Education, organizational changes, and enforcement challenges of the 2019 flavored tobacco sales restriction in Massachusetts.

OBJECTIVES: In November 2019, the Massachusetts legislature passed An Act Modernizing Tobacco Control and became the first state to restrict retail sales of all flavored (including menthol) cigarettes, e-cigarettes, and other tobacco products (the Act). Additional tobacco control policies and health insurance coverage for tobacco treatment were included as part of the Act. Implementation of these policies occurred between November 2019 and June 2020. This study explored challenges and facilitators during the implementation of the Act experienced by public health officials, school personnel, and healthcare providers. METHODS: We conducted in-depth interviews with a purposive sample of 9 public health officials and advocates, 9 school personnel, and 8 healthcare providers from March to December 2021. We conducted thematic analysis of interview transcripts using inductive codes of key themes emerging from the interviews. RESULTS: Interviewees highlighted three key themes that impacted the implementation of the Act: 1) Education of those impacted by the Act, 2) Organizational-level changes to incorporate the Act, and 3) Enforcement challenges. Examples of challenges to the implementation of the Act included COVID-19 pandemic restrictions, navigating tobacco industry tactics around naming flavors, and confusion regarding health insurance coverage for tobacco use cessation programs. Examples of facilitators were enforcement leading to retailer compliance, committed advocacy efforts of leadership/champions, and strong coordination within and between organizations. CONCLUSIONS: These findings of Massachusetts's experience in policy implementation can inform the preparation to implement similar tobacco control policies in other states.

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

Impacts of the Massachusetts 2019 An Act Modernizing Tobacco Control on tobacco retailer settings: A multi-methods study.

BACKGROUND: In November 2019, the Massachusetts legislature passed An Act Modernizing Tobacco Control and became the first state to restrict retail sales of all flavored (including menthol) cigarettes, e-cigarettes, and other tobacco products. Our study aims to provide the retailer experience of the new law from the perspectives of multiple stakeholders, including tobacco retailers themselves, public health officials, and Massachusetts residents. METHODS: We conducted in-depth interviews with seven tobacco retailers and ten public health officials from March 2021 to April 2022. Monthly repeated cross-sectional surveys were administered through the online survey panel Prodege from April 2021 to August 2022 (adult sample: N = 765; adolescent sample: N = 900). Themes from interviews were identified by drawing on deductive codes informed by the interview guide, followed by inductive coding of data. Survey data were descriptively analyzed in R. RESULTS: Key themes included retailer frustration over loss of sales to neighboring states, factors associated with retailer compliance, and the need for increased education regarding the law. Survey results showed that a minority of adolescents (13.3%) and adults (26.1%) who vaped in the past 30-days were traveling to border states to purchase vape products. Less than one-quarter of adolescent participants and less than half of adult participants could correctly identify which products Massachusetts did not sell. CONCLUSIONS: Evidence from the retailer, public health, and end-user perspectives support mutual benefits of adjacent states enacting flavored tobacco sales restrictions, improved policy education for retailers and the public, and improved retailer enforcement.

Social Communication Delay in an Unbiased Sample of Preschoolers With the FMR1 Premutation.

PURPOSE: The Fragile X Messenger Ribonucleoprotein-1 (FMR1) premutation (FXpm) is a genetic variant that is common in the general population and is associated with health symptoms and disease in adulthood. However, poor understanding of the clinical phenotype during childhood has hindered the development of clinical practice guidelines for screening and intervention. Given that social communication difficulties have been widely documented in adults with the FXpm and are linked with reduced psychosocial functioning, the present study aimed to characterize the communication profile of the FXpm during early childhood. METHOD: Eighteen children with the FXpm who were identified through cascade testing (89%) or screening at birth (11%) were compared to 21 matched typically developing children, aged 2-4 years. Participants completed standardized assessments of language (Mullen Scales of Early Learning) and adaptive communication (Vineland Adaptive Behavior Scales-II). Social communication was rated from seminaturalistic interaction samples using the Brief Observation of Social Communication Change. RESULTS: Children with the FXpm showed delayed social communication development, with the magnitude of group differences highlighting social communication as a feature that distinguishes children with the FXpm from their peers (p = .046, ηp2 = .12). The groups did not differ on the standardized language and adaptive communication measures (ps > .297, ηp2s < .03). CONCLUSIONS: Early screening and treatment of social communication delays may be key to optimizing outcomes for children with the FXpm. Further research is needed to replicate findings in a larger sample, delineate the trajectory and consequences of social communication difficulties across the life span in the FXpm, and determine the potential epidemiological significance of FMR1 as a mediator of developmental communication differences within the general population.

