NLRP3 and AIM2 inflammasomes expression is modified by LPS and titanium ions increasing the release of active IL-1ß in alveolar bone-derived MSCs.

Periodontitis and peri-implantitis are inflammatory diseases of infectious etiology that lead to the destruction of the supporting tissues located around teeth or implants. Although both pathologies share several characteristics, it is also known that they show important differences which could be due to the release of particles and metal ions from the implant surface. The activation of the inflammasome pathway is one of the main triggers of the inflammatory process. The inflammatory process in patients who suffer periodontitis or peri-implantitis has been mainly studied on cells of the immune system; however, it is also important to consider other cell types with high relevance in the regulation of the inflammatory response. In that context, mesenchymal stromal cells (MSCs) play an essential role in the regulation of inflammation due to their ability to modulate the immune response. This study shows that the induction of NLRP3 and absent in melanoma 2 (AIM2) inflammasome pathways mediated by bacterial components increases the secretion of active IL-1ß and the pyroptotic process on human alveolar bone-derived mesenchymal stromal cells (hABSCs). Interestingly, when bacterial components are combined with titanium ions, NLRP3 expression is further increased while AIM2 expression is reduced. Furthermore, decrease of NLRP3 or AIM2 expression in hABSCs partially reverses the negative effect observed on the progression of the inflammatory process as well as on cell survival. In summary, our data suggest that the progression of the inflammatory process in peri-implantitis could be more acute due to the combined action of organic and inorganic components.

Impact of trauma exposure and depression comorbidity on response to transdiagnostic behavioral therapy for pediatric anxiety and depression.

By adolescence, two-thirds of youth report exposure to at least one traumatic event, yet the impact of trauma history is not routinely considered when evaluating the effect of psychotherapeutic interventions. Trauma may be a particularly important moderator of the effects of transdiagnostic therapies for emotional disorders, as trauma exposure is associated with risk for the development of comorbid depression and anxiety. The current study examined the history of trauma exposure and the presence of clinically significant depression as moderators of treatment outcomes in the Brief Behavioral Therapy (BBT) trial, the largest study of transdiagnostic psychotherapy for youth. Youths (age 8-16 years) were randomized to BBT (n = 89) based in pediatric primary care or assisted referral to outpatient community care (ARC; n = 86). Clinical response, functioning, anxiety symptoms, and depression symptoms were assessed at post-treatment (Week 16) and at follow-up (Week 32). A significant three-way interaction emerged between the treatment group, comorbid depression, and trauma exposure. BBT was broadly effective for 3/4 of the sample, but, for anxious-depressed youth with trauma exposure, BBT never significantly separated from ARC. Differences in outcome were not accounted for by other participant characteristics or by therapist-rated measures of alliance, youth engagement, or homework completion. Implications for models of learning and for intervention theory and development are discussed.

Autonomic reactivity during acute social stress: exploratory investigation of an interaction by threat interpretation bias and emotion regulation difficulties.

Objective: This preliminary study examined the interactive influences of interpretation bias and emotion dysregulation in predicting autonomic stress response.Methods: Participants (N = 72 college students; ages 18-25, 70% female, 47% Hispanic/Latinx), completed a performance-based assessment of threat interpretation bias and self-report measures of emotion regulation difficulties. Electrodermal activity (EDA; skin conductance level) was collected while participants completed a standardized psychosocial stressor task.Results: Interpretation bias and emotion regulation difficulties interacted to predict EDA trajectories (ß = 0.054, SE = .001, CI:.007, .002, p < .001) during acute stress: presence of either interpretation bias toward threat (ß = 6.950, SE = 2.826, CI: 1.407, 12.488, p = .013) or emotion regulation difficulties (ß = 9.387, SE = 3.685, CI: 2.141, 16.636, p = .011) was associated with greater reactivity and poorer recovery; presence of both was associated with the lowest resting state EDA and blunted reactivity (ß = 1.340, SE = 3.085, CI: -4.721, 7.407, p = .66).Conclusions: Preliminary findings support interpretation bias and emotion regulation difficulties, and their distinct interactive patterns, as predictors of autonomic reactivity trajectories during stress. Interpretation bias modification and emotion regulation skills may be important intervention targets for common psychological conditions that are influenced by aberrant psychophysiological processes.

