A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles.

We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.

Contractile history affects sag and boost properties of unfused tetanic contractions in human quadriceps muscles.

PURPOSE: A period of extra-efficient force production ("boost") followed by a decline in force ("sag") is often observed at the onset of unfused tetanic contractions. We tested the hypothesis that in human muscle boost and sag are diminished in repeated contractions separated by short rest periods and are re-established or enhanced following long rest periods. METHODS: Two sets of 3 unfused tetanic contractions were evoked in the right quadriceps muscle group of 29 participants via percutaneous stimulation of the femoral nerve. Contractions consisted of 20 pulses evoked at inter-pulse intervals of 1.25 × twitch time to peak torque. Contractions were evoked 5 s apart and sets were evoked 5 min apart. RESULTS: The ratio of the angular impulse of pulses 1-10 to the angular impulse of pulses 11-20 was used as the boost indicator. By this metric, boost was higher (P < 0.05) in the first relative to the second and third contractions within a set, but did not differ between sets (Set 1: 1.31 ± 0.15, 1.18 ± 0.12, 1.14 ± 0.12 vs Set 2: 1.34 ± 0.17, 1.17 ± 0.13, 1.14 ± 0.13). Sag (the percent decline in torque within each contraction) was also higher (P < 0.05) in the first relative to the second and third contractions within a set, but did not differ between sets (Set 1: 40.8 ± 7.5%, 35.4 ± 6.8%, 33.2 ± 7.8% vs Set 2: 42.1 ± 8.0%, 35.5 ± 6.8%, 33.9 ± 7.2%). Participants' sex and resistance training background did not influence boost or sag. CONCLUSION: Boost and sag are sensitive to contractile history in whole human quadriceps. Optimizing boost may have application in strength and power sports.

Acoustic phonon lifetimes limit thermal transport in methylammonium lead iodide.

Hybrid organic-inorganic perovskites (HOIPs) have become an important class of semiconductors for solar cells and other optoelectronic applications. Electron-phonon coupling plays a critical role in all optoelectronic devices, and although the lattice dynamics and phonon frequencies of HOIPs have been well studied, little attention has been given to phonon lifetimes. We report high-precision momentum-resolved measurements of acoustic phonon lifetimes in the hybrid perovskite methylammonium lead iodide (MAPI), using inelastic neutron spectroscopy to provide high-energy resolution and fully deuterated single crystals to reduce incoherent scattering from hydrogen. Our measurements reveal extremely short lifetimes on the order of picoseconds, corresponding to nanometer mean free paths and demonstrating that acoustic phonons are unable to dissipate heat efficiently. Lattice-dynamics calculations using ab initio third-order perturbation theory indicate that the short lifetimes stem from strong three-phonon interactions and a high density of low-energy optical phonon modes related to the degrees of freedom of the organic cation. Such short lifetimes have significant implications for electron-phonon coupling in MAPI and other HOIPs, with direct impacts on optoelectronic devices both in the cooling of hot carriers and in the transport and recombination of band edge carriers. These findings illustrate a fundamental difference between HOIPs and conventional photovoltaic semiconductors and demonstrate the importance of understanding lattice dynamics in the effort to develop metal halide perovskite optoelectronic devices.

Effect of Active Lengthening and Shortening on Small-Angle X-ray Reflections in Skinned Skeletal Muscle Fibres.

