Characteristics and Outcomes of Tracheostomized Patients With and Without COVID-19.

Outcomes of tracheostomized patients with COVID-19 are seldomly investigated with conflicting evidence from the existing literature. OBJECTIVES: To create a study evaluating the impact of COVID-19 on tracheostomized patients by comparing clinical outcomes and weaning parameters in COVID-19 positive and negative cohorts. DESIGN SETTING AND PARTICIPANTS: A retrospective observational cohort study of 604 tracheostomized patients hospitalized in 16 ICUs in New York City between March 9, 2020, and September 8, 2021. MAIN OUTCOMES AND MEASURES: Patients were stratified into two cohorts: 398 COVID-19 negative (COVID-ve) and 206 COVID-19 positive (COVID+ve) patients. Clinical characteristics, outcomes, and weaning parameters (first pressure support [PS], tracheostomy collar [TC], speech valve placement, and decannulation) were analyzed. RESULTS: COVID+ve had fewer comorbidities including coronary artery disease, congestive heart failure, malignancy, chronic kidney disease, liver disease, and HIV (p < 0.05). Higher Fio2 (53% vs 44%), positive end-expiratory pressure (PEEP) (7.15 vs 5.69), Pco2 (45.8 vs 38.2), and lower pH (7.41 vs 7.43) were observed at the time of tracheostomy in COVID+ve (p < 0.005). There was no statistical difference in post-tracheostomy complication rates. Longer time from intubation to tracheostomy (15.90 vs 13.60 d; p = 0.002), tracheostomy to first PS (2.87 vs 1.80 d; p = 0.005), and TC placement (11.07 vs 4.46 d; p < 0.001) were seen in COVID+ve. However, similar time to speech valve placement, decannulation, and significantly lower 1-year mortality (23.3% vs 36.7%; p = 0.001) with higher number of discharges to long-term acute care hospital (LTACH) (23.8% vs 13.6%; p = 0.015) were seen in COVID+ve. CONCLUSIONS AND RELEVANCE: Patients with COVID-19 required higher Fio2 and PEEP ventilatory support at the time of tracheostomy, with no observed change in complication rates. Despite longer initial weaning period with PS or TC, similar time to speech valve placement or decannulation with significantly lower mortality and higher LTACH discharges suggest favorable outcome in COVID-19 positive patients. Higher ventilatory support requirements and prolonged weaning should not be a deterrent to pursuing a tracheostomy.

Corrigendum: Rationale and Design of a Pharmacist-led Intervention for the Risk-Based Prevention of Heart Failure: The FIT-HF Pilot Study.

[This corrects the article DOI: 10.3389/fcvm.2021.785109.].

Rationale and Design of a Pharmacist-led Intervention for the Risk-Based Prevention of Heart Failure: The FIT-HF Pilot Study.

Background: Given rising morbidity, mortality, and costs due to heart failure (HF), new approaches for prevention are needed. A quantitative risk-based strategy, in line with established guidelines for atherosclerotic cardiovascular disease prevention, may efficiently select patients most likely to benefit from intensification of preventive care, but a risk-based strategy has not yet been applied to HF prevention. Methods and Results: The Feasibility of the Implementation of Tools for Heart Failure Risk Prediction (FIT-HF) pilot study will enroll 100 participants free of cardiovascular disease who receive primary care at a single integrated health system and have a 10-year predicted risk of HF of ≥5% based on the previously validated Pooled Cohort equations to Prevent Heart Failure. All participants will complete a health and lifestyle questionnaire and undergo cardiac biomarker (B-type natriuretic peptide [BNP] and high-sensitivity cardiac troponin I [hs-cTn]) and echocardiography screening at baseline and 1-year follow-up. Participants will be randomized 1:1 to either a pharmacist-led intervention or usual care for 1 year. Participants in the intervention arm will undergo consultation with a pharmacist operating under a collaborative practice agreement with a supervising cardiologist. The pharmacist will perform lifestyle counseling and recommend initiation or intensification of therapies to optimize risk factor (hypertension, diabetes, and cholesterol) management according to the most recent clinical practice guidelines. The primary outcome is change in BNP at 1-year, and secondary and exploratory outcomes include changes in hs-cTn, risk factor levels, and cardiac mechanics at follow-up. Feasibility will be examined by monitoring retention rates. Conclusions: The FIT-HF pilot study will offer insight into the feasibility of a strategy of quantitative risk-based enrollment into a pharmacist-led prevention program to reduce heart failure risk. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04684264.

Impact of Duration of N-Acetylcysteine in Non-Acetaminophen-Induced Acute Liver Failure.

