ABSTRACT
Birt-Hogg-Dubé (BHD) syndrome patients are uniquely susceptible to all renal tumour subtypes. The underlying mechanism of carcinogenesis is unclear. To study cancer development in BHD, we used human proximal kidney (HK2) cells and found that long-term folliculin (FLCN) knockdown was required to increase their tumorigenic potential, forming larger spheroids in non-adherent conditions. Transcriptomic and proteomic analysis uncovered links between FLCN, cell cycle control and the DNA damage response (DDR) machinery. HK2 cells lacking FLCN had an altered transcriptome profile with cell cycle control gene enrichment. G1/S cell cycle checkpoint signaling was compromised with heightened protein levels of cyclin D1 (CCND1) and hyperphosphorylation of retinoblastoma 1 (RB1). A FLCN interactome screen uncovered FLCN binding to DNA-dependent protein kinase (DNA-PK). This novel interaction was reversed in an irradiation-responsive manner. Knockdown of FLCN in HK2 cells caused a marked elevation of γH2AX and RB1 phosphorylation. Both CCND1 and RB1 phosphorylation remained raised during DNA damage, showing an association with defective cell cycle control with FLCN knockdown. Furthermore, Flcn-knockdown C. elegans were defective in cell cycle arrest by DNA damage. This work implicates that long-term FLCN loss and associated cell cycle defects in BHD patients could contribute to their increased risk of cancer.
ABSTRACT
Induction of commensal-specific immunity contributes to tissue homeostasis, yet the mechanisms underlying induction of commensal-specific B cells remain poorly understood in part due to a lack of tools to identify these cells. Using phage display, we identified segmented filamentous bacteria (SFB) antigens targeted by serum and intestinal antibodies and generated B cell tetramers to track SFB-specific B cells in gut-associated lymphoid tissues. We revealed a compartmentalized response in SFB-specific B cell activation, with a gradient of immunoglobulin A (IgA), IgG1, and IgG2b isotype production along Peyer's patches contrasted by selective production of IgG2b within mesenteric lymph nodes. V(D)J sequencing and monoclonal antibody generation identified somatic hypermutation driven affinity maturation to SFB antigens under homeostatic conditions. Combining phage display and B cell tetramers will enable investigation of the ontogeny and function of commensal-specific B cell responses in tissue immunity, inflammation, and repair.
Subject(s)
B-Lymphocytes , Animals , B-Lymphocytes/immunology , Mice , Mice, Inbred C57BL , Peyer's Patches/immunology , Lymphocyte Activation/immunology , Antigens, Bacterial/immunology , Somatic Hypermutation, Immunoglobulin , Peptide Library , Lymph Nodes/immunology , Cell Surface Display Techniques , Symbiosis/immunology , Immunoglobulin G/immunology , Immunoglobulin A/immunologyABSTRACT
Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.
Subject(s)
CCCTC-Binding Factor , Cell Differentiation , Interferon-gamma , Interleukin-22 , Interleukins , Th1 Cells , Animals , CCCTC-Binding Factor/metabolism , CCCTC-Binding Factor/genetics , Th1 Cells/immunology , Mice , Cell Differentiation/immunology , Interferon-gamma/metabolism , Binding Sites , Interleukins/metabolism , Interleukins/genetics , Enhancer Elements, Genetic/genetics , Mice, Inbred C57BL , Chromatin/metabolism , Toxoplasmosis/immunology , Toxoplasmosis/parasitology , Toxoplasmosis/genetics , Gene Expression Regulation , Toxoplasma/immunology , Cytokines/metabolism , Cell Lineage , Th17 Cells/immunologyABSTRACT
Background: Body dysmorphic disorder (BDD) is severe and undertreated. Digital mental health could be key to expanding access to evidence-based treatments, such as cognitive behavioral therapy for BDD (CBT-BDD). Coach guidance is posited to be essential for effective uptake of digital interventions. However, little is known about how different patients may use coaching, what patterns correspond to meaningful outcomes, and how to match coaching to patient needs. Methods: Participants were 77 adults who received a 12-week guided smartphone CBT-BDD. Bachelor's-level coaches were available via asynchronous messaging. We analyzed the 400 messages sent by users to coaches during treatment. Message content was coded using the efficiency model of support (i.e., usability, engagement, fit, knowledge, and implementation). We aimed to clarify when and for what purposes patients with BDD used coaching, and if we can meaningfully classify patients by these patterns. We then assessed potential baseline predictors of coach usage, and whether distinct patterns relate to clinical outcomes. Results: Users on average sent 5.88 messages (SD = 4.51, range 1-20) and received 9.84 (SD = 5.74, range 2-30). Regarding frequency of sending messages, latent