Reducing LGBTQ+ adolescent mental health inequalities: a realist review of school-based interventions.

BACKGROUND: LGBTQ+ young people have elevated rates of poor mental health in comparison to their cisgender heterosexual peers. School environment is a key risk factor and consistently associated with negative mental health outcomes for LGBTQ+ adolescents. AIMS: To examine how, why, for whom and in what context school-based interventions prevent or reduce mental health problems in LGBTQ+ adolescents. METHODS: A realist review methodology was utilised and focused on all types of school-based interventions and study designs. A Youth Advisory Group were part of the research team. Multiple search strategies were used to locate relevant evidence. Studies were subject to inclusion criteria and quality appraisal, and included studies were synthesised to produce a programme theory. Seventeen studies were included in the review. RESULTS: Eight intervention components were necessary to address LGBTQ+ pupils mental health: affirmative visual displays; external signposting to LGBTQ+ support; stand-alone input; school-based LGBTQ support groups; curriculum-based delivery; staff training; inclusion policies; trusted adult. Few school-based interventions for this population group were identified. CONCLUSIONS: The programme theory indicates that "to work" school-based interventions must have a "whole-school" approach that addresses specifically the dominant cis-heteronormative school environment and hence the marginalisation, silence, and victimisation that LGBTQ+ pupils can experience.

Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK.

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

A case of wild-type rubella-associated cutaneous granuloma in ataxia telangiectasia.

Granulomatous skin disease is known to be associated with various primary immunodeficiencies, including ataxia telangiectasia (AT). Recent reports of persistence of live vaccine strain rubella within such cutaneous granulomas have raised concern regarding the safety of vaccination. Here we report a case of cutaneous granuloma in association with AT, demonstrating wild type, rather than vaccine strain rubella. This supports the persistence of rubella as a causative mechanism, but suggests it is not vaccine strain-specific, and thus may impact the decision of those considering not vaccinating this subset of children.

Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia.

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).

The social determinants of lesbian, gay, bisexual and transgender youth suicidality in England: a mixed methods study.

Background: Lesbian, gay, bisexual and transgender (LGBT) youth have a higher risk of suicidality and self-harm than heterosexual youth populations but little is known about the underlying mechanisms. We aimed to investigate the social determinants of this mental health inequality. Methods: A two-stage sequential mixed method study was conducted. Firstly, 29 semi-structured interviews with LGBT youth (aged 13-25 years old) were completed. Data was analysed thematically. Stage 2 involved a self-completed questionnaire employing an online community-based sampling strategy (n = 789). Logistic regression analysis was performed to predict suicidality. Results: Five social determinants explained suicidal risk: (i) homophobia, biphobia or transphobia; (ii) sexual and gender norms; (iii) managing sexual and gender identities across multiple life domains; (iv) being unable to talk; (v) other life crises. Youth who were transgender (OR = 1.50, P < 0.022), disabled (OR = 2.23, P < 0.000), had self-harmed (OR = 7.45, P < 0.000), were affected by abuse (OR = 2.14, P < 0.000), and affected by not talking about their emotions (OR = 2.43, P < 0.044) were most likely to have planned or attempted suicide. Conclusions: Public health universal interventions that tackle bullying and discrimination in schools, and selected interventions that provide specific LGBT youth mental health support could reduce LGBT mental health inequalities in youth suicidality.

Norms and normalisation: understanding lesbian, gay, bisexual, transgender and queer youth, suicidality and help-seeking.

Young people who identify as lesbian, gay, bisexual, and queer transgender have elevated rates of suicidality. Despite the increased risk, there is a paucity of research on lesbian, gay, bisexual, transgender and queer help-seeking and suicidality. We report on a UK sequential exploratory, two-stage, mixed-method study. Stage 1 involved 29 online and face-to-face semi-structured interviews with lesbian, gay, bisexual, transgender and queer youth aged 16-25 years old. Stage 2 utilised an online youth questionnaire employing a community-based sampling strategy (n = 789). Results indicated that participants only asked for help when they reached a crisis point because they were normalising their emotional distress. Those who self-harmed, had attempted or planned suicide or had experience of abuse related to their sexuality or gender were most likely to seek help. Results suggested that the reluctance to seek help was due to three interconnecting factors: negotiating sexuality, gender, mental health and age norms; being unable to talk about emotions; and coping and self-reliance. Policies aiming to prevent lesbian, gay, bisexual, transgender and queer youth suicide recognise that norms and normalising processes connected to sexual orientation and gender identity are additional difficulties that youth have accessing mental health support.