Our purpose was to use small-angle X-ray diffraction to investigate the structural changes within sarcomeres at steady-state isometric contraction following active lengthening and shortening, compared to purely isometric contractions performed at the same final lengths. We examined force, stiffness, and the 1,0 and 1,1 equatorial and M3 and M6 meridional reflections in skinned rabbit psoas bundles, at steady-state isometric contraction following active lengthening to a sarcomere length of 3.0 µm (15.4% initial bundle length at 7.7% bundle length/s), and active shortening to a sarcomere length of 2.6 µm (15.4% bundle length at 7.7% bundle length/s), and during purely isometric reference contractions at the corresponding sarcomere lengths. Compared to the reference contraction, the isometric contraction after active lengthening was associated with an increase in force (i.e., residual force enhancement) and M3 spacing, no change in stiffness and the intensity ratio I1,1/I1,0, and decreased lattice spacing and M3 intensity. Compared to the reference contraction, the isometric contraction after active shortening resulted in decreased force, stiffness, I1,1/I1,0, M3 and M6 spacings, and M3 intensity. This suggests that residual force enhancement is achieved without an increase in the proportion of attached cross-bridges, and that force depression is accompanied by a decrease in the proportion of attached cross-bridges. Furthermore, the steady-state isometric contraction following active lengthening and shortening is accompanied by an increase in cross-bridge dispersion and/or a change in the cross-bridge conformation compared to the reference contractions.

The experiences of therapists providing psychological treatment for adults with depression and intellectual disabilities as part of a randomised controlled trial.

BACKGROUND: Health professionals were trained to deliver adapted psychological interventions for depression to people with learning disabilities and depression alongside a supporter. Exploring the delivery of psychological interventions can help increase access to therapy. METHOD: Twenty-seven participants took part in six focus groups, and the data were subject to a Framework Analysis. RESULTS: The structure and focus of the manualised therapies, and the use of specific techniques were perceived as key to service-user engagement. Supporters' involvement was valued by therapists if they had a good relationship and regular contact with the individual they supported. Regular clinical supervision was regarded as vital in understanding their role, assessing progress and delivering the interventions. CONCLUSIONS: The findings highlight that health professionals can embrace a focussed therapeutic role and increase access to psychological therapies for people with intellectual disabilities.

The effects of inorganic phosphate on contractile function of slow skeletal muscle fibres are length-dependent.

Muscle operates across a wide range of sarcomere lengths. Inorganic phosphate (Pi) diminishes force output of striated muscle, with greater influence at short relative to long sarcomere lengths in fast skeletal and cardiac muscle fibres. The purpose of this study was to fill a gap in the literature regarding the length-dependent effects of Pi on contractile function of slow skeletal muscle fibres. Permeabilized slow skeletal muscle fibres from rabbit soleus were assessed at average sarcomere lengths of 2.0, 2.4, or 2.8 µm, with and without 20 mM Pi added to activating solutions (22±1 °C). The magnitude of Pi-induced reductions in peak force (43 ± 7% at 2.0 µm, 38 ± 7% at 2.4 µm, and 31 ± 8% at 2.8 µm) and peak stiffness (41 ± 9% at 2.0 µm, 36 ± 8% at 2.4 µm, and 26 ± 9% at 2.8 µm) were length dependent. Peak stiffness was less affected by Pi than peak force. Pi diminished the Ca2+-sensitivity of the force-pCa and stiffness-pCa relationships to a greater extent at 2.8 µm than 2.0 µm. Comparable results were obtained from a cooperative model of Ca2+ and myosin binding to regulated actin. In conclusion, Pi is more detrimental to the peak force output of slow skeletal muscle fibres held at short relative to long sarcomere lengths, whereas Pi has a greater effect on the Ca2+-sensitivity of force production at long relative to short sarcomere lengths. Stiffness data suggest that Pi-induced reductions in force are primarily due to fewer bound cross-bridges, with a lesser contribution attributable to lower average force per cross-bridge.

A brief contraction has complex effects on summation of twitch pairs in human adductor pollicis.

