Engineered transcription activator-like effector dimer proteins confer DNA loop-dependent gene repression comparable to Lac repressor.

Natural prokaryotic gene repression systems often exploit DNA looping to increase the local concentration of gene repressor proteins at a regulated promoter via contributions from repressor proteins bound at distant sites. Using principles from the Escherichia coli lac operon we design analogous repression systems based on target sequence-programmable Transcription Activator-Like Effector dimer (TALED) proteins. Such engineered switches may be valuable for synthetic biology and therapeutic applications. Previous TALEDs with inducible non-covalent dimerization showed detectable, but limited, DNA loop-based repression due to the repressor protein dimerization equilibrium. Here, we show robust DNA loop-dependent bacterial promoter repression by covalent TALEDs and verify that DNA looping dramatically enhances promoter repression in E. coli. We characterize repression using a thermodynamic model that quantitates this favorable contribution of DNA looping. This analysis unequivocally and quantitatively demonstrates that optimized TALED proteins can drive loop-dependent promoter repression in E. coli comparable to the natural LacI repressor system. This work elucidates key design principles that set the stage for wide application of TALED-dependent DNA loop-based repression of target genes.

The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource.

The NHGRI-EBI GWAS Catalog (www.ebi.ac.uk/gwas) is a FAIR knowledgebase providing detailed, structured, standardised and interoperable genome-wide association study (GWAS) data to >200 000 users per year from academic research, healthcare and industry. The Catalog contains variant-trait associations and supporting metadata for >45 000 published GWAS across >5000 human traits, and >40 000 full P-value summary statistics datasets. Content is curated from publications or acquired via author submission of prepublication summary statistics through a new submission portal and validation tool. GWAS data volume has vastly increased in recent years. We have updated our software to meet this scaling challenge and to enable rapid release of submitted summary statistics. The scope of the repository has expanded to include additional data types of high interest to the community, including sequencing-based GWAS, gene-based analyses and copy number variation analyses. Community outreach has increased the number of shared datasets from under-represented traits, e.g. cancer, and we continue to contribute to awareness of the lack of population diversity in GWAS. Interoperability of the Catalog has been enhanced through links to other resources including the Polygenic Score Catalog and the International Mouse Phenotyping Consortium, refinements to GWAS trait annotation, and the development of a standard format for GWAS data.

A phase II trial of nifurtimox combined with topotecan and cyclophosphamide for refractory or relapsed neuroblastoma and medulloblastoma.

Children with relapsed/refractory (R/R) neuroblastoma (NB) and medulloblastoma (MB) have poor outcomes. We evaluated the efficacy of nifurtimox (Nfx) in a clinical trial for children with R/R NB and MB. Subjects were divided into three strata: first relapse NB, multiply R/R NB, and R/R MB. All patients received Nfx (30 mg/kg/day divided TID daily), Topotecan (0.75 mg/m2 /dose, days 1-5) and Cyclophosphamide (250 mg/m2 /dose, days 1-5) every 3 weeks. Response was assessed after every two courses using International Neuroblastoma Response Criteria and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. One hundred and twelve eligible patients were enrolled with 110 evaluable for safety and 76 evaluable for response. In stratum 1, there was a 53.9% response rate (CR + PR), and a 69.3% total benefit rate (CR + PR + SD), with an average time on therapy of 165.2 days. In stratum 2, there was a 16.3% response rate, and a 72.1% total benefit rate, and an average time on study of 158.4 days. In stratum 3, there was a 20% response rate and a 65% total benefit rate, an average time on therapy of 105.0 days. The most common side effects included bone marrow suppression and reversible neurologic complications. The combination of Nfx, topotecan and cyclophosphamide was tolerated, and the objective response rate plus SD of 69.8% in these heavily pretreated populations suggests that this combination is an effective option for patients with R/R NB and MB. Although few objective responses were observed, the high percentage of stabilization of disease and prolonged response rate in patients with multiply relapsed disease shows this combination therapy warrants further testing.

Health Care Utilization among Homeless-Experienced Adults Who Were Seen by a Mobile Addiction Health Clinic in Boston, Massachusetts: A Quasi-Experimental Study.