profile analysis revealed three profiles, characterized by: (1) peak mid-treatment (16.88 %), (2) bimodal/more communication early and late in treatment (10.39 %), and (3) consistent low/no communication (72.73 %). Regarding content, four profiles emerged, characterized by mostly (1) engagement (51.95 %), (2) fit (15.58 %), (3) knowledge (15.58 %), and (4) miscellaneous/no messages (16.88 %). There was a significant relationship between frequency profile and age, such that the early/late peak group was older than the low communication group, and frequency profile and adherence, driven by the mid-treatment peak group completing more modules than the low contact group. Regarding content, the engagement and knowledge groups began treatment with more severe baseline symptoms than the fit group. Content profile was associated with dropout, suggesting higher dropout rates in the miscellaneous/no contact group and reduced rates in the engagement group. There was no relationship between profile membership and other outcomes. Discussion: The majority of participants initiated little contact with their coach and the most common function of communications was to increase engagement. Results suggest that older individuals may prefer or require more support than younger counterparts early in treatment. Additionally, whereas individuals using coaching primarily for engagement may be at lower risk of dropping out, those who do not engage at all may be at elevated risk. Findings can support more personalized, data-driven coaching protocols and more efficient allocation of coaching resources.
ABSTRACT
BACKGROUND: Major depressive disorder affects approximately 1 in 5 adults during their lifetime and is the leading cause of disability worldwide. Yet, a minority receive adequate treatment due to person-level (eg, geographical distance to providers) and systems-level (eg, shortage of trained providers) barriers. Digital tools could improve this treatment gap by reducing the time and frequency of therapy sessions needed for effective treatment through the provision of flexible, automated support. OBJECTIVE: This study aimed to examine the feasibility, acceptability, and preliminary clinical effect of Mindset for Depression, a deployment-ready 8-week smartphone-based cognitive behavioral therapy (CBT) supported by brief teletherapy appointments with a therapist. METHODS: This 8-week, single-arm open trial tested the Mindset for Depression app when combined with 8 brief (16-25 minutes) video conferencing visits with a licensed doctoral-level CBT therapist (n=28 participants). The app offers flexible, accessible psychoeducation, CBT skills practice, and support to patients as well as clinician guidance to promote sustained engagement, monitor safety, and tailor treatment to individual patient needs. To increase accessibility and thus generalizability, all study procedures were conducted remotely. Feasibility and acceptability were assessed via attrition, patient expectations and feedback, and treatment utilization. The primary clinical outcome measure was the clinician-rated Hamilton Depression Rating Scale, administered at pretreatment, midpoint, and posttreatment. Secondary measures of functional impairment and quality of life as well as maintenance of gains (3-month follow-up) were also collected. RESULTS: Treatment credibility (week 4), expectancy (week 4), and satisfaction (week 8) were moderate to high, and attrition was low (n=2, 7%). Participants self-reported using the app or practicing (either on or off the app) the CBT skills taught in the app for a median of 50 (IQR 30-60; week 4) or 60 (IQR 30-90; week 8) minutes per week; participants accessed the app on an average 36.8 (SD 10.0) days and completed a median of 7 of 8 (IQR 6-8) steps by the week 8 assessment. The app was rated positively across domains of engagement, functionality, aesthetics, and information. Participants' depression severity scores decreased from an average Hamilton Depression Rating Scale score indicating moderate depression (mean 19.1, SD 5.0) at baseline to a week 8 mean score indicating mild depression (mean 10.8, SD 6.1; d=1.47; P<.001). Improvement was also observed for functional impairment and quality of life. Gains were maintained at 3-month follow-up. CONCLUSIONS: The results show that Mindset for Depression is a feasible and acceptable treatment option for individuals with major depressive disorder. This smartphone-led treatment holds promise to be an efficacious, scalable, and cost-effective treatment option. The next steps include testing Mindset for Depression in a fully powered randomized controlled trial and real-world clinical settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05386329; https://clinicaltrials.gov/study/NCT05386329?term=NCT05386329.
