Development of Clinical Recommendations for Progressive Return to Activity After Military Mild Traumatic Brain Injury: Guidance for Rehabilitation Providers

Objective: Previously published mild traumatic brain injury (mTBI) management guidelines provide very general recommendations to return individuals with mTBI to activity. This lack of specific guidance creates variation in military rehabilitation. The Office of the Army Surgeon General in collaboration with the Defense and Veterans Brain Injury Center, a component center of the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, convened an expert working group to review the existing literature and propose clinical recommendations that standardize rehabilitation activity progression following mTBI

Use of a multi-level mixed methods approach to study the effectiveness of a primary care progressive return to activity protocol after acute mild traumatic brain injury/concussion in the military

The large number of U.S. service members diagnosed with concussion/mild traumatic brain injury each year underscores the necessity for clear and effective clinical guidance for managing concussion. Relevant research continues to emerge supporting a gradual return to pre-injury activity levels without aggravating symptoms; however, available guidance does not provide detailed standards for this return to activity process. To fill this gap, the Defense and Veterans Brain Injury Center released a recommendation for primary care providers detailing a step-wise return to unrestricted activity during the acute phase of concussion. This guidance was developed in collaboration with an interdisciplinary group of clinical, military, and academic subject matter experts using an evidence-based approach. Systematic evaluation of the guidance is critical to ensure positive patient outcomes, to discover barriers to implementation by providers, and to identify ways to improve the recommendation. Here we describe a multi-level, mixed-methods approach to evaluate the recommendation incorporating outcomes from both patients and providers. Procedures were developed to implement the study within complex but ecologically-valid settings at multiple military treatment facilities and operational medical units. Special consideration was given to anticipated challenges such as the frequent movement of military personnel, selection of appropriate design and measures, study implementation at multiple sites, and involvement of multiple service branches (Army, Navy, and Marine Corps). We conclude by emphasizing the need to consider contemporary approaches for evaluating the effectiveness of clinical guidance

Dissociating wanting and anticipated liking from consummatory liking in smokers with different levels of nicotine dependence

INTRODUCTION: Incentive Sensitisation theory suggests wanting and liking are dissociable concepts, with wanting, but not liking typically increasing with repeated drug use. Wanting is associated with anticipation of reward, whereas liking relates to pleasure derived from consummatory behaviour. However, numerous studies have conceptualised liking as an anticipatory cognition. This study explores whether levels of nicotine dependence differentially effect wanting and liking responses to smoking-related cues, and whether anticipated and consummatory liking are equivalent, and dissociable from wanting. METHOD: Heavy (HS, mean = 16 cigarettes/day) and light non-daily (LS, mean = 2 cigarettes/day) smokers completed wanting and anticipated liking questionnaires pre-, immediately post-exposure to smoking-related and neutral cues and at session-end. Consummatory liking was measured post-session, immediately after smoking. RESULTS: Wanting and anticipated liking responses were comparable. Smoking-related cues increased wanting and anticipated liking compared to neutral cues. This effect was maintained until session-end. No baseline differences were seen between HS and LS on wanting or anticipated liking, however after cue exposure, and at session-end, HS reported greater drug wanting and anticipated liking than LS. Conversely, HS and LS did not differ on consummatory liking. Analyses confirmed the relationship between wanting and anticipated liking was significantly stronger than wanting and consummatory liking or anticipated and consummatory liking. CONCLUSIONS: Wanting and anticipated liking appear to be overlapping constructs assessing expectations of reward, that are dissociable from consummatory liking. Furthermore, heavier smoking increases drug wanting, but not smoking pleasure. Future attempts to dissociate these concepts should ensure liking is measured during/immediately after consumption

Clinical-grade Detection of Microsatellite Instability in Colorectal Tumors by Deep Learning

