsy, particularly for syndromes involving mesial temporal lobe structures. While Ramon y Cajal first detailed the neuroanatomical structure of the hippocampus more than 100 years ago,it was the well-known case of “H.M.” that revealed the prominent role of the hippocampal formation and related structures in declarative memory.Patients undergoing temporal lobe resection for control of pharmacoresistant seizures may experience postoperative memory decline. Preoperative reorganization of the posterior hippocampus with transfer of function to contralateral and extratemporal structures including anterior cingulum and insula may be a key factor in preservation of memory function,and there may be a role for memory functional magnetic resonance imaging studies in individualized outcome prediction.There is also evidence that the choice of surgical approach has important implications for postoperative memory outcomes.Even apart from surgical intervention, memory deficits are a common comorbidity in epilepsy. At the cellular level, seizureinduced epigenetic dysregulation likely plays an important— but little understood role. Abnormally regulated BDNF DNA methylation was explored in a rodent temporal lobe epilepsy model, and was shown to have a dual role in modulating both epileptiform abnormalities and memory impairments.Memory consolidation is an important mechanism supporting long-term memory that may also be disrupted by epileptiform activity. Studies of human multi-scale and animal recordings demonstrated locally recorded cortical replay of waking patterns during subsequent sleep periods.This process involves an intricate coordination of cortical up and down states, hippocampal sharp-wave ripples and thalamocortical spindle activity, with distinct roles played by the anterior and posterior hippocampus. Finally, building on the previous year’s symposium, early results from a recent high-profile study of the use of cortical electrical stimulation to improve memory function were presented.

In a promising development, successful enhancement of hippocampal-dependent memory in patients with epilepsy has now been reported with lateral temporal stimulation and independently in entorhinal white matter using q-burst stimulation.Emilio Perucca, MD, PhD, focused on the rational use of anticonvulsant medication and reviewed a systematic approach to sequencing and combining antiepileptic medications. Given the extensive choice of treatments, an evidence-based systematic approach is important when treating patients.The literature contains a number of comparative studies, though more evidence is needed, particularly when planning polytherapy. Different clinical scenarios were provided to illustrate his approach, and he highlighted areas in which further knowledge must be obtained. This approach to therapy, which is driven by data and experience, offers a masterful way to treat epilepsy. The second lecture, given by Dennis Dlugos, MD, “What’s in the Pipeline? Newly Approved and Almost Ready Antiepileptic Drugs” provided a review of both recently approved medications and drugs that are presently in the pipeline, but anticipated to enter the clinical arena. Professor Dlugos reviewed pivotal trial data, both with regard to efficacy and adverse effects. Pipeline drugs show promise for both generalized and focal epilepsy. It is hoped that the information provided in this lecture will enable the practicing physician to integrate the use of these agents into practice once they are available. The third lecture, delivered by Barbara Dworetzky, MD, reviewed rescue therapy, with a particular focus on new and emerging treatments. Trials have been conducted employing several benzodiazepines, including diazepam, midazolam, and alprazolam. These new therapies may be administered intranasally, or in the case of alprazolam, by inhalation, though the latter agent has only recently entered the trial phase. Professor Dworetzky reviewed the pharmacology and trial results; these preparations do not require rectal administration and may prove a popular choice by patients and their families when rescue is needed. The final lecture, given by Jukka Peltola, MD, reviewed deep brain stimulation of the anterior nucleus of the thalamus for intractable epilepsy. This therapy was recently approved by the Food and Drug Administration in the United States,indoor vertical garden systems but has been in use in Europe since 2011. Professor Peltola reviewed both clinical trial data and the European clinical experience, and proposed suitable indications for employing this therapy.The symposium encompassed topics ranging from basic science, translational research, clinical trials, adverse effects, nutritional guidance, and possible anti-inflammatory benefits. Dr Susan Masino covered “Cellular metabolism as a paradigm for experimental therapeutics in epilepsy.” She discussed the 4 major possible therapeutic targets of metabolism-based therapies: changes in blood and cerebrospinal fluid , improved mitochondrial function and energy reserves, synaptic stability, and cellular changes including alterations in the gut microbiota.Dr Kristina Simeone then tackled “Metabolic approaches for treating complications and comorbidities of epilepsy.” She focused on how these therapies have been shown in preliminary studies to benefit cognition, autism, behavior, sleep, and even SUDEP .Dr Elizabeth Donner reviewed “Clinical evidence for metabolism-based therapies in children: trials and guidelines.” In her lecture, Dr Donner first covered the strong evidence from multiple randomized controlled trials for ketogenic diet therapy, then provided an overview of the updated 2018 revised international consensus guideline.The fourth lecture was given by Dr Anita Devlin and was titled “Ketogenic Diet for Infants?”

Two specific epileptic encephalopathies affecting infants have evidence for treatment response to ketogenic diet.20 Dr Devlin ended by discussing the ongoing “KIWE” trial in the United Kingdom which has been enrolling infants 1 to 24 months of age into a randomized trial of the ketogenic diet versus further antiseizure drugs. Robyn Blackford, RD, provided a dietitian’s perspective on handling the adverse effects from these dietary interventions in a lecture entitled “Safety and prevention of risks from metabolism-based therapies.” Finally, Dr Stephane Auvin ended the symposium with a basic and clinical science lecture on “Are there anti inflammatory effects of metabolic therapies?”, with a focus on refractory status epilepticus and Febrile Infection-Related Epilepsy Syndrome .In summary, this symposium achieved its goal of highlighting how the ketogenic diet and other metabolism-based treatments have become “state of the art.” This symposium addressed bioethics in 4 areas: transition to adult care delivery of behavioral health services using technology self-management interventions and outcome measures, and anti-seizure medication. General ethical principles, including respect for autonomy, nonmaleficence, beneficence, and justice as they pertain to comprehensive care of persons with epilepsy were covered. Dr Eric Racine articulated the nuances of respect for autonomy in the transition from pediatric to adult care for persons with neurodevelopmental disabilities. Autonomy includes 6 component abilities: voluntariness , information , control , deliberation , authenticity , and enactment .Dr Hamada Altalib discussed ethics in employing technology to deliver behavioral health care to PWE, including specifically challenges related to consent, privacy, confidentiality, and the patient–provider relationship. Insight into howtele health and mobile health can improve justice and equity by removing barriers to care such as transportation and resource disparities. The VA Epilepsy Center of Excellence was presented as a model for mobile behavioral health care. Appropriately implemented technology can revolutionize the range and standard of care. Dr Martha Sajatovic covered self-management support and collecting behavioral outcomes. Given the high rate of mental health comorbidities and barriers to in-person behavioral health care, the SMART intervention contains one in-person session with a nurse educator-peer educator dyad and then 7 group sessions in a web-based format. Following SMART, PWE who had experienced a negative health event reported decreased depressive symptoms and improved quality of life versus people on a wait list.23 There are ethical considerations, such as group confidentiality and the role of patients as peer educators. Findings from 5 pooled managing epilepsy well network randomized controlled trials demonstrated a reduction in depressive symptoms following self-management interventions. Research relies on integrated research datasets.However, there are multiple ethical issues to consider, including protected health information, data sharing agreements, firewalls, and authorship. Dr Viet Nguyen addressed ethics in selection of AED therapy. Beneficence and nonmaleficence must be balanced when identifying epilepsy management goals and related costs, and the role of justice was also discussed. Patients express concerns with AED changes, and clinicians must manage adverse effects to promote improved quality of life. Patients have a right to choose their therapy and there must be the balance of autonomy of choice with adequate treatment.Caring for patients with epilepsy is both a science and an art. This statement has never been more accurate than today. Faced with an exponential growth in diagnostic technology and novel therapeutics, the variety of choices that we have to make have become much more complex. Yet, robust data on comparative effectiveness and for evidence-based decision making are lacking. This information deficit is at the root of the significant variation in our practices, and sub-optimal patient care. Considering several current controversies in the management of difficult epilepsies, some challenges stand out. First, the frequency and indications for some tests that are considered cornerstones of our epilepsy management remain highly variable and require balancing multiple factors, including the treatment goals of the patients, risks, alternatives, and cost. The indication for a video EEG study is a perfect example. This inpatient testing is warranted to confirm the diagnosis of epilepsy and rule out psychogenic nonepileptic seizures in patients who continue to have seizures despite 2 or more adequate and appropriate antiepileptic drug trials. Conversely, holding off the initiation of seizure medications until a diagnosis of epilepsy can be positively confirmed with video EEG is clearly inappropriate in patients at high risk of seizure related injuries, nocturnal convulsions with increased risk of sudden death in epilepsy, existing medical comorbidities , severeictal or postictal behavioral disturbance, and in resource-limited communities.

Proposals to equalize these limits would likely spur greater tax revenue collection in certain parts of the state. Thus far, beyond funds earmarked for school construction, marijuana revenue has financed the regulatory apparatus necessary to oversee the state’s growing recreational and medical marijuana marketplace. Marijuana revenue has also been allocated to youth drug prevention, public safety, and public education. State officials have launched several advertising campaigns to inform residents and tourists about marijuana laws and regulations regarding its use. To date, more than $5 million has been spent on these public awareness campaigns with more to come. The amount the state is permitted to spend may depend on whether voters collectively decide to let it keep revenues in excess of TABOR limits. Close to one billion people are affected by mental illness and substance misuse worldwide. In many developed countries, mental illness ranks top for burden of disease , is more common, impactful and costly than other health conditions, and is a core component of overall health. The total cost of mental illness in the USA is estimated to be $2.5 trillion , the global antidepressant market is worth over $13.5billion and the wellness sector is estimated to be worth over $4.5 trillion . Despite record increases in psychiatric medication prescription rates, the prevalence of mental illness is not reducing and may well be increasing in certain populations,flood tables for greenhouse such as the young . There are indications that rates of mental illness have increased during the coronavirus disease 2019 pandemic .

Evidence indicates that the efficacy of leading drug and psychological interventions is modest, and there is scope for improved tolerability and access . Most mental health interventions are reactive. Effective prophylactic intervention would be hugely valuable . Relatedly, early life trauma and mental illness are reliable predictors of future morbidity. There is a legacy of division between the biological and psychological arms of mental health care and research. A notable initiative towards innovation in biomedical psychiatry is the Research Domain Criteria . The main principle of RDoC is that, since diagnostic criteria are a product of clinical expediency, transdiagnostically relevant pathological mechanisms and treatment targets may have been overlooked. Relatedly, there is now good evidence for genetic overlap between psychiatric disorders . RDoC is primarily a biological initiative that aims to translate mental illness into ‘brain illness’, for the purpose of discovering candidate brain biomarkers and treatment targets . Notable initiatives towards innovation in psychological health care include efforts to improve the cost-effectiveness of , access to and reach of psychotherapy – e.g. through utilising technological advances and social and familial networks . So-called ‘third wave’ psychotherapeutic approaches have gained traction, e.g. with a spike in the popularity of mindfulness and growing interest in – and evidence for – acceptance and commitment therapy . Bearing in mind relevance to RDoC, one important characteristic of these approaches is their alleged transdiagnostic relevance, i.e. that they seek to identify and target a common pathological mechanism, but more work is needed to link the relevant psychological constructs, such as ‘psychological flexibility’, with biological processes. There are promising signs of confluence between psychiatry’s biological and psychological divisions however, including a growing appreciation of the value of both psychological and neurobiological accounts of mental illness and its aetiology, as well as how environment, mind, brain and body interface and interact – consistent with the ‘biopsychosocial’ model .

Specific examples of biopsychosocial research in psychiatry include studying: gene × environment and drug × environment interactions – of which drugassisted psychotherapy can be considered an example , neurophenomenology and the biological mechanisms of psychological interventions . Into this arena comes psychedelic therapy, a quintessentially biopsychosocial intervention. Evidence indicates that psychedelic therapy is a particularly promising and progressive mental health care solution . Classic serotonergic psychedelics can be most precisely defined by their pharmacology, i.e. agonist action at the serotonin 2A receptor, which, if blocked, effectively abolishes their signature psychological effects . Psychedelic therapy is defined here as psychologically supported classic psychedelic drug experiences – although we recognise that psychotherapy alongside experiences induced by certain other psychoactive substances, e.g. MDMA and ketamine, bears relation to classic psychedelic therapy. Psychedelic therapy has shown promise for a range of different mental health conditions, including: depression , end-of-life anxiety , addiction and obsessive compulsive disorder . Indirect evidence also supports its potential for treating eating disorders and chronic pain . See Andersen et al. for a review. The Food and Drug Administration has granted ‘breakthrough therapy’ status to two independent multi-site double-blind randomised controlled trials , aiming to bring psilocybin therapy to marketing authorisation for depression, while related work is currently underway across Europe. Population and controlled studies , as well as large retrospective and prospective surveys , are generating evidence for improved mental well-being across a large demographic, potentially opening psychedelic therapy up to a sizeable wellness market. The successful initiative to legalise psilocybin therapy in Oregon, USA, intentionally included access for healthy individuals. In addition to its putative transdiagnostic utility, other reasons to feel optimistic about psychedelic therapy include: its novel action , and rapid and enduring therapeutic impact . Unlike traditional psychiatric drugs, positive effects have been observed for several months after just one or two doses. In terms of safety, psychedelics such as psilocybin have a favourable toxicity profile and therapeutic index, and negligible addiction potential .