OBJECTIVES: Studies of the use of IV N-acetylcysteine in the management of non-acetaminophen-induced acute liver failure have evaluated various dosing regimens. The only randomized trial studying this application described a 72-hour regimen. However, observational studies have reported extended duration until normalization of international normalized ratio. This study seeks to compare differences in patient outcomes based on IV N-acetylcysteine duration. DESIGN: Retrospective cohort study. SETTING: Medical ICU at a large quaternary care academic medical institution and liver transplant center. PATIENTS: Adult patients admitted to the medical ICU who received IV N-acetylcysteine for the treatment of non-acetaminophen-induced acute liver failure. INTERVENTIONS: Patients were divided into cohorts based on duration; standard duration of IV N-acetylcysteine was considered 72 hours, whereas extended duration was defined as continuation beyond 72 hours. MEASUREMENTS AND MAIN RESULTS: The primary outcome was time to normalization of international normalized ratio to less than 1.3 or less than 1.5; secondary outcomes included all-cause mortality and transplant-free survival at 3 weeks. In total, 53 patients were included: 40 in the standard duration cohort and 13 in the extended duration. There were no major differences in baseline characteristics. There was no significant difference in time to international normalized ratio normalization between cohorts. Transplant-free survival was higher with extended duration (76.9% extended vs 41.4% standard; p = 0.03). All-cause mortality at 3 weeks was numerically lower in the extended duration group (0% extended vs 24.1% standard; p = 0.08). CONCLUSIONS: Patients with non-acetaminophen-induced acute liver failure who received extended duration N-acetylcysteine were found to have significantly higher transplant-free survival than patients who received standard duration, although there was no significant difference in time to normalization of international normalized ratio or overall survival. Prospective, randomized, multicenter study is warranted to identify subpopulations of patients with non-acetaminophen-induced acute liver failure who could benefit from extended treatment duration as a bridge to transplant or spontaneous recovery.

A Psychometric Analysis of the Social Anxiety Scale for Adolescents Among Youth With Autism Spectrum Disorder: Caregiver-Adolescent Agreement, Factor Structure, and Validity.

Social anxiety is common among adolescents with autism spectrum disorder (ASD). An ongoing challenge for both research and clinical practice in ASD is the assessment of anxious symptomatology. Despite its widespread use in samples of youth with ASD, the Social Anxiety Scale for Adolescents (SAS-A) has not received psychometric evaluation within this population; thus, the validity of its use in research and clinical practice for ASD remains unclear. The present study conducted a psychometric analysis of caregiver and adolescent SAS-A forms in a sample of adolescents with ASD (N = 197). Results revealed (1) poor caregiver-adolescent item-level agreement, (2) a two-factor structure, (3) lack of measurement invariance between reporters, and (4) modest evidence for convergent and discriminant validity. Overall, findings suggest that this measure demonstrates reasonable psychometric properties in an ASD sample. Lack of measurement invariance, however, calls for careful interpretation of research involving the SAS-A in ASD samples, particularly when the primary goal is to compare adolescent and caregiver reports. The implications of these findings for future research and clinical practice are discussed.

Group Treatment of Fecal Incontinence: A Description of an Interdisciplinary Intervention.

INTRODUCTION: Approximately 5% of children in the United States have chronic fecal incontinence. Unfortunately, standard medical management of fecal incontinence fails in 20% to 60% of cases. A combined medical-behavioral model is often recommended in these cases. The purpose of this pilot study was to describe an interdisciplinary group-based treatment for fecal incontinence in school-aged children, and to present a description of changes in treatment adherence rates that affect clinical effectiveness. METHOD: Poop group employed a developmentally appropriate model of care in which caregivers and children participated in separate but simultaneously held therapy groups. This interdisciplinary 6-week protocol is designed to increase appropriate stooling, decrease soiling events, and increase medication adherence pre- to post-treatment. Group sessions focus on the GI system, medication, toilet sitting posture, hydration, fiber, and behavior contracts. In addition, participant families consult with an Advanced Nurse Practitioner privately at each session discussing symptoms and making medication modifications as needed. RESULTS: Nineteen families completed the 6-week protocol. Appropriate stool frequency was improved (P ≤ 0.01), and soiling was reduced (P ≤ 0.00). Medication adherence was also improved (P ≤ 0.04). Treatment results were maintained at 1-month follow-up. DISCUSSION: A developmentally targeted intervention and interdisciplinary focus of treatment likely account for treatment successes. CONCLUSION: Poop group may be an effective interdisciplinary treatment option for families of children who fail traditional outpatient treatment.

