Ventilator strategies in congenital diaphragmatic hernia.

This review focuses on contemporary mechanical ventilator practices used in the initial management of neonates born with congenital diaphragmatic hernia (CDH). Both conventional and non-conventional ventilation modes in CDH are reviewed. Special emphasis is placed on the rationale for gentle ventilation and the current evidence-based clinical practice guidelines that are recommended for supporting these fragile infants. The interplay between CDH lung hypoplasia and other key cardiopulmonary elements of the disease, namely a reduced pulmonary vascular bed, abnormal pulmonary vascular remodeling, and left ventricular hypoplasia, are discussed. Finally, we provide insights into future avenues for mechanical ventilator research in CDH.

Effect of progestin-based contraceptives on HIV-associated vaginal immune biomarkers and microbiome in adolescent girls.

Adolescent girls bear a disproportionate burden of both the HIV epidemic and unintended pregnancies; yet important questions remain unanswered regarding the effects of hormonal contraceptives on the vaginal immune microenvironment, which can impact HIV susceptibility in this group. Multiple studies report genital immune alterations associated with the progestin-based contraceptive Depot medroxyprogesterone acetate (DMPA) in adult women, but there is little available data in adolescents. The objective of this longitudinal cohort study was to evaluate the effects of short-term use of three progestin-based contraceptives, levonorgestrel intrauterine device (LNG-IUD), subdermal etonogestrel (ETNG), and injectable DMPA, on HIV-associated vaginal immune biomarkers and microbiome in adolescent girls. Fifty-nine sexually active, HIV-uninfected girls aged 15-19, were recruited from the Washington DC metro area and self-selected into Control (condoms only), combined oral contraceptive pills, LNG-IUD, ETNG and DMPA groups. Vaginal swabs were collected at baseline prior to contraceptive use and at 3-month follow-up visit. Vaginal secretions were tested for pro-inflammatory (IL-1α, IL-1ß, TNF-α, IL-6, IL-8, MIP-3α, IP-10, RANTES, MIP-1α, MIP-1ß) and anti-inflammatory/anti-HIV (Serpin-A1, Elafin, Beta-Defensin-2, SLPI) immune biomarkers using ELISA and for anti-HIV activity using TZM-bl assay. Vaginal microbiome was evaluated using 16S rRNA gene sequencing. Data were analyzed using SAS Version 9. Among the 34 participants who completed both visits, no significant changes in median biomarker concentrations, HIV inhibition and microbiome composition were observed between baseline and follow-up visits for any of the contraceptive groups. IL-8 (p<0.01), MIP-3α (0.02), Elafin (p = 0.03) and RANTES (p<0.01) differed significantly by race whereas IL-6 was significantly different by age (p = 0.03). We conclude that 3-month use of LNG-IUD, ETNG and DMPA have minimal effects on adolescent vaginal immune microenvironment, and therefore unlikely to impact HIV risk. Future studies with larger sample size and longer follow-up are recommended to continue to evaluate effects of contraceptives on the lower genital tract immunity and susceptibility to sexually transmitted infections.

Brief School-Based Interventions Targeting Student Mental Health or Well-Being: A Systematic Review and Meta-Analysis.

Brief, school-based mental health interventions hold promise for reducing barriers to mental health support access, a critical endeavor in light of increasing rates of mental health concerns among youth. However, there is no consensus on whether or not brief school-based interventions are effective at reducing mental health concerns or improving well-being. This systematic review and meta-analysis aims to provide consensus and determine directions for future work. Articles were included if they examined a brief (≤ four sessions or 240 min of intervention time) psychosocial intervention, were conducted within a Pre-K through 12th-grade school setting, included at least one treatment outcome evaluating mental health or well-being, and were published since 2000. A total of 6,702 papers were identified through database searching, of which 81 papers (k studies = 75) were ultimately selected for inclusion. A total of 40,498 students were included across studies and a total of 75 unique interventions were examined. A total of 324 effect sizes were extracted. On average, interventions led to statistically significant improvements in mental health/well-being outcomes versus control conditions up to one-month (g = .18, p = .004), six-month (g = .15, p = .006), and one-year (g = .10, p = .03) post-intervention. There may be benefits to brief school-based interventions from a preventative public health standpoint; future research may focus on how to optimize their real-world utility. Prospero pre-registration: CRD42021255079.