NEW FINDINGS: What is the central question of this study? How do contraction-induced reductions in twitch duration, without changes in twitch force, affect summation of twitch pairs into higher force contractions in skeletal muscle? What is the main finding and its importance? Abbreviating twitch duration with a brief contraction resulted in enhanced summation of fully fused twitch pairs, but impaired summation in partially fused twitch pairs even after accounting for the differences in relaxation of the first twitch. An inherent mechanism which enhances relaxation without sacrificing force generation in forceful contractions would benefit cyclic muscle activities, such as locomotion. ABSTRACT: During electrically evoked contractions of skeletal muscle, the interplay between twitch duration and the time between electrical stimuli (inter-pulse interval, IPI) determines how effectively twitch forces summate into high force contractions. A brief muscle contraction can impair summation by abbreviating twitch duration, though it is not clear if these impairments occur at all physiologically relevant IPI. This study was designed to test how a brief contraction affects summation of nominally isometric twitch pairs with IPIs lasting 10-5000 ms. Left adductor pollicis muscles of human participants (n = 9) were electrically activated using stimulus pairs applied both before (Pre) and after (Post) a 10 Hz, 1.0 s contraction. Force-time records were mathematically separated into Pulse 1 (single twitch) and Pulse 2 (summated twitch) components. The ratio of Pulse 2 peak force to Pulse 1 peak force was used as our measure of summation effectiveness. Consistent with the observed decline of Pulse 1 duration at Post relative to Pre (4.7 ± 0.6%; P < 0.001; duration was defined as the time from stimulation to the time required for active force to decline by 50%), summation effectiveness was higher at Pre than at Post at IPIs of 100-333 ms. Summation effectiveness was not different between Pre and Post at IPIs of 50-83 ms or 500-5000 ms. Intriguingly, summation effectiveness was higher at Post than at Pre at IPIs of 10-25 ms. In summary, a brief contraction has complex effects on the relationship between inter-pulse interval and summation effectiveness. Future experiments are needed to reveal the mechanisms behind this novel observation.

Methodological consensus on clinical proton MRS of the brain: Review and recommendations.

Proton MRS (1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.

In vivo 1 H MRS of human gallbladder bile in understanding the pathophysiology of primary sclerosing cholangitis (PSC): Immune-mediated disease versus bile acid-induced injury.

Primary sclerosing cholangitis (PSC) has been considered to be either an "autoimmune disease" or a "bile acid-induced injury." In vitro MRS studies on PSC patients have limitations due to the contamination of bile with contrast agent (commonly administered during endoscopic retrograde cholangiopancreatography) and/or the use of patient cohorts with other diseases as controls. The objective of this study was to quantify biliary metabolites using in vivo 1 H MRS and gain insight into the pathogenesis of PSC. Biliary metabolites in 10 PSC patients and 14 healthy controls were quantified in vivo using 1 H MRS on a 3 T MR scanner. The concentrations of total bile acids plus cholesterol, glycine-conjugated bile acids, taurine-conjugated bile acids, and choline-containing phospholipids (chol-PLs) were compared between the two groups. There were statistically significant decreases in the levels of the above mentioned biliary metabolites in the PSC patients compared with controls. The reduction in bile acid secretion in bile of PSC patients indicates accumulation of bile acids in hepatocytes. Moreover, reduction in the levels of chol-PLs in bile may increase the toxic effects of bile acids. Our findings suggest that the bile duct injury in PSC patients is most likely due to "bile acid-induced injury."

Caffeine attenuates contraction-induced diminutions of the intracellular calcium transient in mouse lumbrical muscle ex vivo.

The amount of calcium released from the sarcoplasmic reticulum in skeletal muscle rapidly declines during repeated twitch contractions. In this study, we test the hypothesis that caffeine can mitigate these contraction-induced declines in calcium release. Lumbrical muscles were isolated from male C57BL/6 mice and loaded with the calcium-sensitive indicator, AM-furaptra. Muscles were then stimulated at 8 Hz for 2.0 s in the presence or absence of 0.5 mM caffeine, at either 30 °C or 37 °C. The amplitude and area of the furaptra-based intracellular calcium transients and force produced during twitch contractions were calculated. For each of these measures, the values for twitch 16 relative to twitch 1 were higher in the presence of caffeine than in the absence of caffeine at both temperatures. We conclude that caffeine can attenuate contraction-induced diminutions of calcium release during repeated twitch contractions, thereby contributing to the inotropic effects of caffeine.