Background: Mobile health clinics improve access to care for marginalized individuals who are disengaged from the healthcare system. This study evaluated the association between a mobile addiction health clinic and health care utilization among people experiencing homelessness. Methods: Using Medicaid claims data, we evaluated adults who were seen by a mobile addiction health clinic in Boston, Massachusetts from 1/16/18-1/15/19 relative to a propensity score matched control cohort. We evaluated both cohorts from four years before to one year after the index visit date with the mobile clinic. The primary outcome was the number of outpatient visits; secondary outcomes were the number of hospitalizations and emergency department (ED) visits. We used Poisson regression to compare changes in outcomes from before to after the index date in a quasi-experimental design. Results: 138 adults were seen by the mobile clinic during the observation period; 29.7% were female, 16.7% were Black, 8.0% Hispanic, 68.1% White, and the mean age was 40.4 years. The mean number of mobile clinic encounters was 3.1. The yearly mean number of outpatient visits increased from 11.5 to 12.1 (p = 0.43; pdiff-in-diff = 0.15), the number of hospitalizations increased from 2.2 to 3.0 (p = 0.04; pdiff-in-diff = 0.87), and the number of ED visits increased from 5.4 to 6.5 (p = 0.04; pdiff-in-diff = 0.40). Conclusions: The mobile addiction health clinic was not associated with statistically significant changes in health care utilization in the first year. Further research in larger samples using a broader set of outcomes is needed to quantify the benefits of this innovative care delivery model.

Breast Milk Feeding of Infants at Birth Among People With Confirmed SARS-CoV-2 Infection in Pregnancy: SET-NET, 5 States, March 29, 2020-December 31, 2020.

Objectives. To describe prevalence of breast milk feeding among people with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and examine associations between breast milk feeding, timing of maternal infection before delivery, and rooming-in status during delivery hospitalization. Methods. We performed a retrospective cohort study using data from Massachusetts, Minnesota, Nebraska, Pennsylvania, and Tennessee of whether people with confirmed SARS-CoV-2 infection during pregnancy in 2020 initiated breast milk feeding at birth. Results. Among 11 114 (weighted number) people with SARS-CoV-2 infection in pregnancy, 86.5% (95% confidence interval [CI] = 82.4%, 87.6%) initiated breast milk feeding during birth hospitalization. People with infection within 14 days before delivery had significantly lower prevalence of breast milk feeding (adjusted prevalence ratio [APR] = 0.88; 95% CI = 0.83, 0.94) than did those with infection at least 14 days before delivery. When stratified by rooming-in status, the association between timing of infection and breast milk feeding remained only among infants who did not room in with their mother (APR = 0.77; 95% CI = 0.68, 0.88). Conclusions. Pregnant and postpartum people with SARS-CoV-2 infection should have access to lactation support and be advised about the importance of breast milk feeding and how to safely feed their infants in the same room. (Am J Public Health. 2022;112(S8):S787-S796. https://doi.org/10.2105/AJPH.2022.307023).

Zika-Associated Birth Defects Reported in Pregnancies with Laboratory Evidence of Confirmed or Possible Zika Virus Infection - U.S. Zika Pregnancy and Infant Registry, December 1, 2015-March 31, 2018.

Zika virus infection during pregnancy can cause serious birth defects of the brain and eyes, including intracranial calcifications, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities (1,2). The frequency of these Zika-associated brain and eye defects, based on data from the U.S. Zika Pregnancy and Infant Registry (USZPIR), has been previously reported in aggregate (3,4). This report describes the frequency of individual Zika-associated brain and eye defects among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Among 6,799 live-born infants in USZPIR born during December 1, 2015-March 31, 2018, 4.6% had any Zika-associated birth defect; in a subgroup of pregnancies with a positive nucleic acid amplification test (NAAT) for Zika virus infection, the percentage was 6.1% of live-born infants. The brain and eye defects most frequently reported included microcephaly, corpus callosum abnormalities, intracranial calcification, abnormal cortical gyral patterns, ventriculomegaly, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities. Among infants with any Zika-associated birth defect, one third had more than one defect reported. Certain brain and eye defects in an infant might prompt suspicion of prenatal Zika virus infection. These findings can help target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.

Retrograde Carotid Stenting Using Newly Released Venous Stent for Cerebral Malperfusion in Type A Aortic Dissection.

Stanford Type A aortic dissections (TAAD) should be considered for repair, given the involvement of branch vessels which can result in malperfusion, specifically cerebral malperfusion secondary to dissection of the innominate and carotid arteries. This is a case report with a focus on four patients presenting with both acute and chronic symptomatic TAAD, with extension into the innominate and common carotid arteries. In all four cases, the decision to intervene utilizing a hybrid endovascular approach was made to increase perfusion to the brain and alleviate symptoms. Through the use of retrograde carotid stenting utilizing both the VICI venous stent (Boston Scientific, Marlborough, MA) and Abre self-expanding Nitinol stent (Medtronic, Minneapolis, MN) we obtained good results, specifically absence of symptoms and return to normal function of the patients.