Crisis leadership behaviors in healthcare: survey validation and influence on staff outcomes in primary care clinics during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic triggered an unprecedented transition from in-person to virtual delivery of primary health care services. Leaders were at the helm of the rapid changes required to make this happen, yet outcomes of leaders' behaviours were largely unexplored. This study (1) develops and validates the Crisis Leadership and Staff Outcomes (CLSO) Survey and (2) investigates the leadership behaviours exhibited during the transition to virtual care and their influence on select staff outcomes in primary care. METHODS: We tested the CLSO Survey amongst leaders and staff from four Community Health Centres in Ontario, Canada. The CLSO Survey measures a range of crisis leadership behaviors, such as showing empathy and promoting learning and psychological safety, as well as perceived staff outcomes in four areas: innovation, teamwork, feedback, and commitment to change. We conducted an exploratory factor analysis to investigate factor structure and construct validity. We report on the scale's internal consistency through Cronbach's alpha, and associations between leadership scales and staff outcomes through odds ratios. RESULTS: There were 78 staff and 21 middle and senior leaders who completed the survey. A 4-factor model emerged, comprised of the leadership behaviors of (1) "task-oriented leadership" and (2) "person-oriented leadership", and select staff outcomes of (3) "commitment to sustaining change" and (4) "performance self-evaluation". Scales exhibited strong construct and internal validity. Task- and person-oriented leadership behaviours positively related to the two staff outcomes. CONCLUSION: The CLSO Survey is a reliable measure of leadership behaviours and select staff outcomes. Our results suggest that crisis leadership is multifaceted and both person-oriented and task-oriented leadership behaviours are critical during a crisis to improve perceived staff performance and commitment to change.

Who follows through? Different factors predict initial commitment vs. Following through in a national survey of organ donor registration.

OBJECTIVE: Little research has investigated factors that determine whether people falter in the face of an obstacle or successfully follow through on an initial commitment to act. We integrated multiple theories (the Reasoned Action Approach [RAA], Prototype Willingness Model, and anticipated regret theory) to test which factors predict initial commitment to register as an organ donor and to discover whether different factors predict initial commitment vs. following through with registration. METHODS: Participants from a nationally representative UK sample (N = 1,008) reported their beliefs about organ donation and indicated their decision to register. An obstacle that participants could not foresee was that they had to complete registration in a second survey 3 days after making their initial commitment. RESULTS: Findings showed that 14.8% of participants followed through, 19.7% demonstrated initial commitment, and 65.5% declined to register. Linear discriminant function analysis derived two functions that distinguished these registration patterns. The first function discriminated participants who declined to register from the other groups. The declined group had lower scores on RAA variables compared to their counterparts. The second function distinguished participants who made an initial commitment to register from those who followed through. Follow-through was associated with less anticipated negative affect, more favorable descriptive norms, and stronger identification with organ donors. CONCLUSIONS: The present findings indicate that even modest friction leads to a large reduction in follow-through. Moreover, different factors influence initial commitment vs. following through. Whereas RAA variables predicted initial commitment, following through was a function of anticipated negative affect and social processes.

Comparison of current to past outcomes in congenital diaphragmatic hernia using mri observed-to-expected total fetal lung volume.

BACKGROUND: Fetal Centers use imaging studies to predict congenital diaphragmatic hernia (CDH) prognosis and the need for fetal therapy. Given improving CDH survival, we hypothesized that current fetal imaging severity predictions no longer reflect true outcomes and fail to justify the risks of fetal therapy. METHODS: We analyzed our single-center contemporary data in a left-sided CDH cohort (n = 58) by prognostic criteria determined by MRI observed-to-expected total fetal lung volumes: severe <25%, moderate 25-35%, and mild >35%. We compared contemporary survival to prior studies and the TOTAL trials. RESULTS: Contemporary survival was significantly higher than past studies for all prognostic classifications (mild 100% vs 80-94%, moderate 95% vs 59-75%, severe 79% vs 13-25%; P < 0.01), and to either control or fetal therapy arms of the TOTAL trials. CONCLUSIONS: Current fetal imaging criteria are overly pessimistic and may lead to unwarranted fetal intervention. Fetal therapies remain experimental. Future studies will require updated prognostic criteria.

