How Does Self-Control Promote Health Behaviors? A Multi-Behavior Test of Five Potential Pathways.

BACKGROUND: Self-control is generally defined as the capacity to override impulses and is a robust predictor of health behaviors. This paper integrates trait, reasoned action, and habit approaches to develop and test a mechanistic account of how self-control influences health actions. PURPOSE: We tested five potential pathways from self-control to behavior, termed the valuation, prioritization, habituation, translation, and inhibition routes. METHODS: At baseline, participants (N = 663 adults) completed survey measures of reasoned action approach variables and habits in relation to eight health behaviors and the Brief Self-Control Scale. Three months later, participants reported their behavior. Multi-level modeling was used to test pathways across behaviors. RESULTS: Supporting the valuation route, affective attitude, cognitive attitude, descriptive norms, and perceived behavioral control mediated the self-control-intention relation, and intentions and perceived behavioral control mediated the relationship between self-control and health behaviors. Self-control also predicted the priority accorded to different considerations during intention formation. Higher self-control was associated with stronger prediction by cognitive attitudes and perceived behavioral control and weaker prediction by habits and injunctive norms. Self-control predicted habit formation, and habits mediated the self-control-behavior relation. Finally, self-control was associated with the improved translation of intentions into health behaviors and with greater inhibition of affective and habitual influences. Findings for the different pathways were not moderated by whether approach (health-protective behaviors) or avoidance responses (health-risk behaviors) were at issue. CONCLUSIONS: The present research offers new insights into why self-control promotes health behavior performance, and how deficits in self-control might be offset in future behavior-change interventions.

Self-control is the capacity to override impulses and is known to predict engagement in health behaviors. This article tests five hypotheses about how self-control drives health actions. We find that high self-control not only helps to override impulses (feelings and habits), it also influences (a) how favorable are people's thoughts, feelings, and intentions about health behaviors, (b) what considerations determine the intention to act (e.g., high self-control means people give higher priority to the perceived healthiness of the behavior and how much control they have over its performance), (c) whether people form habits that make it less effortful to perform health behaviors, and (d) how effectively people translate their "good" intentions into health behaviors. Thus, we find support for five different routes from self-control to engagement in health behaviors.

Which Intervention Strategies Promote the Adoption and Maintenance of Physical Activity? Evidence From Behavioral Trials With Cancer Survivors.

BACKGROUND/PURPOSE: We address four questions about interventions to promote physical activity in cancer survivors: (a) How often is both the adoption and maintenance of behavior change tested in trials? (b) How often do interventions generate adoption-plus-maintenance of behavior change? (c) Are intervention strategies specifically geared at promoting maintenance of behavior change deployed in trials? and (d) Which intervention strategies distinguish trials that promote both the adoption and maintenance of physical activity from trials that promote adoption-only or generate no behavioral changes? METHODS: Computerized literature searches identified 206 reports of randomized trials that measured physical activity in the wake of the intervention. RESULTS: Only 51 reports (24%) measured both behavioral adoption (postintervention) and behavioral maintenance (≥3 months follow-up). The 51 reports included 58 tests of interventions; 22% of tests observed both adoption and maintenance of physical activity, 26% reported adoption-only, and 52% found no change in behavior. Change techniques designed to promote behavioral maintenance were used much less frequently than adoption techniques or adoption and maintenance techniques. Interventions that aimed to improve quality of life, used supervised exercise sessions, were undertaken in community centers, and deployed fewer behavior change techniques were associated with adoption-plus-maintenance of physical activity in cancer survivors. CONCLUSIONS: The present findings offer new insights into the adoption and maintenance of physical activity and highlight the need to routinely assess these forms of behavior change in future trials. More extensive testing of intervention strategies specifically geared at maintenance of behavior change is warranted.