Not wishing to neglect rare cases of putative iatrogenesis, including those of so-called ‘hallucinogen persisting perceptual disorder’ , the main hazards of psilocybin therapy relate to the intensity of the psychological state produced by higher doses, and associated need for a carefully engineered contextual container, e.g. with effective psychological preparation, supervision and aftercare. The utilisation of a drug-induced period of heightened cortical plasticity is likely to be a core component of psychedelic therapy’s mechanism of action and candidate functional and anatomical biomarkers of this are already being examined. In the context of a predictive processing framework, the ability of psychedelic therapy to relax and recalibrate cognitive and behavioural biases may be a central part of its action – as may an accelerated learning rate . How can we best advance the science of psychedelic medicine? Here we advocate pragmatic considerations , the utilisation of ‘basket’ protocols , as well as digitally aided data registries. Distinguishing pragmatic from confirmatory trials, the former refers to the actual, realistic conditions under which a therapeutic intervention will be received , whereas confirmatory trials typically engineer experimental conditions to support strong scientific inferences, but these often poorly reflect real-world conditions. Basket protocols are defined as single protocols, approved by relevant research regulatory bodies, that allow for a single intervention to be tested for multiple different disorders or conditions, such as a single drug for different types of cancer. Developers may be right to adhere to convention in delivering confirmatory trials, but, if resources and conditions allow, considerable benefits could be gained from more explorative study designs. Such exploration may be best served by research that can address a greater range of questions of clinical and real world relevance. Similarly, whereas confirmatory trials may choose to constrain eligibility and treatment criteria, pragmatic trials may benefit from broadening them, while maintaining a sensibly high-bar for contraindication-related exclusion criteria. Easy to sample biometrics and behavioural sampling could accrue large pools of objective data with potential predictive value. If such studies and data registries are designed with careful consideration of data quality and fitness, pragmatic research could create significant value for various different stakeholders, e.g. scientists, clinicians, regulators, health care systems, payers and investors. As has been the case with medical cannabis,indoor growing trays treatment-seeking patients will look for guidance from clinicians who take theirs from scientific evidence. Liberal policy changes occurring prior to the conducting of sufficient research could create similar problems for clinicians as occurred with medical cannabis. Such imperfect clinical scenarios could, however, also represent opportunities for innovative pragmatic and observational research. The creation of electronic data registries, e.g. for prescribers of psilocybin therapy in regions legally permitting access , may be one appealing example, enabling the collection of valuable real-world data. Data registries and pragmatic trials will collect data from broad and diverse samples. Data on use among healthy individuals can be supplemented by data from individuals seeking psychedelic therapy treatment for depression, particularly as safety is being established in this population . An even more ambitious project would be to utilise a protocol to only exclude individuals where there are good reasons to suspect elevated risk and inadequate specialist support. Indeed, future psychedelic therapy clinics in areas supporting legal access and/or operating under a research mandate may support such a scenario. Moreover, utilising digital tools, such as cellphone apps , to track outcomes linked to psychedelic use could generate large data pools that could be mined to inform on such matters as patient screening and treatment optimisation. Whether via data registries annexed to legal-access psychedelic therapy or approved pragmatic research trials, or both, the proposed approaches can serve the agenda of identifying transdiagnostic treatment targets . The RDoC initiative pays selective attention to phenotypes associated with pathology, neglecting parameters associated with wellness, and this may be an oversight. Evidence of reliable and sustained improvements in well-being and lifestyle with psychedelic therapy, as well as the maintenance of psychological wellness , recognition of the bidirectional relationship between psychological and physical health, and awareness of the substantial costs required to implement any human drug study, let alone a clinical trial with a psychedelic, and combined with a need for greater safety data across a diverse demographic, particularly given the liberalising political climate surrounding psychedelics, are all good reasons to justify innovative and pragmatic approaches to researching psychedelic medicine.

Collecting large sample sizes will enable better prediction-of response modelling , which will help mitigate risk and inform the potential customisation of care. A multi-site ‘trial’ or centralised registry would help generate and store the large data needed for reliable prediction-of-response modelling, with the added benefit of being able to assess between site discrepancies and consistencies. Confirmatory trials constrain important treatment parameters such as dosage and frequency of interventions, whereas pragmatic psychedelic trials could exercise flexibility here, particularly given the nascent nature of the treatment model, where practitioners cannot confidently claim to know the best parameters for all individuals and indications. In the context of psychedelic therapy, what dosage, frequency-of-dosing, as well as frequency and nature of post-dosing psychotherapy sessions are optimal, and for which cases, are all key questions that may be best addressed via pragmatic research under a basket protocol – and/or via digital data collection. Upper limits on the number of dosing sessions and lower limits on the intervals between them may be set to reduce the risk of bad practice, but redosing in response to relapse and based on clinical judgement may be permitted, thereby reflecting the conditions of clinical practice post roll-out. Most modern trials of psychedelic therapy have employed just one or two fixed-dose treatment sessions for all participants within relatively small and homogeneous samples, not because of assumptions about best practice, but because of alignment with regulatory traditions and budget constraints. This article argues that carefully designed pragmatic trials implemented under a basket protocol could offer a powerfully progressive model for advancing our understanding of the safety, effectiveness, mechanisms, impact, best-use and pitfalls of a promising but vulnerable new treatment model in psychiatry. Progressive policy changes would likely be needed to actualise the proposed approach – but these are already occurring. For such policy changes to occur, a vision of the societal value of improved mental health care, and how this can be safely and effectively achieved via psychedelic therapy, will need to be well communicated to the public and policy makers. For the time being, DB-RCTs will continue to sway sceptical opinions and aid progress with regulators, who presently base pivotal licensing decisions on data derived from such trials. Our view, however, is that data derived from pragmatic trials may be able to teach us more about how best to deliver the treatment and how it could impact on the lives of a broad cross-section of people. To be clear, the argument here is for the complementary value of pragmatic trials, not for their superiority over DB-RCTs. At the same time, however, we do challenge, as others have previously, the hierarchical preeminence of DB-RCT derived evidence .

Outlier images were modeled as nuisance covariates. Each outlier image was represented by a single regressor in the GLM, with a 1 for the outlier time point and 0s elsewhere. Time series of all the voxels within each seed were averaged, and first-level correlation maps were produced by extracting the residual BOLD time course from each seed and computing Pearson’s correlation coefficients between that time course and the time course of all other voxels. Correlation coefficients were converted to normally distributed z-scores using the Fisher transformation to allow for second-level General Linear Model analyses. DMN connectivity was calculated from the averages of the time series from MPFC and PCC seeds , given their similar connectivity patterns. Functional connectivity of left and right DLPFC were analyzed separately, as were left and right amygdala due to evidence of differential roles in emotion processing . First-level connectivity maps for each participant were entered into a between-group t-test to determine connectivity differences for each seed between groups. Clusters-level threshold was set at p < .05 using false discovery rate correction for multiple comparisons , with voxel-wise t-value threshold of 2.42 . Bonferroni correction was applied to the FDR-corrected cluster-level p-values to correct for multiple comparisons of the five a priori seeds tested . Regions that showed significant connectivity differences between groups were further examined for their connectivity values using one sample t-tests in each group. Based on prior evidence of DMN-sgACC hyperconnectivity in MDD and its implication in depressive rumination ,vertical grow racks for sale we examined the within group correlations between DMN-sgACC connectivity values and CBCL scores. Given the higher CBCL total score in the at-risk group, we re-tested group differences by including CBCL total scores as a covariate. Classification models of at-risk children and controls discrimination.

We trained two linear classification models using logistic regression, implemented in machine learning software Weka , in order to categorize individual participants to the at-risk or control groups based on their rs-fMRI or behavioral data. To create robust prediction models that can be generalized to new cases, we performed leave-one-out cross-validation so that each individual was classified on the basis of data from the other individuals. Specifically, data from all participants except one were used as the training set to build a classification model, and the remaining participant was classified with the model and used as the validation case. This procedure was iterated for each participant and used to estimate specificity/sensitivity from the out-of-sample predictions. In the first model, we used anatomically defined regions-of-interest that were independent from the regions that showed between-group connectivity differences. Connectivity values between the five a priori seeds and 116 clusters defined by the AAL atlas were estimated and used in the prediction model. We constructed a second model based on CBCL scores , to compare with classification accuracies from the model based on rs-fMRI data in anatomically defined ROIs. We found differential intrinsic functional connectivity patterns in unaffected children with familial risk for MDD compared to children without such familial risk in the DMN, the cognitive control network, and the amygdala. At-risk children showed hyperconnectivity between the DMN and the sgACC/OF. Furthermore, although none of the at-risk children was clinically depressed, DMN-sgACC/OFC connectivity was positively correlated with individual CBCL scores among those children. At-risk children also showed hypoconnectivity within the cognitive control networ k, lacked the typical anticorrelation between the DMN and the right parietal region, and exhibited lower connectivity between left DLPFC and sgACC. In addition, at-risk children showed hyperconnectivity between amygdala and the right IFG. Finally, classification between at-risk children and controls based on resting-state connectivity yielded high sensitivity and specificity. These findings appear to identify trait neurobiological underpinnings of risk for major depression in the absence of the state of depression.

Increased connectivity between DMN and sgACC in at-risk children, and the positive correlation between DMN-sgACC connectivity and current symptom scores, are consistent with findings reported in adult and pediatric patients with MDD. The fact that these findings were observed in unaffected children at familial risk for MDD suggests that hyperconnectivity with sgACC is not a consequence or manifestation of MDD, but instead may be a biomarker of predisposed risk for MDD.In line with our finding, stimulation of the sgACC resulted in attenuation of hyperactivation in sgACC and increased activation in previouslyunderactive DLPFC in adults with MDD . The left DLPFC region that showed maximum anticorrelation with the sgACC has been identified as a target for TMS treatment of MDD . A prospective study would be needed to determine if atypical sgACC connectivity at this age predicts later development of MDD. The lack of typical anticorrelation between the DMN and supramarginal gyrus / inferior parietal lobule, an important attention control region , in at-risk children is consistent with cognitive control deficits in depressed adult patients and reduced DMN deactivation during an emotional identification task in depressed adolescents . Greater anticorrelation between DMN and cognitive control networks in healthy adults has been linked to better performance in cognitive control and working memory tasks and may reflect an individual’s capacity to switch between internally and externally focused attention . This dynamic interplay between DMN and cognitive control networks in MDD was examined in a task-based connectivity study. During an external attention condition, adults with MDD exhibited increased DMN connectivity and decreased cognitive control network connectivity . The present study suggests that an imbalance between DMN and cognitive-control networks is a developmental risk factor for MDD. With regards to decreased connectivity within the cognitive control regions in at-risk children, a previous study of adolescents with familial risk for depression also reported reduced connectivity between cognitive control regions . In that study, lower connectivity in the control network was associated with more severe parental depression symptoms. These results in at-risk children and adolescents are consistent with findings from depressed adults of reduced connectivity in attention control regions including the DLPFC .

Studies consistently show that the DLPFC is under-activated in depressed adults , which might contribute to their difficulty in cognitive control and emotion regulation . It is possible that children at-risk for depression have an underconnected control network that is also a developmental risk factor for MDD. There was increased connectivity between the right amygdala and the right IFG and supramarginal gyrus in at-risk children. The right IFG is a key region in emotion regulation . The top-down IFG-amygdala circuitry is disrupted during emotion regulation in adults with mood disorders . A study of children with MDD and children of mothers with MDD also reported reduced negative correlation between the amygdala and lateral parietal regions including the supramarginal gyrus . The atypically high level of connectivity between amygdala and emotion regulation and cognitive-control regions might reflect emotion dysregulation in MDD. To test whether intrinsic functional organization of the brain, as measured by rs-fMRI,rolling hydro tables can be a potential biomarker for risk for depression in children, we performed a classification analysis to discriminate children in the at-risk group and control group based their resting-state functional connectivity data. This classification based on functional connectivity yielded high accuracy, sensitivity, and specificity in discriminating between children at risk for MDD and controls compared to classification based on CBCL scores. Importantly, the rs-fMRI classification was based on analyses that, at the level of each individual child, were independent of the group differences in functional connectivity. Such generalizable and individually robust classification is important if brain measures are to be used for early identification . Future prospective and longitudinal studies can determine whether such biomarkers predict which high-risk children progress to MDD and whether early intervention reduces the likelihood of developing MDD. Also, perhaps such biomarkers may be helpful in identifying children at risk for developing depression independent of parental histories of depression. Our findings need to be viewed in light of some methodological limitations. First, we did not exclude children born prematurely, and premature births can lead to neurological complications. However, we did exclude children with known developmental delays such as autism and intellectual disability. Second, because parental MDD confers a spectrum of risk to offspring , the at risk children were also at risk for anxiety and other disorders. Parents with MDD also have higher rates of comorbid anxiety than the general population. Thus we cannot rule out that the brain differences we found were due to the children being at risk for anxiety and other disorders. Third, although our sample size of at-risk children was moderate, the control group was small .

