NHE3 inhibitor tenapanor maintains intestinal barrier function, decreases visceral hypersensitivity, and attenuates TRPV1 signaling in colonic sensory neurons.

The pathogenesis of irritable bowel syndrome (IBS) is multifactorial, characterized in part by increased intestinal permeability, and visceral hypersensitivity. Increased permeability is associated with IBS severity and abdominal pain. Tenapanor is FDA-approved for the treatment of IBS with constipation (IBS-C) and has demonstrated improvements in bowel motility and a reduction in IBS-related pain; however, the mechanism by which tenapanor mediates these functions remains unclear. Here, the effects of tenapanor on colonic pain signaling and intestinal permeability were assessed through behavioral, electrophysiological, and cell culture experiments. Intestinal motility studies in rats and humans demonstrated that tenapanor increased luminal sodium and water retention and gastrointestinal transit versus placebo. A significantly reduced visceral motor reflex (VMR) to colonic distension was observed with tenapanor treatment versus vehicle in two rat models of visceral hypersensitivity (neonatal acetic acid sensitization and partial restraint stress; both P < 0.05), returning VMR responses to that of nonsensitized controls. Whole cell voltage patch-clamp recordings of retrogradely labeled colonic dorsal root ganglia (DRG) neurons from sensitized rats found that tenapanor significantly reduced DRG neuron hyperexcitability to capsaicin versus vehicle (P < 0.05), an effect not mediated by epithelial cell secretions. Tenapanor also attenuated increases in intestinal permeability in human colon monolayer cultures caused by incubation with proinflammatory cytokines (P < 0.001) or fecal supernatants from patients with IBS-C (P < 0.005). These results support a model in which tenapanor reduces IBS-related pain by strengthening the intestinal barrier, thereby decreasing permeability to macromolecules and antigens and reducing DRG-mediated pain signaling.NEW & NOTEWORTHY A series of nonclinical experiments support the theory that tenapanor inhibits IBS-C-related pain by strengthening the intestinal barrier. Tenapanor treatment reduced visceral motor responses to nonsensitized levels in two rat models of hypersensitivity and reduced responses to capsaicin in sensitized colonic nociceptive dorsal root ganglia neurons. Intestinal permeability experiments in human colon monolayer cultures found that tenapanor attenuates increases in permeability induced by either inflammatory cytokines or fecal supernatants from patients with IBS-C.

Intrinsic functional connectivity in medial temporal lobe networks is associated with susceptibility to misinformation.

Memory is notoriously fallible and susceptible to misinformation. Yet little is known about the underlying cognitive and neural mechanisms that render individuals vulnerable to this type of false memory. The current experiments take an individual differences approach to examine whether susceptibility to misinformation reflects stable underlying factors related to memory retrieval. In Study 1, we report for the first time the existence of substantial individual variability in susceptibility to misinformation in the context of repeated memory retrieval, when the misinformation effect is most pronounced. This variability was not related to an individual's tendency to adopt an episodic retrieval style during remembering (trait mnemonics). In Study 2, we next examined whether susceptibility to misinformation is related to intrinsic functional connectivity in medial temporal lobe (MTL) networks known to coordinate memory reactivation during event retrieval. Stronger resting-state functional connectivity between the MTL and cortical areas associated with visual memory reactivation (occipital cortex) was associated with better protection from misinformation. Together, these results reveal that while memory distortion is a universal property of our reconstructive memory system, susceptibility to misinformation varies at the individual level and may depend on one's ability to reactivate visual details during memory retrieval.

Traumatic brain injuries in paediatric patients: individual vs. team sports-related hospitalizations.

Paediatric sport participation continues to increase in the United States, with a corresponding increase in sports-related concussions or traumatic brain injuries (TBIs). It is important to recognize which sports are at elevated risk and identify risk factors for hospital admission and length of stay (LOS). Paediatric patients (ages 5-18) from 2008 to 2014 were identified from the Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (NIS). Eight hundred and ninety-four patients included those who were hospitalized with a TBI resulting from participation in an individual (451 patients) or team (443 patients) sport. We evaluated the differences in LOS and total charges between individual and team sports and found that compared to team sports, TBI patients in individual sports had significantly longer hospital stays compared to team sports (1.75 days versus 1.34 days, p < 0.001) and costlier ($27,333 versus $19,069, p < 0.001) hospital stays. This may be due to reduced awareness and reduced compliance with return-to-play protocols in individual sports. Safety education information at a young age, increased awareness of TBIs, and additional medical support for individual sports as well as team sports may help mitigate these findings.