Cancer survivors need to not only adopt, but also maintain, physical activity to benefit their health and wellbeing. We undertook a systematic review of interventions to promote the adoption and maintenance of physical activity in cancer survivors. Out of 206 physical activity interventions for cancer survivors that we identified, only 51 (24%) measured both the adoption and maintenance of behavior change. Of these 51 intervention studies, only 22% were effective in promoting both the adoption and maintenance of physical activity. We developed a new classification of behavior change techniques used in interventions and discovered that techniques specifically designed to promote behavioral maintenance were used only rarely. We found that interventions that aimed to improve quality of life, used supervised exercise sessions, and were undertaken in community centers predicted adoption-plus-maintenance of physical activity in cancer survivors. These findings underscore the need for more trials that assess the adoption and maintenance of physical activity and for new research programs focused on evaluating the efficacy of maintenance techniques.

Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice.

Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in micro-RNA biogenesis, is implicated in RPE atrophy. However, the functional implications of DICER1 loss in choroidal and retinal neovascularization are unknown. Here, we report that two independent hypomorphic mouse strains, as well as a separate model of postnatal RPE-specific DICER1 ablation, all presented with spontaneous RPE degeneration and choroidal and retinal neovascularization. DICER1 hypomorphic mice lacking critical inflammasome components or the innate immune adaptor MyD88 developed less severe RPE atrophy and pathological neovascularization. DICER1 abundance was also reduced in retinas of the JR5558 mouse model of spontaneous choroidal neovascularization. Finally, adenoassociated vector-mediated gene delivery of a truncated DICER1 variant (OptiDicer) reduced spontaneous choroidal neovascularization in JR5558 mice. Collectively, these findings significantly expand the repertoire of DICER1 in preserving retinal homeostasis by preventing both RPE degeneration and pathological neovascularization.

High-capacity preconscious processing in concurrent groupings of colored dots.

Grouping is a perceptual process in which a subset of stimulus components (a group) is selected for a subsequent-typically implicit-perceptual computation. Grouping is a critical precursor to segmenting objects from the background and ultimately to object recognition. Here, we study grouping by color. We present subjects with 300-ms exposures of 12 dots colored with the same but unknown identical color interspersed among 14 dots of seven different colors. To indicate grouping, subjects point-click the remembered centroid ("center of gravity") of the set of homogeneous dots, of heterogeneous dots, or of all dots. Subjects accurately judge all of these centroids. Furthermore, after a single stimulus exposure, subjects can judge both the heterogeneous and homogeneous centroids, that is, subjects simultaneously group by similarity and by dissimilarity. The centroid paradigm reveals the relative weight of each dot among targets and distractors to the underlying grouping process, offering a more detailed, quantitative description of grouping than was previously possible. A change detection experiment reveals that conscious memory contains less than two dots and their locations, whereas an ideal detector would have to perfectly process at least 15 of 26 dots to match the subjects' centroid judgments-indicating an extraordinary capacity for preconscious grouping. A different color set yielded identical results. Grouping theories that rely on predefined feature maps would fail to explain these results. Rather, the results indicate that preconscious grouping is automatic, flexible, and rapid, and a far more complex process than previously believed.

Clostridioides difficile-Associated Antibiotics Alter Human Mucosal Barrier Functions by Microbiome-Independent Mechanisms.

A clinically relevant risk factor for Clostridioides difficile-associated disease (CDAD) is recent antibiotic treatment. Although broad-spectrum antibiotics have been shown to disrupt the structure of the gut microbiota, some antibiotics appear to increase CDAD risk without being highly active against intestinal anaerobes, suggesting direct nonantimicrobial effects. We examined cell biological effects of antibiotic exposure that may be involved in bacterial pathogenesis using an in vitro germfree human colon epithelial culture model. We found a marked loss of mucosal barrier and immune function with exposure to the CDAD-associated antibiotics clindamycin and ciprofloxacin, distinct from the results of pretreatment with an antibiotic unassociated with CDAD, tigecycline, which did not reduce innate immune or mucosal barrier functions. Importantly, pretreatment with CDAD-associated antibiotics sensitized mucosal barriers to C. difficile toxin activity in primary cell-derived enteroid monolayers. These data implicate commensal-independent gut mucosal barrier changes in the increased risk of CDAD with specific antibiotics and warrant further studies in in vivo systems. We anticipate this work to suggest potential avenues of research for host-directed treatment and preventive therapies for CDAD.

Prevalence, determinants, and correlates of coagulation necrosis and contraction band necrosis in donor hearts.