Lastly, our resting-state scans were acquired with a repetition time of 6 seconds, which is longer than most resting state fMRI studies so that we could acquire high-resolution whole brain data without the use of parallel imaging. A previous study found there was no significant difference in correlation strengths within and between resting-state functional networks when comparing TR = 2.5 and 5 seconds resting scans, and that correlation strengths stabilized with acquisition time of 5 min . In the current and previous studies using the same acquisition parameters , we observed the typical resting-state network patterns observed in other studies. Nonetheless, an additional issue of the long TR is that cognitive and emotional processes internally initiated at the beginning and the end of each scan can be different. We cannot rule out the possibility that the group difference observed here might be in part due to systematic differences in chronometry between the two groups. The present study consisted of a sample of pre-adolescent children who were at familial risk for depression but not currently affected with depression and therefore functional connectivity differences cannot reflect an expression of depression as could be the case in patients with ongoing MDD. Rather, the differences in intrinsic functional brain architecture likely reflect neural traits that predispose children towards MDD or related disorders. Importantly, we demonstrated that discrimination between at-risk and control children occurred with high sensitivity and specificity based on resting-state functional connectivity. Future studies that track the development of children at familial risk for MDD and determines which children develop MDD or other mood and anxiety disorders are needed to build predictive models based on findings from the present study so as to identify high-risk individuals for early intervention.The regulation of both cognition and emotion is thought to depend upon top-down modulation of multiple neural circuits by prefrontal cortex, and in particular the dorsolateral prefrontal cortex. Because prefrontal-dependent cognitive control mechanisms regulate the focus of attention and regulate mood, it stands to reason that they play a key role in mental health. There is indeed ample evidence that adult psychiatric patients exhibit an attenuation or failure of top down control mechanisms in depression, anxiety, and Attention Deficit Hyperactivity Disorder 14. Given that these prevalent mental health problems tend to emerge during childhood and adolescence, it is important to know whether dysregulated top-down control can be detected even before behavioral symptoms are evident. The strength of coupling between regions involved in top-down control and their targets can be measured with resting state fMRI . Regions of the brain that are highly temporally correlated during rest form resting state profiles which are intrinsic, spontaneous, low-frequency fluctuations in the fMRI blood-oxygen-level dependent signal that define specific networks of the brain in the absence of any task. There is great heterogeneity in the functional organization of the brain that is captured by RSNs. In fact, they may be considered “fingerprints” of the human brain, as they can accurately identify individual subjects from a large group of individuals. Furthermore, RSN profiles are known to be robust and reliable. RSNs are particularly relevant to studying psychiatric and pediatric populations because 1) they are task-independent, so individual differences in task performance cannot explain differences observed in the BOLD data, 2) they are easy and fast to acquire which make them more accessible to a wide variety of subjects including young children and a wide range of clinical populations, and 3) they are plastic and have been shown to change during typical development and can be modulated by behavioral or pharmacological interventions. An RSN that is particularly relevant for mental health is the Central Executive Network , of which the DLPFC is a key node.

This hypothesis ties into a study that assessed “quality of life” based on measures of alcoholism, substance abuse, criminality and a questionnaire in adults with ADHD who had previously been treated with stimulants versus those that had not. This study found that ADHD patients treated as children had a higher quality of life than those treated in adolescence by the researcher’s measured index. This hypothesis – that onset of treatment at a younger age correlates with effectiveness of treatment – may indicate a link between age of prescription and likeliness to experience SUD. A younger child is much less likely to have access to any form of street drug, especially stimulants such as cocaine or methamphetamine. If prescribed at a younger age, amphetamine sensitization would occur during a time in the child’s life in which they would have no outlet through which to act on drug cravings. Since the average duration of treatment lasts between 33.8 to 42 months, the medication would likely stop before the child reaches adolescence. Withdrawal, a series of negative symptoms that occur in the absence of a drug after a prolonged period of abuse, would therefore occur when the individual would most likely have limited access to illegal stimulants. As a result, a young child treated with amphetamines would not necessarily have an increased risk for abuse of other stimulants by the time he or she reached adolescence – when illicit drugs are more readily found. In contrast, if the onset of treatment were to start in the early teens , drug-seeking behavior would peak just as illicit substances became more available. This hypothesis is supported by one study that found that ADHD individuals whose treatment persisted into adolescence were more likely to become dependent on cigarettes than those whose treatment ended earlier. The individuals whose treatment had stopped before adolescence went through the sensitization/withdrawal process before cigarettes became available to them,custom grow rooms either through legal or illegal means.

The effect of amphetamine is also hypothesized to be greater under both temporal and environmental cues previously associated with administration. It is likely that a child treated at a younger age would move out of an environment previously associated with amphetamine and therefore have a decreased sensitivity to amphetamine at an older age compared to an individual who started treatment in adolescence. The child treated at a younger age would therefore be less likely to abuse their prescription and eventually other illicit drugs. Thus, ADHD treatment at a younger age seems to have little or no effect on drug abuse during adolescence and adulthood, while treatment that continues into adolescence may raise the risk of non-prescription stimulant abuse. Lastly, adolescents typically experience much more stressful environments as more responsibility is given to them at both home and school. The stress of adolescence may synergize with the effects described above, and thus further increase the likelihood of stimulant abuse. On the other hand, if amphetamine prescription is initiated before adolescence, the individual will not have the same added level of stress, and thus will be less driven to abuse their medication or drugs with similar effects.Although much evidence points to an increased risk of substance abuse with amphetamine treatment, many investigators have concluded that amphetamine use does not increase a patient’s likelihood of later developing SUD, and that it may actually exert a protective effect against substance abuse later in life based on population-level studies – that is, some have concluded that stimulant-based treatment of ADHD early in life may decrease drug abuse later in life. For instance, Barkley and colleagues, the same group whose results indicated a significant increase in cocaine use amongst ADHD patients treated with stimulants, still concluded that treatment of ADHD had no effect on the likelihood of using a number of drugs. A similar study that followed 56 medicated and 19 unmedicated patients found that there was no association between treatment and drug abuse.

A study that followed 285 treated and 84 untreated ADHD patients also concluded that SUD did not develop as a result of stimulant treatment. A meta-analysis of several studies also found that for any category of drug use, stimulant treatment decreased the risk that an individual would abuse drugs in general. Review papers on the subject of SUD and its relationship with ADHD have also come to the conclusion that childhood treatment with stimulants is negatively correlated with substance abuse.Although many studies conclude that stimulant treatment is protective against the development of SUD when prescribed to ADHD patients, the validity of these studies is questionable. For instance, many of the studies that come to this conclusion are funded in full or in part by drug companies such as Pfizer or Eli Lilly, which manufacture ADHD medications. These studies have clear financial biases in terms of their conclusions. Reviews and meta-analyses are particularly dubious when a conflicting financial interest exists, because they may select papers that suggest a desired result. In addition, studies with larger sample sizes and meta analyses tend to group all types of substance abuse into one category, or simply distinguish between “drug abuse” and “alcohol/ tobacco use” categories. Large bins of categorization produce a confounding variable, because stimulant drugs are known to reinforce and prime other stimulant drugs most reliably. The fact that amphetamine treatment has been suggested to protect against or have no correlation with the use of depressants such as marijuana or alcohol makes placing all drugs of abuse into one category especially problematic. The decreased risk factor for depressant use and the increased risk factor for stimulant use interfere with each other when considered together, thus concealing any specific trends that might exist. Of two predominant studies that separated “substance abuse” into individual drugs or drug subcategories, one study found a significant increase in cocaine use, while the other found no significant increase. However, the latter study had a small sample size of 56 medicated ADHD patients and 19 non-medicated patients. It is possible that if larger sample sizes were obtained, a significant increase would have become apparent.

This conclusion seems increasingly likely since the prevalence of stimulant abuse in society is generally not as high as for other drugs such as cannabis or alcohol, especially amongst ADHD patients in general. Therefore, a much larger sample size is needed to compare stimulant-specific abuse amongst ADHD patients. Furthermore, if treatment with stimulants does in fact exert a protective effect against general drug abuse and not illicit stimulant abuse, the analysis of drug abuse in general as a single category would actually downplay the increase in stimulant abuse amongst patients. Untreated subjects would be much more likely than treated subjects to participate in non-stimulant abuse, confounding a large portion of studies. Based on the idea that those with a later onset of treatment have a higher potential for stimulant abuse, it is probable that if the age of treatment onset were compared, patients with a later onset of treatment would show a specific increase in illicit stimulant abuse in adolescence and possibly into adulthood. However, those treated at a younger age may not have a statistically higher percentage of abuse of any drug. If it is true that subjects treated earlier are less likely to abuse stimulants than those treated later in adolescence, any study that does not compare age of onset and likelihood to develop stimulant-specific abuse possesses a significant weakness. Most of the studies that come to the conclusion of a negative correlation between amphetamine treatment and substance abuse fail to accurately assess age of treatment onset when evaluating data,montel grow racks thus mixing information from individuals that may have a higher risk of drug dependence with those that may have a lower risk of drug dependence because of age of treatment onset. Finally, none of these studies take into account the differences between methylphenidate and amphetamine. Since amphetamine has been shown to have an increased potential for abuse compared to methylphenidate and other ADHD medications, these studies therefore downplay the exposure to risk of substance dependence that is put forth with amphetamine prescription.The majority of population studies that have concluded that stimulant-based treatment has no effect on the development of substance abuse later in life fail to take into account all of the factors necessary to produce accurate correlations.Current knowledge regarding the effects of amphetamines on stimulant-specific abuse in animals and general drug abuse in humans is not consistent. Studies on animal models have concluded that amphetamines specifically raise the tendency to self-administer stimulants, such as cocaine and nicotine, largely due to the sensitization of the rewarding effects of amphetamine that results in drug-seeking behavior.On the other hand, other population-level studies based on surveys and meta-analyses have concluded that stimulant prescription has no correlation with the development of substance abuse. These studies, however, all possess one or more of the following flaws: failing to distinguish between stimulants and depressants in terms of drugs abused by patients; failing to distinguish between amphetamine medication and other stimulant treatment; working with sample sizes far too small to accurately reflect the level of dependence that might develop to stimulants, specifically; and failing to consider the age of the patient at treatment onset. Taken together, evidence suggests that amphetamine treatment of ADHD causes a small increase in potential for stimulant drug abuse and possibly a decreased potential abuse of depressants. The risk for developing stimulant abuse is likely dependent on age of onset of stimulant prescription, with those treated in adolescence and young adulthood at a higher risk. However, there are no conclusive studies to verify this hypothesis. Considering that the amphetamine treatment for ADHD is on the rise, it would be prudent for an independent research group concerned with the health of ADHD patients to conduct a large scale study that accounts for the variables mentioned above, using a large population of both treated and untreated ADHD patients to test specific dependence of stimulant class drugs that arise from treatment with amphetamines.

Another potential method of study might include comparing the number of formerly treated ADHD versus untreated ADHD patients amongst a population known to have abused stimulants, adjusting for the percentage of treated versus untreated ADHD individuals amongst the ADHD population. A conclusive study on this matter would allow parents, schools, and physicians to more accurately consider the treatments available for children with ADHD.Thirty male participants were recruited, among which were 15 pathological gamblers and 15 matched healthy controls . The PET data from these participants have been reported in a previous study comparing baseline dopamine synthesis capacity between groups . PGs were recruited through advertisement and addiction treatment centres and reported not to be medicated or in treatment for their gambling at the time of the PET study. HCs were recruited through advertisement. All gamblers qualified as PGs as they met ≥ 5 DSM-IV-TR criteria for pathological gambling. Current drug use disorder was a reason for exclusion for all participants. Additionally, participants were excluded if they were currently following psychiatric treatment, drank more than four alcoholic beverages daily, used marijuana more than once per month, were using medication, had a lifetime history of schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, autism, bulimia, anorexia, anxiety disorder, obsessive–compulsive disorder or had a past 6-month history of major depressive episode. Nine participants were not included due to technical problems with the electro-oculography recordings . Data loss was related to EOG amplifier saturation . Three participants were kept in the analyses despite minor data loss . One gambler was further excluded because he met the DSM-IV-TR criteria for past year marijuana dependence, which is known to influence sEBR measures . As a result, the final sample comprised 20 participants . All participants provided written informed consent to take part in the study, which was approved by the regional research ethics committee .The study took place at the Radboud University Medical Center. Upon arrival of the participants, spontaneous eye blink rate was measured using EOG recordings . Approximately 1 h before entering the PET scanner, participants received 150 mg of carbidopa and 400 mg of entacapone to reduce peripheral metabolism of [18F]DOPA and increase tracer availability in the brain while having no psychotropic side effects. The participants further performed computerized tasks not reported here.We followed standard procedures for the acquisition, preprocessing and analysis of the EOG data .