Early indicators of response to transdiagnostic treatment of pediatric anxiety and depression.

BACKGROUND: Pediatric anxiety and depression are prevalent, impairing, and highly comorbid. Available evidence-based treatments have an average response rate of 60%. One path to increasing response may be to identify likely non-responders midway through treatment to adjust course prior to completing an episode of care. The aims of this study, thus, were to identify predictors of post-intervention response assessing (a) mid-treatment symptom severity, (b) session-by-session treatment process factors, and (c) a model optimizing the combination of these. METHOD: Data were drawn from the treatment arm (N = 95, ages 8-16) of a randomized transdiagnostic intervention trial (Msessions = 11.2). Mid-point measures of youth- and parent-reported anxiety and depression were collected, and therapists rated homework completion, youth and parent engagement, and youth therapeutic alliance at each session. Logistic regression was used to predict response on the Clinical Global Impression Improvement Scale (CGI-I ≤2) rated by independent evaluators masked to treatment condition. RESULTS: Mid-point symptom measures were significant predictors of treatment response, as were therapist-ratings of youth and parent engagement, therapeutic alliance, and homework completion. Therapist ratings were significant when tested as mean ratings summing across the first eight sessions of treatment (all ps < .004) and at individual session points (all ps <0.05). A combined prediction model included youth-reported anxiety, parent-reported depression, youth engagement at Session 2, and parent engagement at Session 8. This model correctly classified 76.5% of youth as non-responders and 91.3% as responders at post-treatment (Nagelkerke R2 = .59, χ2 (4, 80) = 46.54, p < .001). CONCLUSION: This study provides initial evidence that response to transdiagnostic intervention for pediatric anxiety and depression may be reliably predicted by mid-point. These data may serve as foundational evidence to develop adaptive treatment strategies to personalize intervention, correct treatment course, and optimize outcomes for youth with anxiety and depression.

Characterization of 554 Mexican Patients With Nonsyndromic Cleft Lip and Palate: Descriptive Study.

Orofacial clefts are one of the most common birth defects and the most common craniofacial malformation worldwide. The most common orofacial clefts (OFCs) are congenital cleft lip with or without cleft palate (CL ± P) and isolated cleft palate (CP). The incidence of OFCs varies depending on region and ethnicity; however, it affects approximately 1 in 600 newborns worldwide. In most cases, CL ± P and CP are multifactorial congenital malformations, where both exogenous and genetic factors play an important role. The objective of this study was to describe the frequency of potential risk factors associated with the development of CL ± P and CP in Mexican population. Patients were referred for multisystemic treatment, from private and public institutions in different regions of the country (center, north, and south). Sociodemographic information, prenatal and parental history were obtained through direct interviews with the patients or the patients' mothers in the case of underaged patients. Referred patients were invited to participate in the study. No interventions were applied for this study. The relationship between these factors and the prevalence of CL ± P and CP was studied. A total of 554 patients were included, the majority with CLP (30% to 7%), statistically significant differences were found for folic acid ( P = 0.02) consumption. Familial aggregation did not reach statistical significance for first-degree family members ( P = 0.34) but was significant for second-degree family members ( P = 0.007). More risk factors associated with CL ± P and CP may still be unknown, prompting more epidemiological research and research in other little-studied areas, such as; specific genetic factors in Mexican population.

Lentiviral vectors for inducible, transactivator-free advanced therapy medicinal products: Application to CAR-T cells.

Controlling transgene expression through an externally administered inductor is envisioned as a potent strategy to improve safety and efficacy of gene therapy approaches. Generally, inducible ON systems require a chimeric transcription factor (transactivator) that becomes activated by an inductor, which is not optimal for clinical translation due to their toxicity. We generated previously the first all-in-one, transactivator-free, doxycycline (Dox)-responsive (Lent-On-Plus or LOP) lentiviral vectors (LVs) able to control transgene expression in human stem cells. Here, we have generated new versions of the LOP LVs and have analyzed their applicability for the generation of inducible advanced therapy medicinal products (ATMPs) with special focus on primary human T cells. We have shown that, contrary to all other cell types analyzed, an Is2 insulator must be inserted into the 3' long terminal repeat of the LOP LVs in order to control transgene expression in human primary T cells. Importantly, inducible primary T cells generated by the LOPIs2 LVs are responsive to ultralow doses of Dox and have no changes in phenotype or function compared with untransduced T cells. We validated the LOPIs2 system by generating inducible CAR-T cells that selectively kill CD19+ cells in the presence of Dox. In summary, we describe here the first transactivator-free, all-one-one system capable of generating Dox-inducible ATMPs.