BACKGROUND: Exploration of pathologic changes in donor hearts and finding the association of pathologic findings with potentially reversible cardiac condition may result in allowing such hearts to recover and be used for transplantation. METHODS: We enrolled consecutive donors from one federally designated Organ Procurement Organization for one calendar year. Hearts rejected for transplantation underwent pathological examination. We studied the association of pathologic findings with the mechanism of death. RESULTS: A total of 81 hearts were rejected for transplantation. The most common pathologic findings were coagulation necrosis (CN) in 17.3% and contraction band necrosis (CBN) in 34.6%. Anoxic brain injury was present in 78.6% of the donors who had CN, and only in 29.9% of those without CN (P = 0.002). CBN was more commonly associated with subarachnoid hemorrhage (17.9% vs 1.9% of donors with and without CBN, P = 0.017). Only hearts with CBN had significantly lower LVEF (P = 0.017). CONCLUSION: Coagulation necrosis and CBN are the most common pathologic findings in the hearts rejected for transplantation. While CN is more prevalent in anoxic brain injury, CBN is more often present in subarachnoid hemorrhage. This may be clinically important because CBN is a pathologic hallmark of catecholamine-induced cardiomyopathy which is potentially reversible.

Human attention filters for single colors.

The visual images in the eyes contain much more information than the brain can process. An important selection mechanism is feature-based attention (FBA). FBA is best described by attention filters that specify precisely the extent to which items containing attended features are selectively processed and the extent to which items that do not contain the attended features are attenuated. The centroid-judgment paradigm enables quick, precise measurements of such human perceptual attention filters, analogous to transmission measurements of photographic color filters. Subjects use a mouse to locate the centroid-the center of gravity-of a briefly displayed cloud of dots and receive precise feedback. A subset of dots is distinguished by some characteristic, such as a different color, and subjects judge the centroid of only the distinguished subset (e.g., dots of a particular color). The analysis efficiently determines the precise weight in the judged centroid of dots of every color in the display (i.e., the attention filter for the particular attended color in that context). We report 32 attention filters for single colors. Attention filters that discriminate one saturated hue from among seven other equiluminant distractor hues are extraordinarily selective, achieving attended/unattended weight ratios >20:1. Attention filters for selecting a color that differs in saturation or lightness from distractors are much less selective than attention filters for hue (given equal discriminability of the colors), and their filter selectivities are proportional to the discriminability distance of neighboring colors, whereas in the same range hue attention-filter selectivity is virtually independent of discriminabilty.

How can observers use perceived size? Centroid versus mean-size judgments.

statistical representations are aggregate properties of the environment that are presumed to be perceived automatically and preattentively. We investigated two tasks presumed to involve these representations: judgments of the centroid of a set of spatially arrayed items and judgments of the mean size of the items in the array. The question we ask is: When similar information is required for both tasks, do observers use it with equal postfilter efficiency (Sun, Chubb, Wright, & Sperling, 2016)? We find that, according to instructions, observers can either efficiently utilize item size in making centroid judgments or ignore it almost completely. Compared to centroid judgments, however, observers estimating mean size incorporate the size of individual items into the average with low efficiency.

Variation in target and distractor heterogeneity impacts performance in the centroid task.

In a selective centroid task, the participant views a brief cloud of items of different types-some of which are targets, the others distractors-and strives to mouse-click the centroid of the target items, ignoring the distractors. Advantages of the centroid task are that multiple target types can appear in the same display and that influence functions, which estimate the weight of each stimulus type in the cloud on the perceived centroid for each participant, can be obtained easily and efficiently. Here we document the strong, negative impact on performance that results when the participant is instructed to attend to target dots that consist of two or more levels of a single feature dimension, even when those levels differ categorically from those of the distractor dots. The results also show a smaller, but still observable decrement in performance that results when there is heterogeneity in the distractor dots.

Dry Age-Related Macular Degeneration Pharmacology.