Application of GA to developing na2 tassels enhanced their feminisation, supporting this hypothesis.When considering mutants with pleiotropic phenotypes, it is difficult to ascertain whether we are observing epistasis, additivity, or synergy simply because there may be epistasis for one phenotype, but not for another. Thus it is important to take into account all metrics when evaluating the mutant interactions.The fun and na2 mutants interact both additively and synergistically in different tissues. The fun mutant acts additively with na2 to reduce the overall height of the plant by further affecting the tassel and internodes. Since the d5;na2 double mutant also showed additive effects for height31, this could point to a role for FUN in the GA pathway. On the other hand, the synergistic interaction between fun and na2 at the auricle would point to FUN’s involvement in the BR pathway. These two data need not be in contradiction – Best et al.’s work clearly showed that the BR and GA pathways impinge on one another31, and the FUN protein itself may be involved in this crosstalk. Though there is very mild feminisation in the bri1::RNAi tassel, this is not an originally described phenotype of the bri1::RNAi line, nor is it common in family AV802 . Further, the metric of branch number does not indicate feminisation in the bri1::RNAi tassel, though bri1::RNAi is slightly shorter which can be considered a feminine inflorescence trait. Lack of feminisation in the bri1::RNAi tassel is surprising since removing BR causes feminisation in the tassel in the na1 and na2 mutants. Combining the bri1::RNAi line with fun leads to more feminisation than fun alone, implying not simple epistasis by the feminised tassel of fun, but rather an enhancement of the very mild feminisation caused by bri1::RNAi. Similarly,vertical cannabis grow the reduced height phenotype is enhanced in the double mutant . Phenotype enhancement, or additivity, is also observed at the auricle.

Though auricle size was not found to be smaller in bri1::RNAi plants in family AV802, a smaller auricle in bri1::RNAi plants has been reported75. Thus we can consider the completely absent auricle phenotype observed in bri1::RNAi;fun plants in family AV802, as compared to the bri1::RNAi and fun single mutants of AV802, as an enhancement of the reduced auricle associated with fun. No leaf width phenotype has been reported for bri1::RNAi plants, and fun appears to have simple epistasis of the leaf width phenotype.According to almost all metrics measured, fun is epistatic to bin2::RNAi. The oversized auricle of bin2::RNAi is completely abolished in the double mutant. Since increased leaf angle has been linked to BR hypersensitivity in rice76 as well as appearing in this bin2::RNAi line, it is reasonable to assume that this monstrous auricle is a product of BR hypersensitivity, and by extension, auricle growth is promoted by BR. The fact that the fun mutation abolishes this auricle growth is strong support for the function of FUN in the BR pathway, downstream of bin2::RNAi. On the other hand, the retention of leaf blade margin crenulations in the double mutant does not fit into this explanation, unless FUN is simply not expressed along the margin, which would be consistent with the Wab1;fun double mutant . The strong feminisation seen in the double mutant is further support for the placement of fun downstream of bin2::RNAi in the BR signalling pathway. BR is known to accumulate in developing anthers, and hence is a hormone associated with masculinity in maize. The fact that loss of normal FUN produces feminisation in the bin2::RNAi background also supports the hypothesis that FUN is in the BR pathway, downstream of BIN2. Taking together these phenotypes and interactions, this analysis supports the hypothesis that fun functions late in BR pathway, perhaps at its intersection with GA. Additivity with na2 for height is observed as with the d5 GAknockout mutant. At the same time fun enhances the feminisation phenotype of BR deficient na2 and acts additively with the BR insensitive bri1:RNAi while abolishing the phenotypes of the hyper-responder bin2:RNAi. Figure 4-11 shows FUN’s tentative placement in the BR pathway.

Classical mutants tasselseed1and ts2 were first described by Emerson in 1920 following the “freak” class exhibition of the Annual Corn Show in Lincoln, Nebraska 1913-1487. Together with the classical mutant silkless1, described by Jones in 192588, these mutants have elucidated the role of JA in sex determination in Zea mays. The ts mutants bear tassels that are heavy with seeds, so that they bend over from their own weight at maturity. All or most flowers will be female, but the tassel retains a normal degree of branching that is not seen in the ear or fun mutant tassels87. Upon cloning, ts1 was found to be a lipoxygenase that catalyses a step in the JA biosynthetic pathway35. While the function of the alcohol dehydrogenase encoded by ts236 has not been definitively shown, the similarity of the ts1 and ts2 phenotype, the lack of any interaction in the ts1, ts2 double mutant, and rescue of the ts2 phenotype by JA application35 supports the hypothesis that it is also in the JA pathway. The sk1 mutant is described as developing normal cobs but failing to produce any silks such that even stripping back the husk leaves and pollinating directly onto the ear failed to produce any kernels. No differences in the tassel nor the vegetative parts of the plant were originally noted but it was later observed that sk1 has less tassel branches than normal siblings. Combining sk1 with the mutants ts1 and ts2 put sk1 in the same pathway. Though in the first generations of the double mutant sk1 and ts2, partial epistasis was observed, two further rounds of self pollinations of these double mutants revealed complete epistasis by ts2. That is, both the tassel and the ear bear silks. From this it was concluded that sk1 in some way inhibits the silk killing product of ts292, supposedly, JA35,36. This has been supported by the cloning of SK1 as a uridine diphosphate -glycosyltransferase, the overexpression of which resulted in very low JA accumulation in developing tassels and a feminised tassel phenotype37. In summary: SK1 breaks down JA that would otherwise lead to pistil abortion. In a normal tassel, JA accumulates in the pistils and they abort; in a normal ear, SK1 degrades the JA and prevents silk abortion.Since addition of JA was unable to fully rescue the feminised tassel of fun plants, FUN is unlikely to be deficient in JA.

Though failure to correct the feminised phenotype was more obvious in the first application of JA family AV920 still showed a failure to rescue by JA application when branch number is considered. AV920 was not ideal for this experiment because the fun plants in this family were not heavily feminised. This could have been due to the fact that they were grown in the winter greenhouse – greenhouse grown fun plants have been observed to be less feminised than those grown in the field, and the winter greenhouse is particularly sub-optimal for growing corn. Further these plants were the fun-2 allele, which has not been adequately characterised, but may have lower feminisation severity than the original fun-1 allele. Finally, the genealogy of these plants contains a recent cross to Mo17, which may have reduced the severity of the phenotype ,vertical farming system as well as the fact that some of the fun plants were heterozygous for ts1 . Nevertheless, JA application to fun and ts1 plants in family AV920 did not refute the original experiment showing that JA is unable to fully rescue the feminised tassel phenotype of fun plants. ts1 and fun can be considered additive in their effects on feminisation of the tassel. Double mutant tassels were more heavily feminised than either double mutant, supporting the hypothesis that ts1 and fun are in different pathways. The lack of lower floret abortion in the tassel of ts1 and ts1;fun plants compared to successful lower floret abortion in fun plants further supports the hypothesis that fun is not deficient in JA since JA is required for lower floret abortion in the ear. The loss of silks in the sk1;fun further refutes the hypothesis that FUN is involved in the production of JA. A JA biosynthetic mutant would be expected to retain silks in combination with sk1, as previously shown with ts1 and ts2. The retention of feminised traits in the form of glabrous, thickened glumes in the double mutant implies an additive interaction – the fun mutation is still causing aspects of feminisation in the tassel, though the lack of functional SK1 cannot protect the silk from abortion by the action of JA. Branch loss in both sk1 and fun, and the additivity in the double is a complex set of observations. Though branch loss is a feminine trait since the ear is branchless and tassels are branched, the sk1 mutant also has branch loss. sk1 is presumably high in JA due to the loss of the SK1 gene that is responsible for JA degradation. This high JA allows silk abortion, and so would seem to be a masculine characteristic. Paradoxically, this loss of functional SK1 is also associated with the feminine trait of less branching in the tassel, implying a role for JA in branch inhibition during tassel development. Since there is an additive interaction between the sk1 and fun mutations, and addition of JA to developing fun tassels lead to tassels that resembled the sk1;fun double mutant tassels, the hypothesis of FUN being outside of the JA pathway is supported.If we consider JA and BR as masculinising hormones in Zea mays, GA can be thought of as a feminising hormone. In the 50s, Nickerson showed that application of GA directly to the whorl during tassel development was sufficient to induce feminisation of the terminal inflorescence. In the early 80s it was shown that developing ears have GA levels two orders of magnitude higher than in developing tassels.

The d1 mutant in maize was shown to block steps in the GA biosynthesis pathway and when the gene was cloned it was found to be a GA3 oxidase that catalyses the final step in bioactive GA synthesis. While the most striking phenotype of d1 is its tiny stature, more pertinent to this discussion is its ear phenotype, dubbed “anther ear”. Without the presence of GA, the anthers of the ear do not arrest and instead grow out to produce bisexual flowers in the ear while the flowers of the tassel are normal63. As such it is perhaps erroneous to call GA a simple feminising hormone – rather it is a male killer hormone. The mRNA coding for D1 protein was shown by in situ to accumulate in stamen primordia of the developing ear which undergo cell cycle arrest and ceases growth early in its development. d1 mutant plants do not undergo this stamen primordia arrest in the ear. Since the fun mutant was feminised in the tassel, we made crosses to GA mutants and applied paclobutrazol which is an antagonist of the GA pathway and has applications as a plant growth retardant and fungicide95. PBZ blocks the entkaurene oxidation step of GA biosynthesis, and thus plants treated with this compound are unable to produce GA. PBZ has been used to investigate the role of GA in maize, and to elucidate the nature of dwarf mutants in the GA pathway. The dominant D9 mutant was obtained from the maize stock centre and is similar to the D8 maize mutant, which both bear similarities to the biosynthetic d1 mutant. D8 and D9 are both dwarf, have increased tillering, and display varying degrees of anther ear. All the D8 alleles described have anther ear, while D9 displays full anther ear in some backgrounds, but in others it develops anthers up to the point that they are visible with a magnifying glass. The D8 locus on chromosome 1 encodes a DELLA protein, and D9 has been shown to encode a duplicate of this protein located on chromosome 5. DELLA proteins are part of the Gibberellic Acid signalling pathway, and act to repress the GA response.

By binding to a different, non-competitive allosteric site on the GABAB receptor, PAMs allow endogenous GABA, binding at its original orthosteric site, to retain its potency and efficacy, reducing the risk of tolerance development and side effects. A number of PAMs have been studied as potential pharmacotherapies for AUD, and have demonstrated reductions in alcohol-associated behaviors and ethanol self-administration in preclinical models. When directly contrasted against baclofen, a GABAB PAM had a better profile, with dose-dependent reduction of relapse-like alcohol drinking and with no signs of sedation. One such novel GABAB PAM, ASP8062, appears particularly promising as it has been shown to significantly increase the affinity and efficacy of endogenous GABA binding in human and rat GABAB receptors in vitro and with oral administration in an in vivo rodent model of fbromyalgia, demonstrating the ability of oral formulated ASP8062 to cross the blood-brain-barrier. ASP8062 has recently progressed to clinical development. Two Phase I clinical trials with a combined total of 112 participants evaluated single ascending doses and multiple ascending doses of ASP8062, respectively. These studies found that ASP8062 was well tolerated in humans, with no evidence of drug effects on safety, cognition, drug withdrawal, or suicidal ideation. One additional clinical trial, assessing the safety and efficacy of ASP8062 for alcohol use disorder , is currently underway. Overall, ASP8062, and GABAB PAMs in general, appear to be well tolerated in humans and decrease alcohol self-administration in animals. These agents present a potential pathway to better utilize the GABAergic system and reduce the side effects seen with GABAB agonists.Ghrelin,4×8 tray grow a peptide produced by endocrine cells primarily in the stomach, is thought to regulate growth hormone secretion, food intake, and glucose homeostasis. Ghrelin is also thought to play a role in AUD.