Reduction in avoidance mediates effects of brief behavioral therapy for pediatric anxiety and depression.

Brief behavioral therapy (BBT) is an efficacious transdiagnostic intervention for pediatric anxiety and depression that targets behavioral avoidance as a key mechanism. It is unknown if change in avoidance mediates treatment effects, as theorized. Data on avoidance at baseline and Week 16 were available on 52 youth (ages 8-16 years) from a randomized controlled trial (Weersing, Jeffreys, et al., 2017) comparing BBT and assisted referral to community care (ARC). BBT had significant effects on youth-reported behavioral avoidance, and significant indirect effects on functioning and anxiety, statistically mediated through changes in youth-reported behavioral avoidance. Change in youth-reported avoidance was not a significant mediator of depression. Parent-report of avoidance was not impacted by treatment and was not a significant mediator. Overall, BBT appears to be an effective treatment for targeting behavioral avoidance, which in turn, may improve functioning and lessen anxiety. CLINICAL TRIAL REGISTRATION INFORMATION: https://clinicaltrials.gov; NCT01147614.

Patient-reported symptoms at discharge and risk of complications after gynecologic surgery.

OBJECTIVE: Current gaps in knowledge limit clinicians from fully implementing patient-reported outcomes in routine post-operative care. METHODS: This prospective study assessed symptoms via the gynecologic module of the MD Anderson Symptom Inventory (MDASI-PeriOp-GYN) in patients who underwent open laparotomy. RESULTS: At discharge, patient-reported moderate to severe (≥4 on a 0-10 scale) abdominal bloating or abdominal cramping, combined with length of stay of ≥4 days, were found to be associated with a higher risk of 30-day post-operative grade II-IV complications by the Clavien-Dindo system (all p values <0.01). Also, length of stay of ≥4 days and moderate to severe urinary urgency at discharge were found to be associated with the need for re-admission (all p values <0.01). CONCLUSION: This study defined the clinically meaningful symptoms that related to the risk of developing important complications after discharge from major open gynecological surgery.These findings support the integration of assessment of patient-reported outcomes into patient-centered post-operative care.

Brief Behavioral Therapy for Anxiety and Depression in Pediatric Primary Care: Breadth of Intervention Impact.

OBJECTIVE: To report on broad-based outcomes of the Brief Behavioral Therapy (BBT) trial for pediatric anxiety and depression. Secondary data analyses expand on previous reports by assessing diagnostic remission and independent functioning, impact on targeted psychopathology, and spillover effects on non-targeted outcomes. METHOD: Youth (N = 185; 8-16.9 years; 58% female; 78% White; 21% Hispanic) with anxiety and/or depression were eligible for this multi-site trial. Enrolled youth were randomly assigned to receive 8 to 12 sessions of BBT in primary care or assisted referral to outpatient care (ARC). Assessments were conducted 16 and 32 weeks post randomization. RESULTS: BBT was superior to ARC on remission of all targeted diagnoses (week 16: 56.8% vs 28.2%, p < .001; week 32: 62.5% vs 38.9%, p = .004), clinician-rated independent functioning (week 16: 75.0% vs 45.7%, p < .001; week 32: 81.2% vs 55.7%, p < .001), and on measures of anxiety, depression, suicide items, total comorbid behavioral and emotional problems, and hyperactivity (d = 0.21-0.49). Moderation analyses revealed superior outcomes for Hispanic youth in BBT vs ARC for diagnostic remission, anxiety, emotional problems, and parent-child conflict. Youth depression at baseline moderated effects on peer problems and parent-child conflict, with effects favoring BBT. Significant main and moderated effects of BBT on change in non-targeted outcomes were largely mediated by change in anxiety (24.2%-49.3% of total effects mediated). CONCLUSION: BBT has positive effects on youth, mediated by the strong impact of the intervention on anxiety. Analyses continue to support positive outcomes for Hispanic youth, suggesting that BBT is a broadly effective transdiagnostic treatment option for diverse populations. CLINICAL TRIAL REGISTRATION INFORMATION: Brief Cognitive Behavioral Therapy (CBT) for Pediatric Anxiety and Depression in Primary Care; https://clinicaltrials.gov; NCT01147614.