Age-related macular degeneration (AMD), the most common form of irreversible blindness in the industrially developed world, can present years before a patient begins to lose vision. For most of these patients, AMD never progresses past its early stages to the advanced forms that are principally responsible for the vast majority of vision loss. Advanced AMD can manifest as either an advanced avascular form known as geographic atrophy (GA) marked by regional retinal pigment epithelium (RPE) cell death or as an advanced form known as neovascular AMD marked by the intrusion of fragile new blood vessels into the normally avascular retina. Physicians have several therapeutic interventions available to combat neovascular AMD, but GA has no approved effective therapies as of yet. In this chapter, we will discuss the current strategies for limiting dry AMD in patients. We will also discuss previous attempts at pharmacological intervention that were tested in a clinical setting and consider reasons why these putative therapeutics did not perform successfully in large-scale trials. Despite the number of unsuccessful past trials, new pharmacological interventions may succeed. These future therapies may aid millions of AMD patients worldwide.

Scaling laws governing stochastic growth and division of single bacterial cells.

Uncovering the quantitative laws that govern the growth and division of single cells remains a major challenge. Using a unique combination of technologies that yields unprecedented statistical precision, we find that the sizes of individual Caulobacter crescentus cells increase exponentially in time. We also establish that they divide upon reaching a critical multiple (≈ 1.8) of their initial sizes, rather than an absolute size. We show that when the temperature is varied, the growth and division timescales scale proportionally with each other over the physiological temperature range. Strikingly, the cell-size and division-time distributions can both be rescaled by their mean values such that the condition-specific distributions collapse to universal curves. We account for these observations with a minimal stochastic model that is based on an autocatalytic cycle. It predicts the scalings, as well as specific functional forms for the universal curves. Our experimental and theoretical analysis reveals a simple physical principle governing these complex biological processes: a single temperature-dependent scale of cellular time governs the stochastic dynamics of growth and division in balanced growth conditions.

DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration.

Geographic atrophy, an advanced form of age-related macular degeneration (AMD) characterized by death of the retinal pigmented epithelium (RPE), causes untreatable blindness in millions worldwide. The RPE of human eyes with geographic atrophy accumulates toxic Alu RNA in response to a deficit in the enzyme DICER1, which in turn leads to activation of the NLRP3 inflammasome and elaboration of IL-18. Despite these recent insights, it is still unclear how RPE cells die during the course of the disease. In this study, we implicate the involvement of Caspase-8 as a critical mediator of RPE degeneration. Here we show that DICER1 deficiency, Alu RNA accumulation, and IL-18 up-regulation lead to RPE cell death via activation of Caspase-8 through a Fas ligand-dependent mechanism. Coupled with our observation of increased Caspase-8 expression in the RPE of human eyes with geographic atrophy, our findings provide a rationale for targeting this apoptotic pathway in this disease.

Closing Kynect and Restructuring Medicaid Threaten Kentucky's Health and Economy.

Following passage of the Patient Protection and Affordable Care Act (ACA) in the United States, the Kentucky Health Benefit Exchange, Kynect, began operating in Kentucky in October 2013. Kentucky expanded Medicaid eligibility in January 2014. Together, Kynect and Medicaid expansion provided access to affordable health care coverage to hundreds of thousands of individuals in Kentucky. However, following the Kentucky gubernatorial election in 2015, the newly inaugurated governor moved to dismantle Kynect and restructure the Medicaid expansion, jeopardizing public health gains and the state economy. As the first state to announce both the closure and restructuring of a state health insurance marketplace and Medicaid expansion, Kentucky may serve as a test case for the rest of the nation for reversal of ACA-related health policies. This article describes Kynect and the Kentucky Medicaid expansion and examines the potential short-term and long-term impacts that may occur following changes in state health policy. Furthermore, this article will offer potential strategies to ameliorate the expected negative impacts of disruption of both Kynect and the Medicaid expansion, such as the creation of a new state insurance marketplace under a new governor, the implementation of a private option, and increasing the state minimum wage for workers.

Complete genome sequences of Methylococcus capsulatus (Norfolk) and Methylocaldum szegediense (Norfolk) isolated from a landfill methane biofilter.

Here we report the complete genome sequence of two moderately thermophilic methanotrophs isolated from a landfill methane biofilter, Methylococcus capsulatus (Norfolk) and Methylocaldum szegediense (Norfolk).

Emergent Spatiotemporal Organization in Stochastic Intracellular Transport Dynamics.