Ghrelin signaling is required for stimulation of the reward system by alcohol, and higher ghrelin levels are associated with higher self-reported measures of alcohol craving . In human laboratory studies, intravenous ghrelin administration has been shown to increase the urge to drink, increase alcohol self-administration, and modulate brain activity in regions involved in reward processing and stress regulation. Preclinical studies with ghrelin receptor antagonists have shown reductions in alcohol conditioned place preference, alcohol intake and preference, and alcohol-elicited nucleus accumbens dopamine release in rodents. PF-5190457 is a ghrelin receptor inverse agonist that inhibits GHS-R1a constitutive activity as well as blocking its activation by ghrelin. In a preliminary clinical study in 12 heavy-drinking individuals, PF-5190457, compared to placebo, reduced alcohol craving and cue-reactivity to alcohol. Additionally, when administered in combination with alcohol, PF-5190457 was safe and well-tolerated with no drug-alcohol interactions. This was the first clinical study of a GHS-R1a inverse agonist in a sample of heavy alcohol drinkers. PF-5190457 may increase somnolence, heart rate, and lower blood glucose concentrations, although clinical results indicate that these side effects were not exacerbated by alcohol co-administration and in general PF-5190457 is well tolerated. In summary, preclinical and early clinical evidence support additional research toward investigating PF-5190457 as a pharmacological approach to treat AUD.Cannabidiol , one of the main compounds found in Cannabis sativa, has shown promise as a novel therapeutic to treat AUD. CBD is nonintoxicating and has diverse pharmacological effects throughout the central nervous system, including functioning as a negative allosteric modulator of CB1 and CB2 receptors, and blocking anandamide update and inhibiting enzymatic hydrolysis. CBD may also interact with non-endocannabinoid signaling systems, including the serotonergic system and the opioidergic system, among others. Preclinical studies have shown that CBD reduces alcohol administration, decreases motivation for alcohol, reduces relapse-like behavior, and improves withdrawal symptoms in animals exposed to chronic alcohol.

Evidence in healthy individuals demonstrates that CBD is well tolerated, does not interact with the subjective effects of alcohol, and has no abuse liability. Two recent studies investigated signals for potential efficacy of CBD as a treatment for heroin use disorder and cannabis use disorder. Regarding heroin use disorder, acute CBD reduced cueinduced craving for heroin and reduced anxiety in a sample of 42 abstinent individuals, which was maintained one-week following the last CBD exposure. The cannabis use disorder study found that CBD was more efficacious at reducing cannabis use than placebo in a sample of 48 subjects. In both clinical samples, CBD was well tolerated and not associated with serious adverse events. CBD is currently being evaluated as a potential treatment for AUD, AUD with comorbid PTSD, and alcohol withdrawal in AUD in three clinical trials . In brief, preclinical evidence and clinical evidence in other substance use disorders indicate the promise of CBD as a novel therapeutic for AUD.This qualitative literature review discusses the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD. This information is summarized in Table 1. As of 2018, the APA recommends acamprosate and naltrexone for the treatment of AUD and suggests gabapentin and topiramate for patients with the goal of reducing alcohol consumption or achieving abstinence, while disulfram is suggested for achieving and maintaining abstinence only. Similarly, while not included in the APA’s recommendations, aripiprazole and mifepristone are associated with drinking reduction, while baclofen shows association with abstinence and mixed results with drinking reduction. Additional repurposed medications show clinical effectiveness for the treatment of AUD. Some of these appear to have particular promise in specific cases, such as varenicline’s use for nicotine and alcohol co-users, baclofen for individuals with liver disease, and aripiprazole for more impulsive individuals. Novel agents such as GET73 and ASP8062 have also reduced alcohol intake in preclinical studies.

In summary, while currently approved medications are somewhat effective, there remains a crucial need to develop new and improved pharmacotherapies for AUD. Novel and repurposed agents show significant promise as treatments that may improve upon currently approved pharmacotherapies.While considerable progress has been made in this field, there are a number of areas which require our attention to realize the benefit of AUD pharmacotherapy. First, despite the prevalence of AUD, the rate of seeking treatment for AUD remains very low. In order for anyone to benefit from the advances in medication development reviewed herein, the treatment gap must be closed. This will require engagement at multiple levels, from prevention to public education about AUD and the available treatments. Researchers and clinicians can help in these efforts by reducing stigma surrounding AUD and other substance use disorders by choosing appropriate language to describe these disorders and the people who are affected by them. A related issue is the need to improve access to FDA approved pharmacotherapies for AUD. A recent analysis of the 2019 National Survey on Drug Use and Health found that only 1.6% of people with a past-year AUD received an evidence-based medication to treat their AUD. Medication use was associated with living in a large metropolitan area,horticulture solutions use of the emergency department, and receiving mental health care, indicating that these services and residing in an urban environment appear to increase access to evidence based medications. There is also a great need to improve the education of physicians and clinicians on the availability of evidence-based treatments for AUD. Ongoing efforts in this area are underway by the American Society of Addiction Medicine and the American Academy of Addiction Psychiatry, as well as by the National Institute on Alcohol Abuse and Alcoholism. To further improve access to treatments and increase treatment-seeking, there is a need to increase the menu of approved pharmacological treatments towards AUD, especially those that have shown promise internationally. Currently, the FDA only accepts two primary outcomes for Phase 3 trials: abstinence and no heavy-drinking days. These outcomes do not always mirror the goals of patients with AUD for their recovery, which may be better reflected by a harm reduction endpoint.

Recent work has found that harm reduction endpoints, including reductions in WHO based drinking levels, are associated with improvements in physical health and quality of life and can be used as efficacy outcomes in clinical trials. The acceptance of these outcomes as clinical trial endpoints could have a substantial impact on the medication development field and ultimately result in a larger pharmacotherapy toolbox for clinicians.Another area of development is the move towards personalized treatment, also referred to as precision medication. AUD is a highly heterogenous disorder, and it unlikely that any medication will work for all individuals with an AUD. As such, there have been efforts to use precision medicine approaches to tailor pharmacotherapies to individuals with different presentations of AUD. Studies have taken several approaches towards personalized treatments, such as pharmacogenetics, sex differences, family history, severity of alcohol withdrawal, drinking phenotypes, and biobehavioral markers. However, even these efforts may be overly simplistic given the complex nature of AUD. It is likely that personalized treatment approaches will need to account for multiple factors to truly tailor treatments to individual patients. Conversely, the public health significance of the improved efficacy of AUD pharmacotherapy with clinically accessible phenotypes argue for wider dissemination and implementation of precision treatment recommendations identified to date. A final issue to consider is the need to develop treatments for individuals with AUD and comorbid psychiatric disorders and for individuals with AUD and AALD. AUD often co-occurs with other psychiatric disorders, including other substance use disorders, personality disorders, major depressive disorder, anxiety disorders, and PTSD. The development of integrated treatments, including combined behavioral and pharmacological interventions, which simultaneously address AUD and other cooccurring disorders, is difficult due to the complexity of treating multiple disorders and the limited understanding of the underlying mechanisms. However, this is a necessary area of research given the high rates of comorbidity in the AUD population. Treatment options for individuals with AALD are limited; of the FDA-approved medications, only acamprosate can be used without concerns of hepatotoxicity. Of the non-FDA medications that may prove useful in this population, only baclofen has been evaluated in an RCT. There is a clear need to develop additional treatments for this population.Unisexual flowers are the exception in angiosperms; the vast majority of flowering plants bear hermaphroditic flowers that have both pollen producing stamens and ovule-containing ovaries . Nevertheless, a substantial number of angiosperms produce nonhermaphroditic flowers. In a recent data analysis, 5-6% of plant species were found to be dioecious, but 43% of plant families were shown to contain dioecious members. The rarity of dioecy at the species level, coupled with its widespread occurrence across the angiosperm lineage, shows that dioecy must have evolved multiple times. In this chapter, we will first discuss the possible benefits and costs to producing imperfect flowers, before considering the likely routes evolution has taken to produce these floral types, and the molecular mechanisms that underlie the development of imperfect flowers. Through a sequence of case studies, this chapter will detail a likely route that an ancestor bearing perfect flowers could take to arrive in the derived states of dioecy and monoecy, through the intermediary steps of protogyny and protandry; andro- and gynomonoecy; and andro- and gynodioecy .A historical theory for why imperfect flowers might be beneficial was that it could promote outcrossing. Clearly a dioecious species is an obligate outcrosser, since the male and female flowers exist on separate plants. However, it is not so clear that this would be true for monoecious plants. It was hypothesised that if monoecy were to promote outcrossing inherently, monoecious plants would not have to rely on other costly mechanisms to promote outcrossing such as molecular self-incompatibility . Studies have not shown this to be the case, indeed monoecy is just as common in self-compatible species as it is it in SI species5 , though of course this does not rule out the possibility that avoiding self-fertilisation could still be a factor in the evolution of imperfect flowers, especially for dioecious plants. Instead of making a theory and trying to find data to support it, it is more fruitful to look at the natural world and make a theory to explain it. For this, we might ask: “what kinds of plants are likely to bear imperfect flowers?”. Analysis of large datasets has shown that species with imperfect flowers are likely to be viniferous or woody, wind-pollinated plants with small green flowers, and for dioecious plants, the bearing of fleshy fruits . One theory proposed by Bertin to explain enrichment in wind-pollinated plants is the relatively low cost of their flowers allows for monoecy to develop.

Emerging data indicate that e-cig use may adversely affect the pulmonary and cardiovascular systems. Also, limited evidence exists on the potential of e-cigs to cause carcinogenic effects. To date, clinical studies have primarily investigated the acute effects of vaping. By design, epidemiologic studies have explored the “association” of e-cig use with disease outcomes. So, the “causal” relationship between vaping and disease pathology remains largely unknown. Currently, determining the long-term health consequences of vaping is a top research priority. Of utmost importance is the long-term effects of vaping, especially among adolescents whose developing brains are more susceptible to influences on learning, memory, and attention. Future well-defined controlled experimental studies are needed to establish the mechanisms by which chronic vaping may lead to adverse health consequences in humans. These investigations are expected to identify the constituent of e-cig vapor, which are of most relevance to disease development. Though it is generally accepted that e-cig use exposes the users to fewer and lower levels of toxicants and carcinogens as compared to smoking, the net public health effect of vaping continues to be debated. The scientific community, regulatory authorities, and the general public are faced with competing views on the health risks or benefits of vaping. On the one hand, proponents of e-cigs advocate for: “harm reduction” potential of vaping, especially for smokers who are unable/unwilling to quit; and utility of vaping for smoking cessation. On the other hand, opponents argue against the adoption of an alternative tobacco product whose long-term health effects are yet to be determined. To reach a consensus, more conclusive scientific evidence will be needed; the available data favor the stance that vaping is likely to be less harmful than smoking, with the caveat that it may still pose a health risk on users,dry racks for plants which would otherwise be eliminated if neither product were used.

On June 22, 2009, with broad bipartisan support from Congress, President Obama signed into law the Family Smoking Prevention and Tobacco Control Act , also known as “Tobacco Control Act”. The FSPTCA granted FDA immediate authority and unprecedented power to regulate cigarettes,cigarette tobacco, roll-your-own tobacco, smokeless tobacco, and any other tobacco products that the agency, by regulation, deems to be subject to the law . On August 8, 2016, when FDA’s “Deeming Rule” took effect, many of the regulatory and statutory requirements that had been in place for manufacturers of the originally regulated tobacco products since passage of the FSPTCA in 2009, became applicable to the deemed products, including e-cigs and all other electronic nicotine delivery systems , cigars, pipe tobacco, nicotine gels, hookah tobacco, and any future products meeting the statutory definition of “tobacco product.” The applicable statutory provisions include the requirement that deemed products that meet the definition of a new tobacco product must receive premarket authorization from the FDA to be legally marketed. The premarket authorization requires a Premarket Tobacco Product Application for any new tobacco product seeking an FDA marketing order. In the deeming rule and subsequent guidance documents, FDA stated that it intended to defer enforcing the premarket review requirements, for a period of time, with respect to “deemed” new tobacco products that were on the market as of the effective date of the deeming rule. This policy did not extend to deemed new tobacco products that entered the market after the rule’s effective date . Under a federal court order, manufacturers of deemed new tobacco products that were on the market as of the deeming rule’s effective date, were required to submit premarket review applications by September 9, 2020. Following the court order, FDA accelerated its planning and preparation to receive a large number of applications by the premarket application deadline. Accordingly, the agency received thousands of submissions, representing more than 6.5 million products by the set deadline.