Developmental trajectories of internalizing distress among ethnic minoritized mothers following childbirth: Associations with early child psychological adjustment.

A substantial body of work has established that mothers' internalizing distress can negatively affect children's socioemotional development. Yet few studies have examined how distinct patterns of mothers' distress over time differentially impact child behaviors across early childhood. To address this gap, the current study explored developmental trajectories of mothers' internalizing distress and examined the associations of these patterns with child adjustment outcomes. Mexican immigrant, Dominican immigrant, and African American mothers (N = 272) were annually assessed for internalizing distress over the first 6 years following childbirth. Children's psychological adjustment (internalizing, externalizing, and hyperactivity behaviors) was measured at the last yearly assessment in first grade. A growth mixture model revealed two distinct classes of distress where mothers were classified as having low stable distress (82.4%) or moderate distress that began as stable then declined when their children were 64 months old (17.6%). Children of mothers in the moderate, late decline class showed greater internalizing, externalizing, and hyperactivity behaviors in the first grade compared to children of mothers in the low stable class. Findings highlight the necessity of supporting the mental health of ethnic minoritized mothers following childbirth and further expand our knowledge of family psychopathology to promote healthy psychological adjustment in children.

Phenotypical categorization of indigenous ewes as resistant, resilient or susceptible to Haemonchus contortus.

The economic losses caused by parasite infections, aggravated by resistance to anthelmintics, have generated demand for alternatives involving non-chemical control, such as the selection of resistant animals. The objective of this study was to identify which characteristics best describe animals that are resistant, resilient or susceptible to Haemonchus contortus and estimate the percent number in each category. Sixty-one Morada Nova ewes were evaluated in an extensive system. The performance variables (weight, body condition score), hematological variables (packed cell volume, hemoglobin, white blood cells, segmented neutrophils, lymphocytes, eosinophils, monocytes) and fecal egg counts were measured individually every 14 days during 6 months. The variables were transformed, and analysis of variance was carried out, with construction of a correlation network. Characteristics linked to parasite infection showed variations among the categories, which helped to identify sheep resistant, resilient or susceptible to H. contortus. Based on the analyses performed, 88.3% of the animals were resistant or resilient and only 11.7% were susceptible. Presence of Trichostrongylidae eggs, body condition score, packed cell volume (PCV) and eosinophil counts were found to be good indicators of naturally infected ewes, and there were significant differences between the categories and correlations between the traits.

Promoting Racial/Ethnic Equity in Psychosocial Treatment Outcomes for Child and Adolescent Anxiety and Depression.

Anxiety and depression are the most prevalent and least treated pediatric mental health problems. Racial/ethnic minority youths face greater risks for developing anxiety and depression and experience higher burden as they are less likely to receive adequate mental health services for these conditions or to have their needs met. Further, standard evidence-based interventions for youth anxiety and depression may show diminished effects with racial/ethnic minority youths and with families of lower socioeconomic status. While community-level interventions to combat structural racism and reduce population-level risk are sorely needed, many youths will continue to require acute treatment services for anxiety and depression and interventionists must understand how to bring equity to the forefront of care. In this review, we adopt a health system framework to examine racial/ethnic disparities in system-, intervention-, provider-, and patient-level factors for psychosocial treatment of pediatric anxiety and depression. Current evidence on disparities in access and in efficacy of psychosocial intervention for anxious and depressed youths is summarized, and we use our work in primary care as a case example of adapting an intervention to mitigate disparities and increase equity. We conclude with recommendations for disparity action targets at each level of the health system framework and provide example strategies for intervening on these mechanisms to improve the outcomes of racial/ethnic minority youths.

