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This paper summarizes a conference held at the National Institute of Child Health and Human Development on December 6-7, 1999, on self-injurious behavior [SIB] in developmental disabilities. Twenty-six of the top researchers in the U.S. from this field representing 13 different disciplines discussed environmental mechanisms, epidemiology, behavioral and pharmacological intervention strategies, neurochemical substrates, genetic syndromes in which SIB is a prominent behavioral phenotype, neurobiological and neurodevelopmental factors affecting SIB in humans as well as a variety of animal models of SIB. Findings over the last decade, especially new discoveries since 1995, were emphasized. SIB is a rapidly growing area of scientific interest to both basic and applied researchers. In many respects it is a model for the study of gene-brain-behavior relationships in developmental disabilities.

Tobramycin concentrations have been determined in serum from capillary, venous and arterial blood samples taken from 16 patients during and after surgery. In 73 paired samples the concentrations in capillary samples were not significantly different from those measured in venous samples. The small concentration differences were neither dependent upon sampling time nor core-peripheral temperature differences. In 26 paired samples, concentrations in capillary samples were not significantly different from those determined in arterial samples. We conclude that concentrations in capillary samples are precise and unbiased estimators of venous concentrations and may be used in the adjustment of tobramycin dosage regimens. [ABSTRACT FROM AUTHOR]

Introduction: Prosthetic joint infection (PJI) is a catastrophic complication following arthroplasty surgery. Recently a debridement, antibiotics and implant retention (DAIR) procedure has gained popularity for PJI where a thorough debridement, irrigation and modular component exchange is undertaken., Method: We present the outcome for DAIR, data collected prospectively, in a busy orthopaedic unit but not one specialising in PJI. All patients with PJI were included without loss of data or patients from 2012 to 2018 with a minimum follow-up of 5 years., Results: Four total knee replacements, 17 total hip replacements, one revision total hip replacement and three hip hemiarthroplasties are included with an average duration from onset of symptoms to the DAIR procedure of 11 days (range 1-22 days). Staphylococcus aureus (24%) and Staphylococcus epidermidis (32%) were the most common causative organisms, and the most common antibiotic regimens included intravenous teicoplanin and flucloxacillin. Average follow-up was 67 months (range 9-104 months). Only four patients went on to require revision surgery. An analysis of midterm patient outcome measures for 6 of the total hip replacement (THR) DAIR patients were compared with a database of 792 THRs (with a minimum two-year follow-up) carried out by the same surgeon revealed no significant difference in Oxford hip scores at one-year post-surgery (OHS DAIR 36.2 vs 39 for control group)., Conclusion: This study includes 25 consecutive patients treated with DAIR with only one reinfection, with a mean follow-up period of 5 years. Using a strict protocol, DAIR appears to offer a successful treatment strategy for the management of early PJI.

Rationale: Intense exercise promotes fatigue and can impair cognitive function, particularly toward the end of competition when decision-making is often critical for success. For this reason, athletes often ingest caffeinated energy drinks prior to or during exercise to help them maintain focus, reaction time, and cognitive function during competition. However, caffeine habituation and genetic sensitivity to caffeine (CA) limit efficacy. Paraxanthine (PX) is a metabolite of caffeine reported to possess nootropic properties. This study examined whether ingestion of PX with and without CA affects pre- or post-exercise cognitive function., Methods: 12 trained runners were randomly assigned to consume in a double-blind, randomized, and crossover manner 400 mg of a placebo (PL); 200 mg of PL + 200 mg of CA; 200 mg of PL + 200 mg of PX (ENFINITY®, Ingenious Ingredients); or 200 mg PX + 200 mg of CA (PX+CA) with a 7-14-day washout between treatments. Participants donated fasting blood samples and completed pre-supplementation (PRE) side effects questionnaires, the Berg-Wisconsin Card Sorting Test (BCST), and the Psychomotor Vigilance Task Test (PVTT). Participants then ingested the assigned treatment and rested for 60 minutes, repeated tests (PRE-EX), performed a 10-km run on a treadmill at a competition pace, and then repeated tests (POST-EX). Data were analyzed using General Linear Model (GLM) univariate analyses with repeated measures and percent changes from baseline with 95% confidence intervals., Results: BCST correct responses in the PX treatment increased from PRE-EX to POST-EX (6.8% [1.5, 12.1], p  = 0.012). The error rate in the PL (23.5 [-2.8, 49.8] %, p  = 0.078) and CA treatment (31.5 [5.2, 57.8] %, p  = 0.02) increased from PRE-EX values with POST-EX errors tending to be lower with PX treatment compared to CA (-35.7 [-72.9, 1.4] %, p  = 0.059). POST-EX perseverative errors with PAR rules were significantly lower with PX treatment than with CA (-26.9 [-50.5, -3.4] %, p  = 0.026). Vigilance analysis revealed a significant interaction effect in Trial #2 mean reaction time values ( p  = 0.049, η p 2 = 0.134, moderate to large effect) with POST-EX reaction times tending to be faster with PX and CA treatment. POST-EX mean reaction time of all trials with PX treatment was significantly faster than PL (-23.2 [-43.4, -2.4] %, p  = 0.029) and PX+CA (-29.6 [-50.3, -8.80] %, p  = 0.006) treatments. There was no evidence that PX ingestion adversely affected ratings of side effects associated with stimulant intake or clinical blood markers., Conclusions: Results provide some evidence that pre-exercise PX ingestion improves prefrontal cortex function, attenuates attentional decline, mitigates cognitive fatigue, and improves reaction time and vigilance. Adding CA to PX did not provide additional benefits. Therefore, PX ingestion may serve as a nootropic alternative to CA.