Background and Aims: Microsatellite instability (MSI) and mismatch-repair deficiency (dMMR) in colorectal tumors are used to select treatment for patients. Deep learning can detect MSI and dMMR in tumor samples on routine histology slides faster and cheaper than molecular assays. But clinical application of this technology requires high performance and multisite validation, which have not yet been performed. Methods: We collected hematoxylin and eosin-stained slides, and findings from molecular analyses for MSI and dMMR, from 8836 colorectal tumors (of all stages) included in the MSIDETECT consortium study, from Germany, the Netherlands, the United Kingdom, and the United States. Specimens with dMMR were identified by immunohistochemistry analyses of tissue microarrays for loss of MLH1, MSH2, MSH6, and/or PMS2. Specimens with MSI were identified by genetic analyses. We trained a deep-learning detector to identify samples with MSI from these slides; performance was assessed by cross-validation (n=6406 specimens) and validated in an external cohort (n=771 specimens). Prespecified endpoints were area under the receiver operating characteristic (AUROC) curve and area under the precision-recall curve (AUPRC). Results: The deep-learning detector identified specimens with dMMR or MSI with a mean AUROC curve of 0.92 (lower bound 0.91, upper bound 0.93) and an AUPRC of 0.63 (range, 0.59–0.65), or 67% specificity and 95% sensitivity, in the cross-validation development cohort. In the validation cohort, the classifier identified samples with dMMR with an AUROC curve of 0.95 (range, 0.92–0.96) without image-preprocessing and an AUROC curve of 0.96 (range, 0.93–0.98) after color normalization. Conclusions: We developed a deep-learning system that detects colorectal cancer specimens with dMMR or MSI using hematoxylin and eosin-stained slides; it detected tissues with dMMR with an AUROC of 0.96 in a large, international validation cohort. This system might be used for high-throughput, low-cost evaluation of colorectal tissue specimens

Cohort profile : demographic and clinical characteristics of the MILESTONE longitudinal cohort of young people approaching the upper age limit of their child mental health care service in Europe

Purpose: The presence of distinct child and adolescent mental health services (CAMHS) and adult mental health services (AMHS) impacts continuity of mental health treatment for young people. However, we do not know the extent of discontinuity of care in Europe nor the effects of discontinuity on the mental health of young people. Current research is limited, as the majority of existing studies are retrospective, based on small samples or used non-standardised information from medical records. The MILESTONE prospective cohort study aims to examine associations between service use, mental health and other outcomes over 24 months, using information from self, parent and clinician reports. Participants: Seven hundred sixty-three young people from 39 CAMHS in 8 European countries, their parents and CAMHS clinicians who completed interviews and online questionnaires and were followed up for 2 years after reaching the upper age limit of the CAMHS they receive treatment at. Findings to date: This cohort profile describes the baseline characteristics of the MILESTONE cohort. The mental health of young people reaching the upper age limit of their CAMHS varied greatly in type and severity: 32.8% of young people reported clinical levels of self-reported problems and 18.6% were rated to be ‘markedly ill’, ‘severely ill’ or ‘among the most extremely ill’ by their clinician. Fifty-seven per cent of young people reported psychotropic medication use in the previous half year. Future plans: Analysis of longitudinal data from the MILESTONE cohort will be used to assess relationships between the demographic and clinical characteristics of young people reaching the upper age limit of their CAMHS and the type of care the young person uses over the next 2 years, such as whether the young person transitions to AMHS. At 2 years follow-up, the mental health outcomes of young people following different care pathways will be compared. Trial registration number: NCT03013595

Original Articles Current Recommendations for the Diagnosis and Treatment of Concussion in Sport: A Comparison of Three New Guidelines

Abstract Currently, there is considerable debate within the sports medicine community about the role of concussion and the risk of chronic neurological sequelae. This concern has led to significant confusion among primary care providers and athletic trainers about how to best identify those athletes at risk and how to treat those with concussion. During the first quarter of 2013, several new or updated clinical practice guidelines and position statements were published on the diagnosis, treatment, and management of mild traumatic brain injury/concussion in sports. Three of these guidelines were produced by the American Medical Society for Sports Medicine, The American Academy of Neurology, and the Zurich Consensus working group. The goal of each group was to clearly define current best practices for the definition, diagnosis, and acute and post-acute management of sports-related concussion, including specific recommendations for return to play. In this article, we compare the recommendations of each of the three groups, and highlight those topics for which there is consensus regarding the definition of concussion, diagnosis, and acute care of athletes suspected of having a concussion, as well as return-to-play recommendations

