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The yeast Saccharomyces cerevisiae has evolved to dominate grape juice fermentation. A suite of cellular properties, rapid nutrient depletion, production of inhibitory compounds and the metabolic narrowing of the niche, all enable a minor resident of the initial population to dramatically increase its relative biomass in the ecosystem. This dominance of the grape juice environment is fueled by a rapid launch of glycolysis and energy generation mediated by transport of hexoses and an efficient coupling of transport and catabolism. Fermentation occurs in the presence of molecular oxygen as the choice between respiratory or fermentative growth is regulated by the availability of sugar a phenomenon known as glucose or catabolite repression. Induction of the [GAR + ] prion alters the expression of the major hexose transporter active under these conditions, Hxt3, reducing glycolytic capacity. Bacteria present in the grape juice ecosystem were able to induce the [GAR + ] prion in wine strains of S. cerevisiae. This induction reduced fermentation capacity but did not block it entirely. However, dominance factors such as the rapid depletion of amino acids and other nitrogen sources from the environment were impeded enabling greater access to these substrates for the bacteria. Bacteria associated with arrested commercial wine fermentations were able to induce the prion state, and yeast cells isolated from arrested commercial fermentations were found to be [GAR + ] thus confirming the ecological relevance of prion induction. Subsequent analyses demonstrated that the presence of environmental acetic acid could lead to [GAR + ] induction in yeast strains under certain conditions. The induction of the prion enabled yeast growth on non-preferred substrates, oxidation and reduction products of glucose and fructose, present as a consequence of bacterial energy production. In native ecosystems prion induction never exceeded roughly 50-60% of the population of yeast cells suggesting that the population retains the capacity for maximal fermentation. Thus, the bacterial induction of the [GAR + ] prion represents a novel environmental response: the query of the environment for the presence of competing organisms and the biological decision to temper glucose repression and dominance and enter a metabolic state enabling coexistence.

GA Walker,1 M Xenophontos,2 LC Chen,3 KL Cheung2 1Clinical Oncology, East Midlands Deanery, 2Breast Surgery, School of Graduate Entry Medicine and Health; 3Medicine Use, School of Pharmacy, University of Nottingham, Nottingham, UK Abstract: Exemestane, a steroidal aromatase inhibitor, is licensed for postmenopausal patients with estrogen receptor (ER)-positive breast cancer as second-line therapy in metastatic disease following antiestrogen failure and as part of sequential adjuvant therapy following initial tamoxifen. This study is a systematic literature review, evaluating exemestane in different clinical settings. The Ovid Medline (1948–2012), Embase (1980–2012), and Web of Science (1899–2012) databases were searched. Forty-two relevant articles covering randomized controlled trials were reviewed for efficacy and safety, and three for adherence. With regard to efficacy in metastatic disease, exemestane is superior to megestrol acetate after progression on tamoxifen. There is evidence for noninferiority to fulvestrant (following a prior aromatase inhibitor) and to nonsteroidal aromatase inhibitors in the first-line setting. Combined use with everolimus is shown to be more efficacious than exemestane alone following previous aromatase inhibitor use. In the adjuvant setting, a switch to exemestane after 2–3 years of tamoxifen is superior to 5 years of tamoxifen. Exemestane is noninferior to 5 years of tamoxifen as upfront therapy, and may have a role as an extended adjuvant therapy. Used as neoadjuvant therapy, increased breast conservation is achievable. As chemoprevention, exemestane significantly reduces the incidence of breast cancer in “at-risk” postmenopausal women. Exemestane is associated with myalgias and arthralgias, as well as reduced bone mineral density and increased risk of fracture, which do not appear to persist at follow-up, with subsequent return to pretreatment values. Compared with tamoxifen, there is a reduced incidence of endometrial changes, thromboembolic events, and hot flashes. Limited evidence shows nonadherence in 23%–32% of patients. Evidence is growing in support of exemestane in all clinical settings. It is generally more efficacious and has a better safety profile than tamoxifen. How it compares with the nonsteroidal aromatase inhibitors remains to be established. Further studies are required on adherence to ensure that maximum benefit is obtained. Keywords: breast cancer, exemestane, review, adherence, metastatic, adjuvant