Restricted, repetitive behaviors are common symptoms in neurodevelopmental disorders including autism spectrum disorder. Despite being associated with poor developmental outcomes, repetitive behaviors remain poorly understood and have limited treatment options. Environmental enrichment attenuates the development of repetitive behaviors, but the exact mechanisms remain obscure. Using the C58 mouse model of repetitive behavior, we performed diffusion tensor imaging to examine microstructural alterations associated with the development of repetitive behavior and its attenuation by environmental enrichment. The C57BL/6 mouse strain, which displays little or no repetitive behavior, was used as a control group. We observed widespread differences in diffusion metrics between C58 mice and C57BL/6 mice. In juvenile C58 mice, repetitive motor behavior displayed strong negative correlations with fractional anisotropy in multiple gray matter regions, whereas in young adult C58 mice, high repetitive motor behavior was most strongly associated with lower fractional anisotropy and higher radial diffusivity in the striatum. Environmental enrichment increased fractional anisotropy and axial diffusivity throughout gray matter regions in the brains of juvenile C58 mice and overlapped predominantly with cerebellar and sensory regions associated with repetitive behavior. Our results suggest environmental enrichment reduces repetitive behavior development by altering gray matter microstructure in the cerebellum, medial entorhinal cortex, and sensory processing regions in juvenile C58 mice. Under standard laboratory conditions, early pathology in these regions appears to contribute to later striatal and white matter dysfunction in adult C58 mice. Future studies should examine the role these regions play in the development of repetitive behavior and the relationship between sensory processing and cerebellar deficits and repetitive behavior., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Farmer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The aim of this study was to identify risk factors for abdominal aortic aneurysm (AAA) from the largest Welsh screening cohort to date. Patients were recruited from 1993 (to 2015) as part of the South East Wales AAA screening programme through general practitioners. Demographic data and risk factors were collected by means of a self-report questionnaire. Statistical tests were performed to determine whether associations could be observed between AAA and potential risk factors. Odds ratios (OR) were also calculated for each of the risk factors identified. A total of 6879 patients were included in the study. Two hundred and seventy-five patients (4.0%) presented with AAA, of which 16% were female and 84% were male. Patients with AAA were older than the (no AAA) control group (p < 0.0001). The following risk factors were identified for AAA: family history of AAA (p < 0.0001); history of vascular surgery (p < 0.0001), cerebrovascular accident (p < 0.0001), coronary heart disease (p < 0.0001), diabetes (p < 0.0001), medication (p = 0.0018), claudication (p < 0.0001), smoking history (p = 0.0001) and chronic obstructive pulmonary disorder (p = 0.0007). AAA is associated with classical vascular risk factors, in addition to other less-well-documented risk factors including previous vascular surgery. These findings have practical implications with the potential to improve future clinical screening of patients in order to reduce AAA mortality., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The mammalian target of rapamycin (mTOR), and specifically the mTOR complex 1 (mTORC1) is the central regulator of anabolism in skeletal muscle. Among the many functions of this kinase complex is the inhibition of the catabolic process of autophagy; however, less work has been done in investigating the role of autophagy in regulating mTORC1 signaling. Using an in vitro model to better understand the pathways involved, we activated mTORC1 by several different means (growth factors, leucine supplementation, or muscle contraction), alone or with the autophagy inhibitor NSC185058. We found that inhibiting autophagy with NSC185058 suppresses mTORC1 activity, preventing any increase in cellular protein anabolism. These decrements were the direct result of action on the mTORC1 kinase, which we demonstrate, for the first time, cannot function when autophagy is inhibited by NSC185058. Our results indicate that, far from being a matter of unidirectional action, the relationship between mTORC1 and the autophagic cascade is more nuanced, with autophagy serving as an mTORC1 input, and mTORC1 inhibition of autophagy as a form of homeostatic feedback to regulate anabolic signaling. Future studies of cellular metabolism will have to consider this fundamental intertwining of protein anabolism and catabolism, and how it ultimately serves to regulate muscle proteostasis., (© 2024. The Author(s).)