Towards Quantifying the Uncertainty in Estimating Observed Scaling Rates.

Short-duration precipitation extremes (PE) increase at a rate of around 7%/K explained by the Clausius-Clapeyron relationship. Previous studies show uncertainty in the extreme precipitation-temperature relationship (scaling) due to various thermodynamic/dynamic factors. Here, we show that uncertainty may arise from the choice of data and methods. Using hourly precipitation (PPT) and daily dewpoint temperature (DPT) across 2,905 locations over the United States, we found higher scaling for quality-controlled data, all locations showing positive (median 6.2%/K) scaling, as compared to raw data showing positive (median 5.3%/K) scaling over 97.5% of locations. We found higher scaling for higher measurement precision of PPT (0.25 mm: median 7.8%/K; 2.54 mm: median 6.6%/K). The method that removes seasonality in PPT and DPT gives higher (with seasonality: median 6.2%/K; without seasonality: median 7.2%/K) scaling. Our results demonstrate the importance of quality-controlled, high-precision observations and robust methods in estimating accurate scaling for a better understanding of PE change with warming.

Effects of Peripheral Arterial Disease Interventions on Survival: A Propensity-Score Matched Analysis Using VQI Data.

BACKGROUND: Atherectomy is currently being used extensively for occlusive peripheral artery disease (PAD) interventions without proven benefits. This analysis examines the effects of atherectomy and other endovascular interventions on patient survival. OBJECTIVES: The aim of this study is to compare overall survival for patients undergoing PAD endovascular interventions, such as plain old balloon angioplasty (POBA), stent deployment and atherectomy. METHODS: Propensity score matched cohorts were constructed to conduct pairwise comparisons of overall survival in patients who underwent stenosis and occlusive PAD interventions between May 2011 and February 2020 using Vascular Quality Initiative (VQI) regional registry data. Inverse probability treatment weighting method was used to compare secondary outcomes of in-hospital mortality, length of stay, complications and major amputations. Comparative analysis was performed for POBA vs stenting, POBA vs atherectomy, and stenting vs atherectomy. RESULTS: A total number of 15281 eligible cases were identified. After propensity score matching, 6094, 4032, and 3312 cases were used to compare POBA versus stent deployment, POBA versus atherectomy and stent versus atherectomy, respectively. Stent deployment had significantly better overall survival compared with POBA and atherectomy (P < 0.001). Multivariable Cox proportional hazard models suggested stenting was associated with a reduction in mortality hazard by 30% compared with POBA (HR: 0.7; 95% CI: 0.6-0.82; P < 0.001) and a 40% mortality reduction compared with atherectomy (HR: 0.6; 95% CI: 0.48-0.75; P < 0.001). No significant difference was found between POBA and atherectomy. There was no statistical difference in other secondary outcomes which were comparable among all cohorts. CONCLUSIONS: Stent deployment was significantly superior to POBA and atherectomy in terms of overall survival with comparable complication and amputation rates. The natural history of PAD patients presenting with claudication is associated with an extremely low annual mortality risk. Therefore, further examinations of outcomes, especially in regards to mortality rates, both POBA and atherectomy on the management of PAD patients especially those presenting with claudication is warranted.

Non-destructive determination of functionalized polyelectrolyte placement in layer-by-layer films by IR ellipsometry.

Layer-by-layer (LbL) assembly facilitates controlled coatings on a variety of surfaces with the ability to manipulate the composition through the thickness by selection of the complementary pairs. However, the characterization of these composition profiles tends to be destructive and requires significant compositional differences that can limit their utility. Here, we demonstrate the ability to non-destructively quantify the depth dependence of the allyl content associated with the selective incorporation of poly(sodium acrylate-co-allylacrylamide) (84 : 16 mol : mol) (allyl-PAA) in LbL films based on the assembly of poly(diallyldimethylammonium chloride) (PDAC)/poly(acrylic acid) (PAA) and PDAC/allyl-PAA. Although the atomic composition of the film is not dramatically influenced by the change between PAA and allyl-PAA, the absorption in the IR near 1645 cm-1 by the allyl group provides sufficient optical contrast to distinguish the LbL components with spectroscopic ellipsometry. The use of IR spectroscopic ellipsometry can determine the thickness of layers that contain allyl-PAA and also gradients that develop due to re-arrangements during the LbL process. With multiple films fabricated simultaneously, the location of the gradient between the 1st and 2nd series of multilayers (e.g., first PDAC/PAA bilayers and then PDAC/allyl-PAA bilayers) can be readily assessed. The results from a variety of different multilayer architectures indicate that the gradient is located within the thickness expected for the 1st deposited bilayer stack (PDAC/PAA or PDAC/allyl-PAA). These results are indicative of a dynamic dissolution-deposition process (in- and out- diffusion) during the fabrication of these LbL films. These results provide additional evidence into the mechanisms for exponential growth in LbL assemblies. The ability to quantify a gradient with the low contrast system examined indicates that spectroscopic IR ellipsometry should be able to non-destructively determine compositional gradients for most polymer films where such gradients exist.