GZ17-6.02 kills PDX isolates of uveal melanoma.

GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.

Key Informants' Perceptions of Health Equity and Racial Justice Impacts of the 2019 Massachusetts An Act Modernizing Tobacco Control.

INTRODUCTION: The Massachusetts legislature passed An Act Modernizing Tobacco Control in November 2019 to restrict retail sales of flavored commercially manufactured tobacco products including menthol products, increase penalties for violating the law's provisions, and provide health insurance coverage for tobacco treatment. AIMS AND METHODS: This study explores key informants' perceptions of intended and unintended impacts of implementation of the 2019 Massachusetts statewide law through a health equity and racial justice lens. We conducted in-depth interviews with 25 key informants from three key informant groups (public health officials and advocates, clinicians, and school staff) between March 2021 and April 2022. Using deductive codes on unintended impacts of the implementation of the law's policies, we conducted a focused analysis to identify impacts that were perceived and observed by informants from different key informant groups. RESULTS: Perceived or observed impacts of the law were identified across multiple levels by key informants and included concerns related to three broad themes: 1) intended impacts on health equity and racial justice, 2) ongoing availability of restricted products undermining the intended impact of the law, and 3) inequitable targeting by the policies and enforcement among communities of color. CONCLUSIONS: Future evaluation is needed to assess the intended and unintended impacts of implementation of the Massachusetts law to maximize the potential of the policies to reduce tobacco-related health disparities. We discuss implications and recommendations for achieving a national policy and equitable enforcement of flavored tobacco sales restrictions. IMPLICATIONS: This qualitative study among 25 key informants including public health and tobacco control advocates, clinicians, and school staff obtained perspectives of intended and unintended health equity and racial justice impacts of the 2019 Massachusetts An Act Modernizing Tobacco Control. Findings and recommendations from this study can inform monitoring efforts to assess the law's impacts in Massachusetts and the adoption of similar flavored tobacco sales restrictions and other tobacco control policies in other states to maximize the health equity benefits and minimize unintended impacts.

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

Developmental associations between motor and communication outcomes in Fragile X syndrome: Variation in the context of co-occurring autism.

LAY ABSTRACT: Fragile X syndrome (FXS), the leading heritable cause of intellectual disability, has a co-occurrence rate of autism spectrum disorder (ASD) estimated at ~60%. Children with FXS experience delayed achievement and slower development of key motor abilities, which happens to an even greater extent for children with both FXS and ASD. A multitude of studies have demonstrated that motor abilities are foundational skills related to later communication outcomes in neurotypical development, as well as in the context of ASD. However, these associations remain unexamined in FXS, or FXS + ASD. In this study, we aimed to determine the associations between early motor skills and their rate of development on communication outcomes in FXS. Furthermore, we investigated whether these associations varied in the context of co-occurring FXS + ASD. Results revealed within-FXS variation in the context of co-occurring ASD between some aspects of motor development and communication outcomes, yet within-FXS consistency between others. Findings provide evidence for variability in developmental processes and outcomes in FXS in the context of co-occurring ASD and offer implications for intervention.

GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells.

GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types. GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent. The drug combination of GZ17-6.02 and bortezomib activated ATM, the AMPK and PERK and inactivated ULK1, mTORC1, eIF2α, NFκB and the Hippo pathway. The combination increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM, and reduced the levels of BCL-XL and MCL1. GZ17-6.02 interacted with bortezomib to enhance autophagosome formation and autophagic flux, and knock down of ATM, AMPKα, ULK1, Beclin1 or ATG5 significantly reduced both autophagy and tumor cell killing. Knock down of BAK and BIM significantly reduced tumor cell killing. The expression of HDACs1/2/3 was significantly reduced beyond that previously observed in solid tumor cells and required autophagy. This was associated with increased acetylation and methylation of histone H3. Combined knock down of HDACs1/2/3 caused activation of ATM and the AMPK and caused inactivation of ULK1, mTORC1, NFκB and the Hippo pathway. HDAC knock down also enhanced ATG13 phosphorylation, increased BAK levels and reduced those of BCL-XL. Collectively, our present studies support performing additional in vivo studies with multiple myeloma cells.

GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells.

GZ17-6.02, composed of curcumin, harmine and isovanillin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) with an RP2D of 375 mg PO BID. The biology of GZ17-6.02 in malignant T cells and in particular those derived from mycosis fungoides (MF) patients, has not been studied. GZ17-6.02 alone and in combination with standard-of-care agents was effective in killing MF cells. All three components are necessary for optimal killing of MF cells. GZ17-6.02 activated ATM, the AMPK, NFκB and PERK and inactivated ERK1/2, AKT, ULK1, mTORC1, eIF2α, and reduced the expression of BCL-XL and MCL1. GZ17-6.02 increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM. GZ17-6.02 in a dose-dependent fashion enhanced autophagosome formation and autophagic flux, and tumor cell killing. Signaling by ATM and AMPK were both required for efficient killing but not for the dose-response effect whereas ER stress (eIF2α) and macroautophagy (Beclin1, ATG5) were required for both efficient killing and the dose-response. Knock down of the death receptor CD95 reduced killing by ~20% and interacted with autophagy inhibition to further reduce killing, collectively, by ~70%. Inhibition of autophagy and knock down of death-mediators downstream of the mitochondrion, AIF and caspase 3, almost abolished tumor cell killing. Hence in MF cells, GZ17-6.02 is a multi-factorial killer, utilizing ER stress, macroautophagy, death receptor signaling and directly causing mitochondrial dysfunction.

Similar Gap-Overlap Profiles in Children with Fragile X Syndrome and IQ-Matched Autism.

PURPOSE: Fragile X syndrome (FXS) is a single-gene disorder characterized by moderate to severe cognitive impairment and a high association with autism spectrum disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). Atypical visual attention is a feature of FXS, ASD, and ADHD. Thus, studying early attentional patterns in young children with FXS can offer insight into early emerging neurocognitive processes underlying challenges and contribute to our understanding of common and unique features of ASD and ADHD in FXS. METHODS: The present study examined visual attention indexed by the gap-overlap paradigm in children with FXS (n = 39) compared to children with ASD matched on intellectual ability and age (n = 40) and age-matched neurotypical controls (n = 34). The relationship between gap-overlap performance and intellectual ability, ASD, and ADHD across groups was characterized. Saccadic reaction times (RT) were collected across baseline, gap, and overlap conditions. RESULTS: Results indicate no group differences in RT for any conditions. However, RT of the ASD and NT groups became slower throughout the experiment whereas RT of the FXS group did not change, suggesting difficulties in habituation for the FXS group. There was no relationship between RT and intellectual ability, ADHD, or ASD symptoms in the FXS and ASD groups. In the NT group, slower RT was related to elevated ADHD symptoms only. CONCLUSION: Taken together, findings suggest that the social attention differences documented in FXS and ASD may be due to other cognitive factors, such as reward or motivation, rather than oculomotor control of visual attention.

Autophagy as a therapeutic mechanism to kill drug-resistant cancer cells.

