Optimizing discharge opioid prescribing in trauma patients: A quasi-experimental study.

BACKGROUND: Patients prescribed higher opioid dosages are at increased risk of overdose and death without added pain reduction. Increases in opioid prescribing continue to fuel the epidemic. We hypothesized a comprehensive guideline to standardize opioid prescribing would decrease postdischarge dosages for patients experiencing trauma without requiring additional refills. METHODS: This quasiexperimental study compared opioid prescribing by trauma providers before and after the implementation of a departmental guideline on April 1, 2019, aimed at aligning opioid prescription patterns with Centers for Disease Control and Prevention recommendations. Patients prescribed opioids before implementation were the control group, whereas patients prescribed opioids after were the intervention group. The primary outcome was the proportion of patients receiving ≥50 morphine milligram equivalents per day. RESULTS: We identified 293 and 280 patients experiencing trauma in the control and intervention groups, respectively. There were no differences between the groups' Injury Severity Score (P = .69) or the frequency of having a procedure performed (P = .80). Total morphine milligram equivalents and maximum morphine milligram equivalents per day were 16% and 25% lower, respectively, in the intervention group compared with the control group (P < .001). The proportion of trauma patients prescribed ≥50 morphine milligram equivalents per day at discharge decreased from 57% to 18% after implementation (P < .001). The proportion of trauma patients prescribed ≥90 morphine milligram equivalents per day also decreased, from 37% to 14% (P < .001). There was no significant increase in the frequency of refill requests (P = .105) or refill prescriptions (P = .099) after discharge. CONCLUSION: A departmental guideline aimed at optimizing opioid prescription patterns successfully lowers the amount of morphine milligram equivalents prescribed to trauma patients and improves compliance with Centers for Disease Control and Prevention recommendations.

Rapid evolution of blood-brain-barrier-penetrating AAV capsids by RNA-driven biopanning.

Therapeutic payload delivery to the central nervous system (CNS) remains a major challenge in gene therapy. Recent studies using function-driven evolution of adeno-associated virus (AAV) vectors have successfully identified engineered capsids with improved blood-brain barrier (BBB) penetration and CNS tropism in mouse. However, these strategies require transgenic animals and thus are limited to rodents. To address this issue, we developed a directed evolution approach based on recovery of capsid library RNA transcribed from CNS-restricted promoters. This RNA-driven screen platform, termed TRACER (Tropism Redirection of AAV by Cell-type-specific Expression of RNA), was tested in the mouse with AAV9 peptide display libraries and showed rapid emergence of dominant sequences. Ten individual variants were characterized and showed up to 400-fold higher brain transduction over AAV9 following systemic administration. Our results demonstrate that the TRACER platform allows rapid selection of AAV capsids with robust BBB penetration and CNS tropism in non-transgenic animals.

A General Method for Targeted Quantitative Cross-Linking Mass Spectrometry.

Chemical cross-linking mass spectrometry (XL-MS) provides protein structural information by identifying covalently linked proximal amino acid residues on protein surfaces. The information gained by this technique is complementary to other structural biology methods such as x-ray crystallography, NMR and cryo-electron microscopy[1]. The extension of traditional quantitative proteomics methods with chemical cross-linking can provide information on the structural dynamics of protein structures and protein complexes. The identification and quantitation of cross-linked peptides remains challenging for the general community, requiring specialized expertise ultimately limiting more widespread adoption of the technique. We describe a general method for targeted quantitative mass spectrometric analysis of cross-linked peptide pairs. We report the adaptation of the widely used, open source software package Skyline, for the analysis of quantitative XL-MS data as a means for data analysis and sharing of methods. We demonstrate the utility and robustness of the method with a cross-laboratory study and present data that is supported by and validates previously published data on quantified cross-linked peptide pairs. This advance provides an easy to use resource so that any lab with access to a LC-MS system capable of performing targeted quantitative analysis can quickly and accurately measure dynamic changes in protein structure and protein interactions.