Social Cognitive Predictors of Health Promotion Self-Efficacy Among Older Adults During the COVID-19 Pandemic.

PURPOSE: To examine the relative importance of social cognitive predictors (ie, performance accomplishment, vicarious learning, verbal persuasion, affective state) on health promotion self-efficacy among older adults during COVID-19. DESIGN: Cross-sectional. SETTING: Data collected online from participants in British Columbia (BC), Canada. SUBJECTS: Seventy-five adults (n = 75) aged ≥65 years. MEASURES: Health promotion self-efficacy was measured using the Self-Rated Abilities for Health Practices Scale. Performance accomplishment was assessed using the health directed behavior subscale of the Health Education Impact Questionnaire; vicarious learning was measured using the positive social interaction subscale of the Medical Outcomes Survey - Social Support Scale (MOS-SSS); verbal persuasion was assessed using the informational support subscale from the MOS-SSS; and affective state was assessed using the depression subscale from the Depression Anxiety Stress Scale (DASS-21). ANALYSIS: Multiple linear regression was used to investigate the relative importance of each social cognitive predictor on self-efficacy, after controlling for age. RESULTS: Our analyses revealed statistically significant associations between self-efficacy and performance accomplishment (health-directed behavior; ß = .20), verbal persuasion (informational support; ß = .41), and affective state (depressive symptoms; ß = -.44) at P < .05. Vicarious learning (ß = -.15) did not significantly predict self-efficacy. The model was statistically significant (P < .001) explaining 43% of the self-efficacy variance. CONCLUSION: Performance accomplishment experiences, verbal persuasion strategies, and affective states may be the target of interventions to modify health promotion self-efficacy among older adults, in environments that require physical and social distancing.

Conversational assessment using artificial intelligence is as clinically useful as depression scales and preferred by users.

BACKGROUND: Depression is prevalent, chronic, and burdensome. Due to limited screening access, depression often remains undiagnosed. Artificial intelligence (AI) models based on spoken responses to interview questions may offer an effective, efficient alternative to other screening methods. OBJECTIVE: The primary aim was to use a demographically diverse sample to validate an AI model, previously trained on human-administered interviews, on novel bot-administered interviews, and to check for algorithmic biases related to age, sex, race, and ethnicity. METHODS: Using the Aiberry app, adults recruited via social media (N = 393) completed a brief bot-administered interview and a depression self-report form. An AI model was used to predict form scores based on interview responses alone. For all meaningful discrepancies between model inference and form score, clinicians performed a masked review to determine which one they preferred. RESULTS: There was strong concurrent validity between the model predictions and raw self-report scores (r = 0.73, MAE = 3.3). 90 % of AI predictions either agreed with self-report or with clinical expert opinion when AI contradicted self-report. There was no differential model performance across age, sex, race, or ethnicity. LIMITATIONS: Limitations include access restrictions (English-speaking ability and access to smartphone or computer with broadband internet) and potential self-selection of participants more favorably predisposed toward AI technology. CONCLUSION: The Aiberry model made accurate predictions of depression severity based on remotely collected spoken responses to a bot-administered interview. This study shows promising results for the use of AI as a mental health screening tool on par with self-report measures.

PIEZO1 loss-of-function compound heterozygous mutations in the rare congenital human disorder Prune Belly Syndrome.

Prune belly syndrome (PBS), also known as Eagle-Barret syndrome, is a rare, multi-system congenital myopathy primarily affecting males. Phenotypically, PBS cases manifest three cardinal pathological features: urinary tract dilation with poorly contractile smooth muscle, wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, and intra-abdominal undescended testes. Genetically, PBS is poorly understood. After performing whole exome sequencing in PBS patients, we identify one compound heterozygous variant in the PIEZO1 gene. PIEZO1 is a cation-selective channel activated by various mechanical forces and widely expressed throughout the lower urinary tract. Here we conduct an extensive functional analysis of the PIEZO1 PBS variants that reveal loss-of-function characteristics in the pressure-induced normalized open probability (NPo) of the channel, while no change is observed in single-channel currents. Furthermore, Yoda1, a PIEZO1 activator, can rescue the NPo defect of the PBS mutant channels. Thus, PIEZO1 mutations may be causal for PBS and the in vitro cellular pathophysiological phenotype could be rescued by the small molecule, Yoda1. Activation of PIEZO1 might provide a promising means of treating PBS and other related bladder dysfunctional states.