Background: Restricted repetitive behavior (RRB) is one of two behavioral domains required for the diagnosis of autism spectrum disorder (ASD). Neuroimaging is widely used to study brain alterations associated with ASD and the domain of social and communication deficits, but there has been less work regarding brain alterations linked to RRB., Methods: We utilized neuroimaging data from the National Institute of Mental Health Data Archive to assess basal ganglia and cerebellum structure in a cohort of children and adolescents with ASD compared to typically developing (TD) controls. We evaluated regional gray matter volumes from T1-weighted anatomical scans and assessed diffusion-weighted scans to quantify white matter microstructure with free-water imaging. We also investigated the interaction of biological sex and ASD diagnosis on these measures, and their correlation with clinical scales of RRB., Results: Individuals with ASD had significantly lower free-water corrected fractional anisotropy (FA T ) and higher free-water (FW) in cortico-basal ganglia white matter tracts. These microstructural differences did not interact with biological sex. Moreover, both FA T and FW in basal ganglia white matter tracts significantly correlated with measures of RRB. In contrast, we found no significant difference in basal ganglia or cerebellar gray matter volumes., Limitations: The basal ganglia and cerebellar regions in this study were selected due to their hypothesized relevance to RRB. Differences between ASD and TD individuals that may occur outside the basal ganglia and cerebellum, and their potential relationship to RRB, were not evaluated., Conclusions: These new findings demonstrate that cortico-basal ganglia white matter microstructure is altered in ASD and linked to RRB. FW in cortico-basal ganglia and intra-basal ganglia white matter was more sensitive to group differences in ASD, whereas cortico-basal ganglia FA T was more closely linked to RRB. In contrast, basal ganglia and cerebellar volumes did not differ in ASD. There was no interaction between ASD diagnosis and sex-related differences in brain structure. Future diffusion imaging investigations in ASD may benefit from free-water estimation and correction in order to better understand how white matter is affected in ASD, and how such measures are linked to RRB., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The extent to which patients with an abdominal aortic aneurysm (AAA) should exercise remains unclear, given theoretical concerns over the perceived risk of blood pressure-induced rupture, which is often catastrophic. This is especially pertinent during cardiopulmonary exercise testing, when patients are required to perform incremental exercise to symptom-limited exhaustion for the determination of cardiorespiratory fitness. This multimodal metric is being used increasingly as a complementary diagnostic tool to inform risk stratification and subsequent management of patients undergoing AAA surgery. In this review, we bring together a multidisciplinary group of physiologists, exercise scientists, anaesthetists, radiologists and surgeons to challenge the enduring 'myth' that AAA patients should be fearful of and avoid rigorous exercise. On the contrary, by appraising fundamental vascular mechanobiological forces associated with exercise, in conjunction with 'methodological' recommendations for risk mitigation specific to this patient population, we highlight that the benefits conferred by cardiopulmonary exercise testing and exercise training across the continuum of intensity far outweigh the short-term risks posed by potential AAA rupture., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The purpose of this study was to examine the effects of intermittent versus continuous energy restriction on body composition, resting metabolic rate, and eating behaviors in resistance-trained females. Thirty-eight resistance-trained females (mean ± standard deviation age: 22.3 ± 4.2 years) were randomized to receive either six weeks of a continuous 25% reduction in energy intake (n = 18), or one week of energy balance after every two weeks of 25% energy restriction (eight weeks total; n = 20). Participants were instructed to ingest 1.8 g protein/kilogram bodyweight per day and completed three weekly supervised resistance training sessions throughout the intervention. There were no differences between groups for changes over time in body composition, resting metabolic rate, or seven of the eight measured eating behavior variables (p > 0.05). However, a significant group-by-time interaction for disinhibition (p < 0.01) from the Three-Factor Eating Questionnaire was observed, with values (± standard error) in the continuous group increasing from 4.91 ± 0.73 to 6.17 ± 0.71, while values in the intermittent group decreased from 6.80 ± 0.68 to 6.05 ± 0.68. Thus, diet breaks do not appear to induce improvements in body composition or metabolic rate in comparison with continuous energy restriction over six weeks of dieting, but may be employed for those who desire a short-term break from an energy-restricted diet without fear of fat regain. While diet breaks may reduce the impact of prolonged energy restriction on measures of disinhibition, they also require a longer time period that may be less appealing for some individuals., Competing Interests: The authors declare no relevant financial conflicts of interest. B.I.C. was a member of the scientific advisory board for Dymatize Athletic Nutrition Institute at the time of the study's design and execution, but not at the time of submission of the manuscript for publication. E.T.T. earns income as a writer, practitioner, and consultant within the fitness industry., (Copyright: © Academy of Physical Education in Katowice.)