Herein we discuss multiple pre-clinical projects developed by our group that have been translated into patients at Massey Cancer Center. Our work has used multi-kinase inhibitors, for example, sorafenib, regorafenib and neratinib, and combined with additional agents, for example, histone deacetylase inhibitors, the thymidylate synthase inhibitor pemetrexed, and PDE5 inhibitors. In broad-brush terms, our experience has been that these drug combinations enhance signaling by ATM-AMPK-ULK-1 and decrease signaling from growth factor receptors and RAS proteins, thereby lowering the activities of the intracellular signaling kinase ERK1/2, AKT, mTOR and p70 S6K . This collectively results in reduced protein synthesis and the induction of an endoplasmic reticulum stress response alongside autophagosome formation and autophagic flux. The rupture of autolysosomes, releasing proteases such as cathepsin B into the cytosol results in the cleavage and activation of the toxic BH3 domain protein BID which cooperates with BAX, BAK and BIM to cause mitochondrial dysfunction, leading to the release of cytochrome c and AIF, which then execute the tumor cell. For each of our two-drug combinations, we then performed additional laboratory-based studies to define the development of evolutionary resistance mechanisms, with the long-term concept of performing new three-drug clinical trials to prolong therapeutic efficacy and disease control.

Neural correlates of face processing among preschoolers with fragile X syndrome, autism spectrum disorder, autism siblings, and typical development.

The current study examined patterns of event-related potential (ERP) responses during a face processing task in groups of preschoolers uniquely impacted by autism spectrum disorder (ASD), including (1) children with ASD; (2) children with fragile X syndrome (FXS); (3) children with familial risk for ASD, but without a diagnosis (i.e., ASIBs); and (4) a low-risk control (LRC) group. Children with FXS have a high incidence of ASD diagnoses, but there have been no studies of the ERP response to faces in children with FXS and little work focused on children with ASD who have cognitive impairment. The current study examined children's ERP responses to faces and houses in four groups: LRC (N = 28, age = 5.2 years), ASIB (N = 23, age = 5.5 years), FXS (N = 19, age = 5.82 years), and ASD (N = 23, age = 5.5 years). The FXS and ASD groups were characterized by the presence of cognitive impairment. Pictures of upright and inverted faces and houses were presented while recording EEG with a 128-channel system. The N170 occurred at about 200 ms post stimulus onset, was largest on the posterior-lateral electrodes, and was larger for faces than houses. The P1 and N170 ERP components were larger for the FXS group than for the other three groups. The N170 ERP amplitude for the ASD and ASIB groups was smaller than both the LRC and FXS groups, and the LRC and FXS groups had the largest N170 responses on the right side. No difference was found in N170 latency between groups. The similarity of the ASD and ASIB responses suggest a common genetic or environmental origin of the reduced response. Although children with FXS have a high incidence of ASD outcomes, they differed from ASD and ASIB children in this study. Specifically, the children with FXS were hyperresponsive to all stimulus types while the ASD and ASIB groups showed attenuated responses for specific stimuli.

The Effect of Anxiety and Autism Symptom Severity on Restricted and Repetitive Behaviors Over Time in Children with Fragile X Syndrome.

Background: Restricted and repetitive behaviors (RRBs) are highly prevalent and reduce function in individuals with fragile X syndrome (FXS). As transdiagnostic features of intellectual disability, elevated rates of RRBs in FXS could represent various underlying known co-occurring conditions in FXS such as anxiety or autism spectrum disorder (ASD), yet this distinction has not been investigated. Further, delineating whether RRBs are more indicative of anxiety or ASD in FXS may clarify phenotypic profiles within FXS and improve differential assessment. Methods: We longitudinally examined the potentially independent or multiplicative effect of ASD and anxiety symptom severity on RRBs in 60 children with FXS. Anxiety was measured using the Child Behavior Checklist (CBCL), ASD severity was measured using the Childhood Autism Rating Scale (CARS), and RRBs were measured using The Repetitive Behavior Scale - Revised (RBS-R). We estimated a series of moderated regression models with anxiety and ASD symptoms at the initial assessment (Time 1) as predictors of RRBs at the outcome assessment two years later (Time 2), along with an anxiety-by-ASD interaction term to determine the potential multiplicative effect of these co-occurring conditions on RRBs. Results: Results identified a significant interaction between ASD and anxiety symptom severity at the initial assessment that predicted elevated sensory-motor RRBs two years later. Increased sensory-motor RRBs were predicted by elevated ASD symptoms only when anxiety symptom severity was low. Likewise, increased sensory-motor RRBs were predicted by elevated anxiety symptoms only when ASD symptom severity was low. Interestingly, this relationship was isolated to Sensory-Motor RRBs, with evidence that it could also apply to total RRBs. Conclusions: Findings suggest that ASD and anxiety exert independent and differential effects on Sensory-Motor RRBs when at high severity levels and a multiplicative effect when at moderate levels.