P008 A Novel Smartphone Application to Reduce Infusion Suite Wait Times.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are often treated with biologic medications that require visits to an infusion suite. Due to the high cost of biologics, they are not mixed and released from the pharmacy until patient arrival. This typically leads to long wait times after patient check in. An investigator-developed novel smartphone application (app) titled Almost There was created to reduce wait times through the use of geofences to notify the infusion suite when patients are nearing their destination (the hospital). Our aim was to perform a pilot study to assess the feasibility of Almost There for patients with IBD coming for infusions at a rural academic medical center. METHODS: Adult patients with Crohn's disease (CD) or ulcerative colitis (UC) currently receiving intravenous biologic therapy were recruited for this pilot study. Patients received instructions on how to download the app onto their smartphone. Patients activated the application prior to leaving their homes and answered standard screening questions to assess for active infections. Using geofences, the app automatically notified the infusion suite when the patient was within 10 miles of the hospital. The infusion suite alerted the pharmacy who immediately proceeded with medication preparation. Patients completed surveys upon arrival to the infusion suite collecting basic demographics and disease information, perceived wait times for that visit and previous visits prior to using the app. The infusion suite staff recorded actual wait times from check in to medication administration. RESULTS: The app was trialed successfully for 12 total visits among 9 patients (5 CD, 4 UC). 78% of app users were 25-44 years old and 22% were 45 years and older. 56% of patients were receiving infliximab and 44% were receiving vedolizumab. 11 patients were recruited and 9 patients out of 11 were able to successfully use the app. Reasons for app failure included one user who forgot their phone at home, one with loss of cell service, and one app malfunction. The median actual wait time from when patients arrived at the infusion suite to the start of the infusion was 38-40 minutes. In 67% of visits, there was decreased perceived wait time for patients using the app compared to their prior visits. When using the app, perceived wait times were shorter than actual wait times in 75% percent of patients. CONCLUSION: In this pilot feasibility study, the Almost There app led to decreased perceived wait times for IBD patients coming for biologic infusions. The application was not effective for 18% of patients for a variety of reasons. If this or a similar app was improved to allow for more consistent usability it should be studied compared to a control group to evaluate if it leads to decreased wait times for any medical infusion.

p66ShcA functions as a contextual promoter of breast cancer metastasis.

BACKGROUND: The p66ShcA redox protein is the longest isoform of the Shc1 gene and is variably expressed in breast cancers. In response to a variety of stress stimuli, p66ShcA becomes phosphorylated on serine 36, which allows it to translocate from the cytoplasm to the mitochondria where it stimulates the formation of reactive oxygen species (ROS). Conflicting studies suggest both pro- and anti-tumorigenic functions for p66ShcA, which prompted us to examine the contribution of tumor cell-intrinsic functions of p66ShcA during breast cancer metastasis. METHODS: We tested whether p66ShcA impacts the lung-metastatic ability of breast cancer cells. Breast cancer cells characteristic of the ErbB2+/luminal (NIC) or basal (4T1) subtypes were engineered to overexpress p66ShcA. In addition, lung-metastatic 4T1 variants (4T1-537) were engineered to lack endogenous p66ShcA via Crispr/Cas9 genomic editing. p66ShcA null cells were then reconstituted with wild-type p66ShcA or a mutant (S36A) that cannot translocate to the mitochondria, thereby lacking the ability to stimulate mitochondrial-dependent ROS production. These cells were tested for their ability to form spontaneous metastases from the primary site or seed and colonize the lung in experimental (tail vein) metastasis assays. These cells were further characterized with respect to their migration rates, focal adhesion dynamics, and resistance to anoikis in vitro. Finally, their ability to survive in circulation and seed the lungs of mice was assessed in vivo. RESULTS: We show that p66ShcA increases the lung-metastatic potential of breast cancer cells by augmenting their ability to navigate each stage of the metastatic cascade. A non-phosphorylatable p66ShcA-S36A mutant, which cannot translocate to the mitochondria, still potentiated breast cancer cell migration, lung colonization, and growth of secondary lung metastases. However, breast cancer cell survival in the circulation uniquely required an intact p66ShcA S36 phosphorylation site. CONCLUSION: This study provides the first evidence that both mitochondrial and non-mitochondrial p66ShcA pools collaborate in breast cancer cells to promote their maximal metastatic fitness.