Background:  In the United Kingdom, the most common surgical approach for repair of open abdominal aortic aneurysms (AAAs) is transperitoneal (TP). However, retroperitoneal (RP) approach is favored in those with more complex vascular anatomy often requiring a cross-clamp on the aorta superior to the renal arteries. This study compared these approaches in patients matched on all major demographic, comorbid, anatomic, and physiological variables., Methods:  Fifty-seven patients (TP: n  = 24; RP: n  = 33) unsuitable for endovascular aneurysm repair underwent preoperative cardiopulmonary exercise testing prior to open AAA repair. The surgical approach undertaken was dictated by individual surgeon preference. Postoperative mortality, complications, and length of hospital stay (LoS) were recorded. Patients were further stratified according to infrarenal (IR) or suprarenal/supraceliac (SR/SC) surgical clamping. Systemic inflammation (C-reactive protein) and renal function (serum creatinine and estimated glomerular filtration rate) were recorded., Results:  Twenty-three (96%) of TP patients only required an IR clamp compared with 12 (36%) in the RP group. Postoperative systemic inflammation was lower in RP patients ( p  = 0.002 vs. TP) and fewer reported pulmonary/gastrointestinal complications whereas renal impairment was more marked in those receiving SR/SC clamps ( p  < 0.001 vs. IR clamp). RP patients were defined by lower LoS ( p  = 0.001), while mid-/long-term mortality was low/comparable with TP, resulting in considerable cost savings., Conclusion:  Despite the demands of more complicated vascular anatomy, the clinical and economic benefits highlighted by these findings justify the more routine adoption of the RP approach for complex AAA repair., Competing Interests: The authors declare no conflict of interest related to this article., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

In December 2020, the U.S. Food and Drug Administration (FDA) expanded the list of CFTR variants approved for treatment with CFTR modulators drugs from 39 to 183. Clinicians should be aware that individuals harboring certain variants approved for treatment may not respond to or benefit from this therapy. After review, the expert panel leading the CFTR2 project identified four categories of variants that may not result in a clinical response to modulator treatment: 15 variants assigned as non CF-causing; 45 variants of unknown significance; six variants known or suspected to cause mis-splicing as their primary defect rather than an amino acid substitution; and eight variants known to occur together in cis with another deleterious variant not expected to lead to CFTR protein (nonsense or frameshift). The potential risks and benefits of CFTR modulator therapy should be considered carefully for individuals harboring these variants., Competing Interests: Declaration of Competing Interest CC serves on advisory boards for Vertex Pharmaceuticals, Mylan, Chiesi Farmaceutici, and Actelion. GRC served as a consultant for Vertex Pharmaceuticals and has a relative employed by Vertex Pharmaceuticals. All other authors report none., (Copyright © 2022. Published by Elsevier B.V.)

Aims: "Get It Right First Time" (GIRFT) and NHS England's Best Practice Tariff (BPT) have published directives advising that patients over the ages of 65 (GIRFT) and 69 years (BPT) receiving total hip arthroplasty (THA) should receive cemented implants and have brought in financial penalties if this policy is not observed. Despite this, worldwide, uncemented component use has increased, a situation described as a 'paradox'. GIRFT and BPT do, however, acknowledge more data are required to support this edict with current policies based on the National Joint Registry survivorship and implant costs., Methods: This study compares THA outcomes for over 1,000 uncemented Corail/Pinnacle constructs used in all age groups/patient frailty, under one surgeon, with identical pre- and postoperative pathways over a nine-year period with mean follow-up of five years and two months (range: nine months to nine years and nine months). Implant information, survivorship, and regular postoperative Oxford Hip Scores (OHS) were collected and two comparisons undertaken: a comparison of those aged over 65 years with those 65 and under and a second comparison of those aged 70 years and over with those aged under 70., Results: Overall revision rate was 1.3% (13/1,004). A greater number of revisions were undertaken in those aged over 65 years, but numbers were small and did not reach significance. The majority of revisions were implant-independent. Single component analysis revealed a 99.9% and 99.6% survival for the uncemented cup and femoral component, respectively. Mean patient-reported outcome measures (PROMs) improvement for all ages outperformed the national PROMs and a significantly greater proportion of those aged over 65/69 years reached and maintained a meaningful improvement in their OHS earlier than their younger counterparts (p < 0.05/0.01 respectively)., Conclusion: This study confirms that this uncemented THA system can be used safely and effectively in patient groups aged over 65 years and those over 69 years, with low complication and revision rates. Cite this article: Bone Jt Open  2021;2(5):293-300.