Mental Health Staff Perceptions and Practice Regarding Self-Harm, Suicidality and Help-Seeking in LGBTQ Youth: Findings from a Cross-Sectional Survey in the UK.

Young people who identify as lesbian, gay, bisexual, transgender or queer (LGBTQ) experience higher levels of suicidality compared to heterosexual or cisgender peers, and face significant barriers accessing mental health services including prejudice from staff. In a cross-sectional survey, mental health staff who reported receiving LGBT awareness training were significantly more likely to report in relation to working with LGBT youth that they routinely discussed issues of sexuality and gender (χ2=8.782, df=2, p < 0.05); to feel that their organisation supported them to work with this group (χ2=14.401, df=2, p < 0.001); and report that they had access to adequate skills training that supported their work with suicidality and self-harm with this group (χ2=21.911, df=2, p <0.001). There is a need to enhance the mental health workforce in LGBTQ awareness, and these findings indicate that awareness training could impact positively on practice.

A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing.

TNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory disease caused by mutations in TNF Receptor 1 (TNFR1). Current therapies for TRAPS are limited and do not target the pro-inflammatory signalling pathways that are central to the disease mechanism. Our aim was to identify drugs for repurposing as anti-inflammatories based on their ability to down-regulate molecules associated with inflammatory signalling pathways that are activated in TRAPS. This was achieved using rigorously optimized, high through-put cell culture and reverse phase protein microarray systems to screen compounds for their effects on the TRAPS-associated inflammatory signalome. 1360 approved, publically available, pharmacologically active substances were investigated for their effects on 40 signalling molecules associated with pro-inflammatory signalling pathways that are constitutively upregulated in TRAPS. The drugs were screened at four 10-fold concentrations on cell lines expressing both wild-type (WT) TNFR1 and TRAPS-associated C33Y mutant TNFR1, or WT TNFR1 alone; signalling molecule levels were then determined in cell lysates by the reverse-phase protein microarray. A novel mathematical methodology was developed to rank the compounds for their ability to reduce the expression of signalling molecules in the C33Y-TNFR1 transfectants towards the level seen in the WT-TNFR1 transfectants. Seven high-ranking drugs were selected and tested by RPPA for effects on the same 40 signalling molecules in lysates of peripheral blood mononuclear cells (PBMCs) from C33Y-TRAPS patients compared to PBMCs from normal controls. The fluoroquinolone antibiotic lomefloxacin, as well as others from this class of compounds, showed the most significant effects on multiple pro-inflammatory signalling pathways that are constitutively activated in TRAPS; lomefloxacin dose-dependently significantly reduced expression of 7/40 signalling molecules across the Jak/Stat, MAPK, NF-κB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing.

Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study.

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases. OBJECTIVES: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. METHODS: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. RESULTS: Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. CONCLUSION: APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.

A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS).

Mutations in TNFRSF1A encoding TNF receptor 1 (TNFR1) cause the autosomal dominant TNF receptor-associated periodic syndrome (TRAPS): a systemic autoinflammatory disorder. Misfolding, intracellular aggregation, and ligand-independent signaling by mutant TNFR1 are central to disease pathophysiology. Our aim was to understand the extent of signaling pathway perturbation in TRAPS. A prototypic mutant TNFR1 (C33Y), and wild-type TNFR1 (WT), were expressed at near physiological levels in an SK-Hep-1 cell model. TNFR1-associated signaling pathway intermediates were examined in this model, and in PBMCs from C33Y TRAPS patients and healthy controls. In C33Y-TNFR1-expressing SK-Hep-1 cells and TRAPS patients' PBMCs, a subtle, constitutive upregulation of a wide spectrum of signaling intermediates and their phosphorylated forms was observed; these were associated with a proinflammatory/antiapoptotic phenotype. In TRAPS patients' PBMCs, this upregulation of proinflammatory signaling pathways was observed irrespective of concurrent treatment with glucocorticoids, anakinra or etanercept, and the absence of overt clinical symptoms at the time that the blood samples were taken. This study reveals the pleiotropic effect of a TRAPS-associated mutant form of TNFR1 on inflammatory signaling pathways (a proinflammatory signalome), which is consistent with the variable and limited efficacy of cytokine-blocking therapies in TRAPS. It highlights new potential target pathways for therapeutic intervention.

Community as a source of health in three racial/ethnic communities in Oregon: a qualitative study.