Islet autotransplantation improves glycemic control in patients undergoing elective distal pancreatectomy for benign inflammatory disease.

Islet autotransplantation (IAT) is increasingly being performed to mitigate against the diabetic complications of pancreatic resection in patients with benign inflammatory pancreatic disorders; however, the glycemic benefit of IAT in patients undergoing partial pancreatic resection is not known. We aimed to determine whether IAT improved glycemic outcomes in patients undergoing distal pancreatectomy for benign inflammatory disease. We performed a multicenter, retrospective case-control study of patients who underwent distal pancreatic resection with IAT at two U S tertiary care centers. The primary outcome was the mean change in pre- vs post-operative HgA1c following transplant as well as the development of new post-operative diabetes. Nine patients requiring distal pancreatectomy for benign disease underwent IAT and were compared to 13 historical controls without IAT. Baseline characteristics were similar between groups. With a median follow-up of 22 months, those who received an IAT had a smaller increase in their pre- vs post-operative HgA1c (0.42 vs 2.83, P = .004), and one case patient (14.3%) vs three control patients (23.1%) developed new post-operative diabetes (P = .581). We conclude that patients undergoing distal pancreatic resection for benign inflammatory disease should be considered for IAT, as long-term glycemic outcomes appear to be improved in those undergoing transplant.

Sacroiliac joint cut accuracy: Comparing new technologies in an idealized sawbones model.

BACKGROUND AND OBJECTIVES: The anatomical complexity of the pelvis creates challenges for orthopaedic oncologists to accurately and safely resect tumors involving the sacroiliac joint. Current technology may help overcome these obstacles. METHODS: Four fellowship-trained orthopaedic oncologists performed 22 all-posterior sacroiliac cuts using freehand, computerized navigation, and patient-specific cutting guides on a Sawbones male pelvis model. Cut accuracies to preoperative planned margins were analyzed via a high-resolution optical scanner. Soft tissue damage was determined by visually inspecting the Sawbones foam placed on the far side of the cut. RESULTS: Within 5 mm of the margins, the freehand technique resulted in 67.0% cut accuracy, the navigation technique had 71.1%, and the patient-specific cutting guide technique had 85.6% (P = .093). Within 2 mm, the techniques showed an accuracy of 25.8%, 32.5%, and 47.5%, respectively (P = .022). Regarding soft tissue damage, the freehand technique exhibited minimal penetration damage for 16.7% of the cuts, while navigation and patient-specific guide techniques exhibited 25.0% and 75.0%, respectively (P = .046). Years of surgical experience of the operator (1-7) did not influence the cut accuracy for any method. CONCLUSIONS: Under ideal conditions, patient-specific guide technology possesses the same or better accuracy as other cutting techniques as well as the circumvention of soft tissue damage.

Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice.

Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance. Agonist activity, binding selectivity, toxicity, solubility, and permeability of RDX8940 were characterized in standard in vitro models. RDX8940 pharmacokinetics and effects on GLP secretion, insulin sensitivity, and liver steatosis were assessed in C57BL/6 mice fed normal or Western diet chow and given single or repeated doses of RDX8940 or vehicle, with or without dipeptidyl peptidase-4 (DPP4) inhibitors. Gallbladder effects were assessed in CD-1 mice fed normal chow and given RDX8940 or a systemic TGR5 agonist or vehicle. Our results showed that RDX8940 is minimally systemic, potent, and selective, and induces incretin (GLP-1, GLP-2, and peptide YY) secretion. RDX8940-induced increases in plasma active GLP-1 (aGLP-1) levels were enhanced by repeated dosing and by coadministration of DPP4 inhibitors. RDX8940 increased hepatic exposure to aGLP-1 without requiring coadministration of a DPP4 inhibitor. In mice fed a Western diet, RDX8940 improved liver steatosis and insulin sensitivity. Unlike systemic TGR5 agonists, RDX8940 did not inhibit gallbladder emptying. These results indicate that RDX8940 may have therapeutic potential in patients with NAFLD/NASH. NEW & NOTEWORTHY Takeda G protein-coupled receptor 5 (TGR5) agonists have potential as a treatment for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD) but have until now been associated with undesirable side effects associated with systemic TGR5 agonism, including blockade of gallbladder emptying. We demonstrate that RDX8940, a potent, selective, minimally systemic oral TGR5 agonist, improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and does not inhibit gallbladder emptying in mice.

Psychiatric hospital treatment of youth with autism spectrum disorder in the United States: needs, outcomes, and policy.

Children with Autism Spectrum Disorder (ASD) are admitted to inpatient psychiatric units at markedly high rates. As health insurance companies and government healthcare systems and regulators seek more evidence for healthcare outcomes, it is important to learn more about the effectiveness of psychiatric inpatient admissions for children with ASD to best inform decisions on provision and access to this level of care. Evidence for models of inpatient treatment for youth with ASD is presented, and key characteristics and consensus recommendations for care are discussed.

Telephone administration of the aberrant behavior checklist: a pilot study of feasibility in children with intellectual disability and autism.

To advance clinical care and research in children with intellectual disability and autism there is a growing need for efficient means to measure behavioral severity and response to treatment. The objective of this study was to assess the feasibility of telephone administration of the Aberrant Behavior Checklist-Irritability Subscale (ABC-I). The ABC-I was administered by telephone to the primary caregivers of 39 subjects with intellectual disability and/or autism. The same primary caregiver of each subject was also mailed a written copy of the ABC-I with a self-addressed, stamped envelope. Scores obtained by telephone and written administration were highly correlated (r = 0.827, p < 0.001). Telephone administration of the ABC-I may be a feasible and efficient means of determining response to treatment in children with intellectual disability and/or autism, though these pilot findings need to be replicated in a larger sample.

The Relationship Between Augmentative and Alternative Communication Use by Pediatric Psychiatric Inpatients With Autism Spectrum Disorder and Interfering Behaviors.

PURPOSE: Previous research conducted by Williams et al. (2018) using data from the Autism Inpatient Collection (AIC) found a weak and inconsistent association between verbal ability and the severity of interfering behaviors; however, adapting/coping scores were significantly associated with self-injury, stereotypy, and irritability (including aggression and tantrums). The previous study did not account for access to or use of alternative forms of communication in their sample population. This study uses retrospective data to investigate the association between verbal ability and augmentative and alternative communication (AAC) use and the presence of interfering behaviors in individuals with autism who have complex behavioral profiles. METHOD: The sample included 260 autistic inpatients, ages 4-20 years, from six psychiatric facilities, enrolled during the second phase of the AIC when detailed information about AAC use was collected. Measures included AAC use, method, and function; comprehension and production of language; receptive vocabulary; nonverbal IQ; severity of interfering behaviors; and the presence and severity of repetitive behaviors. RESULTS: Lower language/communication abilities were related to increased repetitive behaviors and stereotypies. More specifically, these interfering behaviors appeared to be related to communication in those individuals who were candidates for AAC but who were not reported to have access to it. Although the use of AAC did not predict a decrease in interfering behaviors, receptive vocabulary scores-as measured by the Peabody Picture Vocabulary Test-Fourth Edition-were positively correlated with the presence of interfering behaviors in participants with the most complex communication needs. CONCLUSIONS: The communication needs of some individuals with autism may be unmet, prompting the use of interfering behaviors as a form of communication. Further investigation of the functions of interfering behaviors and the related functions of communication skills may provide greater support for an increased focus on the provision of AAC to prevent and ameliorate interfering behaviors in individuals with autism.