Biopsychosocial Model Social Anxiety and Substance Use Revised.

PURPOSE OF REVIEW: To review data published in the past 5 years to evaluate the utility of our biopsychosocial model of social anxiety's relation to substance misuse to evaluate the model's utility and update it. RECENT FINDINGS: Data support the utility of our revised model-e.g., socially anxious persons report using substances to manage subjective anxiety, despite evidence that some substances may not have a direct effect on physiological responding. Other factors with promise include social influence, cognitive processes (e.g., post-event processing), and avoidance. Data highlight the importance of context as socially anxious persons use some substances more in some high-risk situations, despite lack of relation between social anxiety and use generally. Sociocultural factors remain understudied. This updated model is a theory- and data-driven model of the relations between social anxiety and substance misuse that can inform future work to improve substance-related outcomes among this especially vulnerable group.

Towards advancing scientific knowledge of climate change impacts on short-duration rainfall extremes.

A large number of recent studies have aimed at understanding short-duration rainfall extremes, due to their impacts on flash floods, landslides and debris flows and potential for these to worsen with global warming. This has been led in a concerted international effort by the INTENSE Crosscutting Project of the GEWEX (Global Energy and Water Exchanges) Hydroclimatology Panel. Here, we summarize the main findings so far and suggest future directions for research, including: the benefits of convection-permitting climate modelling; towards understanding mechanisms of change; the usefulness of temperature-scaling relations; towards detecting and attributing extreme rainfall change; and the need for international coordination and collaboration. Evidence suggests that the intensity of long-duration (1 day+) heavy precipitation increases with climate warming close to the Clausius-Clapeyron (CC) rate (6-7% K-1), although large-scale circulation changes affect this response regionally. However, rare events can scale at higher rates, and localized heavy short-duration (hourly and sub-hourly) intensities can respond more strongly (e.g. 2 × CC instead of CC). Day-to-day scaling of short-duration intensities supports a higher scaling, with mechanisms proposed for this related to local-scale dynamics of convective storms, but its relevance to climate change is not clear. Uncertainty in changes to precipitation extremes remains and is influenced by many factors, including large-scale circulation, convective storm dynamics andstratification. Despite this, recent research has increased confidence in both the detectability and understanding of changes in various aspects of intense short-duration rainfall. To make further progress, the international coordination of datasets, model experiments and evaluations will be required, with consistent and standardized comparison methods and metrics, and recommendations are made for these frameworks. This article is part of a discussion meeting issue 'Intensification of short-duration rainfall extremes and implications for flash flood risks'.

Difficulties with emotion regulation and drinking during the COVID-19 pandemic among undergraduates: the serial mediation of COVID-related distress and drinking to cope with the pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has contributed to thousands of hospitalizations and deaths worldwide. Although alcohol use has increased in response to the pandemic, no known studies have identified transdiagnostic risk factors for greater drinking in response to COVID-related distress. Individuals with more difficulty with emotion regulation may drink more during the pandemic to manage pandemic-related distress. The current study tested whether difficulty with emotion regulation was related to greater estimated blood alcohol content (eBAC) during a typical week in the past month and if this was due to COVID-related distress and drinking to cope with the pandemic. The sample consisted of 347 past-month drinking undergraduates in Louisiana, a state with some of the U.S. highest rates of COVID-19 infections and related deaths. Difficulty with engaging in goal-directed behaviors was related to greater past-month eBAC and this relation was mediated by the sequential effects of COVID-related worry and drinking to cope with the pandemic. Results indicate that individuals with difficulty engaging in goal-directed behaviors are especially vulnerable to greater eBAC during the COVID-19 pandemic which may be due in part to their vulnerability to more COVID-related worry which may lead to more drinking to cope with the pandemic.