Subject(s)
Cognitive Behavioral Therapy , Depressive Disorder, Major , Mobile Applications , Adult , Humans , Depression/therapy , Depressive Disorder, Major/therapy , Feasibility Studies , Quality of LifeABSTRACT
BACKGROUND: Body dysmorphic disorder (BDD) is a severe, chronic disorder if untreated. Smartphone cognitive behavioral therapy (CBT) for BDD is efficacious and can reduce key treatment barriers (e.g., lack of clinicians, cost, stigma). While promising, little is known about who is more or less likely to benefit from this approach. METHODS: This is a secondary data analysis of a randomized, waitlist-controlled trial of smartphone CBT for BDD. Participants (N = 80) were recruited nationally and randomized to receive a 12-week, coach-guided CBT for BDD app, either immediately or after a 12-week waitlist. The main outcome for this analysis was BDD severity (BDD-YBOCS) over time (baseline, week 6, week 12) during the active app use phase in each randomized group (n = 74). Secondary outcomes included treatment response (≥30 % reduction in BDD-YBOCS) and remission (total BDD-YBOCS ≤16) at end-of-treatment. RESULTS: Immediate (vs. delayed) CBT predicted better outcomes (symptom improvement), as did gender identity (symptom improvement), higher baseline treatment credibility and expectancy (response, remission), lower baseline BDD severity (remission), and sexual minority status (vs. heterosexual; response, remission). LIMITATIONS: Limitations include the relatively small sample, drop-out rate of 22 %, and limited gender and racial-ethnic diversity. CONCLUSIONS: These results highlight a potential advantage of smartphone CBT in historically marginalized populations, and the importance of efforts to hasten treatment access, bolster confidence in the treatment at treatment onset, and develop stratified care models to optimize treatment allocation and efficacy.
Subject(s)
Body Dysmorphic Disorders , Cognitive Behavioral Therapy , Humans , Male , Female , Treatment Outcome , Body Dysmorphic Disorders/therapy , Body Dysmorphic Disorders/psychology , Smartphone , Gender Identity , Cognitive Behavioral Therapy/methodsABSTRACT
The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide calcitonin gene-related peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. The neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.
Subject(s)
Calcitonin Gene-Related Peptide , Neuroimmunomodulation , Calcitonin Gene-Related Peptide/genetics , Receptor Activity-Modifying Protein 1/genetics , Receptors, Calcitonin Gene-Related Peptide , Adaptive ImmunityABSTRACT
BACKGROUND: Body dysmorphic disorder (BDD) is severe, undertreated, and relatively common. Although gold-standard cognitive behavioral therapy (CBT) for BDD has strong empirical support, a significant number of patients do not respond. More work is needed to understand BDD's etiology and modifiable barriers to treatment response. Given its high prevalence and impact on the development, maintenance, and treatment of related, frequently comorbid disorders, sleep disruption is a compelling, but not-yet studied factor. METHODS: Data were drawn from a randomized controlled trial of guided smartphone app-based CBT for BDD. Included participants were offered 12-weeks of treatment, immediately (n = 40) or after a 12-week waitlist (n = 37). Sleep disruption and BDD symptom severity were assessed at baseline, week-6, and week-12. RESULTS: Hypotheses and analysis plan were pre-registered. Two-thirds of patients reported significant insomnia symptoms at baseline. Baseline severity of sleep disruption and BDD symptoms were not related (r = 0.02). Pre-treatment sleep disruption did not predict BDD symptom reduction across treatment, nor did early sleep improvements predict greater BDD symptom improvement. Early BDD symptom improvement also did not predict later improvements in sleep. LIMITATIONS: Limitations include the small sample, restricted ranges of BDD symptom severity and treatment response, and few metrics of sleep disruption. CONCLUSIONS: Although insomnia was disproportionately high in this sample and both BDD symptoms and sleep improved in treatment, results suggest sleep and BDD symptoms may function largely independent of one another. More work is encouraged to replicate and better understand findings as well as potential challenges and benefits of addressing sleep in BDD.