Per the court order, products for which applications were submitted by the deadline of September 9, 2020, could generally remain on the market for up to a year from the date of the application—or until September 9, 2021, at the latest—pending FDA review, although FDA retains enforcement discretion. Over the last year, FDA has worked to review thousands of PMTAs, representing products from roughly 500 companies.The vast majority of the PMTAs are for ENDS products. Under the PMTA pathway, manufacturers or importers must demonstrate to the FDA that permitting the marketing of the new tobacco product would be “appropriate for the protection of the public health,” among other things. That statutory standard requires the FDA to consider the risks and benefits to the population as a whole, including users and non-users of tobacco products. The FDA’s review of PMTAs includes assessment of a tobacco product’s components, ingredients, additives, toxicological profile, and health effects, as well as its manufacturing, packaging, and labeling processes, and data from consumer perception research , and the applicant’s description of marketing plans for the product. When reviewing PMTAs for ENDS products, FDA’s task is to follow the direction Congress provided in the law by taking into account the increased or decreased likelihood that existing users of tobacco products will stop using such products, as well as the increased or decreased likelihood that those who do not use tobacco products will start using such products. In making this determination, the impact of such products on youth initiation and use is a critical consideration. So far, the FDA has issued ruling on over 96% of the PMTAs submitted on or before the September 9, 2020 deadline, including 295 marketing denial orders for more than 1,089,000 flavored ENDS products. Products subject to a MDO for a premarket application may not be introduced or delivered for introduction into interstate commerce. If the product is already on the market, the product must be removed from the market or risk enforcement. On October 12, 2021, the FDA granted permission to R.J. Reynolds to market its Vuse Solo closed ENDS device and two accompanying tobacco-flavored e-liquid pods with a nicotine strength of 4.8%, which approximates the nicotine content of a pack of cigarettes.

The FDA simultaneously issued MDOs for ten other flavors submitted under Vuse Solo but declined to state which ones. RJR is the second-largest tobacco company in the United States , and a wholly owned subsidiary of Reynolds American Inc., after merging with the U.S. operations of British American Tobacco in 2004 . In a statement announcing the decision, the FDA said that “The authorized products’ aerosols are significantly less toxic than combusted cigarettes based on available data.” The statement concluded that “For these products, the FDA determined that the potential benefit to smokers who switch completely or significantly reduce their cigarette use, would outweigh the risk to youth,4 x 8 grow tray provided the applicant follows postmarketing requirements aimed at reducing youth exposure and access to the products”. The FDA’s decision came on the heels of the 2021 NYTS report showing an estimated 2.06 million U.S. middle and high school students as current users of e-cigs, with Puff Bar, Vuse, and Juul among the most popular brands. In its decision, the FDA stated that it was aware that 10% of high school students who used e-cigs, named Vuse as their favorite brand in the 2021 NYTS. Vuse has become the fastest-growing e-cig brand, accounting for over 26% market share in the top five markets, being the market leader in Canada, the UK, France, and Germany . In the United States, Vuse continues to outperform other brands, becoming the second largest and fastest growing player in the market in 2021. Currently, Vuse owns 33% of the market share in the United States whereas Juul owns 40%. The FDA’s decision to grant marketing orders for Vuse Solo and accompanying e-liquid pods marks a milestone in vaping regulations as this is the first time ever that a set of vaping products gets clearance from the agency. The cleared products can now be mass marketed and sold legally in the United States. As expected, the watershed decision by the FDA to green light Vuse Solo vaping products has been praised by the industry as well as proponents of e-cigs for harm reduction. Simultaneously, there have been swift and harsh criticisms of the decision by many experts in public health and medicine and numerous healthcare advocacy groups. As the FDA continues its premarket reviewing of the remaining PMTAs for ENDS products, including major brands such as Juul, and while teens’ favorite products, specifically Puff Bars , are being ordered off the market , Vuse is expected to continue its growth momentum owing to its “first-mover” advantage and industry leading FEELM ceramic coil. Alcohol use disorder is a highly prevalent, chronic, relapsing condition characterized by an impaired ability to stop or control alcohol use despite clinically significant impairment, distress, or other adverse consequences. It is the most common substance use disorder: in 2016, 100.4 million people globally were estimated to have an AUD. This disorder represents a significant public health concern. The WHO estimates that alcohol consumption is responsible for 5.9% of all deaths and 5.1% of global disease burden. Alcohol use and misuse is thought to contribute to over 200 related diseases and health conditions globally, including cardiovascular disease, cancer, liver cirrhosis, and injuries. AUD is also often comorbid with other substance use disorders, major depressive disorder, bipolar disorder, and other psychiatric disorders. In the USA alone, AUD is estimated to contribute to about 88,000 deaths each year. An estimated 44.6 million adults per year in the USA suffer from AUD, and 93.4 million adults in the USA will meet or have met AUD criteria at some point in their life.

Furthermore, the economic burden of AUD is estimated to be approximately $250 billion across the USA. Although AUD is an important public health concern, the disorder remains severely under treated with only 7% of adults with AUD in the USA and less than 10% in Europe receiving pharmacotherapy and/or psychotherapy treatment. Furthermore, the lag between the age at which AUD onsets and the age of first AUD treatment has been estimated to be eight years on average. Pharmacotherapies have seen limited use in the treatment of AUD, partially due to lack of addiction treatment training for medical professionals, lack of awareness regarding medication options , reluctance to prescribe and take medications, perceived low efficacy of medication, and stigma surrounding treatment. Indeed, only three pharmacotherapies are approved by the US Food and Drug Administration for use in AUD treatment. These medications are disulfram , acamprosate, and naltrexone. The European Medicines Agency similarly recognizes only these same three medications, as well as nalmefene, as established pharmacotherapies for AUD. These medications are only modestly effective and are under-utilized in treatment. A study conducted in 2019 found that only 1.6% of adults in the USA with past-year AUD received evidence-based AUD pharmacotherapies. Treatment outcomes for AUD differ widely across patients and medications. While abstinence may be desirable, it is infrequently obtained, such that only 16% of individuals in treatment for AUD achieve abstinence. Furthermore, evidence does not support abstinence as the only approach in the treatment of AUD. Not all individuals with AUD consider abstinence to be a goal of their recovery; only 2–6% of goals set in patient-driven treatment center on attaining alcohol abstinence. Non-abstinent recovery, including reductions in drinking and heavy drinking in particular , has been recognized to have health and societal value and has gained traction as a treatment target. Indeed, non-abstinent AUD recovery has been shown to be sustainable for up to 10 years following treatment. Despite growing recognition of the benefits of harm reduction, however, the most commonly prescribed pharmacotherapy to treat AUD remains disulfram, a medication advised strictly for abstinence. Furthermore, the heterogeneity of AUD suggests that it will be unlikely that one single medication will be effective for all individuals with an AUD. Therefore, there is a pressing need for the development of novel, diverse, and effective pharmacological treatment options for AUD with the hopes of increasing utilization and improving care.Specifically, this review provides a brief overview of currently approved medications and identifies new and repurposed agents “on the horizon” for which evidence indicates a potentially effective application toward AUD treatment.The following sections examine pharmacotherapies approved or in-development for AUD. Medications were selected for this qualitative review by considering gaps in existing review articles and the expertise of all authors; information was gathered via qualitative PubMed literature searches.

MANCOVA revealed significant between groups differences in SOPS P, GAF, and the 15-Analyte Index. Post-Hoc analyses using Bonferroni correction revealed that CHR- CTrauma subjects with a history of childhood trauma demonstrated significantly higher SOPS positive symptom scores than CHR- CNoTrauma, and CHR- NCTrauma, CHR- NCNoTrauma subjects. Given that criteria for conversion to psychosis is based on increased scores in the SOPS Positive scale, total childhood trauma may be an important independent variable associated with increased baseline SOPS positive symptoms and help identify a category of individual who are highest risk for conversion to psychosis. Further, CHR-CTrauma demonstrated lower GAF as compared to CHRNCNoTrauma subjects, whereas CHR- CNoTrauma did not demonstrate differences in GAF scores compared to either group of CHR-NC subjects. This again may imply that history of childhood trauma may be an important independent variable associated with increased baseline global functioning and thus help identify a category of clinical high-risk subjects who demonstrate the lowest global functioning. Finally, the 15-Analyte index did not differ between CHR-CTrauma and CHR-CNoTrauma subjects but did differ between CHR-NCTrauma and CHR-NCNoTrauma groups. Given that higher scores on the 15-Analyte index are associated with higher SOPS overall symptoms, lower global functioning, and lower social/role functioning, this finding may be interpreted to mean that CHR subjects with any history of trauma may demonstrate a unique population of subjects with worse clinical outcomes who would benefit most from early intervention. There are several possible limitations of this study that may explain the non-significant association between history of childhood trauma and pro-inflammatory cytokines . While sample size was adequate to detect small to medium between subjects’ effects,indoor cannabis grow system due to employing multiple between-subjects comparisons, risk for Type I error was increased.

Future research may consider use of open public data sets or consortium efforts in order to pool resources and maximize recruitment of sufficient samples to conduct analyses that require a large sample of subjects, such as exploratory factor analyses of inflammatory analytes. Further, measurement of childhood trauma in this study prevents evaluation of the effect of chronicity and severity of trauma to be evaluated. Future studies should consider use of the non-abbreviated Childhood Trauma Questionnaire: CTQ, in order to capture severity and chronicity of each individual sub-type of trauma endorsed. A review by Schafer and Fisher determined that instruments assessing childhood trauma, such as the CTQ, that were originally developed for the general population are also appropriate for use among people with psychosis. However, the use of self-report measures of childhood trauma is additionally prone to bias, particularly when subjects are under the age of 18. Thus, in order to prevent bias in reporting, future studies should employ use of informants that may be able to verify experience of childhood trauma in order to increase reliability of reporting. Moreover, inflammatory analytes and childhood trauma were only evaluated from one time point. Due to the age range of the at-risk sample , this might mean that ongoing changes in inflammatory analytes and additional trauma experiences that occurred during the course of the study, were not captured. Ongoing sampling of childhood trauma on inflammation must be evaluated across time in order to establish more reliable measures of these dynamic processes. The use of cross-sectional data for mediation analyses is limited, as temporal precedence cannot be established thereby preventing implications to be drawn regarding the causal effect of childhood trauma or inflammatory markers on clinical outcomes. While a study by Simpson et al. demonstrated that self-report measurement of childhood trauma in a first episode psychosis sample remained stable and consistent across multiple time points, they found that severity of trauma reported did fluctuate across multiple assessments. If unable to collect multiple biological samples from different time points, implementation of a stress test design with blood marker sampling would allow for testing the impact of trauma on stress reactivity and inflammatory response during the course of one visit.

Additionally, the validation of inflammatory markers in psychosis is ongoing; therefore, selection of specific markers of inflammation to measure at various phases of illness is not well established, nor is there a clear understanding of what inflammatory analytes may be differentially impacted by environmental stress as compared to disease progression. Measuring a large panel of serum markers of inflammation is preferable, but studies must be well-powered in order to establish reliable effects. Evaluating profile networks of inflammatory analytes is needed to understand the dynamic activation and suppression of analytes and provide a clearer understanding of immune system regulation as a whole, as compared to understanding of single analytes. Measurement of single inflammatory analytes provides only a small snapshot of a much larger and more complex picture that is the immune system. Finally, this study lacked assessment of variables known to affect inflammatory analyte levels, namely body mass index . While this study controlled for the effects of antipsychotic, antidepressant, tobacco, and cannabis use, BMI is highly associated with inflammation and thus may have confounded findings in inflammatory analytes. Taken together these results confirm existing research that individuals at CHR for psychosis demonstrate higher total childhood trauma as compared to unaffected comparison subjects and that history of childhood trauma is associated with increased positive psychosis-risk symptoms and worse global functioning. However, total childhood trauma was not associated with inflammation in this sample, thus analyses of the mediating effect of inflammatory analytes in the relationships between childhood trauma and clinical outcomes was non-significant. Instead, this study suggests that total childhood trauma and inflammatory analytes independently predict positive psychosis risk symptoms and lower global functioning; thus, these independent effects are additive. These findings confirm the importance of assessing for childhood trauma and blood-based inflammation in at-risk subjects as a means to identify individuals who may be at the highest risk for poor clinical and functional outcome. Childhood trauma and inflammation may seem difficult variables to target through existing evidence-based psychotherapy interventions. However, there is a growing body of research that supports the use of complementary and alternative medicine psychosocial interventions that may effectively target these factors in psychosis. The goal of research of CAM in psychosis is to replicate results from studies conducted in the general population demonstrating that the use of mind-body interventions reduces reactivity to stress and chronic inflammation.