Biocontrol using non-aflatoxigenic strains of Aspergillus flavus has the greatest potential to mitigate aflatoxin contamination in agricultural produce. However, factors that influence the efficacy of biocontrol agents in reducing aflatoxin accumulation under field conditions are not well-understood. Shifts in the genetic structure of indigenous soil populations of A. flavus following application of biocontrol products Afla-Guard and AF36 were investigated to determine how these changes can influence the efficacy of biocontrol strains in reducing aflatoxin contamination. Soil samples were collected from maize fields in Alabama, Georgia, and North Carolina in 2012 and 2013 to determine changes in the population genetic structure of A. flavus in the soil following application of the biocontrol strains. A. flavus L was the most dominant species of Aspergillus section Flavi with a frequency ranging from 61 to 100%, followed by Aspergillus parasiticus that had a frequency of <35%. The frequency of A. flavus L increased, while that of A. parasiticus decreased after application of biocontrol strains. A total of 112 multilocus haplotypes (MLHs) were inferred from 1,282 isolates of A. flavus L using multilocus sequence typing of the trpC, mfs , and AF17 loci. A. flavus individuals belonging to the Afla-Guard MLH in the IB lineage were the most dominant before and after application of biocontrol strains, while individuals of the AF36 MLH in the IC lineage were either recovered in very low frequencies or not recovered at harvest. There were no significant ( P > 0.05) differences in the frequency of individuals with MAT1-1 and MAT1-2 for clone-corrected MLH data, an indication of a recombining population resulting from sexual reproduction. Population mean mutation rates were not different across temporal and spatial scales indicating that mutation alone is not a driving force in observed multilocus sequence diversity. Clustering based on principal component analysis identified two distinct evolutionary lineages (IB and IC) across all three states. Additionally, patristic distance analysis revealed phylogenetic incongruency among single locus phylogenies which suggests ongoing genetic exchange and recombination. Levels of aflatoxin accumulation were very low except in North Carolina in 2012, where aflatoxin levels were significantly ( P < 0.05) lower in grain from treated compared to untreated plots. Phylogenetic analysis showed that Afla-Guard was more effective than AF36 in shifting the indigenous soil populations of A. flavus toward the non-toxigenic or low aflatoxin producing IB lineage. These results suggest that Afla-Guard, which matches the genetic and ecological structure of indigenous soil populations of A. flavus in Alabama, Georgia, and North Carolina, is likely to be more effective in reducing aflatoxin accumulation and will also persist longer in the soil than AF36 in the southeastern United States.

Historically, monitoring nematode movement and mortality in response to various potential nematicide treatments usually involved tedious manual microscopic analysis. High-content analysis instrumentation enables rapid and high-throughput collection of experimental data points on large numbers of individual worms simultaneously. The high-throughput platform outlined here should accelerate discovery of unique classes and types of promising lead molecules and sample types to control these plant pests. Also, the ability to automate the data analysis pipeline rather than relying on manual scoring reduces a potential source of data variance. Here we describe a high-throughput process based on high-content imaging. We demonstrate the use of time-lapse image acquisition to measure movement, and viability staining to confirm nematode mortality (versus paralysis) in targeted plant-pathogenic nematodes. We present screening results from a microbial-exudate library generated from approximately 2,300 microbial fermentations that demonstrate the robustness of this high-throughput process. The described methods should be applicable to other relevant nematode parasites with human, crop, or animal hosts., Competing Interests: The authors have read the journal's policy and the authors of this manucsript have the following competing interests: Novozymes NA provided support in the form of salaries for all authors. Novozymes NA is a commercial organization with interest in the eventual commercialization of products, specific data identifying the source strains for samples used for high throughput testing described in this manuscript was not allowed to be released. Beyond this specific data release, the authors did not alter our adherence to the PLOS ONE policies on sharing of data and materials.