Subject(s)
Body Dysmorphic Disorders , Cognitive Behavioral Therapy , Sleep Initiation and Maintenance Disorders , Humans , Body Dysmorphic Disorders/psychology , Sleep Initiation and Maintenance Disorders/diagnosis , Sleep Initiation and Maintenance Disorders/therapy , Treatment Outcome , Cognitive Behavioral Therapy/methods , SleepABSTRACT
E-cadherin plays a central role in cell-cell adhesion. The ectodomains of wild-type cadherins form a crystalline-like two-dimensional lattice in cell-cell interfaces mediated by both trans (apposed cell) and cis (same cell) interactions. In addition to these extracellular forces, adhesive strength is further regulated by cytosolic phenomena involving α and ß catenin-mediated interactions between cadherin and the actin cytoskeleton. Cell-cell adhesion can be further strengthened under tension through mechanisms that have not been definitively characterized in molecular detail. Here we quantitatively determine the role of the cadherin ectodomain in mechanosensing. To this end, we devise an E-cadherin-coated emulsion system, in which droplet surface tension is balanced by protein binding strength to give rise to stable areas of adhesion. To reach the honeycomb/cohesive limit, an initial emulsion compression by centrifugation facilitates E-cadherin trans binding, whereas a high protein surface concentration enables the cis-enhanced stabilization of the interface. We observe an abrupt concentration dependence on recruitment into adhesions of constant crystalline density, reminiscent of a first-order phase transition. Removing the lateral cis interaction with a "cis mutant" shifts this transition to higher surface densities leading to denser, yet weaker adhesions. In both proteins, the stabilization of progressively larger areas of deformation is consistent with single-molecule experiments that show a force-dependent lifetime enhancement in the cadherin ectodomain, which may be attributed to the "X-dimer" bond.
Subject(s)
Biomimetics , Cadherins , Emulsions , Cadherins/metabolism , Cell Adhesion , Protein BindingABSTRACT
Introduction: Robot-assisted thoracoscopic surgery (RATS) is an alternative to video-assessed thoracoscopic surgery (VATS) for the treatment of lung cancer but concern exists regarding the high associated costs. The COVID-19 pandemic added further financial pressure to healthcare systems. This study investigated the impact of the learning curve on the cost-effectiveness of RATS lung resection and the financial impact of the COVID-19 pandemic on a RATS program. Methods: Patients undergoing RATS lung resection between January 2017 and December 2020 were prospectively followed. A matched cohort of VATS cases were analyzed in parallel. The first 100 and most recent 100 RATS cases performed at our institution were compared to assess the learning curve. Cases performed before and after March 2020 were compared to assess the impact of the COVID-19 pandemic. A comprehensive cost analysis of multiple theatre and postoperative data points was performed using Stata statistics package (v14.2). Results: 365 RATS cases were included. Median cost per procedure was £7,167 and theatre cost accounted for 70%. Major contributing factors to overall cost were operative time and postoperative length of stay. Cost per case was £640 less after passing the learning curve (p < 0.001) largely due to reduced operative time. Comparison of a post-learning curve RATS subgroup matched to 101 VATS cases revealed no significant difference in theatre costs between the two techniques. Overall cost of RATS lung resections performed before and during the COVID-19 pandemic were not significantly different. However, theatre costs were significantly cheaper (£620/case; p < 0.001) and postoperative costs were significantly more expensive (£1,221/case; p = 0.018) during the pandemic. Discussion: Passing the learning curve is associated with a significant reduction in the theatre costs associated with RATS lung resection and is comparable with the cost of VATS. This study may underestimate the true cost benefit of passing the learning curve due to the effect of the COVID-19 pandemic on theatre costs. The COVID-19 pandemic made RATS lung resection more expensive due to prolonged hospital stay and increased readmission rate. The present study offers some evidence that the initial increased costs associated with RATS lung resection may be gradually offset as a program progresses.
ABSTRACT
Smartphone psychotherapies are growing in popularity, yet little is understood about (1) how people prefer to engage with psychotherapy apps, or (2) which engagement patterns constitute effective engagement. The present study uses secondary data from a 12-week randomized waitlist-controlled trial of smartphone-delivered cognitive behavioral therapy (CBT) for body dysmorphic disorder (BDD) (N = 77) to address these aims. Additionally, using the present study as a use-case, we seek to provide a roadmap for how researchers may improve upon methodological limitations of existing smartphone psychotherapy engagement research. We measured behavioral engagement via 19 objective variables derived from phone analytics data, which we reduced via factor analysis into two factors: 1) use volume and frequency, and 2) session duration. Cluster analysis based on engagement factors yielded three engager types, which mapped onto "deep" users, "samplers," and "light" users. The clusters did not differ significantly in improvement in BDD severity across treatment, although deep users improved more than light users at a marginally significant level. Results suggest that varying patterns of preferred engagement may be efficacious. Moreover, the study's methods provide an example of how researchers can measure and study behavioral engagement comprehensively and objectively. Trial Registration: ClinicalTrials.gov Identifier: NCT04034693.