Psychiatric Symptoms in Youth with a History of Autism and Optimal Outcome.

Since autism spectrum disorder (ASD) is often comorbid with psychiatric disorders, children who no longer meet criteria for ASD (optimal outcome; OO) may still be at risk for psychiatric disorders. A parent interview for DSM-IV psychiatric disorders (K-SADS-PL) for 33 OO, 42 high-functioning autism (HFA) and 34 typically developing (TD) youth, ages 8-21, showed that OO and HFA groups had elevated current ADHD and specific phobias, with tics in HFA. In the past, the HFA group also had elevated depression and ODD, and the OO group had tics. The HFA group also showed subthreshold symptoms of specific and social phobias, and generalized anxiety. Psychopathology in the OO group abated over time as did their autism, and decreased more than in HFA.

Branched dimerization of Tat peptide improves permeability to HeLa and hippocampal neuronal cells.

A dimeric branched peptide TATp-D designed as an analogue of the HIV-Tat protein transduction domain (TATp), a prototypical cell penetrating peptide (CPP), demonstrates significantly enhanced cell uptake at 0.25 to 2.5 µM. Live cell confocal laser scanning microscopy revealed that multivalency dramatically improved the permeation potency of TATp-D to HeLa and primary hippocampal neuronal cells. The observed enhanced ability of TATp-D to translocate through the membrane is highlighted by a non-linear dependence on concentration, exhibiting the greatest uptake at sub-micromolar concentrations as compared to TATp. Multimerization via bis-Fmoc Lysine offered a synthetically straightforward method to investigate the effects of multivalent CPPs while offering orthogonal handles for cargo attachment, increasing the utility of CPPs at significantly lower concentrations.

Social Function and Communication in Optimal Outcome Children and Adolescents with an Autism History on Structured Test Measures.

Youth who lose their ASD diagnosis may have subtle social and communication difficulties. We examined social and communication functioning in 44 high-functioning autism (HFA), 34 optimal outcome (OO) and 34 typically developing (TD) youth. Results indicated that OO participants had no autism communication symptoms, no pragmatic language deficits, and were judged as likable as TD peers. Some group differences were found: OO youth had less insight into social relationships and poorer friendship descriptions than TD youth. OO participants had attention, self-control, and immaturity difficulties that may impact social abilities. However, OO participants were most engaged, friendliest, warmest, and most approachable. Overall, OO participants had no social and communicative impairments, although some exhibited mild social difficulties that often accompany attentional problems.

The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system.

A subset of angiotensin IV (AngIV)-related molecules are known to possess procognitive/antidementia properties and have been considered as templates for potential therapeutics. However, this potential has not been realized because of two factors: 1) a lack of blood-brain barrier-penetrant analogs, and 2) the absence of a validated mechanism of action. The pharmacokinetic barrier has recently been overcome with the synthesis of the orally active, blood-brain barrier-permeable analog N-hexanoic-tyrosine-isoleucine-(6) aminohexanoic amide (dihexa). Therefore, the goal of this study was to elucidate the mechanism that underlies dihexa's procognitive activity. Here, we demonstrate that dihexa binds with high affinity to hepatocyte growth factor (HGF) and both dihexa and its parent compound Norleucine 1-AngIV (Nle(1)-AngIV) induce c-Met phosphorylation in the presence of subthreshold concentrations of HGF and augment HGF-dependent cell scattering. Further, dihexa and Nle(1)-AngIV induce hippocampal spinogenesis and synaptogenesis similar to HGF itself. These actions were inhibited by an HGF antagonist and a short hairpin RNA directed at c-Met. Most importantly, the procognitive/antidementia capacity of orally delivered dihexa was blocked by an HGF antagonist delivered intracerebroventricularly as measured using the Morris water maze task of spatial learning.

Restricted and repetitive behaviors in individuals with a history of ASDs who have achieved optimal outcomes.