For example, research Breines et al. demonstrated that higher levels of “self-compassion,” defined by Neff as “the attitude of treating oneself with kindness and non-judgmental understanding,” are associated with reduced IL-6 response in reaction to stress. More importantly, it has been demonstrated that self-compassion is not a “trait,” but rather a modifiable and alterable “state.” Cognitively-Based Compassion Training is a meditation-based program derived from Tibetan Buddhist mind-training that has been demonstrated to enhance empathy and compassion for oneself and others. Research on CBCT in medically stable populations by Pace et al. reveals 6 weeks of compassion meditation training reduced stress-induced immune responses in a stress-test design. Further, Pace et al. demonstrate that strength of reduction in immune response was not mediated by time spent meditating, indicating that benefits of compassion training are not dependent on long hours of practice. This is very relevant to the application and effectiveness of such techniques in children or adolescents,equipment for growing weed particularly those currently experiencing mental health concerns, given that it would be impractical to expect children with mental health concerns to engage in lengthy meditation practice. In fact, Pace et al. demonstrated the feasibility of CBCT in not only adolescents, but those in foster care with a history of early life adversity. Moreover, foster care program adolescents with a history of childhood trauma demonstrated significant reductions in salivary CRP after just 6-weeks of compassion training. Compassion training has not yet been evaluated in CHR population, but there is evidence that adapted mindfulness-based interventions are not only safe and therapeutic for use in chronic psychosis populations, but also may help to decrease individual distress around positive psychosis symptoms, such as auditory hallucinations and delusions . A recent systematic review by Louise, Fitzpatrick, Strauss, Rossell, and Thomas on “third-wave” cognitive behavioral interventions in psychosis, reveals that acceptance-based interventions show moderate effects in reducing depressive symptoms, but no effect in reducing distress around psychosis symptoms or improving functional outcome. Randomized-controlled clinical trials utilizing mindfulness-based interventions for early-psychosis are currently lacking. Nonetheless, these techniques represent a promising category of psychosocial intervention warranting further study as they may modify reactivity to stress and immune response. Other CAM interventions that warrant further study in psychosis populations to target immune response and clinical outcomes include exercise, diet, and cannabidiol. Exercise and diet have been shown to have robust effects on reducing chronic inflammation and improving health outcomes in the adolescents . Research on aerobic exercise in psychosis groups has demonstrated very promising findings, indicating that moderately intense exercises, such as walking or bike riding, may improve positive and negative psychosis risk symptomatology, cognition, and functional outcome . Further, these effects have been replicated in CHR populations .For example, a recently review by Stogios et al. reveals that unmedicated individuals with psychosis demonstrate increased appetite and cravings for fatty foods, which contribute to weight gain and metabolic disturbances known to be associated with higher levels of inflammation. Wu, Wang, Bai, Huang, and Lee revealed that a 6-month combined diet and physical activity program in schizophrenia subjects resulted in reduced BMI, improved metabolic profiles of insulin and triglycerides, as well as improved psychotic symptoms. Cahn, Goodman, Peterson, Maturi, and Mills demonstrated a 3- month mindfulness, diet, and yoga combined intervention resulted in increased levels of BDNF and increased cortisol awakening response in a population of medically stable adults.

Research on novel therapeutics, such as cannabidiol , as a potential treatment for psychosis have demonstrated that CBD may not only have neuroprotective, antioxidant, and anti-inflammatory effects, but also improve disease trajectory of psychosis by reducing positive psychosis symptoms, anxiety, and cognitive deficits in first episode psychosis groups . To date, there are no studies evaluating the effects of diet, exercise, CBD, or combined interventions on immune response to stress in CHR psychosis populations; however, there is strong evidence to warrant further study of these interventions in CHR psychosis groups. Finally, therapeutic interventions that are known to improve clinical outcomes for individuals who have experienced childhood trauma may be particularly important in mitigating long term functional impairments in youth at clinical high risk for psychosis. Bendall, AlvarezJimenez, Nelson, and McGorry describe several recommendations to be considered for good, quality, assessment and intervention withing individuals at risk for psychosis endorsing a history of childhood trauma, including, systematic inquiry about childhood trauma for all individuals with psychosis, and development of individualized treatment plan adapted from cognitive behavioral therapy approaches for the treatment of psychosis and trauma, paying particular attention to pacing of treatment and repeated assessment. Evidence based psychotherapies for trauma that include focus on stress management and interpersonal effectiveness such as Skills Training in Affect and Interpersonal Regulation , may be particularly meaningful for CHR subjects who have a history of childhood trauma. Schafer and Fisher demonstrated the effectiveness and tolerability of STAIR for individuals at clinical high risk for psychosis with history of childhood trauma. However, there has been little research evaluating the effectiveness of evidence-based trauma-focused treatments in this complex population. Studies evaluating the effectiveness of trauma focused interventions may include individuals with psychosis as only a small sub-sample of participants included in the research, but co-occurring psychosis spectrum disorders are often included as exclusionary criteria in evaluation of trauma-focused treatments for individuals with a history of trauma . As previously discussed, compassion training, such as CBCT, may represent a unique category of psychosocial intervention that helps to improve stress reactivity in youth who have experienced early life adversity . Moreover, PoehlmannTynan et al. demonstrated when parents completed 8-10 weeks of CBCT their children demonstrated reduced cortisol, indicating that compassion training for parents may have cascading effects of cumulative stress on their children. Although difficult to achieve, prevention of the occurrence of childhood trauma would be an ultimate goal. Varese et al. maintain that if childhood trauma was removed from the population entirely, the number of individuals presenting with psychosis would be reduced by 33%. Thus, assessment of childhood trauma is an essential first step toward not only early intervention in, but also ultimately prevention of psychosis spectrum disorders.

Similarly, in a study of undergraduate men and women, researchers found that negative urgency, a component of emotion dysregulation that includes the tendency to act rashly when distressed, was significantly associated with problematic alcohol use and disordered eating . Finally, Loxton and Dawe found that adolescent girls who abused alcohol and engaged in disordered eating were more sensitive to reward than adolescent girls who did not engage in any of these behaviors. Overall, extant literature highlights the complex nature of ED-SUD presentations. Thus, traditional treatment programs have targeted EDs and SUDs sequentially. However, interest in integrated treatment approaches has grown , and research indicates that patients who do not receive integrated treatment have poorer treatment outcomes . Nevertheless, there is limited research on what such an integrated approach should optimally target, and there is no consensus in the field about the best treatment modality for the ED-SUD population. One potentially promising intervention for ED-SUD is Dialectical Behavior Therapy , which is a treatment based on an emotion regulation model . In DBT, psycho education on this model is provided, and patients are encouraged to accept and learn to tolerate their emotional experiences, while also learning alternative methods of coping with their emotions. DBT is a well-established treatment for individuals with multiple and severe psychological disorders , and has been adapted for use with EDs . Its further adaptation and testing for individuals with co-occurring SUDs and BPD support its use to target multiple problem areas in an integrated manner.Findings from this study are promising, suggesting that integrated DBT for EDSUD treatment is associated with decreased substance use severity and frequency,vertical farming units decreased emotional eating, and increased levels of confidence in ability to resist urges for substance use .

Given the limited research on DBT for ED-SUD, a better understanding of factors associated with ED-SUD compared to ED or SUD alone may be helpful in identifying potential treatment targets to address both disorders simultaneously. The impetus for the current study was to add to this limited literature by reproducing previous research findings in a treatment-seeking ED population and discussing how these empirical findings can guide treatment recommendations for ED-SUD. Consequently, the present study examined differences between patients with EDs only to patients with ED-SUD on demographics, psychiatric comorbidity, and self-reported eating disorder and related psychopathology. Given previous research findings, we hypothesized that individuals with EDSUD would be more likely than ED only to engage in binge eating/purging, and to have a bulimic-spectrum eating disorder, BPD symptoms, higher rates of psychiatric comorbidities, self-harm, and suicidality, greater difficulties with emotion regulation, and more reward sensitivity.Participants were 98 adult patients admitted to a partial hospital program for EDs between August 2016 and November 2018. Participants completed clinical interviews and survey measures within 14 days of treatment admission. Eating disorder and comorbidities were diagnosed using either the Mini Neuropsychiatric Interview or the Structured Clinical Interview for DSM-5 Disorder administered by trained, bachelor’s-level research assistants. Suicidality risk was assessed using the MINI suicidality module. Thirty-six patients were diagnosed with a SUD. Of those, 19.4% were diagnosed with an alcohol use disorder and 25.5% were diagnosed with a non-alcohol SUD . Of the 25 patients with a nonalcohol SUD, 20% had a sedative-hypnotic-anxiolytic use disorder , 52% had a cannabis use disorder , 20% had a stimulant use disorder , 8% had an opioid use disorder , and 4% had a hallucinogen use disorder .Table 1 presents demographic differences between ED and ED-SUD patients.

There were no significant differences in age, BMI, length of illness, history of previous treatment, gender, ethnicity, diagnosis, or engagement in purging behaviors between groups, and only trend-level differences in racial background and the likelihood of engaging in objective binge eating episodes. Table 2 presents differences in comorbidity and psychotropic medication use at admission between ED and ED-SUD patients. ED-SUD patients had a significantly greater number of psychiatric comorbidities and were more likely to be taking a mood stabilizer at treatment admission compared to ED patients. There was a trend towards ED-SUD patients being more likely to be diagnosed with panic disorder and posttraumatic stress disorder compared to ED patients. Table 3 presents the differences between ED and ED-SUD patients on self-reported measures of eating disorder and related psychopathology. ED-SUD patients had higher scores on multiple sub-scales of the DERS—DERS Goals, DERS Impulse, and DERS Strategies—compared to ED patients. Additionally, ED-SUD patients reported significantly greater SPSRQ-Reward scores than those without a SUD. There was a trend towards individuals with a SUD reporting greater STAI-Trait, DERS Total, and SPSRQ-Punishment scores.The present study sought to describe differences between ED patients with and without a SUD at treatment admission. Results demonstrated that ED-SUD patients reported a greater number of comorbid psychiatric diagnoses and were more likely to be prescribed mood stabilizers. They also reported greater difficulty engaging in goal-directed activity, higher impulsivity, more limited access to emotion regulation strategies, and higher reward sensitivity. There were trend-level differences suggesting that individuals with ED-SUD were more likely to engage in objective binge episodes, be diagnosed with panic disorder and post traumatic stress disorder, and to report higher trait anxiety, global emotion dysregulation, and sensitivity to punishment. Results are largely consistent with our hypotheses and previous research demonstrating higher rates of psychiatric comorbidity , emotion regulation difficulties, and reward sensitivity in ED-SUD samples. Partially consistent with previous research , our results suggested a trend towards a higher frequency of binge eating in ED-SUD, although there were no differences between ED and ED-SUD groups on purging. Furthermore, patients with bulimic syndromes were not significantly more likely to have a SUD.

While this is somewhat inconsistent with previous research , results support examining substance use across ED diagnoses. In contrast, with previous research, we did not find evidence for higher levels of self-harm or BPD symptoms in the ED-SUD group. Previous research supporting increased self harm in ED-SUD has been in adolescent samples , which may also explain this discrepancy. While previous research has found higher cluster B symptoms in ED-SUD , the lack of significant differences between ED and ED-SUD in our sample may be due to the relatively high scores on the BEST in both groups. Indeed, both groups scored similarly to patient samples with BPD .Overall, results demonstrating a greater number of comorbid diagnoses for the ED-SUD group support the need for integrated treatment, which is consistent with recent calls from experts within the field . DBT takes a behavioral approach, treating behaviors, regardless of their diagnostic association, according to a specific hierarchy. Given the complexity of ED-SUD cases and the tendency for these patients to vacillate between ED and substance use behaviors over time , an integrated, transdiagnostic approach may be useful in treating both behavioral presentations. Importantly, we did not find evidence for ED diagnostic differences between ED-SUD and ED only groups, lending further support for a transdiagnostic approach to ED-SUD treatment. DBT provides a comprehensive framework for effectively working with the multiple comorbidities observed in ED-SUD patients. In particular, the focus on the DBT hierarchy may help address vacillation between ED-SUD and other comorbid symptoms. The DBT hierarchy systematically addresses the most severe and life-threatening symptoms first, to help avoid shifting treatment targets throughout treatment. Additionally,weed drying room skills generalization may be particularly important in this population. Phone coaching, which is a part of DBT, may be useful in helping patients to generalize skills to multiple behaviors across environments. Regarding specific disorders, the non-statistically significant elevation in the likelihood of PTSD in the ED-SUD group compared to the ED alone group suggests that trauma symptoms may be a relevant treatment target for ED patients generally. Indeed, groups are working to develop protocols for the concurrent treatment of ED and PTSD , while existing trauma protocols are commonly used to treat PTSD in these populations such as the DBT/Prolonged Exposure protocol .Our study shows that ED-SUD patients report significantly greater difficulties with emotion regulation. More specifically, ED-SUD patients in our sample endorsed difficulties with regulating behavior when distressed, engaging in goal directed behavior when distressed, and accessing strategies for feeling better when distressed. Moreover, ED-SUD patients were more likely to already be prescribed a mood stabilizer; thus, despite previous treatment for emotion dys regulation they continued to have difficulty in this area. This is consistent with our hypothesis and points to emotion regulation as a critical treatment target. As previously discussed, DBT was specifically developed to provide education on emotion dys regulation and provide individuals with adaptive emotion regulation skills. Several skills were added to the DBT for SUD model to specifically address the heightened impulsivity reported by ED-SUD patients. These skills include Burning Bridges to persons, places, and things associated with substance abuse and Adaptive Denial of urges for substance use.The present findings that patients with ED-SUD report higher reward sensitivity to highlight the importance of assessing for and addressing temperament in this treatment population. Reward sensitivity may be an underlying mechanism that drives an individual’s substance use and ED behaviors. For instance, substance use and ED behaviors may be highly rewarding in the moment; hence, patients seek the short-term rewards of addictive behaviors despite their long-term, negative consequences. Furthermore, a potential obstacle to abstinence from ED behaviors and substances of abuse is the non-rewarding aspect of abstinence . Several skills taught in DBT for SUDs target these barriers. Contingency management strategies to reduce cues and access to substances and behaviors , as well as reinforcement of adaptive behavior, are essential to treatment. Specifically, Community Reinforcement , and Abstinence Sampling focus on the reinforcement of healthy behaviors. In conjunction with findings on reward sensitivity, the trend towards the significance of increased punishment sensitivity in this ED-SUD population suggests that for some patients, holding patients accountable to treatment goals and implementing consequences and rewards accordingly may be important for behavior change.