Repetitive behaviors are seemingly purposeless patterns of behavior that vary little in form and are characteristic of many neurodevelopmental, psychiatric, and neurologic disorders. Our work has identified an association between hypofunctioning of the indirect basal ganglia pathway and the expression of repetitive behavior in the deer mouse model. In this study, we targeted indirect pathway cells of the striatum with single drugs and drug combinations that bind to dopamine D 2 , adenosine A 2A , and glutamate mGlu 5 receptors. These receptors function both individually and as receptor heteromers. We found that only the triple drug cocktail (L-741,626+CGS21680+CDPPB) that was designed to increase striatal indirect basal ganglia pathway cell function reduced repetitive behavior in adult male deer mice. No single drug or double drug combinations were effective at selectively reducing repetitive behavior. We found this triple drug cocktail reduced repetitive behavior in both short-acting and long-acting formulations and was effective throughout 7 days of daily administration. Conversely, another triple drug cocktail (quinpirole+SCH58261+MTEP) that was designed to further reduce striatal indirect basal ganglia pathway cell function caused a significant increase in repetitive behavior. Significant and behaviorally selective effects on repetitive behavior were only achieved with the triple drug cocktails that included doses of L-741,626 and quinpirole that have off-target effects (e.g., dopamine D 3 receptors). These data further a role for decreased indirect basal ganglia pathway activation in repetitive behavior and suggest that targeting these receptors and/or heteromeric complexes on the indirect pathway neurons of the striatum may offer pharmacotherapeutic benefit for individuals with repetitive behavior disorders., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Repetitive motor behaviors are common in neurodevelopmental, psychiatric and neurological disorders. Despite their prevalence in certain clinical populations, our understanding of the neurobiological cause of repetitive behavior is lacking. Likewise, not knowing the pathophysiology has precluded efforts to find effective drug treatments. Our comparisons between mouse strains that differ in their expression of repetitive behavior showed an important role of the subthalamic nucleus (STN). In mice with high rates of repetitive behavior, we found significant differences in dendritic spine density, gene expression and neuronal activation in the STN. Taken together, these data show a hypoglutamatergic state. Furthermore, by using environmental enrichment to reduce repetitive behavior, we found evidence of increased glutamatergic tone in the STN with our measures of spine density and gene expression. These results suggest the STN is a major contributor to repetitive behavior expression and highlight the potential of drugs that increase STN function to reduce repetitive behavior in clinical populations., (© 2018 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

New Findings: What is the central question of this study? To what extent cardiorespiratory fitness is impaired in patients with abdominal aortic aneurysmal (AAA) disease and corresponding implications for postoperative survival requires further investigation. What is the main finding and its importance? Cardiorespiratory fitness is impaired in patients with AAA disease. Patients with peak oxygen uptake of <13.1 ml O 2  kg -1  min -1 and ventilatory equivalent for carbon dioxide at anaerobic threshold ≥34 are associated with increased risk of postoperative mortality at 2 years. These findings demonstrate that cardiorespiratory fitness can predict mid-term postoperative survival in AAA patients, which may help to direct care provision., Abstract: Preoperative cardiopulmonary exercise testing is a standard assessment of cardiorespiratory fitness (CRF) and risk stratification. However, to what extent CRF is impaired in patients undergoing surgical repair of abdominal aortic aneurysm (AAA) disease and the corresponding implications for postoperative outcome requires further investigation. We measured CRF during an incremental exercise test to exhaustion using online respiratory gas analysis in patients with AAA disease (n = 124, aged 72 ± 7 years) and healthy sedentary control subjects (n = 104, aged 70 ± 7 years). Postoperative survival was examined for association with CRF, and threshold values were calculated for independent predictors of mortality. Patients who underwent preoperative cardiopulmonary exercise testing before surgical repair had lower CRF [age-adjusted mean difference of 12.5 ml O 2  kg -1  min -1 for peak oxygen uptake ( V ̇ O 2 peak ), P < 0.001 versus control subjects]. After multivariable analysis, both V ̇ O 2 peak and the ventilatory equivalent for carbon dioxide at anaerobic threshold ( V ̇ E / V ̇ C O 2 - AT ) were independent predictors of mid-term postoperative survival (2 years). Hazard ratios of 5.27 (95% confidence interval 1.62-17.14, P = 0.006) and 3.26 (95% confidence interval 1.00-10.59, P = 0.049) were observed for V ̇ O 2 peak  < 13.1 ml O 2  kg -1  min -1 and V ̇ E / V ̇ C O 2 - AT ≥ 34, respectively. Thus, CRF is lower in patients with AAA, and those with a V ̇ O 2 peak  < 13.1 ml O 2  kg -1  min -1 and V ̇ E / V ̇ C O 2 - AT ≥ 34 are associated with a markedly increased risk of postoperative mortality. Collectively, our findings demonstrate that CRF can predict mid-term postoperative survival in AAA patients, which may help to direct care provision., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

Scientists are beginning to understand more about the role of host genetics in individuals' responses to influenza virus exposure. This fictional case addresses a situation in which a health care organization proposes requiring all health care practitioners with direct patient care responsibilities to undergo mandatory genetic testing for genetic variants used to (1) predict individuals' responses to the influenza vaccine, (2) determine individual susceptibility to influenza infection, and (3) identify individuals at increased risk for severe disease. This commentary will discuss ethical and legal issues associated with use of genetic test results to determine employee work assignments during an influenza pandemic., (© 2018 American Medical Association. All Rights Reserved.)