Do Intra-articular Corticosteroid Injections Prior to Total Knee Arthroplasty Increase Postoperative Complication Rates: A Retrospective Review.

There is conflicting literature suggesting that intra-articular corticosteroid injections before total knee arthroplasty (TKA) may lead to an increase in the rate of postoperative complications, specifically periprosthetic joint infection (PJI). Thus, this retrospective review of all TKAs performed at a large, urban hospital will add valuable evidence to help guide future patient care. After exclusion criteria, we retrospectively reviewed 417 patients who received a TKA from a group of fellowship-trained orthopaedic surgeons between 2009 and 2016 at a single academic medical center. Minimum follow-up time was 1 year. Patients were separated into two groups: those who received a preoperative intra-articular corticosteroid injection and those who did not receive an injection. Subgroups were created based on the timing of their most recent preoperative injection: 0 to 3 months, 3 to 6 months, 6 to 12 months, 12+ months, and an unknown time period. Postoperative outcomes for PJI, revision TKA, and manipulation under anesthesia (MUA) were analyzed via a Chi-square test. No statistically significant postoperative differences were observed between groups: PJI (p = 0.904), revision TKA (p = 0.206), and MUA (p = 0.163). The temporal subgroups also failed to demonstrate a statistically significant result: PJI (p = 0.348), revision TKA (p = 0.701), and MUA (p = 0.512). This study revealed no absolute or temporal association between preoperative, intra-articular corticosteroid injections, and complications after TKA. Because these injections are a commonly used treatment modality prior to TKA, further studies should be conducted on a nationwide basis to draw more concrete conclusions.

From Alert Child to Sleepy Adolescent: Age Trends in Chronotype, Social Jetlag, and Sleep Problems in Youth with Autism.

PURPOSE: Developmental changes in sleep in youth with autism spectrum disorder (ASD) are understudied. In non-ASD youth, adolescents exhibit a "night owl chronotype" (i.e., later sleep/wake timing) and social jetlag (i.e., shifts in sleep timing across school nights and weekends), with corresponding sleep problems. The purpose of this study is to evaluate age trends in chronotype, social jetlag, and sleep problems in high-risk youth with ASD. METHODS: Youth with ASD (N = 171), ages 5-21 years old, were enrolled at the time of admission to specialized psychiatric units. Caregivers reported children's demographic information, habitual sleep timing, and sleep problems. Multivariate analyses evaluated the effect of age on chronotype, social jetlag, and sleep problems and the effects of chronotype and social jetlag on sleep problems. Covariates and moderators included sex, race, verbal ability, autism symptom severity, supplemental melatonin, and pubertal status. RESULTS: Older age was associated with later chronotype, more social jetlag, fewer sleep anxiety/co-sleeping problems, fewer night waking and parasomnia problems, and more daytime alertness problems. The effect of age on chronotype was stronger for youth with greater social affective symptom severity. Mediation analyses showed that later chronotype statistically mediated the association between age and daytime alertness problems. CONCLUSIONS: Youth with ASD may exhibit night owl chronotype behavior and social jetlag as they enter adolescence. Shifts toward a later chronotype may be exacerbated by autism severity and may contribute to alertness problems and sleepiness during the day. Chronotype is modifiable and may be leveraged to improve daytime functioning in youth with ASD.

Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials.

BACKGROUND: Celiac disease is the most common hereditary autoimmune disease in humans. The only treatment option for non-refractory celiac disease patients is adherence to a strict life-long gluten-free diet, which often fails to normalize small bowel histology. ALV003 is a mixture of two proteases that degrades gluten and is in clinical development as an oral therapy for patients with celiac disease. AIMS: The safety, tolerability, and activity of ALV003 were assessed in two phase 1 clinical trials. METHODS: In study 1 (N = 28) the study drug was administered in the fasted state; in study 2 (N = 53) the study drug was administered together with a gluten-containing meal. Both studies were single-dose, single-blind, placebo-controlled, cross-over trials. ALV003 was dosed at escalating dose levels by cohort (100, 300, 900, and 1,800 mg) and gastric samples were aspirated using a nasogastric tube. Adverse events, serum drug levels, and anti-drug antibody titers were measured. Gastric samples were assessed for ALV003 enzymatic activity over time (gastric pharmacokinetics) and gluten degradation (gastric pharmacodynamics). RESULTS: All doses were well tolerated, and no serious adverse events or allergic reactions were observed. Gastric aspirates collected 30 min following a meal showed that 100 and 300 mg ALV003 degraded 75 ± 10% (N = 8) and 88 ± 5% (N = 8), respectively, of one gram of wheat bread gluten. CONCLUSIONS: ALV003 is an orally active protease that appears to be stable in the fed stomach and degrades dietary gluten in this compartment. Single doses of oral ALV003 were not associated with serious adverse reactions.