ABSTRACT
OBJECTIVES: To demonstrate the safety and feasibility of advanced nurse practitioner-led (ANP-led) outpatient follow-up after discharge with ambulatory chest drains for prolonged air leak and excessive fluid drainage. METHODS: Patients discharged with ambulatory chest drains between January 2017 and December 2019 were retrospectively reviewed. Discharge criteria included air leak < 200 ml/min or fluid drainage > 100 ml/24 h on a digital drain. Patients were reviewed weekly in the clinic by ANPs, a highly skilled cohort of nurses with physician support available. Outcomes included length of stay, duration of air or fluid leak and complications. RESULTS: Two-hundred patients were included, amounting to 368 clinic episodes. The median age was 68 ± 13 years and 119 (60%) were male. 112 (56%) patients underwent anatomical lung resection (total anatomical lung resections during the study period = 917) equating to a discharge with ambulatory chest drain rate of 12.2% in this group. The median length of stay was 6 ± 3 days and 176 (88%) patients were discharged with air leak versus 24 (12%) with excessive fluid drainage. The median time to drain removal was 12 ± 11 days. Complications occurred in 16 patients (8%) and 12 (6%) required readmission. An estimated 2075 inpatient days were saved over the study period equating to an annual cost saving of £123,167 (US$149,032) per annum. CONCLUSIONS: Patients with air leak or excessive fluid drainage can safely be discharged with ambulatory chest drains, allowing them to return to their familiar home environment safely and quickly. ANP-led clinics are a robust and cost-effective follow-up strategy and are associated with a low complication rate.
Subject(s)
Patient Discharge , Thoracic Surgery , Humans , Male , Middle Aged , Aged , Aged, 80 and over , Female , Pneumonectomy/adverse effects , Follow-Up Studies , Retrospective Studies , Drainage/adverse effects , Chest Tubes , Length of StayABSTRACT
BACKGROUND: Few patients receive cognitive behavioral therapy, the gold-standard for body dysmorphic disorder (CBT-BDD). Smartphones can make evidence-based interventions, like CBT-BDD, more accessible and scalable. A key question is: how do patients view it? Low credibility and expectancy would likely translate to low uptake and engagement outside of research settings, diminishing the impact. Thus, it is important to understand patients' beliefs about digital CBT-BDD. METHODS: We compared credibility and expectancy in a coach-guided app-based CBT-BDD trial (N=75) to a previous in-person CBT-BDD trial (N = 55). We further examined the relationship of perceptions of digital CBT-BDD to baseline clinical and demographic factors and dropout. RESULTS: Credibility did not differ between the in-person (M=19.3) and digital (M=18.3) trials, p=.24. Expectancy for improvement was moderately higher for in-person (M=58.4) than digital (M=48.3) treatment, p=.005. In the digital trial, no demographic variables were associated with credibility or expectancy. Better BDD-related insight and past non-CBT BDD therapy were associated with greater expectancy. Credibility was associated with lower likelihood of dropout. DISCUSSION: Digital CBT-BDD was regarded as similarly credible to in-person CBT-BDD but with lower expectancy. Tailored expectancy-enhancing strategies could strengthen this novel approach, particularly among those with poorer insight and without prior BDD treatment.
ABSTRACT
The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide Calcitonin Gene-Related Peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo . Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8 + T lymphocytes induced by skin commensal colonization. Neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology. Significance statement: Multisystem coordination at barrier surfaces is critical for optimal tissue functions and integrity, in response to microbial and environmental cues. In this study, we identified a novel neuroimmune crosstalk mechanism between the sensory nervous system and the adaptive immune response to the microbiota, mediated by the neuropeptide CGRP and its receptor RAMP1 on skin microbiota-induced T lymphocytes. The neuroimmune CGPR-RAMP1 axis constrains adaptive immunity to the microbiota and overall limits the activation status of the skin epithelium, impacting tissue responses to wounding. Our study opens the door to a new avenue to modulate adaptive immunity to the microbiota utilizing neuromodulators, allowing for a more integrative and tailored approach to harnessing microbiota-induced T cells to promote barrier tissue protection and repair.
ABSTRACT
Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu.
