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Introduction: We report caregiver agreement to attend telehealth neurodevelopmental consultation during COVID-19, demographic differences in agreement, reasons families declined, and clinical access metrics before and during COVID-19., Method: Data were gathered from telehealth referrals and consultations from April to July 2020. Schedulers documented agreement status and reasons for the decline. Wait time, lag time, and missed appointment rates were calculated to measure access., Results: Ninety-one percent agreed to attend telehealth consultation; 55% of those who declined preferred in-person services. There were no demographic differences between those who accepted, declined, or did not respond. The median wait time from referral to appointment was 60 days. Missed appointment rates were consistent with prepandemic rates., Discussion: Findings support literature suggesting patients are agreeable to telehealth. They diverged from evidence suggesting telehealth reduces missed appointments. Overall, results indicate telehealth is an acceptable alternative; however, further telehealth innovation is needed to address existing disparities., (Copyright © 2022 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

The present study examines provider and caregiver satisfaction with telehealth evaluation of autism spectrum disorder (ASD) in young children during the coronavirus SARS-CoV-2 (COVID-19) pandemic. A telehealth model of ASD evaluation was implemented with 308 children ages 14 to 78 months between May 2020 to June 2021. Data were gathered from electronic health records, autism-specific telehealth diagnostic tools, and post-evaluation surveys. Overall, the majority of providers and caregivers were satisfied with telehealth ASD evaluation. Multiple variables were associated with ratings of satisfaction, differing by providers and caregivers. Findings have important implications for the feasibility and acceptability of telehealth ASD evaluations, in addition to key factors to consider in optimizing and sustaining telehealth evaluations beyond the COVID-19 pandemic., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A growing body of research suggests that locus coeruleus-norepinephrine (LC-NE) system may function differently in individuals with autism spectrum disorder (ASD). Understanding the dynamics of both tonic (resting pupil diameter) and phasic (pupil dilation response [PDR] and event-related potential [ERP]) indices may provide meaningful insights about the nature of LC-NE function in ASD. Twenty-four children with ASD and 27 age- and nonverbal-IQ matched typically developing (TD) children completed two experiments: (1) a resting eye-tracking task to measure tonic pupil diameter, and (2) a three-stimulus oddball paradigm to measure phasic responsivity using PDR and ERP. Consistent with prior reports, our results indicate that children with ASD exhibit increased tonic (resting pupil diameter) and reduced phasic (PDR and ERP) activity of the LC-NE system compared to their TD peers. For both groups, decreased phasic responsivity was associated with increased resting pupil diameter. Lastly, tonic and phasic LC-NE indices were primarily related to measures of attention-deficit/hyperactivity disorder (ADHD), and not ASD, symptomatology. These findings expand our understanding of neurophysiological differences present in ASD and demonstrate that aberrant LC-NE activation may be associated with atypical arousal and decreased responsivity to behaviorally-relevant information in ASD., (© 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Mechanical signals, such as those evoked by maximal-intensity contractions (MICs), can induce an increase in muscle mass. Rapamycin-sensitive signaling events are widely implicated in the regulation of this process; however, recent studies indicate that rapamycin-insensitive signaling events are also involved. Thus, to identify these events, we generate a map of the MIC-regulated and rapamycin-sensitive phosphoproteome. In total, we quantify more than 10,000 unique phosphorylation sites and find that more than 2,000 of these sites are significantly affected by MICs, but remarkably, only 38 of the MIC-regulated events are mediated through a rapamycin-sensitive mechanism. Further interrogation of the rapamycin-insensitive phosphorylation events identifies the S473 residue on Tripartite Motif-Containing 28 (TRIM28) as one of the most robust MIC-regulated phosphorylation sites, and extensive follow-up studies suggest that TRIM28 significantly contributes to the homeostatic regulation of muscle size and function as well as the hypertrophy that occurs in response to increased mechanical loading., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Given new clinical recommendations, we sought to better understand the perspectives and practices of primary care providers (PCPs) around pediatric academic concerns. Practicing PCPs were recruited to complete an 8-item self-report survey; 163 PCPs were included in the final analysis. Results indicated that 84% of PCPs perceived their role in addressing patients' academic concerns as highly important; yet there was variability in the frequency with which PCPs reported engaging in activities around these educational needs. There was a significant positive relationship between perception of role importance and engagement in clinical supports. Some differences were present in responses across PCP specialty area. More information about practice differences between provider types, rural versus urban practices, and how perceptions/practices differ based on provider demographics are likely to be useful areas for future consideration. Our findings highlight the need to advance PCP instruction for practical implementation to increase rates of engagement in these activities.