Background: Cardiorespiratory fitness can inform patient care, although to what extent natural variation in CRF influences clinical practice remains to be established. We calculated natural variation for cardiopulmonary exercise test (CPET) metrics, which may have implications for fitness stratification., Methods: In a two-armed experiment, critical difference comprising analytical imprecision and biological variation was calculated for cardiorespiratory fitness and thus defined the magnitude of change required to claim a clinically meaningful change. This metric was retrospectively applied to 213 patients scheduled for colorectal surgery. These patients underwent CPET and the potential for misclassification of fitness was calculated. We created a model with boundaries inclusive of natural variation [critical difference applied to oxygen uptake at anaerobic threshold (V˙O 2 -AT): 11 ml O 2  kg -1  min -1 , peak oxygen uptake (V˙O 2 peak): 16 ml O 2  kg -1  min -1 , and ventilatory equivalent for carbon dioxide at AT (V̇ E /V̇CO 2 -AT): 36]., Results: The critical difference for V˙O 2 -AT, V˙O 2 peak, and V˙ E /V˙CO 2 -AT was 19%, 13%, and 10%, respectively, resulting in false negative and false positive rates of up to 28% and 32% for unfit patients. Our model identified boundaries for unfit and fit patients: AT <9.2 and ≥13.6 ml O 2  kg -1  min -1 , V˙O 2 peak <14.2 and ≥18.3 ml kg -1  min -1 , V˙ E /V˙CO 2 -AT ≥40.1 and <32.7, between which an area of indeterminate-fitness was established. With natural variation considered, up to 60% of patients presented with indeterminate-fitness., Conclusions: These findings support a reappraisal of current clinical interpretation of cardiorespiratory fitness highlighting the potential for incorrect fitness stratification when natural variation is not accounted for., (Copyright © 2018 British Journal of Anaesthesia. All rights reserved.)

Stereotyped motor behavior manifests as rhythmic, repetitive movements. It is common in several neurologic and psychiatric disorders where it is considered maladaptive. However, it also occurs early in typical development where it serves an adaptive function in the development of complex, controlled motor behavior. Currently, no framework accounts for both adaptive and maladaptive forms of motor stereotypy. We propose a conceptual model that implicates sensorimotor mechanisms in the phenomenology of adaptive and maladaptive stereotypy. The extensive structural and functional connectivity between sensory and motor neural circuits evidences the importance of sensory integration in the production of controlled movement. In support of our model, motor stereotypy in normative development occurs when the sensory and motor brain regions are immature and the infant has limited sensory and motor experience. With maturation and experience, complex movements develop and replace simple, stereotyped movements. This developmental increase in motor complexity depends on the availability of sensory feedback indicating that the integration of sensory information with ongoing movement allows individuals to adaptively cater their movements to the environmental context. In atypical development, altered neural function of sensorimotor circuitry may limit an individual's ability to integrate sensory feedback to adapt movements to appropriately respond to environmental conditions. Consequently, the motor repertoire would remain relatively simple, resulting in the persistence of motor stereotypy. A framework that considers motor stereotypy as a manifestation of low motor complexity resulting from poor sensorimotor integration has many implications for research, identification and treatment of motor stereotypy in a variety of developmental disorders.

Carotid endarterectomy (CEA) is a surgical procedure to remove stenotic atherosclerotic plaque from the origin of the carotid artery to reduce the risk of major stroke. Its impact on postoperative cognitive function (POCF) remains controversial; complicated, in part, by a traditional failure to account for practice effects incurred during consecutive psychometric testing. To address this for the first time, we performed psychometric testing (learning and memory, working memory, attention and information processing, and visuomotor coordination) in 15 male patients aged 68  ±  8 years with symptomatic carotid stenosis the day before and 24 h following elective CEA (two consecutive tests, 48 h apart). Multiple baselining was also performed in a separate cohort of 13 educationally, anthropometrically and age-matched controls (63  ±  9 years) not undergoing revascularization at identical time points with additional measures performed over a further 96 h (four consecutive tests, each 48 h apart). A single consecutive test in the control group resulted in progressive improvements in learning and memory, working memory, and attention and information ( P  <   0.05 vs. Test 1), with three tests required before cognitive performance stabilized. Following correction for practice effects in the patient group, CEA was associated with a deterioration rather than an improvement in learning and memory as originally observed ( P  <   0.05). These findings highlight the potential for the clinical misinterpretation of POCF unless practice effects are taken into account and provide practical recommendations for implementation within the clinical setting., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