Characterization of Dog Glutathione Transferase P1-1, an Enzyme Relevant to Veterinary Medicine.

Glutathione transferases (GSTs) form a family of detoxication enzymes instrumental in the inactivation and elimination of electrophilic mutagenic and carcinogenic compounds. The Pi class GST P1-1 is present in most tissues and is commonly overexpressed in neoplastic cells. GST P1-1 in the dog, Canis lupus familiaris, has merits as a marker for tumors and as a target for enzyme-activated prodrugs. We produced the canine enzyme CluGST P1-1 by heterologous bacterial expression and verified its cross-reactivity with antihuman-GST P1-1 antibodies. The catalytic activity with alternative substrates of biological significance was determined, and the most active substrate found was benzyl isothiocyanate. Among established GST inhibitors, Cibacron Blue showed positive cooperativity with an IC50 value of 43 nM. Dog GST P1-1 catalyzes activation of the prodrug Telcyta, but the activity is significantly lower than that of the human homolog.

A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.

Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event-free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease-free after completion of standard upfront therapy and did not receive DFMO. The 2- and 5-year EFS were 86.4% [95% confidence interval (CI) 79.3%-94.2%] and 85.2% [77.8%-93.3%] for the NMTRC003/003b subset vs 78.3% [69.5%-88.3%] and 65.6% [55.5%-77.5%] for the historical control group. The 2- and 5-year OS were 98.8% [96.4-100%] and 95.1% [90.5%-99.9%] vs 94.4% [89.3%-99.9%] and 81.6% [73.0%-91.2%], respectively. DFMO maintenance for HRNB after completion of standard of care therapy was associated with improved EFS and OS relative to historical controls treated at the same institutions. These results support additional investigations into the potential role of DFMO in preventing relapse in HRNB.

Loss of Sarm1 does not suppress motor neuron degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

Axon degeneration occurs in all neurodegenerative diseases, but the molecular pathways regulating axon destruction during neurodegeneration are poorly understood. Sterile Alpha and TIR Motif Containing 1 (Sarm1) is an essential component of the prodegenerative pathway driving axon degeneration after axotomy and represents an appealing target for therapeutic intervention in neurological conditions involving axon loss. Amyotrophic lateral sclerosis (ALS) is characterized by rapid, progressive motor neuron degeneration and muscle atrophy, causing paralysis and death. Patient tissue and animal models of ALS show destruction of upper and lower motor neuron cell bodies and loss of their associated axons. Here, we investigate whether loss of Sarm1 can mitigate motor neuron degeneration in the SOD1G93A mouse model of ALS. We found no change in survival, behavioral, electrophysiogical or histopathological outcomes in SOD1G93A mice null for Sarm1. Blocking Sarm1-mediated axon destruction alone is therefore not sufficient to suppress SOD1G93A-induced neurodegeneration. Our data suggest the molecular pathways driving axon loss in ALS may be Sarm1-independent or involve genetic pathways that act in a redundant fashion with Sarm1.

Birth and Infant Outcomes Following Laboratory-Confirmed SARS-CoV-2 Infection in Pregnancy - SET-NET, 16 Jurisdictions, March 29-October 14, 2020.

Pregnant women with coronavirus disease 2019 (COVID-19) are at increased risk for severe illness and might be at risk for preterm birth (1-3). The full impact of infection with SARS-CoV-2, the virus that causes COVID-19, in pregnancy is unknown. Public health jurisdictions report information, including pregnancy status, on confirmed and probable COVID-19 cases to CDC through the National Notifiable Diseases Surveillance System.* Through the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET), 16 jurisdictions collected supplementary information on pregnancy and infant outcomes among 5,252 women with laboratory-confirmed SARS-CoV-2 infection reported during March 29-October 14, 2020. Among 3,912 live births with known gestational age, 12.9% were preterm (<37 weeks), higher than the reported 10.2% among the general U.S. population in 2019 (4). Among 610 infants (21.3%) with reported SARS-CoV-2 test results, perinatal infection was infrequent (2.6%) and occurred primarily among infants whose mother had SARS-CoV-2 infection identified within 1 week of delivery. Because the majority of pregnant women with COVID-19 reported thus far experienced infection in the third trimester, ongoing surveillance is needed to assess effects of infections in early pregnancy, as well the longer-term outcomes of exposed infants. These findings can inform neonatal testing recommendations, clinical practice, and public health action and can be used by health care providers to counsel pregnant women on the risks of SARS-CoV-2 infection, including preterm births. Pregnant women and their household members should follow recommended infection prevention measures, including wearing a mask, social distancing, and frequent handwashing when going out or interacting with others or if there is a person within the household who has had exposure to COVID-19.†.