A Qualitative Investigation on Chronic Disease Management and Prevention Among Older Adults During the COVID-19 Pandemic.

PURPOSE: To qualitatively describe experiences of chronic disease management and prevention in older adults (age ≥65 years) during COVID-19. APPROACH: Qualitative descriptive approach. SETTING: Data collected online via telephone and video-conferencing technologies to participants located in various cities in British Columbia, Canada. Data analyzed by researchers in the cities of Vancouver and Kelowna in British Columbia. PARTICIPANTS: Twenty-four community-living older adults (n = 24) age ≥65 years. METHODS: Each participant was invited to complete a 30-to-45-minute virtual, semi-structured, one-on-one interview with a trained interviewer. Interview questions focused on experiences managing health prior to COVID-19 and transitioning experiences of practicing health management and prevention strategies during COVID-19. Audio recordings of interviews were transcribed verbatim and analyzed thematically. RESULTS: The sample's mean age was 73.4 years (58% female) with 75% reporting two or more chronic conditions (12.5% none, 12.5% one). Three themes described participants' strategies for chronic disease management and prevention: (1) having a purpose to optimize health (i.e., managing health challenges and maintaining independence); (2) internal self-control strategies (i.e., self-accountability and adaptability); and (3) external support strategies (i.e., informational support, motivational support, and emotional support). CONCLUSION: Helping older adults identify purposes for their own health management, developing internal control strategies, and optimizing social support opportunities may be important person-centred strategies for chronic disease management and prevention during unprecedented times like COVID-19.

Prevalence of Chlamydia infection detected by immunohistochemistry in patients with anorectal ulcer and granulation tissue.

Anorectal ulcer with granulation tissue is typically associated with left-sided inflammatory bowel disease or infection. Due to emerging cases of Chlamydia proctitis, we aim to investigate the prevalence of Chlamydia infection using immunohistochemistry (IHC) in anorectal biopsies showing ulcer and granulation tissue. Seventy-seven patients including 60 males and 17 females with mean age of 51 years old were retrospectively identified in surgical pathology archives. Chlamydia IHC was validated with a monoclonal antibody on an index who was positive for Chlamydia by rectal swab nucleic acid amplification test (NAAT), then performed on formalin fixed and paraffin embedded (FFPE) tissue sections. Confirmative molecular test using real-time PCR was performed on DNA extractions of 14 IHC-positive and 14 IHC-negative FFPEs, 18 NAAT-positive, and 5 NAAT-negative cytology specimens. Chlamydia IHC showed strong intracytoplasmic or extracellular sphere morphology in 14 of 77 (18.2 %) FFPEs, including 11 of 60 (18.3 %) males and 3 of 17 (17.6 %) females (age 11-84 years). Eight of 14 (57.1 %) Chlamydia-IHC positive patients had known history of STDs, high-risk behavior, or immunosuppressive conditions. One of 14 (7.1 %) IHC-positive FFEP and 15 of 18 (83.3 %) NAAT-positive cytology cases were confirmed by real-time PCR. Chlamydia inclusions were detected in all 4 randomly selected NAAT and PCR-positive cytology specimens by IHC. Our data suggested that Chlamydia infection is more prevalent than we thought in patients with active proctitis and ulceration. Chlamydia IHC may be performed as a screening test in biopsies to facilitate early detection of this treatable proctitis in high-risk population.

Identifying Mitral Valve Prolapse at Risk for Arrhythmias and Fibrosis From Electrocardiograms Using Deep Learning.