Social difficulties in youth with autism with and without anxiety and ADHD symptoms.

Social difficulties inherent to autism spectrum disorder are often linked with co-occurring symptoms of anxiety and attention deficit hyperactivity disorder (ADHD). The present study sought to examine the relation between such co-occurring symptoms and social challenges. Parents of adolescents with autism (N = 113) reported upon social challenges via the social responsiveness scale (SRS) and anxiety and ADHD symptomatology via the Child Behavior Checklist. Results revealed differences in SRS scores across co-occurring symptom subgroups (Anxiety, ADHD, Both, Neither)-namely, adolescents with autism and anxiety as well as those with autism, anxiety, and ADHD showed greater scores on the SRS than the other groups. Implications for research and clinical practice are discussed and recommendations are offered. Autism Research 2018, 11: 1679-1689. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Anxiety and attention deficit hyperactivity disorder (ADHD) symptoms are related to greater social challenges for adolescents with autism spectrum disorder. The present study found that autism with anxiety and autism with anxiety and ADHD, was related to greater social difficulties than autism alone. Findings provide further support for the intertwined nature of anxiety and ADHD symptoms in autism. What this may mean for research and clinical practice is considered and recommendations are suggested.

Behavioral inhibition and activation as a modifier process in autism spectrum disorder: Examination of self-reported BIS/BAS and alpha EEG asymmetry.

The Modifier Model of autism spectrum disorder (ASD) suggests that phenotypic variability within ASD is rooted in modifier processes, such as the behavioral inhibition system (BIS) and behavioral activation system (BAS). Among a sample of 53 adolescents with ASD, this study examined associations between (a) self-reported BIS/BAS and frontal and parietal alpha electroencephalogram asymmetry and whether these indices related to (b) ASD severity (via the Autism Quotient), and/or (c) co-occurring anxiety and attention-deficit hyperactivity disorder (via Youth Self Report and Child Behavior Checklist). Findings showed that alpha asymmetry was associated with self-reported BAS scores, such that greater BAS was related to greater right-frontal hemisphere activation and relatively greater left-parietal hemisphere activation. Additionally, associations emerged between ASD severity and self-reported BAS and alpha asymmetry, and between anxiety symptoms and self-reported BIS and alpha asymmetry. Furthermore, mediation analyses revealed that BAS mediated the association between asymmetry and autism severity. Therefore, alpha asymmetry and BIS/BAS activity may provide insight into how ASD presents in adolescence as well as who might be at greater risk for developing co-occurring psychopathologies. This study highlights the importance of considering motivational systems to elucidate individual differences among youth with ASD and working toward the longer term goal of better understanding differential responses to treatment. Autism Research 2018, 11: 1653-1666. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Differences in the likelihood to avoid (behavioral inhibition system; BIS) or approach (behavioral activation system; BAS) situations are thought to relate to patterns of brain activity (via electroencephalogram asymmetry asymmetry). This study revealed that these tendencies may influence the presentation of autism spectrum disorder (ASD) and symptoms of anxiety in adolescents with ASD.

Examining the Links Between Challenging Behaviors in Youth with ASD and Parental Stress, Mental Health, and Involvement: Applying an Adaptation of the Family Stress Model to Families of Youth with ASD.

Raising a child with autism spectrum disorder (ASD) poses unique challenges that may impact parents' mental health and parenting experiences. The current study analyzed self-report data from 77 parents of youth with ASD. A serial multiple mediation model revealed that parenting stress (SIPA) and parental mental health (BAI and BDI-II) appears to be impacted by challenging adolescent behaviors (SSIS-PBs) and, in turn, affect parental involvement (PRQ), controlling for social skills (SSIS-SSs). Further, the study explored the malleability of parents' mental health over the course of a social skills intervention, and provides modest evidence that parent depressive symptoms decline across intervention. This study illustrates the importance of considering the entire family system in research on youth with ASD.

Changes in Depressive Symptoms Among Adolescents with ASD Completing the PEERS® Social Skills Intervention.

Depression is a common concern among people with autism spectrum disorder (ASD) and is often associated with social skills and relationship challenges. The present data, from a randomized controlled trial, examined the effect of PEERS® on self-reported depressive symptoms via the Children's Depression Inventory (CDI) among 49 adolescents with ASD. Findings revealed that many CDI subscale scores declined (p's < 0.05) and were related to direct social contact on the Quality of Socialization Questionnaire at posttest (p's < 0.05). Exploratory analyses uncovered that suicidality was less evident following PEERS®. Findings support the notion that social functioning and depression may be intimately intertwined in ASD; therefore, bolstering social skills in ASD may positively influence other domains of functioning, including mental health.