How service-users with intellectual disabilities understand challenging behaviour and approaches to managing it.

BACKGROUND: This study explored understandings that service-users with intellectual disabilities and challenging behaviour held around their behaviour, what shaped these understandings, and the relationship between how behaviours are managed and well-being. METHODS: Eight participants (three female, five male) partook in individual semi-structured qualitative interviews. Interviews were transcribed and analysed using interpretative phenomenological analysis. RESULTS: Three master themes emerged from this analysis: (a) challenging behaviour can be explained via an internal or external frame of reference, with each framework having different implications for how participants attempted to manage behaviour. (b) Positive relationships provide a long-term buffer to challenging behaviour, with positive relationships with family, staff and peers operating through different mechanisms to achieve this. (c) A greater ability to exert power and control in day-to-day life was perceived to reduce challenging behaviour in the long term. CONCLUSIONS: Implications for practice are discussed.

Adapting dialectical behaviour therapy in forensic learning disability services: A grounded theory informed study of "what works".

BACKGROUND: Emerging evidence indicates effectiveness of dialectical behaviour therapy (DBT) for people with intellectual disabilities (PWID) in forensic settings; however, little is known about "what works" facilitating engagement and change. METHODS: Eleven interviews were conducted with nine service users across two secure inpatient services. Grounded theory was used to develop a model of perceived engagement and change. RESULTS: The model provides insights into how change occurs during DBT delivered in forensic settings. DBT constitutes a challenging journey, yet provides the motivation and means to address individual's intra-/interpersonal aggression and progress towards release. Participants experienced engaging with DBT as difficult and coercive, moving from compliance and avoidance to acceptance and change. Key factors included participants' motivation, beliefs about safety and ability to change, and interactions with staff. CONCLUSION: Recommendations are made for increasing intrinsic motivation, reducing perceived coercion and distress, and for future research to address potential aversive elements and enhance effectiveness.

De-escalation techniques for managing non-psychosis induced aggression in adults.

BACKGROUND: Aggression occurs frequently within health and social care settings. It can result in injury to patients and staff and can adversely affect staff performance and well-being. De-escalation is a widely used and recommended intervention for managing aggression, but the efficacy of the intervention as a whole and the specific techniques that comprise it are unclear. OBJECTIVES: To assess the effects of de-escalation techniques for managing non-psychosis-induced aggression in adults in care settings, in both staff and service users. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and 14 other databases in September 2017, plus three trials registers in October 2017. We also checked references, and contacted study authors and authorities in the field to identify additional published and unpublished studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing de-escalation techniques with standard practice or alternative techniques for managing aggressive behaviour in adult care settings. We excluded studies in which participants had psychosis. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: This review includes just one cluster-randomised study of 306 older people with dementia and an average age of 86 years, conducted across 16 nursing homes in France. The study did not measure any of our primary or secondary outcomes but did measure behavioural change using three measurement scales: the Cohen-Mansfield Agitation Inventory (CMAI; 29-item scale), the Neuropsychiatric Inventory (NPI; 12-item scale), and the Observation Scale (OS; 25-item scale). For the CMAI, the study reports a Global score (29 items rated on a seven-point scale (1 = never occurs to 7 = occurs several times an hour) and summed to give a total score ranging from 29 to 203) and mean scores (evaluable items (rated on the same 7-point scale) divided by the theoretical total number of items) for the following four domains: Physically Non-Aggressive Behaviour, such as pacing (13 items); Verbally Non-Aggressive Behaviour, such as repetition (four items); Physically Aggressive Behaviour, such as hitting (nine items); and Verbally Aggressive Behaviour, such as swearing (three items). Four of the five CMAI scales improved in the intervention group (Global: change mean difference (MD) -5.69 points, 95% confidence interval (CI) -9.59 to -1.79; Physically Non-Aggressive: change MD -0.32 points, 95% CI -0.49 to -0.15; Verbally Non-Aggressive: change MD -0.44 points, 95% CI -0.69 to -0.19; and Verbally Aggressive: change MD -0.16 points, 95% CI -0.31 to -0.01). There was no difference in change scores on the Physically Aggressive scale (MD -0.08 points, 95% CI -0.37 to 0.21). Using GRADE guidelines, we rated the quality of this evidence as very low due to high risk of bias and indirectness of the outcome measures. There were no differences in NPI or OS change scores between groups by the end of the study.We also identified one ongoing study. AUTHORS' CONCLUSIONS: The limited evidence means that uncertainty remains around the effectiveness of de-escalation and the relative efficacy of different techniques. High-quality research on the effectiveness of this intervention is therefore urgently needed.