The interior of a living cell is an active, fluctuating, and crowded environment, yet it maintains a high level of coherent organization. This dichotomy is readily apparent in the intracellular transport system of the cell. Membrane-bound compartments called endosomes play a key role in carrying cargo, in conjunction with myriad components including cargo adaptor proteins, membrane sculptors, motor proteins, and the cytoskeleton. These components coordinate to effectively navigate the crowded cell interior and transport cargo to specific intracellular locations, even though the underlying protein interactions and enzymatic reactions exhibit stochastic behavior. A major challenge is to measure, analyze, and understand how, despite the inherent stochasticity of the constituent processes, the collective outcomes show an emergent spatiotemporal order that is precise and robust. This review focuses on this intriguing dichotomy, providing insights into the known mechanisms of noise suppression and noise utilization in intracellular transport processes, and also identifies opportunities for future inquiry. Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Associations Between a Primary Care-Delivered Alcohol-Related Brief Intervention and Subsequent Opioid-Related Outcomes.

OBJECTIVE: The co-occurrence of unhealthy alcohol use and opioid misuse is high and associated with increased rates of overdose, emergency health care utilization, and death. The current study examined whether receipt of an alcohol-related brief intervention is associated with reduced risk of negative downstream opioid-related outcomes. METHODS: This retrospective cohort study included all VISN-6 Veterans Affairs (VA) patients with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) screening results (N=492,748) from 2014 to 2019. Logistic regression was used to examine the association between documentation of an alcohol-related brief intervention and probability of a new 1) opioid prescription, 2) opioid use disorder (OUD) diagnosis, or 3) opioid-related hospitalization in the following year, controlling for demographic and clinical covariates. RESULTS: Of the veterans, 13% (N=63,804) had "positive" AUDIT-C screen results. Of those, 72% (N=46,216) had a documented alcohol-related brief intervention. Within 1 year, 8.5% (N=5,430) had a new opioid prescription, 1.1% (N=698) had a new OUD diagnosis, and 0.8% (N=499) had a new opioid-related hospitalization. In adjusted models, veterans with positive AUDIT-C screen results who did not receive an alcohol-related brief intervention had higher odds of new opioid prescriptions (adjusted odds ratio [OR]=1.10, 95% CI=1.03-1.17) and new OUD diagnoses (adjusted OR=1.19, 95% CI=1.02-1.40), while new opioid-related hospitalizations (adjusted OR=1.19, 95% CI=0.99-1.44) were higher although not statistically significant. Removal of medications for OUD (MOUD) did not impact associations. All outcomes were significantly associated with an alcohol-related brief intervention in unadjusted models. CONCLUSIONS: The VA's standard alcohol-related brief intervention is associated with subsequent lower odds of a new opioid prescription or a new OUD diagnosis. Results suggest a reduction in a cascade of new opioid-related outcomes from prescriptions through hospitalizations.

Scaling of stochastic growth and division dynamics: A comparative study of individual rod-shaped cells in the Mother Machine and SChemostat platforms.

Microfluidic platforms enable long-term quantification of stochastic behaviors of individual bacterial cells under precisely controlled growth conditions. Yet, quantitative comparisons of physiological parameters and cell behaviors of different microorganisms in different experimental and device modalities is not available due to experiment-specific details affecting cell physiology. To rigorously assess the effects of mechanical confinement, we designed, engineered, and performed side-by-side experiments under otherwise identical conditions in the Mother Machine (with confinement) and the SChemostat (without confinement), using the latter as the ideal comparator. We established a protocol to cultivate a suitably engineered rod-shaped mutant of Caulobacter crescentus in the Mother Machine and benchmarked the differences in stochastic growth and division dynamics with respect to the SChemostat. While the single-cell growth rate distributions are remarkably similar, the mechanically confined cells in the Mother Machine experience a substantial increase in interdivision times. However, we find that the division ratio distribution precisely compensates for this increase, which in turn reflects identical emergent simplicities governing stochastic intergenerational homeostasis of cell sizes across device and experimental configurations, provided the cell sizes are appropriately mean-rescaled in each condition. Our results provide insights into the nature of the robustness of the bacterial growth and division machinery.

An immune-competent human gut microphysiological system enables inflammation-modulation by Faecalibacterium prausnitzii.