Brief Report: Does Gender Matter in Intervention for ASD? Examining the Impact of the PEERS® Social Skills Intervention on Social Behavior Among Females with ASD.

A paucity of research has been conducted to examine the effect of social skills intervention on females with ASD. Females with ASD may have more difficulty developing meaningful friendships than males, as the social climate can be more complex (Archer, Coyne, Personality and Social Psychology Review 9(3):212-230, 2005). This study examined whether treatment response among females differed from males. One hundred and seventy-seven adolescents and young adults with ASD (N = 177) participated in this study. When analyzed by group, no significant differences by gender emerged: PEERS® knowledge (TASSK/TYASSK, p = .494), direct interactions (QSQ, p = .762), or social responsiveness (SRS, p = .689; SSIS-RS, p = .482). Thus, females and males with ASD respond similarly to the PEERS® intervention.

A Replication and Extension of the PEERS® for Young Adults Social Skills Intervention: Examining Effects on Social Skills and Social Anxiety in Young Adults with Autism Spectrum Disorder.

Young adults with ASD experience difficulties with social skills, empathy, loneliness, and social anxiety. One intervention, PEERS® for Young Adults, shows promise in addressing these challenges. The present study replicated and extended the original study by recruiting a larger sample (N = 56), employing a gold standard ASD assessment tool, and examining changes in social anxiety utilizing a randomized controlled trial design. Results indicated improvements in social responsiveness (SSIS-RS SS, p = .006 and CPB, p = .005; SRS, p = .004), PEERS® knowledge (TYASSK, p = .001), empathy (EQ, p = .044), direct interactions (QSQ-YA, p = .059), and social anxiety (LSAS-SR, p = .019). Findings demonstrate further empirical support for the intervention for individuals with ASD.

Brief Report: Assessment of Intervention Effects on In Vivo Peer Interactions in Adolescents with Autism Spectrum Disorder (ASD).

This study aimed to evaluate the effectiveness of a randomized controlled trial of a social skills intervention, the Program for the Education and Enrichment of Relational Skills (PEERS: Laugeson et al. in J Autism Dev Disord 39(4): 596-606, 2009), by coding digitally recorded social interactions between adolescent participants with ASD and a typically developing adolescent confederate. Adolescent participants engaged in a 10-min peer interaction at pre- and post-treatment. Interactions were coded using the Contextual Assessment of Social Skills (Ratto et al. in J Autism Dev Disord 41(9): 1277-1286, 2010). Participants who completed PEERS demonstrated significantly improved vocal expressiveness, as well as a trend toward improved overall quality of rapport, whereas participants in the waitlist group exhibited worse performance on these domains. The degree of this change was related to knowledge gained in PEERS.

Parent and family outcomes of PEERS: a social skills intervention for adolescents with autism spectrum disorder.

Raising a child with an autism spectrum disorder (ASD) is associated with increased family chaos and parent distress. Successful long-term treatment outcomes are dependent on healthy systemic functioning, but the family impact of treatment is rarely evaluated. The Program for the Education and Enrichment of Relational Skills (PEERS) is a social skills intervention designed for adolescents with high-functioning ASD. This study assessed the impact of PEERS on family chaos, parenting stress, and parenting self-efficacy via a randomized, controlled trial. Results suggested beneficial effects for the experimental group in the domain of family chaos compared to the waitlist control, while parents in the PEERS experimental group also demonstrated increased parenting self-efficacy. These findings highlight adjunctive family system benefits of PEERS intervention and suggest the need for overall better understanding of parent and family outcomes of ASD interventions.

Measuring the plasticity of social approach: a randomized controlled trial of the effects of the PEERS intervention on EEG asymmetry in adolescents with autism spectrum disorders.

This study examined whether the Program for the Education and Enrichment of Relational Skills (PEERS: Social skills for teenagers with developmental and autism spectrum disorders: The PEERS treatment manual, Routledge, New York, 2010a) affected neural function, via EEG asymmetry, in a randomized controlled trial of adolescents with Autism spectrum disorders (ASD) and a group of typically developing adolescents. Adolescents with ASD in PEERS shifted from right-hemisphere gamma-band EEG asymmetry before PEERS to left-hemisphere EEG asymmetry after PEERS, versus a waitlist ASD group. Left-hemisphere EEG asymmetry was associated with more social contacts and knowledge, and fewer symptoms of autism. Adolescents with ASD in PEERS no longer differed from typically developing adolescents in left-dominant EEG asymmetry at post-test. These findings are discussed via the Modifier Model of Autism (Mundy et al. in Res Pract Persons Severe Disabl 32(2):124, 2007), with emphasis on remediating isolation/withdrawal in ASD.