BACKGROUND: Mitral valve prolapse (MVP) is a common valvulopathy, with a subset developing sudden cardiac death or cardiac arrest. Complex ventricular ectopy (ComVE) is a marker of arrhythmic risk associated with myocardial fibrosis and increased mortality in MVP. OBJECTIVES: The authors sought to evaluate whether electrocardiogram (ECG)-based machine learning can identify MVP at risk for ComVE, death and/or myocardial fibrosis on cardiac magnetic resonance (CMR) imaging. METHODS: A deep convolutional neural network (CNN) was trained to detect ComVE using 6,916 12-lead ECGs from 569 MVP patients from the University of California-San Francisco between 2012 and 2020. A separate CNN was trained to detect late gadolinium enhancement (LGE) using 1,369 ECGs from 87 MVP patients with contrast CMR. RESULTS: The prevalence of ComVE was 28% (160/569). The area under the receiver operating characteristic curve (AUC) of the CNN to detect ComVE was 0.80 (95% CI: 0.77-0.83) and remained high after excluding patients with moderate-severe mitral regurgitation [0.80 (95% CI: 0.77-0.83)] or bileaflet MVP [0.81 (95% CI: 0.76-0.85)]. AUC to detect all-cause mortality was 0.82 (95% CI: 0.77-0.87). ECG segments relevant to ComVE prediction were related to ventricular depolarization/repolarization (early-mid ST-segment and QRS from V1, V3, and III). LGE in the papillary muscles or basal inferolateral wall was present in 24% patients with available CMR; AUC for detection of LGE was 0.75 (95% CI: 0.68-0.82). CONCLUSIONS: CNN-analyzed 12-lead ECGs can detect MVP at risk for ventricular arrhythmias, death and/or fibrosis and can identify novel ECG correlates of arrhythmic risk. ECG-based CNNs may help select those MVP patients requiring closer follow-up and/or a CMR.

Safe and valid? A systematic review of the psychometric properties of culturally adapted depression scales for use among Indigenous populations.

Background: Implementing culturally sensitive psychometric measures of depression may be an effective strategy to improve acceptance, response rate, and reliability of psychological assessment among Indigenous populations. However, the psychometric properties of depression scales after cultural adaptation remain unclear. Methods: We screened the Ovid Medline, PubMed, Embase, Global Health, PsycInfo, and CINAHL databases through three levels of search terms: Depression, Psychometrics, and Indigenous, following the PRISMA guidelines. We assessed metrics for reliability (including Cronbach's alpha), validity (including fit indices), and clinical utility (including predictive value). Results: Across 31 studies included the review, 13 different depression scales were adapted through language or content modification. Sample populations included Indigenous from the Americas, Asia, Africa, and Oceania. Most cultural adaptations had strong psychometric properties; however, few and inconsistent properties were reported. Where available, alphas, inter-rater and test-retest reliability, construct validity, and incremental validity often indicated increased cultural sensitivity of adapted scales. There were mixed results for clinical utility, criterion validity, cross-cultural validity, sensitivity, specificity, area under the receiver operating characteristic curve, predictive value, and likelihood ratio. Conclusions: Modifications to increase cultural relevance have the potential to improve fit and acceptance of a scale by the Indigenous population, however, these changes may decrease specificity and negative predictive value. There is an urgent need for suitable tools that are useful and reliable for identifying Indigenous individuals for clinical treatment of depression. This awaits future work for optimal specificity and validated cut-off points that take into account the high prevalence of depression in these populations.

Rare Pleomorphic Liposarcoma Presented as Jejunal Obstruction.

Pleomorphic liposarcoma (PLS) is typically found in the lower and upper extremities. PLS arising in the gastrointestinal (GI) tract is extremely rare. Here, we reported a case of a 71-year-old female with a history of rectal adenocarcinoma presenting with small bowel obstruction. Small bowel resection was performed and revealed a 7.8 cm transmural mass in the jejunum. Histology reviewed a heterogenous epithelioid malignant tumor with intracytoplasmic fatty droplets scalloping the nucleus consistent with lipoblasts in some cells and others with numerous PAS/diastase+intracytoplasmic eosinophilic globules. Scattered multinucleated giant cells were also present. Mitotic count was up to 80/10 HPFs including some bizarre mitotic figures, and Ki67 proliferation index was approximately 60%. Immunohistochemistry demonstrated that the malignant cells were negative for pancytokeratin, CD117, DOG1, SMA, desmin, MyoD1, ERG1, CD34, CD31, SOX10, Melan A, and S100. INI1 was retained. Beta-catenin showed normal membranous staining. P53 was diffusely positive suggestive of mutant phenotype. Fluorescence in situ hybridization (FISH) assay was negative for MDM2 amplification and DDIT3 rearrangement. The overall morphologic and immunohistochemical features supported a diagnosis of high-grade pleomorphic liposarcoma. Diagnosis of PLS can be challenging due to its rarity in GI tract and lack of specific biomarkers, and histomorphology with identification of lipoblasts remains the gold standard.