Behavioural and physiological indicators of anxiety reflect shared and distinct profiles across individuals with neurogenetic syndromes.

Anxiety is heightened in individuals with intellectual disability, particularly in those with specific neurogenetic syndromes. Assessment of anxiety for these individuals is hampered by a lack of appropriate measures that cater for communication impairment, differences in presentation, and overlapping features with co-occurring conditions. Here, we adopt a multi-method approach to identify fine-grained behavioural and physiological (via salivary cortisol) responses to anxiety presses in people with fragile X (FXS; n = 27; Mage = 20.11 years; range 6.32 - 47.04 years) and Cornelia de Lange syndromes (CdLS; n = 27; Mage = 18.42 years; range 4.28 - 41.08 years), two neurogenetic groups at high risk for anxiety, compared to neurotypical children (NT; n = 21; Mage = 5.97 years; range 4.34 - 7.30 years). Results indicate that physical avoidance of feared stimuli and proximity seeking to a familiar adult are prominent behavioural indicators of anxiety/stress in FXS and CdLS. Heightened pervasive physiological arousal was identified in these groups via salivary cortisol. An association between autistic characteristics and anxiety was evident in the FXS group but not in the CdLS group pointing to syndrome-specific nuances in the association between anxiety and autism. This study furthers understanding of the behavioural and physiological presentation of anxiety in individuals with intellectual disability and progresses theoretical developments regarding the development and maintenance of anxiety at the intersection of autism.

Business-nonprofit hybrid organizing: a dynamic approach to balancing benefits and costs.

Introduction: Efforts to address complex public health challenges can benefit from cross-sector collaboration, while also fostering growing business sector engagement in promoting health equity. What form business-nonprofit collaboration should take, however, is a difficult question for managers and leaders. Hybrid organizational forms, which combine for-profit and nonprofit elements within a single organization in unconventional ways, offer an innovative and potentially promising approach. Yet, while existing typologies of cross-sector collaboration have identified hybrid forms at one end of a continuum of possible forms of collaboration, these typologies do not differentiate the diversity such hybrid forms may take, and the costs and benefits of these innovative hybrid forms are poorly understood. This leaves managers interested in promoting public health through business-nonprofit hybrid organizing with limited guidance about how to maximize potential merits while mitigating drawbacks. Methods: We performed a qualitative comparative case study of three examples of business-nonprofit hybrid organizing. Data collection included 113 interviews with representatives from 42 organizations and observation of case study activities. We used thematic analysis within and across cases to characterize the form of hybrid organizing in each case and to examine benefits and costs of different forms for supporting initiatives. Results: We identified two hybrid, collaborative forms - Appended and Blended forms. Each form had benefits and costs, the significance of which shifted over time contingent on changing strategic priorities and operating environments. Benefits and costs of particular forms become more or less important for establishing and sustaining initiatives under different conditions, requiring a dynamic view. Discussion: No particular form of business-nonprofit hybrid organizing is inherently better than another. Optimizing hybrid organizing and ensuring resilient collaborations may mean allowing collaborative forms to evolve. Practitioners can manage tradeoffs between benefits and costs through an ongoing process of assessing the fit between a given collaborative form, strategic priorities, and relevant features of the operating environment. This dynamic view offers important insights for ensuring the resilience of business-nonprofit collaborative efforts to enhance public health.

Building resilient partnerships: How businesses and nonprofits create the capacity for responsiveness.