Resting State Psychophysiology in Youth with OCD and Their Caregivers: Preliminary Evidence for Trend Synchrony and Links to Family Functioning.

The burden of OCD in children and adolescents extends to their caregivers. Prior work in other disorders and unaffected youth has found synchrony in psychophysiological arousal for youth-caregiver dyads. This preliminary study explored whether psychophysiological trend synchrony in youth-caregiver dyads (N = 48) occurred and was moderated by youth OCD diagnosis. We also explored whether psychophysiological indices (i.e., electrodermal activity, heart rate, respiratory sinus arrhythmia) were correlated with reported family functioning in the OCD subsample (n = 25). Youth with OCD had higher resting heart rate than unaffected peers; this was not replicated in caregivers. Trend synchrony was found across the full sample of dyads for electrodermal activity and heart rate, with no moderation by diagnostic group. In the OCD group, youth heart rate was correlated with family conflict and caregiver heart rate with expressiveness. Findings provide preliminary support for further examination of heart rate and family factors in OCD-affected youth and their caregivers.

Use of failure-to-rescue after emergency surgery as a dynamic indicator of hospital resilience during the COVID-19 pandemic. A multicenter retrospective propensity score-matched cohort study.

BACKGROUND: Surgical failure-to-rescue (FTR, death rate following complications) is a reliable cross-sectional quality of care marker, but has not been evaluated dynamically. We aimed to study changes in FTR following emergency surgery during the COVID-19 pandemic. MATERIAL AND METHODS: Matched cohort study including all COVID-19-non-infected adult patients undergoing emergency general surgery in 25 Spanish hospitals during COVID-19 pandemic peak (March-April 2020), non-peak (May-June 2020), and 2019 control periods. A propensity score-matched comparative analysis was conducted using a logistic regression model, in which period was regressed on observed baseline characteristics. Subsequently, a mixed effects logistic regression model was constructed for each variable of interest. Main variable was FTR. Secondary variables were post-operative complications, readmissions, reinterventions, and length of stay. RESULTS: 5003 patients were included (948, 1108, and 2947 in the pandemic peak, non-peak, and control periods), with comparable clinical characteristics, prognostic scores, complications, reintervention, rehospitalization rates, and length of stay across periods. FTR was greater during the pandemic peak than during non-peak and pre-pandemic periods (22.5% vs. 17.2% and 12.7%), being this difference confirmed in adjusted analysis (odds ratio [OR] 2.13, 95% confidence interval [95% CI] 1.27-3.66). There was sensible inter-hospital variability in FTR changes during the pandemic peak (median FTR change +8.77%, IQR 0-29.17%) not observed during the pandemic non-peak period (median FTR change 0%, IQR -6.01-6.72%). Greater FTR increase was associated with higher COVID-19 incidence (OR 2.31, 95% CI 1.31-4.16) and some hospital characteristics, including tertiary level (OR 3.07, 95% CI 1.27-8.00), medium-volume (OR 2.79, 95% CI 1.14-7.34), and high basal-adjusted complication risk (OR 2.21, 95% CI 1.07-4.72). CONCLUSION: FTR following emergency surgery experienced a heterogeneous increase during different periods of the COVID-19 pandemic, suggesting it to behave as an indicator of hospital resilience. FTR monitoring could facilitate identification of centres in special needs during ongoing health care challenges.

Erratum: Physiological lentiviral vectors for the generation of improved CAR-T cells.

[This corrects the article DOI: 10.1016/j.omto.2022.05.003.].

Physiological lentiviral vectors for the generation of improved CAR-T cells.