BACKGROUND: A 2011 report by the Oregon Health Authority and the Department of Human Services documented disparities in its Latino and American Indian populations on multiple individual-level health indicators. However, research is lacking on the social contexts in which Latinos and American Indians in Oregon live and how these environments influence the health of communities as a whole. To help fill this gap, this study sought to contextualize the social environments that influence the health of Latinos and American Indian residents in three Oregon communities. METHODS: Guided by an ecological framework, we conducted one-time semi-structured qualitative interviews with 26 study participants to identify the prominent health-related issues in the communities and to examine the factors that study participants perceived as enabling or inhibiting healthy lifestyles of community residents. We used a grounded theory approach to perform content and thematic analyses of the data. RESULTS: Study participants identified preventable chronic conditions, such as diabetes, obesity, and hypertension, as the most pressing health concerns in their communities. Results showed that traditional and cultural activities and strong family and community cohesion were viewed as facilitators of good community health. Poverty, safety concerns, insufficient community resources, and discrimination were perceived as barriers to community health. Three themes emerged from the thematic analyses: social connectedness is integral to health; trauma has an ongoing negative impact on health; and invisibility of residents in the community underlies poor health. CONCLUSIONS: This study's findings provide insight to the social contexts which operate in the lives of some Latinos and American Indians in Oregon. While participants identified community-level factors as important to health, they focused more on the social connections of individuals to each other and the relationships that residents have with their communities at-large. Our findings may also help to explain how the intra- and inter-personal levels, the community/institutional level, and the macro level/public policy contexts can serve to influence health in these communities. For example, trauma and invisibility are not routinely examined in community health assessment and improvement planning activities; nonetheless, these factors appear to be at play affecting the health of residents.

"What Works" to Support LGBTQ+ Young People's Mental Health: An Intersectional Youth Rights Approach.

Despite overwhelming international evidence of elevated rates of poor mental health in LGBTQ+ youth compared to their cis-heterosexual peers, we know relatively little about effective mental health services for this population group. This study aims to produce the first early intervention model of "what works" to support LGBTQ+ youth with emerging mental health problems. Utilizing a mixed method case study, we collected data across 12 UK mental health service case study sites that involved: (a) interviews with young people, parents, and mental health practitioners (n = 93); (b) documentary analysis; (c) nonparticipant observation. The data analysis strategy was theoretical using the "explanation-building" analytical technique. Our analysis suggests an intersectional youth rights approach with 13 principles that must be enacted to provide good mental health services as advocated by the United Nations Convention on the Rights of the Child and World Health Organization. This approach should address the multiple forms of marginalization and stigmatization that LGBTQ+ youth may experience, enable informed independent decision-making, and uphold the right to freedom of safe self-expression. A rights-based approach to mental health services for LGBTQ+ young people is not prominent. This needs to change if we are to tackle this mental health inequality and improve the mental well-being of LGBTQ+ youth worldwide.

Respiratory Outcomes at 5-Year Follow-Up in Children with Mannose-Binding Lectin Deficiency: A Retrospective Cohort Study.

OBJECTIVE: Mannose-binding lectin deficiency may predispose children to having increased infection susceptibility. However, there is no conclusive evidence that mannose-binding lectin deficiency is associated with adverse respiratory consequences in children. We aimed to evaluate the effects of mannose-binding lectin deficiency (defined as a level of less than 0.6 mg/L) on clinical, radiological, and microbiological characteristics in children presenting with troublesome respiratory symptoms, as compared to those who are mannosebinding lectin-sufficient. MATERIAL AND METHODS: We conducted a retrospective cohort study to investigate the association between mannose-binding lectin deficiency and respiratory outcomes in children over a period of 10 years in a large teaching hospital. Children presenting with frequent or persistent respiratory symptoms such as a chronic wet cough lasting more than 4 weeks, recurrent lower respiratory tract infections (≥4 infections in a year), or severe respiratory tract infections requiring admission to intensive care or to high dependency unit were included in the study. RESULTS: The study showed no significant difference in clinical outcomes with mannose-binding lectin deficiency and sufficiency. Thirty-two percent of children with mannose-binding lectin deficiency and 30% of those with mannose-binding lectin sufficiency had positive respiratory microbiology. Twenty-three percent of children with mannose-binding lectin deficiency and 24% of those with mannose-binding lectin sufficiency had radiological changes on plain radiographs; also the prevalence of bronchiectasis was similar in both groups. The rates of admission to pediatric intensive care unit were comparable in the 2 groups. CONCLUSIONS: Children with mannose-binding lectin deficiency and sufficiency showed similar clinical, radiological, and microbiological characteristics. Our study suggests that there are no childhood adverse respiratory consequences with mannose-binding lectin deficiency.

Understanding How School-Based Interventions Can Tackle LGBTQ+ Youth Mental Health Inequality: A Realist Approach.