Increasingly, businesses are eager to partner with nonprofit organizations to benefit their communities. In spite of good intentions, differences between nonprofit and business organizations can limit the ability of potential partnerships to respond to a changing economic and public health landscape. Using a retrospective, multiple-case study, we sought to investigate the managerial behaviors that enabled businesses and nonprofits to be themselves together in sustainable partnerships. We recruited four nonprofit-business partnerships in the Boston area to serve as cases for our study. Each was designed to address social determinants of health. We thematically analyzed qualitative data from 113 semi-structured interviews, 9 focus groups and 29.5 h of direct observations to identify organizational capacities that build resilient partnerships. Although it is common to emphasize the similarities between partners, we found that it was the acknowledgement of difference that set partnerships up for success. This acknowledgement introduced substantial uncertainty that made managers uncomfortable. Organizations that built the internal capacity to be responsive to, but not control, one another were able to derive value from their unique assets.

Identification and treatment of individuals with attention-deficit/hyperactivity disorder and substance use disorder: An expert consensus statement.

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with substance use (SU) and/or substance use disorder (SUD). Individuals with concurrent ADHD and SU/SUD can have complex presentations that may complicate diagnosis and treatment. This can be further complicated by the context in which services are delivered. Also, when working with young people and adults with co-existing ADHD and SU/SUD, there is uncertainty among healthcare practitioners on how best to meet their needs. In February 2022, the United Kingdom ADHD Partnership hosted a meeting attended by multidisciplinary experts to address these issues. Following presentations providing attendees with an overview of the literature, group discussions were held synthesizing research evidence and clinical experience. Topics included: (1) A review of substances and reasons for use/misuse; (2) identification, assessment and treatment of illicit SU/SUD in young people and adults with ADHD presenting in community services; and (3) identification, assessment and treatment of ADHD in adults presenting in SU/SUD community and inpatient services. Dis-cussions highlighted inter-service barriers and fragmentation of care. It was concluded that a multimodal and multi-agency approach is needed. The consensus group generated a table of practice recommendations providing guidance on: identification and assessment; pharmacological and psychological treatment; and multi-agency interventions.

Brief Report: Prevalence and Predictors of DSM-Specific and Distinct Anxiety in Cognitively Impaired Autistic Preschool Children.

Autistic individuals are twice as likely to meet criteria for anxiety than neurotypical children; yet we lack understanding of early presentations of anxiety in young autistic children, especially those with cognitive impairment. This study is the first to utilize an autism-specific anxiety diagnostic interview with 28 preschool cognitively impaired, autistic children and 18 neurotypical, age-matched controls. Results indicate that 64% of autistic children met criteria for DSM-specified or "other specified," herein referred to as "distinct," anxiety disorders; 32% met criteria for multiple anxiety disorders, with phobias occurring most often. Results indicate that anxiety is highly prevalent in cognitively-impaired, autistic preschool children, highlighting the need for developmentally-tailored assessment and treatment in early childhood.

Negative affect and respiratory sinus arrhythmia are differentially related to social anxiety and autism features in autistic preschoolers contrasted to fragile X syndrome.

Introduction: Autism spectrum disorder (ASD) is a highly heterogeneous and complex disorder with co-occurring disorders commonplace. This presents tremendous diagnostic challenges given the phenotypic overlap between autism and other diagnoses, including social anxiety, as well as variance in specific genetic disorders like fragile X syndrome (FXS). Biobehavioral measurement approaches integrate behavioral and biological data, and by so doing have the potential to address diagnostic challenges and shed light on the mechanisms underlying social impairments. Methods: The present study utilized a biobehavioral approach to evaluate how biologically based indices of baseline respiratory sinus arrhythmia (RSA) and temperamental negative affect differ and predict autism and anxiety in a sample of 120 preschoolers with non-syndromic autism (nsASD) with co-occurring intellectual impairment, FXS, and neurotypical (NT) development. Results: Results indicated that children with nsASD display elevated negative affect compared to both FXS and NT controls which did not differ from each other and females exhibited more negative affect relative to males. Interestingly, elevated negative affect predicted social anxiety, but not ASD in FXS. Baseline RSA did not differ across the groups; however, reduced RSA predicted elevated autism severity for the nsASD group but not those with FXS or NT development. Discussion: Taken together, biobehavioral markers differentiated the groups in discrete ways that advance our understanding of autism and promote improved diagnostic clarity using objective measurement.