Studies of autism spectrum disorders (ASDs) suggest that restricted and repetitive behaviors (RRBs) are particularly difficult to remediate. We examined present and past RRBs in 34 individuals who achieved optimal outcomes (OOs; lost their ASD diagnosis), 45 high-functioning individuals with ASD (HFA) and 34 typically developing (TD) peers. The OO group exhibited minimal residual RRBs at the time of the study. All OO participants were reported to have at least one RRB in early childhood and almost 90 % met the RRB cutoff for ASD in early childhood, but RRBs were not more present in the OO than the TD group at the time of the study. History of RRBs in the HFA and OO groups differed only in oversensitivity to noise and insistence on sameness. Reports of current behavior indicated that RRB's had almost totally disappeared in the OO group. Thus, although RRB's were present in the OO group in childhood, they resolved along with social and communication deficits.

Intervention for optimal outcome in children and adolescents with a history of autism.

OBJECTIVE: Autism spectrum disorders (ASDs) were once considered lifelong disorders, but recent findings indicate that some children with ASDs no longer meet diagnostic criteria for any ASD and reach normal cognitive function. These children are considered to have achieved "optimal outcomes" (OO). The present study aimed to retrospectively examine group differences in the intervention history of children and adolescents with OO and those with high-functioning autism (HFA). METHOD: The current study examined intervention histories in 25 individuals with OO and 34 individuals with HFA (current age, 8-21 years), who did not differ on age, sex, nonverbal intelligence, or family income. Intervention history was collected through detailed parent questionnaires. RESULTS: Children in the OO group had earlier parental concern, received earlier referrals to specialists, and had earlier and more intensive intervention than those in the HFA group. Substantially more children with OO than HFA received applied behavior analysis (ABA) therapy, although for children who received ABA, the intensity did not differ between the groups. Children in the HFA group were more likely to have received medication, especially antipsychotics and antidepressants. There were no group differences in the percent of children receiving special diets or supplements. CONCLUSION: These data suggest that OO individuals generally receive earlier, more intense interventions, and more ABA, whereas HFA individuals receive more pharmacologic treatments. Although the use of retrospective data is a clear limitation to the current study, the substantial differences in the reported provision of early intervention, and ABA in particular, is highly suggestive and should be replicated in prospective studies.

Academic abilities in children and adolescents with a history of autism spectrum disorders who have achieved optimal outcomes.

This study examines the academic abilities of children and adolescents who were once diagnosed with an autism spectrum disorder, but who no longer meet diagnostic criteria for this disorder. These individuals have achieved social and language skills within the average range for their ages, receive little or no school support, and are referred to as having achieved "optimal outcomes." Performance of 32 individuals who achieved optimal outcomes, 41 high-functioning individuals with a current autism spectrum disorder diagnosis (high-functioning autism), and 34 typically developing peers was compared on measures of decoding, reading comprehension, mathematical problem solving, and written expression. Groups were matched on age, sex, and nonverbal IQ; however, the high-functioning autism group scored significantly lower than the optimal outcome and typically developing groups on verbal IQ. All three groups performed in the average range on all subtests measured, and no significant differences were found in performance of the optimal outcome and typically developing groups. The high-functioning autism group scored significantly lower on subtests of reading comprehension and mathematical problem solving than the optimal outcome group. These findings suggest that the academic abilities of individuals who achieved optimal outcomes are similar to those of their typically developing peers, even in areas where individuals who have retained their autism spectrum disorder diagnoses exhibit some ongoing difficulty.

Executive functioning in individuals with a history of ASDs who have achieved optimal outcomes.