The sag response in human muscle contraction.

PURPOSE: We examined how muscle length and time between stimuli (inter-pulse interval, IPI) influence declines in force (sag) seen during unfused tetani in the human adductor pollicis muscle. METHODS: A series of 16-pulse contractions were evoked with IPIs between 1 × and 5 × the twitch time to peak tension (TPT) at large (long muscle length) and small (short muscle length) thumb adduction angles. Unfused tetani were mathematically deconstructed into a series of overlapping twitch contractions to examine why sag exhibits length- and IPI-dependencies. RESULTS: Across all IPIs tested, sag was 62% greater at short than long muscle length, and sag increased as IPI was increased at both muscle lengths. Force attributable to the second stimulus increased as IPI was decreased. Twitch force declined from maximal values across all IPI tested, with the greatest reductions seen at short muscle length and long IPI. At IPI below 2 × TPT, the twitch with highest force occurred earlier than the peak force of the corresponding unfused tetani. Contraction-induced declines in twitch duration (TPT + half relaxation time) were only observed at IPI longer than 1.75 × TPT, and were unaffected by muscle length. CONCLUSIONS: Sag is an intrinsic feature of healthy human adductor pollicis muscle. The length-dependence of sag is related to greater diminution of twitch force at short relative to long muscle length. The dependence of sag on IPI is related to IPI-dependent changes in twitch duration and twitch force, and the timing of peak twitch force relative to the peak force of the associated unfused tetanus.

Contraction-induced enhancement of relaxation during high force contractions of mouse lumbrical muscle at 37°C.

Repeated stimulation of unfatigued rodent fast-twitch skeletal muscle accelerates the kinetics of tension relaxation through an unknown mechanism. This effect varies with muscle type and stimulation parameters, and has been observed at physiological temperatures for submaximal but not maximal contractions. The purpose of this study was to compare relaxation kinetics of C57BL/6 mouse lumbrical muscles ex vivo from maximal isometric force (500 Hz for 20 ms) when evoked before (pre) and after (post) an intervening tetanic contraction at 37°C. During post contractions, we noted significant increases in the rate of tension decline during both the slow linear phase and the fast exponential phase of relaxation, as well as a reduced duration of the slow phase of relaxation compared with pre contractions (all P<0.05). This is the first demonstration of enhanced slow and fast relaxation phases from maximal isometric tension induced by prior stimulation in intact muscle at a physiological temperature.

Chemical Approaches to Addressing the Instability and Toxicity of Lead-Halide Perovskite Absorbers.

The impressive rise in efficiencies of solar cells employing the three-dimensional (3D) lead-iodide perovskite absorbers APbI3 (A = monovalent cation) has generated intense excitement. Although these perovskites have remarkable properties as solar-cell absorbers, their potential commercialization now requires a greater focus on the materials' inherent shortcomings and environmental impact. This creates a challenge and an opportunity for synthetic chemists to address these issues through the design of new materials. Synthetic chemistry offers powerful tools for manipulating the magnificent flexibility of the perovskite lattice to expand the number of functional analogues to APbI3. To highlight improvements that should be targeted in new materials, here we discuss the intrinsic instability and toxicity of 3D lead-halide perovskites. We consider possible sources of these instabilities and propose methods to overcome them through synthetic design. We also discuss new materials developed for realizing the exceptional photophysical properties of lead-halide perovskites in more environmentally benign materials. In this Forum Article, we provide a brief overview of the field with a focus on our group's contributions to identifying and addressing problems inherent to 3D lead-halide perovskites.