Electroencephalogram coherence in children with and without autism spectrum disorders: decreased interhemispheric connectivity in autism.

Electroencephalogram coherence was measured in children with autism spectrum disorders (ASD) and control children at baseline and while watching videos of a familiar and unfamiliar person reading a story. Coherence was measured between the left and right hemispheres of the frontal, parietal, and temporal-parietal lobes (interhemispheric) and between the frontal and parietal lobes in each hemisphere (intrahemispheric). A data-reduction technique was employed to identify the frequency (alpha) that yielded significant differences in video conditions. Children with ASD displayed reduced coherence at the alpha frequency between the left and right temporal-parietal lobes in all conditions and reduced coherence at the alpha frequency between left and right frontal lobes during baseline. No group differences in intrahemispheric coherence at the alpha frequency emerged at the chosen statistical threshold. Results suggest decreased interhemispheric connectivity in frontal and temporal-parietal regions in children with ASD compared to controls.

A replication and extension of the PEERS intervention: examining effects on social skills and social anxiety in adolescents with autism spectrum disorders.

This study aimed to evaluate the Program for the Education and Enrichment of Relational Skills (PEERS: Laugeson et al. in J Autism Dev Disord 39(4):596-606, 2009). PEERS focuses on improving friendship quality and social skills among adolescents with higher-functioning ASD. 58 participants aged 11-16 years-old were randomly assigned to either an immediate treatment or waitlist comparison group. Results revealed, in comparison to the waitlist group, that the experimental treatment group significantly improved their knowledge of PEERS concepts and friendship skills, increased in their amount of get-togethers, and decreased in their levels of social anxiety, core autistic symptoms, and problem behaviors from pre-to post-PEERS. This study provides the first independent replication and extension of the empirically-supported PEERS social skills intervention for adolescents with ASD.

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486.

Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO mouse displays phenotypes similar to symptoms in the human condition--including hyperactivity, repetitive behaviors, and seizures--as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor--which we call FRAX486--also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.

Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132.

MicroRNAs (miRNAs) are noncoding RNAs that suppress translation of specific mRNAs. The miRNA machinery interacts with fragile X mental retardation protein (FMRP), which functions as translational repressor. We show that miR-125b and miR-132, as well as several other miRNAs, are associated with FMRP in mouse brain. miR-125b and miR-132 had largely opposing effects on dendritic spine morphology and synaptic physiology in hippocampal neurons. FMRP knockdown ameliorates the effect of miRNA overexpression on spine morphology. We identified NMDA receptor subunit NR2A as a target of miR-125b and show that NR2A mRNA is specifically associated with FMRP in brain. In hippocampal neurons, NR2A expression is negatively regulated through its 3' UTR by FMRP, miR-125b, and Argonaute 1. Regulation of NR2A 3'UTR by FMRP depends in part on miR-125b. Because NMDA receptor subunit composition profoundly affects synaptic plasticity, these observations have implications for the pathophysiology of fragile X syndrome, in which plasticity is altered.

Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice.

Fragile X syndrome (FXS), the most commonly inherited form of mental retardation and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene and consequent loss of the fragile X mental retardation protein. Despite growing evidence suggesting a role of specific receptors and biochemical pathways in FXS pathogenesis, an effective therapeutic method has not been developed. Here, we report that abnormalities in FMR1 knockout (KO) mice, an animal model of FXS, are ameliorated, at least partially, at both cellular and behavioral levels, by an inhibition of the catalytic activity of p21-activated kinase (PAK), a kinase known to play a critical role in actin polymerization and dendritic spine morphogenesis. Greater spine density and elongated spines in the cortex, morphological synaptic abnormalities commonly observed in FXS, are at least partially restored by postnatal expression of a dominant negative (dn) PAK transgene in the forebrain. Likewise, the deficit in cortical long-term potentiation observed in FMR1 KO mice is fully restored by the dnPAK transgene. Several behavioral abnormalities associated with FMR1 KO mice, including those in locomotor activity, stereotypy, anxiety, and trace fear conditioning are also ameliorated, partially or fully, by the dnPAK transgene. Finally, we demonstrate a direct interaction between PAK and fragile X mental retardation protein in vitro. Overall, our results demonstrate the genetic rescue of phenotypes in a FXS mouse model and suggest that the PAK signaling pathway, including the catalytic activity of PAK, is a novel intervention site for development of an FXS and autism therapy.