Executive functioning (EF) is examined among children and adolescents once diagnosed with an autism spectrum disorder (ASD), but who no longer meet diagnostic criteria. These individuals have average social and language skills, receive minimal school support and are considered to have achieved "optimal outcomes" (OOs). Since residual impairments in these individuals might be expected in deficits central to autism, and in developmentally advanced skills, EF was examined in 34 individuals who achieved OOs, 43 individuals with high-functioning autism (HFA), and 34 typically developing (TD) peers. Groups were matched on age (M = 13.49), gender, and nonverbal IQ (NVIQ) but differed on verbal IQ (VIQ; HFA < TD, OO). On direct assessment, all three groups demonstrated average EF; however, the OO and HFA groups exhibited more impulsivity and less efficient planning and problem-solving than the TD group, and more HFA participants exhibited below average inhibition than did OO and TD participants. Parent-report measures revealed average EF among the OO and TD groups; however, the OO group exhibited more difficulty than the TD group on set-shifting and working memory. HFA participants demonstrated more difficulty on all parent-reported EF domains, with a clinical impairment in attention-shifting. Results suggest that EF in OO appears to be within the average range, even for functions that were impaired among individuals with HFA. Despite their average performance, however, the OO and TD groups differed on measures of impulsivity, set-shifting, problem-solving, working memory, and planning, suggesting that the OO group does not have the above-average EF scores of the TD group despite their high-average IQs.

Language and verbal memory in individuals with a history of autism spectrum disorders who have achieved optimal outcomes.

Some individuals who lose their autism spectrum disorder diagnosis may continue to display subtle weaknesses in language. We examined language and verbal memory in 44 individuals with high-functioning autism (HFA), 34 individuals with "optimal outcomes" (OO) and 34 individuals with typical development (TD). The OO group scored in the average range or above on all measures and showed few differences from the TD group. The HFA group performed within the average range but showed significantly lower mean performance than the other groups on multiple language measures, even when controlling for verbal IQ. Results also indicate that OO individuals show strong language abilities in all areas tested, but that their language may show greater reliance on verbal memory.

Optimal outcome in individuals with a history of autism.

BACKGROUND: Although autism spectrum disorders (ASDs) are generally considered lifelong disabilities, literature suggests that a minority of individuals with an ASD will lose the diagnosis. However, the existence of this phenomenon, as well as its frequency and interpretation, is still controversial: were they misdiagnosed initially, is this a rare event, did they lose the full diagnosis, but still suffer significant social and communication impairments or did they lose all symptoms of ASD and function socially within the normal range? METHODS: The present study documents a group of these optimal outcome individuals (OO group, n=34) by comparing their functioning on standardized measures to age, sex, and nonverbal IQ matched individuals with high-functioning autism (HFA group, n=44) or typical development (TD group, n=34). For this study, 'optimal outcome' requires losing all symptoms of ASD in addition to the diagnosis, and functioning within the nonautistic range of social interaction and communication. Domains explored include language, face recognition, socialization, communication, and autism symptoms. RESULTS: Optimal outcome and TD groups' mean scores did not differ on socialization, communication, face recognition, or most language subscales, although three OO individuals showed below-average scores on face recognition. Early in their development, the OO group displayed milder symptoms than the HFA group in the social domain, but had equally severe difficulties with communication and repetitive behaviors. CONCLUSIONS: Although possible deficits in more subtle aspects of social interaction or cognition are not ruled out, the results substantiate the possibility of OO from autism spectrum disorders and demonstrate an overall level of functioning within normal limits for this group.

Differentiating high-functioning autism and social phobia.

Both high-functioning autism (HFA) and social phobia (SP) involve profound social interaction deficits. Although these disorders share some similar symptoms, they are conceptualized as distinct. Because both HFA and SP are defined behaviorally, the degree of overlap between the two disorders may result in misinterpretation of symptoms. However, the deficits in each disorder differ, particularly in areas of social interaction, emotion recognition and expression, and communication. This paper reviews the literature that informs our current understanding of the behavioral overlaps and differences in HFA and SP. The review also addresses the implications of our current knowledge of these two disorders for differential diagnosis, treatment, and future research. Interdisciplinary, developmentally-oriented research may help extend current approaches to HFA and SP.