It is well known that an increase in mechanical loading can induce skeletal muscle hypertrophy, and a long standing model in the field indicates that mechanical loads induce hypertrophy via a mechanism that requires signaling through the mechanistic target of rapamycin complex 1 (mTORC1). Specifically, it has been widely proposed that mechanical loads activate signaling through mTORC1 and that this, in turn, promotes an increase in the rate of protein synthesis and the subsequent hypertrophic response. However, this model is based on a number of important assumptions that have not been rigorously tested. In this study, we created skeletal muscle specific and inducible raptor knockout mice to eliminate signaling by mTORC1, and with these mice we were able to directly demonstrate that mechanical stimuli can activate signaling by mTORC1, and that mTORC1 is necessary for mechanical load-induced hypertrophy. Surprisingly, however, we also obtained multiple lines of evidence that indicate that mTORC1 is not required for a mechanical load-induced increase in the rate of protein synthesis. This observation highlights an important shortcoming in our understanding of how mechanical loads induce hypertrophy and illustrates that additional mTORC1-independent mechanisms play a critical role in this process.-You, J.-S., McNally, R. M., Jacobs, B. L., Privett, R. E., Gundermann, D. M., Lin, K.-H., Steinert, N. D., Goodman, C. A., Hornberger, T. A. The role of raptor in the mechanical load-induced regulation of mTOR signaling, protein synthesis, and skeletal muscle hypertrophy.

Introduction: Children and youth with special health care needs (CYSHCN) need, but do not have, adequate care coordination (CC); CC leads to better pediatric care, improved family/professional experience of care, and enhanced population health. Current CC initiatives are promising but lack adherence to emerging definitions/standards. A Lucile Packard Report provides guidelines for using a Shared Plan of Care (SPoC) as a CC approach; studied implementation is needed., Purpose: The studied implementation of the Riley Care Coordination Program (RCCP) set out to: 1) illuminate components of family-centered, interdisciplinary, team-based care/coordination and SPoC, use 2) underscore family participation/engagement 3) reveal implementation processes/lessons learned., Methods: Children (ages 2-10) with neurodevelopmental disabilities were referred by subspecialists; families agreed to participate in RCCP from a children's hospital ambulatory care setting. RCCP team used a five-phase workflow to implement CC: (1) Family Outreach/Engagement 2) Family and Team Pre-Visit Work, 3) Population-Based Teamwork, 4) Planned-Care Visits/SPOC "Co-Production", 5) Ongoing Care Coordination and Community Transfer. Family surveys and SPoC goals informed an evaluation., Results: Children (268) with neurodevelopmental disabilities enrolled/completed the 6-month RCCP; it was a feasible endeavor. The co-produced SPoC supported families/care neighborhood partners to meet goals/unmet needs. Team plan-do-study-act improvement cycles informed RCCP enhancements., Discussion/conclusion: Eliciting/using family goals to drive CC emphasized family priorities; children/families gained interventions, treatments, confidence and navigation skills. Going beyond episodic, reactive care, RCCP achieved better CC with care neighborhood learning partnerships. Investing in this quality care coordination with fidelity to national standards holds promise., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Key Points: Mechanical signals play a critical role in the regulation of muscle mass, but the molecules that sense mechanical signals and convert this stimulus into the biochemical events that regulate muscle mass remain ill-defined. Here we report a mass spectrometry-based workflow to study the changes in protein phosphorylation that occur in mouse skeletal muscle 1 h after a bout of electrically evoked maximal-intensity contractions (MICs). Our dataset provides the first comprehensive map of the MIC-regulated phosphoproteome. Using unbiased bioinformatics approaches, we demonstrate that our dataset leads to the identification of many well-known MIC-regulated signalling pathways, as well as to a plethora of novel MIC-regulated events. We expect that our dataset will serve as a fundamentally important resource for muscle biologists, and help to lay the foundation for entirely new hypotheses in the field., Abstract: The maintenance of skeletal muscle mass is essential for health and quality of life. It is well recognized that maximal-intensity contractions, such as those which occur during resistance exercise, promote an increase in muscle mass. Yet, the molecules that sense the mechanical information and convert it into the signalling events (e.g. phosphorylation) that drive the increase in muscle mass remain undefined. Here we describe a phosphoproteomics workflow to examine the effects of electrically evoked maximal-intensity