Subject(s)
Coleoptera , Colitis , Humans , Mice , Animals , Lymphocyte Count , Immunologic Surveillance , Colitis/chemically induced , CytokinesABSTRACT
INTRODUCTION: Body dysmorphic disorder (BDD) is severe, chronic, and undertreated. Apps could substantially improve treatment access. OBJECTIVE: We provide an initial test of the usability and efficacy of coach-supported app-based cognitive behavioral therapy (CBT) for BDD. The Perspectives app covers core treatment components: psychoeducation, cognitive restructuring, exposure with response prevention, mindfulness, attention retraining, and relapse prevention. METHODS: A randomized waitlist-controlled trial was conducted. Adults (N = 80) with primary BDD were assigned to 12 weeks of Perspectives or waitlist. Coaches promoted engagement and answered questions via in-app messaging and phone calls. BDD severity was measured at baseline, mid-treatment, and end of treatment by blinded independent evaluators (Yale-Brown Obsessive Compulsive Scale Modified for BDD; BDD-YBOCS). Secondary outcomes included BDD-related insight, depression, quality of life, and functioning. RESULTS: App uptake and satisfaction were high. In intent-to-treat analyses, Perspectives app-based CBT was associated with significantly lower BDD-YBOCS severity at end of treatment (M [SD]: 16.8 [7.5]) compared to the waitlist (26.7 [6.2]; p < 0.001, d = 1.44). App-based CBT was associated with greater improvements across all secondary measures, with medium to large effects. CONCLUSIONS: Perspectives, supported by a bachelor's-level coach, is an efficacious, scalable treatment for adults with BDD.
Subject(s)
Body Dysmorphic Disorders , Cognitive Behavioral Therapy , Mobile Applications , Adult , Body Dysmorphic Disorders/psychology , Body Dysmorphic Disorders/therapy , Humans , Quality of Life/psychology , Treatment OutcomeABSTRACT
The timely identification of patients who are at risk of a mental health crisis can lead to improved outcomes and to the mitigation of burdens and costs. However, the high prevalence of mental health problems means that the manual review of complex patient records to make proactive care decisions is not feasible in practice. Therefore, we developed a machine learning model that uses electronic health records to continuously monitor patients for risk of a mental health crisis over a period of 28 days. The model achieves an area under the receiver operating characteristic curve of 0.797 and an area under the precision-recall curve of 0.159, predicting crises with a sensitivity of 58% at a specificity of 85%. A follow-up 6-month prospective study evaluated our algorithm's use in clinical practice and observed predictions to be clinically valuable in terms of either managing caseloads or mitigating the risk of crisis in 64% of cases. To our knowledge, this study is the first to continuously predict the risk of a wide range of mental health crises and to explore the added value of such predictions in clinical practice.
Subject(s)
Electronic Health Records , Mental Health , Humans , Machine Learning , Prospective Studies , ROC CurveABSTRACT
Th17 cells play crucial roles in host-microbe interactions, but can also promote chronic inflammation and tissue pathology. Factors influencing Th17 cell heterogeneity and effector functions in different inflammatory contexts remain unclear. Schnell et al. demonstrate that intestinal Th17 cells form a reservoir from which pathogenic Th17 cells can be elicited during severe tissue inflammation.
Subject(s)
Inflammation , Th17 Cells , Homeostasis , Humans , Inflammation/pathologyABSTRACT
Retinol is shuttled to myeloid cells for conversion to retinoic acid, but the receptor facilitating uptake of SAA:retinol complexes on myeloid cells is unknown. In a recent issue of Science, Bang et al. (2021) use genetic and biochemical approaches to reveal this critical receptor to be LRP1 and show that this axis is essential for intestinal innate and adaptive immune responses.
Subject(s)
Tretinoin , Vitamin A , Carrier Proteins , Tretinoin/metabolism , Vitamin A/metabolismABSTRACT
E-cadherins play a critical role in the formation of cell-cell adhesions for several physiological functions, including tissue development, repair, and homeostasis. The formation of clusters of E-cadherins involves extracellular adhesive (trans-) and lateral (cis-) associations between E-cadherin ectodomains and stabilization through intracellular binding to the actomyosin cytoskeleton. This binding provides force to the adhesion and is required for mechanotransduction. However, the exact role of cytoskeletal force on the clustering of E-cadherins is not well understood. To gain insights into this mechanism, we developed a computational model based on Brownian dynamics. In the model, E-cadherins transit between structural and functional states; they are able to bind and unbind other E-cadherins on the same and/or opposite cell(s) through trans- and cis-interactions while also creating dynamic links with the actomyosin cytoskeleton. Our results show that actomyosin force governs the fraction of E-cadherins in clusters and the size and number of clusters. For low forces (below 10 pN), a large number of small E-cadherin clusters form with less than five E-cadherins each. At higher forces, the probability of forming fewer but larger clusters increases. These findings support the idea that force reinforces cell-cell adhesions, which is consistent with differences in cluster size previously observed between apical and lateral junctions of epithelial tissues.