For example, using behavioral contracts and administering drug analysis screens to monitor substance use may be helpful. The DBT skill of Pros and Cons may help patients to identifying negative consequences of substance use.The present study has several strengths, including the use of structured clinical interviews to assess diagnoses and an examination of a broad range of constructs theoretically relevant to eating and substance use disorders. As such, this study adds to the limited literature investigating factors characterizing the ED-SUD population. However, there are several limitations worth noting. First, participants were drawn from a treatment-seeking sample presenting at a higher level of care. As such, results may not be representative of individuals with ED-SUD in the broader community. The modest ED-SUD sample size may have limited our ability to detect significant differences between groups. Additionally, the present study did not assess tobacco use or caffeine use disorders, which may also be relevant substances for ED groups, given their association with appetite suppression. Further, although the present sample included males and non-binary individuals, the smaller numbers in these groups limits the generalizability of the results beyond females. Importantly, we did not assess the past history of SUD, so the relative influences of active substance use versus traits underlying substance use on our findings cannot be determined. Finally, this study reviewed factors that provide a rationale for the applicability of DBT to treat EDs and co-occurring substance use in a cross-sectional study; however, future longitudinal studies and randomized controlled trials are needed to examine outcomes to determine the efficacy of DBT to treat ED-SUDs.Psychoneuroimmunology refers to the study of interactions between behavior, neural and endocrine systems, and the immune system . Alder and Cohen state that the field of psychoneuroimmunology is intended to “emphasize the functional significance” of the relationship between mind and body systems “in addition to” and “not in place of analysis of the mechanisms governing functions within a single system.” This growing field seeks to understand the associations between environmental exposures and neural, endocrine, and immune systems, as well as the consequences of inflammatory responses on human behavior, to allow for new insights into mechanistic pathways that are involved in the development of psychopathology. Thus, identifying the impact of early life adverse experiences, such as childhood trauma, on immune system regulation, and subsequent clinical outcomes, such as functioning, provides important information regarding possible therapeutic targets for early intervention and prevention of psychopathology.

Falls result from an interaction between an individual’s underlying vulnerabilities and their exposure to environmental conditions.People experiencing homelessness have a high prevalence of factors known to be associated with falls in the general population, including chronic diseases, functional impairment, alcohol and opioid use problems.Homeless older adults have high prevalence of other factors that could be associated with falls, such as substance use and heightened exposure to physical violence.People who are homeless live in a variety of environments, including homeless shelters and unsheltered spaces that expose them to environmental hazards and violence. In each of these settings, homeless individuals have limited control over their environment, especially when living in unsheltered environments. We examined the prevalence of and risk factors for falls in a longitudinal cohort of adults aged 50 and older who were homeless at study entry. We hypothesized that homeless adults would have a high prevalence of falls and high exposure to environmental hazards. We hypothesized that factors known to be associated with falls in the general population would be associated with falls in our cohort. We further hypothesized that several factors that are plausibly related, but have not been studied , would be associated. We conducted a 3-year prospective cohort study of 350 homeless adults aged 50 and older, the Health Outcomes in People Experiencing Homelessness in Older Middle agE study.We interviewed participants at baseline and every 6 months for three years; at each interview, trained research staff administered a structured interview and conducted clinical assessments. The institutional review board of the University of California, San Francisco approved this study. The datasets we analyzed during the current study are available from the corresponding author on request. Between July 2013 and June 2014,vertical grow systems we recruited 350 adults age 50 or older who were homeless at study entry.

We recruited from all local shelters open to older adults , all free and low-cost meal programs that served at least three meals a week , one recycling center, and areas where adults slept unsheltered in Oakland, California . To create a sample that best represented the target population, including the high number of people living unsheltered in Oakland, we randomly selected potential participants using sampling frames that included encampment sites, recycling centers, shelters, and meal programs.We describe our Methods in more detail elsewhere .Eligibility criteria included: homeless according to the Homeless Emergency Assistance and Rapid Transition to Housing Act definition that includes any person living unsheltered, staying in an emergency shelter, or facing eviction in the next 14 days, age 50 years or older, English-speaking, and able to provide informed consent as determined by a teach-back mechanism.20Participants received $25 for the screening and enrollment interview, $5 for monthly check-ins, and $15 for follow-up interviews. Our primary outcome was self-reported falls in the prior six months, assessed at each study interview. We defined falling as “a sudden, unintentional change in position from an upright posture coming to rest on the floor or ground.” For descriptive purposes, among participants who reported a fall, we asked how many times the participant fell and whether they sought medical treatment for their fall. We identified demographic risk factors as time-constant and other risk factors, health status, and health-related behaviors as time-varying . We assessed age, gender, and race/ethnicity.In our analyses, we dichotomized race as Black versus non-Black. Participants reported their highest educational attainment. We classified participants as having graduated from high school or earned a General Educational Development certificate versus no high school diploma/GED. Using modified questions from the National Health and Nutrition Examination Survey , we asked participants whether a healthcare provider told them they had: myocardial infarction, congestive heart failure, stroke, arthritis, diabetes, or chronic lung disease ; we included these as separate variables.If a participant reported a medical condition at any time point, we considered them to have that condition in subsequent visits. We assessed visual impairment using the Snellen test, and defined visual impairment as corrected visual acuity <20/100.We defined hearing impairment as self-reported difficulty hearing.

To evaluate cognitive impairment, we used the Modified Mini-Mental State Examination . Those who scored below the 7th percentile or were unable to complete the assessment were defined as cognitively impaired. We asked participants about their ability to complete activities of daily living . We defined an ADL impairment as reporting difficulty with bathing, transferring, toileting, dressing or eating.We assessed lower extremity function with the Short Physical Performance Battery test and classified those who scored ≤10 as having reduced physical performance.We assessed urinary incontinence in the past six months by asking participants whether they had “leaked urine, even a small amount.” To assess exposure to environmental hazards at each visit, we used a residential follow-back calendar in which we asked participants to report each place they had stayed and number of nights in each setting during the prior six months.We considered being unsheltered as indicative of the highest environmental exposure. We defined an unsheltered environment as sleeping outdoors or any place not meant for human habitation .In preliminary analyses, we evaluated nights unsheltered as a 3-level variable and as a 6-level variable . Neither alternative exhibited a dose-response effect. Therefore, we used a dichotomous measure of any nights unsheltered in our analysis. Statistical Analyses To identify risk factors for falls, we chose independent variables based on our hypotheses. We assessed bivariate associations between a priori independent variables and recent falls using generalized estimating equations . We built our multivariable model by including variables with bivariate Type 1 p-values <0.20. If a categorical variable had more than two levels, we included all levels in our multivariable model if any Type 1 p-value was p<0.20. We reduced the model using backwards elimination retaining variables with p-values <0.05 in our final multivariable model. We conducted our analysis in SAS 9.4 using complete case analysis and robust confidence intervals . In a sensitivity analysis, we assessed whether we had underestimated the probability of falls due to incomplete follow-up or mortality. We examined the prevalence of falls amongthose: 1) with complete follow-up, 2) who had died during follow-up, or 3) who had not died but had missed any study visits over the 36-month study period. We used GEE to examine whether those who had died or missed visits were more likely to have experienced a fall in the past 6 months than those with complete follow-up. We included participants with a minimum of two visits.

We used weighted linear regression with a second order polynomial and zero intercept term to plot a trend line.At baseline,curing marijuana over one-third reported one or more falls in the past six months. Of the 118 participants who reported falling at baseline, 28.0% reported 4 or more falls, 35.6% two to three falls, and 36.4% one fall. One-third of participants who fell required medical treatment due to a fall. During the 36-month study, 28 participants died. Of those who survived, 183 completed all six follow-up interviews; 72 completed 4-5, 32 completed 2-3, and 21 completed one follow-up interview. We found a higher mean number of falls at baseline among those who died during follow-up 0.50) and those who had not died but had missed visits than among those who completed follow-up . Of the 350 participants, 218 reported one or more falls in at least one study visit; 107 reported falls in at least half of the visits; and 34 reported falls at all visits. Factors Associated with Falls Those who reported falls at baseline had a higher prevalence of known risk factors for falls than those who had not fallen . People with falls were significantly more likely to have less than a high school education, a history of stroke, difficulty with ADLs, mobility impairment, use of assistive device, increased urinary incontinence, and depressive symptoms. We found that those who fell were more likely to have moderate-to-high risk opioid and marijuana use, fewer social confidants, have spent at least one night unsheltered, or experienced physical assault. In models adjusted for key covariates, individual risk factors associated with significantly higher odds of falls included older age 1.00-1.06), being a woman , having non-Black race , having a history of stroke , reporting an ADL impairment , urinary incontinence , and use of an assistive device . Moderate-to-severe marijuana use and moderate-tosevere opioid use were associated with increased odds of falling. Experiencing physical assault and spending any night unsheltered in the last six months were as well. In this longitudinal study of adults 50 and older who were homeless at study enrollment, we found a high prevalence of falls. Despite a median age of 58 years, study participants reported a prevalence of falls higher than older adults with a mean age of 78 in the general population.3 Many participants fell repeatedly throughout the three-year study period; over a third of the cohort reported falls in at least half of their study visits. We found an association between falls and several factors known to increase fall risk within the general population, including older age, gender, functional impairment, urinary incontinence, use of an assistive device, and stroke. Our findings indicate that the increased risk for falls in homeless older adults results, in part, from a high prevalence of geriatric conditions and substance use known to increase fall risk.2 Some of these risk factors may be modifiable via physical and occupational therapy, although it is more difficult to intervene while someone is experiencing homelessness. As the average age of the homeless population continues to increase, the population will have increasing prevalence of geriatric risk factors.We identified novel risk factors: using marijuana, experiencing physical assault, and spending time unsheltered that contributed to the high fall prevalence in our population. Both opioid use and marijuana use were associated with increased odds of falling. Opioid use is associated with increased fall risk among older adults in the general population.However,despite research on marijuana use and injuries in community-dwelling older adults, little is known about how marijuana use impacts falls.Marijuana—like opioids—may increase falls by affecting the sensorium, inducing dizziness, confusion, and drowsiness.We found a high prevalence of marijuana use among study participants. People born in the study’s age cohort have had high prevalence of marijuana use their whole lives, including in older adulthood.As marijuana use among older adults increases, due to changes in legal status and cohort effects, there may be increased falls associated with its use. Experiencing physical assault is common among older adults who are homeless.Physical assault can increase fall risk directly , or indirectly, by causing injuries that enhance underlying individual vulnerabilities associated with falls.Future research should evaluate the role of marijuana use and physical assault in falls among housed older adults to determine whether these risk factors are unique to older adults experiencing homelessness. People who are unsheltered have increased exposure to unsafe environments, with minimal control. They may stay in isolated locations with uneven surfaces and physical barriers, such as abandoned buildings, under bridges, or along highways. Unsheltered environments lack lighting or protection against environmental hazards. Avoiding falls requires intact executive function and physical agility to be able to process external stimuli and modify movements to remain upright.For older adults with vulnerabilities—such as those common among homeless older adults—small external triggers may precipitate falls. Housed older adults are able to modify their behaviors to avoid high-risk environmental exposures that predispose them to falls. For example, they can decrease how often they walk outside on uneven surfaces or minimize their public transit use. In contrast, adults living in unsheltered settings have less ability to avoid high-risk environmental exposures.Our finding that non-Black race was associated with increased falls is consistent with research in housed adults.Homelessness is caused by an interaction between structural factors and individual risk factors. Because Black Americans face structural racism, Black Americans with less individual vulnerability are at risk for homelessness. While we adjusted for these conditions, there may be unmeasured confounders that we were unable to account for.Our study has several limitations. We rely on six-month recall of falls. Other studies of falls in older adults use time frames that range from monthly to biennial.Participants without complete study follow-up had a higher prevalence of falls, indicating that our model may have underestimated the odds of experiencing falls.