contractions (MICs) on protein phosphorylation in mouse skeletal muscle. While a preliminary phosphoproteomics experiment successfully identified a number of MIC-regulated phosphorylation events, a large proportion of these identifications were present on highly abundant myofibrillar proteins. We subsequently incorporated a centrifugation-based fractionation step to deplete the highly abundant myofibrillar proteins and performed a second phosphoproteomics experiment. In total, we identified 5983 unique phosphorylation sites of which 663 were found to be regulated by MIC. GO term enrichment, phosphorylation motif analyses, and kinase-substrate predictions indicated that the MIC-regulated phosphorylation sites were chiefly modified by mTOR, as well as multiple isoforms of the MAPKs and CAMKs. Moreover, a high proportion of the regulated phosphorylation sites were found on proteins that are associated with the Z-disc, with over 74% of the Z-disc proteins experiencing robust changes in phosphorylation. Finally, our analyses revealed that the phosphorylation state of two Z-disc kinases (striated muscle-specific serine/threonine protein kinase and obscurin) was dramatically altered by MIC, and we propose ways these kinases could play a fundamental role in skeletal muscle mechanotransduction., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Mechanistic target of rapamycin (mTOR) signaling is necessary to generate a mechanically induced increase in skeletal muscle mass, but the mechanism(s) through which mechanical stimuli regulate mTOR signaling remain poorly defined. Recent studies have suggested that Ras homologue enriched in brain (Rheb), a direct activator of mTOR, and its inhibitor, the GTPase-activating protein tuberin (TSC2), may play a role in this pathway. To address this possibility, we generated inducible and skeletal muscle-specific knock-out mice for Rheb (iRhebKO) and TSC2 (iTSC2KO) and mechanically stimulated muscles from these mice with eccentric contractions (EC). As expected, the knock-out of TSC2 led to an elevation in the basal level of mTOR signaling. Moreover, we found that the magnitude of the EC-induced activation of mTOR signaling was significantly blunted in muscles from both inducible and skeletal muscle-specific knock-out mice for Rheb and iTSC2KO mice. Using mass spectrometry, we identified six sites on TSC2 whose phosphorylation was significantly altered by the EC treatment. Employing a transient transfection-based approach to rescue TSC2 function in muscles of the iTSC2KO mice, we demonstrated that these phosphorylation sites are required for the role that TSC2 plays in the EC-induced activation of mTOR signaling. Importantly, however, these phosphorylation sites were not required for an insulin-induced activation of mTOR signaling. As such, our results not only establish a critical role for Rheb and TSC2 in the mechanical activation of mTOR signaling, but they also expose the existence of a previously unknown branch of signaling events that can regulate the TSC2/mTOR pathway., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: Phosphatidic acid (PA) is a diacyl-glycerophospholipid that acts as a signaling molecule in numerous cellular processes. Recently, PA has been proposed to stimulate skeletal muscle protein accretion, but mechanistic studies are lacking. Furthermore, it is unknown whether co-ingesting PA with other leucine-containing ingredients can enhance intramuscular anabolic signaling mechanisms. Thus, the purpose of this study was to examine if oral PA feeding acutely increases anabolic signaling markers and muscle protein synthesis (MPS) in gastrocnemius with and without whey protein concentrate (WPC)., Methods: Overnight fasted male Wistar rats (~250 g) were randomly assigned to four groups: control (CON, n = 6-13), PA (29 mg; n = 8), WPC (197 mg; n = 8), or PA + WPC (n = 8). Three hours post-feeding, gastrocnemius muscle was removed for markers of Akt-mTOR signaling, gene expression patterns related to skeletal muscle mass regulation and metabolism, and MPS analysis via the SUnSET method., Results: Compared to CON rats, PA, WPC and PA + WPC resulted in a significant elevation in the phosphorylation of mTOR (Ser2481) and rps6 (Ser235/236) (p < 0.05) in the gastrocnemius though there were no differences between the supplemented groups. MPS levels in the gastrocnemius were significantly (p < 0.05) elevated in WPC versus CON rats, and tended to be elevated in PA versus CON rats (p = 0.08), though MPS was less in PA + WPC versus WPC rats (p < 0.05) in spite of robust increases in mTOR pathway activity markers in the former group. C2C12 myoblast data agreed with the in vivo data herein showing that PA increased MPS levels 51% (p < 0.001) phosphorylated p70s6k (Thr389) levels 67% (p < 0.001)., Conclusions: Our results are the first in vivo evidence to demonstrate that PA tends to increases MPS 3 h post-feeding, though PA may delay WPC-mediated MPS kinetics within a 3 h post-feeding window.