Neuromuscular manifestations of work-related myalgia in women specific to extensor carpi radialis brevis.

This study assessed neuromuscular function in the extensor carpi radialis brevis (ECRB) of female workers diagnosed with work-related myalgia (WRM, n = 14, age 45.2 ± 1.9 years) and the ECRB of healthy controls (CON, n = 10, age 34.6 ± 2.5 years). Groups were compared on voluntary and electrically evoked functional responses at rest (Pre), immediately following a 5 min repetitive task (Post-0) performed at 60% maximal voluntary contraction (MVC), and after 5 min of recovery (Post-5). Despite near complete motor unit activation (MUA) (CON 98% ± 1% vs. WRM 99% ± 1%), at Pre, WRM produced 26% less (P < 0.05) MVC force than CON. Following an MVC, twitch force was increased (P < 0.05) by 94% ± 13% and 54% ± 11% in CON and WRM, respectively (CON vs. WRM; P < 0.05). The peak force and the maximal rates of force development and decline of electrically evoked contractions (10-100 Hz) were generally depressed (P < 0.05) at Post-0 and Post-5 relative to Pre. The response pattern to increasing frequencies of stimulation was not different (P > 0.05) between groups and MUA was not impaired (CON 97% ± 1% vs. WRM 97% ± 1%; P > 0.05). In conclusion, the peripheral weakness observed in the ECRB in WRM at rest does not result in abnormal fatigue or recovery responses after performing a task controlled for relative demand (60% MVC).

The experiences of staff who support people with intellectual disability on issues about death, dying and bereavement: A metasynthesis.

BACKGROUND: Historically, people with intellectual disabilities have tended to be excluded from knowing about death, dying and bereavement. Staff in intellectual disability services can play a valuable role in improving understanding of these issues in those they support. This qualitative metasynthesis aimed to understand the experiences of staff supporting adults with intellectual disabilities with issues of death, dying and bereavement. METHOD: Thirteen papers were identified following a systematic review of six databases. RESULTS: Three themes were developed following a lines-of-argument synthesis: (i) talking about death is hard: negotiating the uncertainty in death, dying and bereavement; (ii) the commitment to promoting a "good death"; and (iii) the grief behind the professional mask. "A cautious silence: The taboo of death" was an overarching theme. CONCLUSIONS: A more open culture around issues of death, dying and bereavement in intellectual disability settings is essential and could be promoted through staff training and support.

Understanding How People with Mental Health Difficulties Experience Substance Use.

BACKGROUND: Quantitative studies dominate research exploring reasons for substance use and experiences of substance use by people with mental health difficulties. This limits the depth of understanding which can be gained about these experiences. OBJECTIVES: In the present article, we synthesized current qualitative research in this area to provide enhanced theoretical knowledge of these experiences. METHODS: Following a systematic literature search, we identified 12 studies which explored how people with mental health difficulties experienced using substances, and which met additional inclusion criterion. We used Noblit and Hare's metaethnographic approach to qualitatively synthesize these studies. RESULTS: Synthesis led to the development of two themes; "substance use mediates acceptance and social inclusion" and "substance use provides perceived opportunities for control and power." CONCLUSIONS/IMPORTANCE: The findings suggest that in the studies reviewed people's motivation for substance use was embedded in social and psychological contexts. It indicated that substance use could provide perceived benefits such as mediating the impact of mental health stigma, enabling the development of alternative identities, increasing their sense of power and providing opportunities for social inclusion. Mental health and substance use workers should therefore aim to develop alternative opportunities for people with co-occurring disorders to gain such benefits, and seek to challenge mental health stigma.