Electroconvulsive therapy in an adolescent with autism and bipolar I disorder.

OBJECTIVES: We report a positive response to electroconvulsive therapy in a severely functionally impaired adolescent with autistic disorder and classic bipolar I disorder, including an episodic pattern of decreased need for sleep, hypersexuality, expansive and agitated affect, aggression, self-injury, and property destruction. METHODS: After ineffective trials of mood stabilizers and antipsychotics as well as inability to sustain a positive response to lithium due to medication noncompliance, a course of acute and maintenance electroconvulsive therapy was attempted. RESULTS: A marked and sustained improvement across all symptom categories, as measured by directly observed frequency counts of target behaviors in an inpatient setting, was obtained. CONCLUSIONS: Electroconvulsive therapy should be considered a potentially useful intervention in cases of children with autistic disorder and a severe comorbid affective disorder.

Mapping the time course of overt emotion dysregulation, self-injurious behavior, and aggression in psychiatrically hospitalized autistic youth: A naturalistic study.

Challenges with emotion dysregulation, self-injurious behavior (SIB), and aggression are common in autistic individuals. Prior research on the relationships between these behaviors is limited mainly to cross-sectional correlations of parent-report data. Understanding how emotion dysregulation, SIB, and aggression present and relate to one another in real-time could add to our understanding of the context and function of these behaviors. The present study examined the real-time occurrence and temporal relationships between these behaviors in 53 psychiatrically hospitalized autistic youth. Over 500 hours of behavioral observation occurred during everyday activities in the hospital. Start and stop times for instances of overt emotion dysregulation, SIB, and aggression were coded live using a custom mobile phone app. Results indicated large individual variability in the frequency and duration of these behaviors and their co-occurrence. Both SIB and aggression co-occurred with overt emotion dysregulation at above-chance levels, suggesting a role for emotional distress in the occurrence of these behaviors. However, there was substantial variability within and between individuals in co-occurrence, and SIB and aggression often (and for some individuals, almost always) occurred without overt emotion dysregulation. Relatedly, cross-recurrence quantitative analysis revealed that SIB and aggression preceded emotion dysregulation more often than emotion dysregulation preceded SIB and aggression. Future research, perhaps using ambulatory psychophysiological measures, is needed to understand whether emotion dysregulation may sometimes be present but not easily observed during SIB and aggression. LAY SUMMARY: This study provides insight into how overt emotion dysregulation (i.e., visible distress), aggression, and self-injury unfold in real-time for autistic individuals. Participants were 53 autistic youth staying in a psychiatric hospital. Research staff observed participants in everyday activities on the hospital unit and noted instances of aggression, self-injurious behavior, and emotion dysregulation. Results suggest that aggression and self-injury sometimes occur with visible signs of distress but also often occur without visible distress. In addition, observable distress was more common in the moments after these behaviors than in the moments before.

Long-Term Postoperative Total Knee Arthroplasty Flexion Scores in Relation to Body Mass Index.