Role of a Cytoplasmic Dual-function Glycosyltransferase in O2 Regulation of Development in Dictyostelium*

In the social amoeba Dictyostelium, a terminal step in development is regulated by environmental O2. Prolyl 4-hydroxylase-1 (P4H1) was previously implicated in mediating the O2 signal, and P4H1-null cells require elevated O2 to culminate. The E3-ubiquitin ligase adaptor Skp1 is a P4H1 substrate, and here we investigate the function of PgtA, a dual function β3-galactosyltransferase/α2-fucosyltransferase that contributes the 2nd and 3rd sugars of the pentasaccharide cap formed on Skp1 hydroxyproline. Although pgtA-null cells, whose Skp1 contains only a single sugar (N-acetylglucosamine or GlcNAc), show wild-type O2 dependence of culmination, cells lacking AgtA, an α3-galactosyltransferase required to extend the trisaccharide, require elevated O2 as for P4H1-null cells. Skp1 is the only detectable protein modified by purified PgtA added to pgtA-null extracts. The basis for specificity of PgtA was investigated using native Skp1 acceptor glycoforms and a novel synthetic peptide containing GlcNAcα1,4-hydroxy(trans)proline. Cysteine-alkylation of Skp1 strongly inhibited modification by the PgtA galactosyltransferase but not the fucosyltransferase. Furthermore, native and synthetic Skp1 glycopeptides were poorly galactosylated, not processively fucosylated, and negligibly inhibitory, whereas the fucosyltransferase was active toward small substrates. In addition, the galactosyltransferase exhibited an atypical concentration dependence on UDP-galactose. The results provide the first evidence that Skp1 is the functional target of P4H1 in O2 regulation, indicate a gatekeeper function for the β3-galactosyltransferase in the PgtA dual reaction, and identify an unexpected P4H1-dependent yet antagonistic function for PgtA that is reversed by AgtA

Does Isolation of Enterococcus Affect Outcomes in Intra-Abdominal Infections?

Enterococci are isolated frequently as pathogens in patients with intra-abdominal infections (IAIs) and may predict poor clinical outcomes. It remains controversial whether enterococci warrant an altered treatment approach with regard to antimicrobial treatment. The study population was derived from the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial database. Through post hoc analysis subjects were stratified into two groups based on isolation of Enterococcus. Fifty subjects of the cohort (n = 518) had Enterococcus isolated. Uni-variable and multi-variable analyses were conducted to determine whether isolation of Enterococcus constituted an independent predictor of the pre-defined STOP-IT composite outcome (surgical site infection, recurrent IAI, or death) and the individual components of the composite outcome. From the cohort of 50 subjects, we identified 52 isolates of Enterococcus spp. with a predominance of Enterococcus faecalis (40%) followed by other Enterococcus spp. (37%) and Enterococcus faecium (17%). Baseline demographic characteristics were statistically similar between the two groups. Antibiotic utilization distribution remained balanced between the Enterococcus and no Enterococcus groups with the majority receiving piperacillin-tazobactam (62% and 54%, respectively). The groups had comparable infection characteristics including setting of acquisition (>50% community acquired) and origin of infection (predominantly colon or rectum). Individual and composite clinical outcomes were not different statistically between the Enterococcus and no Enterococcus groups: surgical site infection (10% vs. 7.5%; p = 0.53), recurrent IAI (20% vs. 14.1%; p = 0.26), death (2% vs. 1%; p = 0.40), and composite of all three (30% vs. 20.9%; p = 0.14], respectively. Multi-variable analysis revealed that isolation of Enterococcus did not predict independently the incidence of the composite outcome (odds ratio [OR] 1.53 [95% confidence interval {CI} = 0.78-3.01]; p = 0.22; c-statistic = 0.65; goodness of fit, p = 0.71). Enterococcus was not a more common pathogen in health-care-associated IAIs and was not an independent risk factor for the composite outcome. The isolation of Enterococcus from IAIs may not warrant an alternative treatment approach but larger studies are needed to validate these findings