New Findings: What is the central question of this study? To what extent focal abdominal aortic aneurysmal (AAA) disease is associated with systemic remodelling of the vascular tree remains unknown. The present study examined whether anatomical differences exist between distances of the intervisceral artery origins and AAA location/size in patients with disease compared with healthy patients. What is the main finding and its importance? Intervisceral artery distances were shown to be consistently greater in AAA patients, highlighting the systemic nature of AAA disease that extends proximally to the abdominal aorta and its branches. The anatomical description of the natural variation in visceral artery origins has implications for the design of stent grafts and planning complex open aortic surgery. The initial histopathology of abdominal aortic aneurysmal (AAA) disease is atherosclerotic, later diverting towards a distinctive dilating rather than occlusive aortic phenotype. To what extent focal AAA disease is associated with systemic remodelling of the vascular tree remains unknown. The present study examined whether anatomical differences exist between the intervisceral artery origins and AAA location/size in patients with AAA disease (AAA+) relative to those without (AAA-). Preoperative contrast-enhanced computerized tomograms were reviewed in 90 consecutive AAA+ patients scheduled for open repair who underwent an infrarenal (n = 45), suprarenal (n = 26) or supracoeliac clamp (n = 19). These were compared with 39 age-matched AAA- control patients. Craniocaudal measurements were recorded from the distal origin of the coeliac artery to the superior mesenteric artery and from the origin of the superior mesenteric artery to both renal artery origins. Serial blood samples were obtained for estimation of the glomerular filtration rate before and after surgery. Intervisceral artery origins were shown to be consistently greater in AAA+ patients (P < 0.05 versus AAA-), although unrelated to AAA diameter (P > 0.05). Postoperative renal function became progressively more impaired the more proximal the clamp placement (estimated glomerular filtration rate for supracoeliac < suprarenal < infrarenal clamps, P < 0.05). These findings highlight the systemic nature of AAA disease that extends proximally to the abdominal aorta and its branches. The anatomical description of the natural variation in visceral artery origins has implications for the design of stent grafts and planning complex open aortic surgery., (© 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.)

Caudate nucleus volume is enlarged in autism spectrum disorder (ASD) and is associated with restricted and repetitive behaviors (RRBs). However, the trajectory of caudate nucleus volume in RRBs of young children remains unclear. Caudate nucleus volume was measured in 36 children with ASD and 18 matched 2-3-year-old subjects with developmentally delayed (DD) at baseline (Time 1) and at 2-year follow-up (Time 2). The differential growth rate in caudate nucleus volume was calculated. Further, the relationships between the development of caudate nucleus volume and RRBs were analyzed. Our results showed that caudate nucleus volume was significantly larger in the ASD group at both time points and the magnitude of enlargement was greater at Time 2. The rate of caudate nucleus growth during this 2-year interval was faster in children with ASD than DD. Right caudate nucleus volume growth was negatively correlated with RRBs. Findings from this study suggest developmental abnormalities of caudate nucleus volume in ASD. Longitudinal MRI studies are needed to explore the correlation between atypical growth patterns of caudate nucleus and phenotype of RRBs., (Copyright © 2016. Published by Elsevier Ltd.)

Repetitive behavior refers to a highly heterogeneous set of responses associated with a wide range of conditions, including normative development. Treatment studies for aberrant repetitive behavior are limited although one promising approach involves conceptualizing such behavior as a generalized inflexibility or lack of variability in responding. Relatively little is known about the neurobiological mechanisms that mediate the development and expression of repetitive behavior, information critical to the design of effective pharmacotherapies, early interventions, and prevention strategies. We will review clinical findings in repetitive behavior as well as findings from animal models highlighting environmental factors and the role of cortical-basal ganglia circuitry in mediating the development and expression of these behaviors. Findings from animal models have included identification of a specific neural pathway important in mediating repetitive behavior. Moreover, pharmacological studies that support the importance of this pathway have led to the identification of novel potential therapeutic targets. Expanding the evidence base for environmental enrichment-derived interventions and focusing on generalized variability in responding will aid in addressing the broader problem of rigidity or inflexibility.