Real-time virtual supports improving health equity and access in British Columbia.

In British Columbia (BC) and across the territories of over 200 First Nations and 39 Métis Nation Chartered communities, the COVID-19 pandemic catalyzed a group of partner organizations to rapidly establish seven virtual care pathways under the Real-Time Virtual Support (RTVS) network. They aimed to address inequitable access and multiple barriers to healthcare faced by rural, remote, and Indigenous communities, and provide pan-provincial services. Mixed-method evaluation assessed implementation, patient and provider experience, quality improvement, cultural safety, and sustainability. Pathways supported 38,905 patient encounters and offered 29,544 hours of peer-to-peer support from April 2020 to March 2021. Mean monthly encounter growth was 178.0% (standard deviation = 252.1%). Ninety percent of patients were satisfied with the care experience; 94% of providers enjoyed delivering virtual care. Consistent growth suggests that the virtual pathways met the needs of providers and patients in rural, remote, and Indigenous communities, and supported virtual access to care in BC.

OnabotulinumtoxinA improves oral aperture in patients with scleroderma: A small clinical trial.

BACKGROUND: Reduced oral aperture (ROA), resulting from systemic sclerosis (SSc), is a debilitating condition with limited treatment options. Improvement in oral function has been reported with perioral administration of botulinum toxin type A. OBJECTIVE: To prospectively evaluate the efficacy of onabotulinumtoxinA (onabotA) injection in improving oral opening and quality of life in SSc patients with ROA. METHODS: Seventeen women with SSc and ROA were treated with 16 units of onabotA in 8 different sites around the cutaneous lips. Measurements of maximum mouth opening were taken before treatment, at 2 weeks posttreatment, and at 3 months posttreatment. Function and quality of life were also assessed via surveys. RESULTS: Interincisor and interlabial distances were significantly increased 2 weeks after treatment with onabotA (P < .001) but not 3 months after. Subjective improvement in quality of life was noted. LIMITATIONS: This single-institution study enrolled 17 patients and did not have a placebo control group. CONCLUSION: OnabotA appears to have a strong short-term symptomatic benefit in patients with ROA due to SSc, with possible benefit to quality of life.

Evidence that Mental Contrasting Reduces Health Information Avoidance.

BACKGROUND: Although learning health information is beneficial for physical well-being, many people opt to avoid learning this information due to its potentially threatening nature. Such avoidance can lead to delays in seeking treatment. PURPOSE: This study tested the effectiveness of a self-regulation technique, mental contrasting (MC), specifically MC of a negative future with a positive current reality, in reducing health information avoidance regarding skin cancer (melanoma). We hypothesized that participants who engaged in MC would be more likely to choose to learn about their melanoma risk than those who completed a control, reflection activity. METHODS: We conducted a randomized controlled trial (N = 354). Participants were assigned to complete a MC or reflection (control) exercise prior to filling out a melanoma risk calculator. Participants were then asked whether they wanted to learn their melanoma risk, and how much information they would like to know. RESULTS: Chi-Square tests revealed that MC decreased melanoma risk information avoidance compared to the reflection activity (12% vs. 23.4%) but did not make participants more likely seek additional information. CONCLUSION: MC is a brief, engaging, and effective strategy for reducing health information avoidance that could prove useful in medical settings.

It is important to know about the status of one's health in order to take necessary precautions for positive health outcomes. However, people may often engage in "information avoidance," which is the tendency to neglect seeking available and potentially valuable health information. Avoiding health information, especially with regards to one's risk for various diseases, is harmful because it can delay timely treatment. In this study, we tested the effectiveness of mental contrasting­a self-regulation technique­in reducing information avoidance for melanoma skin cancer risk. We recruited 354 participants, and they were randomly assigned to engage in the mental contrasting exercise or reflection (control) exercise. The participants then filled out a melanoma risk calculator and were asked whether they would like to learn their risk for melanoma, and how much information they would like to know. The results showed that mental contrasting decreased melanoma risk information avoidance compared to the reflection activity (12% vs. 23.4%) but did not make participants more likely seek additional information. These findings suggest that mental contrasting can be a brief, engaging, and effective strategy for reducing health information avoidance.