Crosstalk of microbes with human gut epithelia and immune cells is crucial for gut health. However, there is no existing system for a long-term co-culture of human innate immune cells with epithelium and oxygen-intolerant commensal microbes, hindering the understanding of microbe-immune interactions in a controlled manner. Here, we established a gut epithelium-microbe-immune (GuMI) microphysiological system to maintain the long-term continuous co-culture of Faecalibacterium prausnitzii/Faecalibacterium duncaniae with colonic epithelium, antigen-presenting cells (APCs, herein dendritic cells and macrophages), and CD4+ naive T cells circulating underneath the colonic epithelium. In GuMI-APC condition, multiplex cytokine assays suggested that APCs contribute to the elevated level of cytokines and chemokines secreted into both apical and basolateral compartments compared to GuMI condition that lacks APC. In GuMI-APC with F. prausnitzii (GuMI-APC-FP), F. prausnitzii increased the transcription of pro-inflammatory genes such as toll-like receptor 1 (TLR1) and interferon alpha 1 (IFNA1) in the colonic epithelium, without a significant effect on cytokine secretion, compared to the GuMI-APC without bacteria (GuMI-APC-NB). In contrast, in the presence of CD4+ naive T cells (GuMI-APCT-FP), TLR1, IFNA1, and IDO1 transcription levels decreased with a simultaneous increase in F. prausnitzii-induced secretion of pro-inflammatory cytokines (e.g., IL8) compared to GuMI-APC-FP that lacks T cells. These results highlight the contribution of individual innate immune cells in regulating the immune response triggered by the gut commensal F. prausnitzii. The integration of defined populations of immune cells in the gut microphysiological system demonstrated the usefulness of GuMI physiomimetic platform to study microbe-epithelial-immune interactions in healthy and disease conditions.

The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor.

BACKGROUND: To survive dynamic environments, it is essential for all animals to appropriately modulate their behavior in response to various stimulus intensities. For instance, the nematode Caenorhabditis elegans suppresses the rate of egg-laying in response to intense mechanical stimuli, in a manner dependent on the mechanosensory neurons FLP and PVD. We have found that the unilaterally placed single interneuron ALA acted as a high-threshold mechanosensor, and that it was required for this protective behavioral response. RESULTS: ALA was required for the inhibition of egg-laying in response to a strong (picking-like) mechanical stimulus, characteristic of routine handling of the animals. Moreover, ALA did not respond physiologically to less intense touch stimuli, but exhibited distinct physiological responses to anterior and posterior picking-like touch, suggesting that it could distinguish between spatially separated stimuli. These responses required neither neurotransmitter nor neuropeptide release from potential upstream neurons. In contrast, the long, bilaterally symmetric processes of ALA itself were required for producing its physiological responses; when they were severed, responses to stimuli administered between the cut and the cell body were unaffected, while responses to stimuli administered posterior to the cut were abolished. CONCLUSION: C. elegans neurons are typically classified into three major groups: sensory neurons with specialized sensory dendrites, interneurons, and motoneurons with neuromuscular junctions. Our findings suggest that ALA can autonomously sense intense touch and is thus a dual-function neuron, i.e., an interneuron as well as a novel high-threshold mechanosensor.

Routine depression screening in an HIV clinic cohort identifies patients with complex psychiatric co-morbidities who show significant response to treatment.

This study described characteristics, psychiatric diagnoses and response to treatment among patients in an outpatient HIV clinic who screened positive for depression. Depressed (25 %) were less likely to have private insurance, less likely to have suppressed HIV viral loads, had more anxiety symptoms, and were more likely to report current substance abuse than not depressed. Among depressed, 81.2 % met diagnostic criteria for a depressive disorder; 78 % for an anxiety disorder; 61 % for a substance use disorder; and 30 % for co-morbid anxiety, depression, and substance use disorders. Depressed received significantly more treatment for depression and less HIV primary care than not depressed patients. PHQ-9 total depression scores decreased by 0.63 from baseline to 6-month follow-up for every additional attended depression treatment visit. HIV clinics can routinely screen and treat depressive symptoms, but should consider accurate psychiatric diagnosis as well as co-occurring mental disorders.