Globally, research indicates that LGBTQ+ young people have elevated rates of poor mental health in comparison with their cisgender heterosexual peers. The school environment is a major risk factor and is consistently associated with negative mental health outcomes for LGBTQ+ young people. The aim of this UK study was to develop a programme theory that explained how, why, for whom, and in what context school-based interventions prevent or reduce mental health problems in LGBTQ+ young people, through participation with key stakeholders. Online realist interviews were conducted in the UK with (1) LGBTQ+ young people aged between 13-18 years attending secondary schools (N = 10); (2) intervention practitioners (N = 9); and (3) school staff (N = 3). A realist retroductive data analysis strategy was employed to identify causal pathways across different interventions that improved mental health outcomes. The programme theory we produced explains how school-based interventions that directly tackle dominant cisgender and heterosexual norms can improve LGBTQ+ pupils' mental health. We found that context factors such as a 'whole-school approach' and 'collaborative leadership' were crucial to the delivery of successful interventions. Our theory posits three causal pathways that might improve mental health: (1) interventions that promote LGBTQ+ visibility and facilitate usualising, school belonging, and recognition; (2) interventions for talking and support that develop safety and coping; and (3) interventions that address institutional school culture (staff training and inclusion polices) that foster school belonging, empowerment, recognition, and safety. Our theoretical model suggests that providing a school environment that affirms and usualises LGBTQ+ identities and promotes school safety and belonging can improve mental health outcomes for LGBTQ+ pupils.

Development of cancer surveillance guidelines in ataxia telangiectasia: A Delphi-based consensus survey of international experts.

BACKGROUND/OBJECTIVES: Ataxia telangiectasia (A-T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A-T. We aimed to understand the current international practice regarding cancer surveillance in A-T and agreed-upon approaches to develop cancer surveillance in A-T. DESIGN/METHODS: We used a consensus development method, the e-Delphi technique, comprising three rounds. Round 1 consisted of a Delphi questionnaire and a survey that collected the details of respondents' professional background, experience, and current practice of cancer surveillance in A-T. Rounds 2 and 3 were designed based on previous rounds and modified according to the comments made by the panellists. The pre-specified consensus threshold was ≥75% agreement. RESULTS: Thirty-five expert panellists from 13 countries completed the study. The survey indicated that the current practice of cancer surveillance varies widely between experts and centres'. Consensus was reached that evidence-based guidelines are needed for cancer surveillance in people with A-T, with separate recommendations for adults and children. Statements relating to the tests that should be included, the age for starting and stopping cancer surveillance and the optimal surveillance interval were also agreed upon, although in some areas, the consensus was that further research is needed. CONCLUSION: The international expert consensus statement confirms the need for evidence-based cancer surveillance guidelines in A-T, highlights key features that the guidelines should include, and identifies areas of uncertainty in the expert community. This elucidates current knowledge gaps and will inform the design of future clinical trials.

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom.

BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.

Pathological healing response of explanted MitraClip devices.

BACKGROUND: The safety and effectiveness of the MitraClip device (Abbott Vascular, Menlo Park, CA) is being evaluated in the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) clinical studies. The healing response after device implantation has not previously been characterized in humans. METHODS AND RESULTS: A total of 67 explanted devices (implantation duration, 1 to 1878 days) from 50 patients were submitted for histological evaluation. Explants were analyzed in 4 implantation intervals: acute (≤30 days; n=7), subacute (31 to 90 days; n=23), chronic (91 to 300 days; n=18), and long term (>300 days; n=19). The acute healing response consisted of platelet/fibrin deposition. The subacute response exhibited granulation tissue with early fibrous encapsulation (pannus). The chronic response was characterized by various degrees of tissue bridging between the device arms. The long-term healing response demonstrated collagen-rich matrix (by type I collagen), incorporating the device components with complete encapsulation by organized, fibrous growth. In long-term devices with minimal surgical disruption, a fibrous tissue bridge (mean area, 7.39±4.3 mm(2)) was observed over and between the device arms, resulting in atrial tissue continuity between the 2 valve leaflets. Devices demonstrated no evidence of endocarditis, mechanical wear, component fracture, or corrosion up to the time of explantation (median, 119 days; first and third quartiles, 42 and 365 days). CONCLUSIONS: In all patients, device mechanical integrity was maintained up to the time of explantation. Four phases of physiological healing were observed: platelet and fibrin deposition, inflammation, granulation tissue, and finally, fibrous encapsulation. Long-term device fibrous encapsulation with extension over adjacent mitral leaflets and tissue bridge formation adds structural stability. Clinical Trial Registration- URL: http://clinicaltrials.gov/show/NCT00209274. Unique identifiers: NCT00209339 and NCT00209274.