IMPlementation of An online Relatives' Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use.

BACKGROUND: Despite the potential of digital health interventions to improve the delivery of psychoeducation to people with mental health problems and their relatives, and substantial investment in their development, there is little evidence of successful implementation into clinical practice. We report the first implementation study of a digital health intervention: Relatives Education And Coping Toolkit (REACT), into routine mental healthcare. Our main aim was to identify critical factors affecting staff uptake and use of this online self-management tool for relatives of people with psychosis or bipolar. METHODS: A mixed-methods, theory-driven (Normalisation Process Theory), iterative multiple case study approach using qualitative analysis of interviews with staff and quantitative reporting of uptake. Carer researchers were part of the research team. RESULTS: In all, 281 staff and 159 relatives from Early Intervention teams across six catchment areas (cases) in England registered on REACT; 129 staff took part in qualitative interviews. Staff were positive about REACT helping services improve support and meet clinical targets. Implementation was hindered by: high staff caseloads and difficulties prioritising carers; perception of REACT implementation as research; technical difficulties using REACT; poor interoperability with trust computer systems and care pathways; lack of access to mobile technology and training; restricted forum populations; staff fears of risk, online trolling, and replacement by technology; and uncertainty around REACT's long-term availability. CONCLUSIONS: Digital health interventions, such as REACT, should be iteratively developed, evaluated, adapted and implemented, in partnership with the services they aim to support, and as part of a long term national strategy to co-develop integrated technology-enabled mental healthcare. Implementation strategies must instil a sense of ownership for staff and ensure they have adequate IT training, appropriate governance protocols for online working, and adequate mobile technologies. Wider contextual factors including adequate funding for mental health services and prioritisation of carer support, also need to be addressed for successful implementation of carer focussed digital interventions. TRIAL REGISTRATION: Study registration: ISCTRN 16267685.

Cannabis-Related Impairment and Social Anxiety: The Role of Use to Manage Negative and Positive Affect in Social Situations.

Background and Objectives: Individuals with elevated social anxiety are thought to be at high risk for developing cannabis-related problems because they use cannabis to cope with anxiety-provoking social situations. Social anxiety is unique among the anxiety conditions in that it is characterized by both elevated negative affect (NA) and lower positive affect (PA). Yet it is unclear whether persons with elevated social anxiety use cannabis to decrease their NA or to increase their PA. Methods: This study examined the role of PA and NA (including cannabis use to increase PA and to decrease NA in social situations) on cannabis use frequency and related problems among current (past three-month) cannabis users (N = 278). Results: Social anxiety was significantly correlated with NA, PA, cannabis use to decrease NA, and use to increase PA. Serial mediation analyses tested the paths between social anxiety, affect, use to manage affect, typical cannabis use frequency, and cannabis use-related problems. Contrary to prediction, social anxiety was not indirectly related to use frequency or related problems via NA or PA generally. Rather, social anxiety was indirectly related to cannabis problems via the serial effect of use to cope with NA and typical use frequency and via the serial effect of use to increase PA and typical use frequency. Conclusions/Importance: Social anxiety may be associated with using cannabis to decrease NA and increase PA specifically in social situations, which increases cannabis use frequency and thus, problem risk.

Smoking and social anxiety: the role of false safety behaviors.

Despite the negative health consequences associated with smoking, most smokers find it difficult to quit. This is especially true for smokers with elevated social anxiety. One factor that may play a role in maintaining smoking with elevated anxiety is false safety behavior (FSB), behaviors geared toward decreasing anxiety short-term but that maintain or increase anxiety long-term. The present study tested whether FSB explained the relation of social anxiety severity with smoking among 71 current smokers. Avoidance-related FSB was the only type of FSB related to cigarettes smoked per day (CPD) and it was robustly related to more CPD. Further, social anxiety was related to CPD indirectly via FSB-Avoidance. Findings suggest that more frequent use of avoidance behaviors to manage anxiety may maintain smoking and may partially explain the high rates of smoking among those with elevated social anxiety. Thus, FSB may be a promising target in smoking cessation interventions, especially among those with elevated social anxiety.