Mechanically-induced skeletal muscle growth is regulated by mammalian/mechanistic target of rapamycin complex 1 (mTORC1). Yes-Associated Protein (YAP) is a mechanically-sensitive, and growth-related, transcriptional co-activator that can regulate mTORC1. Here we show that, in skeletal muscle, mechanical overload promotes an increase in YAP expression; however, the time course of YAP expression is markedly different from that of mTORC1 activation. We also show that the overexpression of YAP induces hypertrophy via an mTORC1-independent mechanism. Finally, we provide preliminary evidence of possible mediators of YAP-induced hypertrophy (e.g. increased MyoD and c-Myc expression, and decreased Smad2/3 activity and muscle ring finger 1 (MuRF1) expression)., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Myostatin, a member of the TGF superfamily, is sufficient to induce skeletal muscle atrophy. Myostatin-induced atrophy is associated with increases in E3-ligase atrogin-1 expression and protein degradation and decreases in Akt/mechanistic target of rapamycin (mTOR) signaling and protein synthesis. Myostatin signaling activates the transcription factor Smad3 (Small Mothers Against Decapentaplegic), which has been shown to be necessary for myostatin-induced atrogin-1 expression and atrophy; however, it is not known whether Smad3 is sufficient to induce these events or whether Smad3 simply plays a permissive role. Thus, the aim of this study was to address these questions with an in vivo model. To accomplish this goal, in vivo transfection of plasmid DNA was used to create transient transgenic mouse skeletal muscles, and our results show for the first time that Smad3 expression is sufficient to stimulate atrogin-1 promoter activity, inhibit Akt/mTOR signaling and protein synthesis, and induce muscle fiber atrophy. Moreover, we propose that Akt/mTOR signaling is inhibited by a Smad3-induced decrease in microRNA-29 (miR-29) expression and a subsequent increase in the translation of phosphatase and tensin homolog (PTEN) mRNA. Smad3 is also sufficient to inhibit peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) promoter activity and to increase FoxO (Forkhead Box Protein, Subclass O)-mediated signaling and the promoter activity of plasminogen activator inhibitor 1 (PAI-1). Combined, this study provides the first evidence that Smad3 is sufficient to regulate many of the events associated with myostatin-induced atrophy and therefore suggests that Smad3 signaling may be a viable target for therapies aimed at preventing myostatin-induced muscle atrophy.

The sequence of cDNA clones representing the 5' non-coding regions (NCR) and capsid regions of two bovine enteroviruses (strains PS-87 and RM-2; serotype two viruses) have been determined and compared with that obtained from a serotype one strain (VG-5-27). All three strains showed a longer 5' NCR compared to human enteroviruses and rhinoviruses due in part to a hundred residue insertion approximately at a hundred residues in from the 5' end. However, another domain occurring at nucleotide 187-222 in poliovirus is absent in each bovine enterovirus. Comparisons of the predicted structural protein amino acid sequences indicate that PS-87 shares most sequence identity with RM-2 and then with VG-5-27 in that order. The VP1 protein of PS-87 and RM-2 are shorter than the equivalent VP1 of VG-5-27 due in part to a truncation at their C-terminii. VP3 is only slightly smaller than VP2 in each virus.

The range and resistance patterns of organisms causing urinary tract infections (UTI) vary with time and place. A prospective study of midstream urine (MSU) specimens, received over a 3 month period, was therefore undertaken. The antibiotic sensitivities of 528 isolates from 196 domiciliary and 332 hospitalised patients with significant bacteriuria (> 10(5) organisms/ml) were determined using the modified Stokes method. Escherichia coli accounted for 79% of domiciliary isolates and 57% in hospitalised patients. Gram positive organisms causing UTI have become increasingly common and were isolated from 8% and 15% of domiciliary and hospitalised patients respectively. Resistance levels for co-amoxiclav (Augmentin) were low (7% domiciliary, 14% hospitalised). However 46 Gram negative isolates (10%) had intermediate sensitivities to co-amoxiclav on disc testing. Breakpoint testing showed 89% of these to be sensitive at the urinary breakpoint but only 52% were sensitive at the systemic breakpoint. Forty nine percent of E. coli from hospital specimens were resistant to pipercillin, due to TEM-1 beta lactamase production. A 6% resistance level to ciprofloxacin in domiciliary E. coli is considerably higher than previous reports and gives cause for concern. Gentamicin resistance was found in 4% of Gram negative hospital isolates, a finding of some significance in the empiric treatment of septicaemia of urinary tract origin.