Anti-CD19 chimeric antigen receptor (CAR)-T cells have achieved impressive outcomes for the treatment of relapsed and refractory B-lineage neoplasms. However, important limitations still remain due to severe adverse events (i.e., cytokine release syndrome and neuroinflammation) and relapse of 40%-50% of the treated patients. Most CAR-T cells are generated using retroviral vectors with strong promoters that lead to high CAR expression levels, tonic signaling, premature exhaustion, and overstimulation, reducing efficacy and increasing side effects. Here, we show that lentiviral vectors (LVs) expressing the transgene through a WAS gene promoter (AW-LVs) closely mimic the T cell receptor (TCR)/CD3 expression kinetic upon stimulation. These AW-LVs can generate improved CAR-T cells as a consequence of their moderate and TCR-like expression profile. Compared with CAR-T cells generated with human elongation factor α (EF1α)-driven-LVs, AW-CAR-T cells exhibited lower tonic signaling, higher proportion of naive and stem cell memory T cells, less exhausted phenotype, and milder secretion of tumor necrosis factor alpha (TNF-α) and interferon (IFN)-É£ after efficient destruction of CD19+ lymphoma cells, both in vitro and in vivo. Moreover, we also showed their improved efficiency using an in vitro CD19+ pancreatic tumor model. We finally demonstrated the feasibility of large-scale manufacturing of AW-CAR-T cells in guanosine monophosphate (GMP)-like conditions. Based on these data, we propose the use of AW-LVs for the generation of improved CAR-T products.

Isogenic GAA-KO Murine Muscle Cell Lines Mimicking Severe Pompe Mutations as Preclinical Models for the Screening of Potential Gene Therapy Strategies.

Pompe disease (PD) is a rare disorder caused by mutations in the acid alpha-glucosidase (GAA) gene. Most gene therapies (GT) partially rely on the cross-correction of unmodified cells through the uptake of the GAA enzyme secreted by corrected cells. In the present study, we generated isogenic murine GAA-KO cell lines resembling severe mutations from Pompe patients. All of the generated GAA-KO cells lacked GAA activity and presented an increased autophagy and increased glycogen content by means of myotube differentiation as well as the downregulation of mannose 6-phosphate receptors (CI-MPRs), validating them as models for PD. Additionally, different chimeric murine GAA proteins (IFG, IFLG and 2G) were designed with the aim to improve their therapeutic activity. Phenotypic rescue analyses using lentiviral vectors point to IFG chimera as the best candidate in restoring GAA activity, normalising the autophagic marker p62 and surface levels of CI-MPRs. Interestingly, in vivo administration of liver-directed AAVs expressing the chimeras further confirmed the good behaviour of IFG, achieving cross-correction in heart tissue. In summary, we generated different isogenic murine muscle cell lines mimicking the severe PD phenotype, as well as validating their applicability as preclinical models in order to reduce animal experimentation.

Upfront surgery versus self-expanding metallic stent as bridge to surgery in left-sided colonic cancer obstruction: A multicenter observational study.

BACKGROUND: Oncological outcomes of self-expanding metallic stent used as a bridge to surgery in potential curative patients with left-sided colonic cancer obstruction remain unclear. The aim of this study was to investigate perioperative and mid-term oncological outcomes of 2 of the currently most commonly performed treatments in left-sided colonic cancer obstruction. METHODS: This is a retrospective multicenter study including patients with left-sided colonic cancer obstruction treated with curative intent between 2013 and 2017. The presence of metastasis at diagnosis was an exclusion criterion. The primary outcome was to evaluate the noninferiority, in terms of overall survival, of bridge to surgery strategy compared with emergency colonic resection. The secondary outcomes were perioperative morbimortality, disease free survival, local recurrence, and distant recurrence. RESULTS: A total of 564 patients were included, 320 in the emergency colonic resection group and 244 in the bridge to surgery group. Twenty-seven patients of the bridge-to-surgery group needed urgent operation. Postoperative morbidity rates were statistically higher in the emergency colonic resection group (odds ratio [95% confidence interval] 0.37 [0.24-0.55], P < .001). There was no difference in 90-day mortality between groups (odds ratio [95% confidence interval] 0.85 [0.36-1.99], P = .702). The median follow-up was 3.80 years (2.29-4.92). The results show the noninferiority of bridge to surgery versus emergency colonic resection in terms of overall survival (hazard ratio [95% confidence interval) 0.78 [0.56-1.07], P = .127). There were no differences in disease free survival, distant recurrence, and local recurrence rates between bridge to surgery and emergency colonic resection groups. CONCLUSION: Self-expanding metallic stent as bridge to surgery might not lead to a negative impact on the long-term prognosis of the tumor compared with emergency colonic resection in expert hands and selected patients.