An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance.

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

A Virtual Reality-Assisted Cognitive Behavioral Therapy for and With Inuit in Québec: Protocol for a Proof-of-Concept Randomized Controlled Trial.

BACKGROUND: Emotion regulation is an ability related to psychological well-being; when dysregulated, individuals may have psychiatric symptoms and maladapted physiological responses. Virtual reality-assisted cognitive behavioral therapy (VR-CBT) is an effective psychotherapy to target and strengthen emotion regulation; however, it currently lacks cultural sensitivity and can be improved by adapting it to the cultural context of service users. During previous participatory research, we co-designed a culturally adapted cognitive behavioral therapy (CBT) manual and 2 virtual reality (VR) environments to function as a complement to therapy (VR-CBT) for Inuit who would like to access psychotherapy. Emotion regulation skill building will occur in virtual environments that have interactive components such as heart rate biofeedback. OBJECTIVE: We describe a protocol for a proof-of-concept 2-arm randomized controlled trial (RCT) with Inuit (n=40) in Québec. The primary aims of this research are to investigate the feasibility, benefits, and challenges of the culturally adapted VR-CBT intervention versus an established VR self-management that is available commercially. We will also investigate self-rated mental well-being and objective psychophysiological measures. Finally, we will use proof-of-concept data to identify suitable primary outcome measures, conduct power calculations in a larger trial for efficacy, and collect information about preferences for on-site or at-home treatment. METHODS: Trial participants will be randomly assigned to an active condition or active control condition in a 1:1 ratio. Inuit aged 14 to 60 years will receive a culturally adapted and therapist-guided VR-CBT with biofeedback or a VR relaxation program with nonpersonalized guided components over a 10-week period. We will collect pre- and posttreatment measures of emotion regulation and biweekly assessments over the treatment and at 3-month follow-up. The primary outcome will be measured by the Difficulties in Emotion Regulation Scale (DERS-16) and a novel psychophysiological reactivity paradigm. Secondary measures include psychological symptoms and well-being via rating scales (eg, anxiety or depressive symptoms). RESULTS: As this is the prospective registration of an RCT protocol, we do not yet report any results from the trial. Funding was confirmed in January 2020, and recruitment is expected to start in March 2023 and is set to finish in August 2025. The expected results are to be published in spring 2026. CONCLUSIONS: The proposed study responds to the community's desire for accessible and appropriate resources for psychological well-being, as it was developed in active collaboration with the Inuit community in Québec. We will test feasibility and acceptance by comparing a culturally adapted, on-site psychotherapy with a commercial self-management program while incorporating novel technology and measurement in the area of Indigenous health. We also aim to fulfill the needs for RCT evidence of culturally adapted psychotherapies that are lacking in Canada. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 21831510; https://www.isrctn.com/ISRCTN21831510. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/40236.

Development and pilot testing of internet-delivered, family-based cognitive behavioral therapy for anxiety and obsessive-compulsive disorders in autistic youth.

Cognitive behavioral therapy adapted for autistic youth with anxiety and/or OCD has a strong evidence base, but few have access. A 12-week family-based, Internet-delivered cognitive behavioral therapy (iCBT) program for 7-15 year-old autistic youth with anxiety and/or OCD was developed as a potential method to address this problem. Quantitative and qualitative feedback from stakeholders (parents, youth, clinicians) was gathered on an initial draft of content before conducting a pilot trial. This feedback suggested high quality, engagement, usability, and informativeness of the material. Suggestions were incorporated into the treatment program that was tested in a pilot trial. Eight families were randomized to the iCBT program with either 1) weekly email support or 2) weekly email support plus biweekly telehealth check-ins, and seven of these families completed pre- and post-treatment assessments. An average reduction of 39% in anxiety severity was found, with six of the seven being classified as responders. Preliminary evidence suggests that family-based iCBT is an acceptable and promising treatment for autistic youth with anxiety and/or obsessive-compulsive disorders that should be further modified and tested in future work.