Knee range of motion (ROM) is an important postoperative measure of total knee arthroplasty (TKA). There is conflicting literature whether patients who are obese have worse absolute ROM outcomes than patients who are not obese. This study analyzed whether preoperative body mass index (BMI) influences knee ROM after patients' primary TKA. A retrospective investigation was performed on patients, who underwent primary TKA at an academic institution, by one of three fellowship-trained adult reconstruction surgeons. Patients were stratified according to their preoperative BMI into nonobese (BMI < 30.0 kg/m2) and obese (BMI ≥ 30.0 kg/m2) classifications. Passive ROM was assessed preoperatively as well as postoperatively at patients' most recent follow-up visit that was greater than 2 years. Mann-Whitney U tests were performed to determine statistical significance at p-value <0.05 for ROM outcomes. No statistically significant differences were observed when ROM in the nonobese group was compared with ROM in the obese group both preoperatively (105.73 ± 11.58 vs. 104.14 ± 13.58 degrees, p-value = 0.417) and postoperatively (105.83 ± 14.19 vs. 104.49 ± 13.52 degrees, p-value = 0.777). Mean follow-up time for all patients was 4.49 ± 1.92 years. In conclusion, long-term postoperative ROM outcomes were similar between patients who were nonobese and patients who were obese.

Sex differences in the response to poly(ADP-ribose) polymerase-1 deletion and caspase inhibition after stroke.

BACKGROUND AND PURPOSE: Emerging data suggest that the molecular cell death pathways triggered by ischemic insults differ in the male and female brain. Cell death in males is initiated by poly(ADP-ribose) polymerase-1 (PARP-1) activation; however, manipulation of this pathway paradoxically increases ischemic damage in females. In contrast, females are exquisitely sensitive to caspase-mediated cell death. The effect of caspase inhibition in PARP-1 knockout mice was evaluated to determine if the detrimental effects of PARP deletion in females were secondary to increased caspase activation. METHODS: Focal stroke was induced by transient or permanent middle cerebral artery occlusion (MCAO) in wild-type (WT) and PARP-1(-/-) mice of both sexes. The pan-caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh), was administered 90 minutes after middle cerebral artery occlusion. Infarct size and neurological sores were assessed. Separate cohorts were used for protein analysis for PAR, Apoptosis inducing factor (AIF), caspase-9, and caspase-3. RESULTS: WT mice of both sexes had increased nuclear AIF after stroke compared to PARP-1(-/-) mice. PARP-1(-/-) females had higher mitochondrial cytochrome C and activated caspase-9 and -3 levels than WT female mice. PARP-1(-/-) females also had an increase in stroke-induced cytosolic cytochrome C release compared with WT females, which was not seen in males. Q-VD-OPh decreased caspase-9 in both males and females but only led to reduction of infarct in females. PARP-1(-/-) males had smaller infarcts, whereas PARP-1(-/-) females had larger strokes compared with WT. Q-VD-OPh significantly decreased infarct in both WT and PARP-1(-/-) females in both transient and permanent MCAO models, but had no effect in males. CONCLUSIONS: Deletion of PARP-1 reduces infarct in males but exacerbates injury in females. PARP-1(-/-) females have enhanced caspase activation. The detrimental effects of PARP loss in females can be reversed with caspase inhibition.

Insomnia subtypes and clinical impairment in hospitalized children with autism spectrum disorder.

LAY ABSTRACT: Insomnia subtypes are not well understood in the most severely affected children with autism spectrum disorder. We examined length of hospital stay, autism severity, nonverbal intelligence quotient, and behavioral functioning across insomnia subtypes in 427 psychiatrically hospitalized children with autism spectrum disorder (mean age = 12.8 ± 3.4; 81.3% male). Per parent report, 60% (n = 257) of children had at least one type of insomnia. The distribution of subtypes was difficulty falling asleep (26.1%, n = 67), difficulty staying asleep (24.9%, n = 64), early morning awakening (4.3%, n = 11), and multiple insomnia symptoms (44.7%, n = 115). Difficulty staying asleep and early morning awakenings were associated with longer hospital stays. Early morning awakening was also associated with higher autism symptom severity. In general, children with difficulty staying asleep or multiple insomnia symptoms scored lower on adaptive behaviors (e.g. communication, self-care, socialization) and higher on maladaptive behaviors (e.g. irritability, hyperactivity, emotional reactivity, and emotional dysphoria). Difficulty staying asleep or having multiple insomnia symptoms appears to be most strongly related to impaired behavioral functioning. Conversely, early morning awakenings may be more closely tied with autism spectrum disorder itself. Further research is needed regarding insomnia subtypes at the severe end of the autism spectrum.