Objective: We examined post-concussion symptom presentation, exercise, and sleep among pediatric athletes who sustained concussion during the school year vs. summer months., Methods: We evaluated athletes 6-18 years old within 21-days of concussion. They reported symptoms (Health and Behavior Inventory), with cognitive/somatic domain sub-scores calculated, and indicated if they had exercised or experienced sleep problems since injury. We grouped patients by injury season: summer months (June-August) vs. school year (September-May)., Results: 350 patients (14.4 ± 2.4 years old; 37% female; initial visit 8.8 ± 5.3 days post-concussion) were seen for care: 24% sustained a concussion during summer months, 76% during the school year. Lower cognitive (median = 7 [IQR = 1, 15] vs. 9.5 [4, 17]; p  = 0.01), but not somatic (7 [2.5, 11] vs. 8 [4, 13]; p  = 0.06), HBI scores were observed for patients injured during the summer. Groups were similar in proportion exercising (16% vs 17%) and endorsing sleep problems (29% vs 31%). After adjustments, sustaining a concussion during the summer predicted total (β=-3.43; 95%CI = -6.50, -0.36; p  = 0.029) and cognitive (β = -2.29; 95%CI = -4.22, -0.36; p  = 0.02), but not somatic (β=-1.46; 95%CI = -2.84, -0.08; p  = 0.04), symptom severity., Conclusion: Pediatric patients with concussion may present with greater cognitive symptoms during the school year, compared to summer months.

Context: The abrupt cessation of school and sport participation during the COVID-19 pandemic may have negative implications for adolescent mental health., Objectives: To (1) compare mental, physical, and social health and behaviors during pandemic-related stay-at-home mandates with the same measures collected 1 to 2 years earlier and (2) evaluate the relationships between physical activity and sleep during the pandemic and changes in anxiety, fatigue, and peer relationships between assessment times., Design: Cohort study., Setting: Pediatric sports medicine center., Patients or Other Participants: A total of 39 high school athletes (25 adolescent girls, 14 adolescent boys; age = 16.2 ± 0.9 years)., Main Outcome Measure(s): Patient-Reported Outcome Measurement System anxiety, fatigue, and peer relationships short forms and the Pittsburgh Sleep Quality Index were completed twice (initial assessment in May 2018 or 2019, follow-up assessment in May or June 2020). Frequency and duration of physical activity and frequency of interaction with other individuals (family, peers, sport coaches, etc) were self-reported at follow-up assessment for the 2 weeks before school or sport closure and the 2 weeks before questionnaire completion., Results: Higher levels of anxiety (5.5 ± 4.0 versus 3.6 ± 3.4 points; P = .003) and fatigue (5.4 ± 3.7 versus 2.3 ± 2.5 points; P < .001) and worse sleep quality (6.6 ± 2.9 versus 4.3 ± 2.3 points; P < .001) were observed during the pandemic compared with previous assessments. Reductions in physical activity were noted between assessments (exercise duration: 86.4 ± 41.0 versus 53.8 ± 30.0 minutes; P < .001). Sleep quality but not physical activity during the pandemic predicted changes in fatigue (P = .03, β = 0.44 [95% CI = 0.06, 0.83]) and peer relationships (P = .01, β = -0.65 [95% CI = -1.16, -0.15]) from initial to follow-up assessment., Conclusions: Mental and physical health declined during stay-at-home mandates compared with assessments 1 to 2 years earlier. Physical activity behaviors and sources of social interaction underwent changes after school and sport cessation. Sleep quality may have provided some protection against declining adolescent mental health during the pandemic, although this relationship requires further investigation., (© by the National Athletic Trainers’ Association, Inc.)

We examined perceived risk of future sports injury and athlete burnout among uninjured adolescent athletes. Uninjured high school athlete participants completed the Athlete Burnout Questionnaire (ABQ) and a questionnaire assessing attitudes toward likelihood of sustaining a future sport-related injury. We compared ABQ responses between injury risk perception groups: those who expected injury versus those who did not. Half of the participants reported a somewhat/very high likelihood of future sport-related injury ( n = 98; 52% female; age = 15.3 ± 1.9 years), while the other half reported it was unlikely/not possible ( n = 98; 45% female; age = 15.3 ± 1.3 years). A significantly greater proportion of those in the expected injury group reported a history of bone/muscle/ligament/tendon injury (56% vs 24%; P < .001). Those in the expected injury group reported higher athlete burnout scores (median = 28 [interquartile range = 25-34] vs 25 [23-30]; P = .002). Adolescent athletes who reported they were likely to experience a future injury in their sport also reported greater levels of burnout.

Objectives: Researchers have recommended that youth athletes limit their practice volume to the number of hours/week that they are old in years. We examined sport perceptions, burnout, anxiety, and depressive symptoms among youth athletes who did and did not report playing more hours/week of organized sports than their age., Methods: Uninjured athletes aged 13-18 years old completed questionnaires documenting demographics, sport participation volume, health and injury history, depressive symptoms, anxiety, burnout, and sport perceptions during a pre-participation physical examination. We grouped participants as those who reported more hours/week in organized sports than their age (exceeds age/volume recommendation) vs. those who reported equal/less hours/week in organized sports than their age (meets age/volume recommendation)., Results: Of 161 participants, 21% (n = 33) were in the 'exceeds age/volume recommendation' group (age = 15.2 ± 1.3 years; 55% female; 18.7 ± 4.0 hours/week) and 79% (n = 128) were in the 'meets age/volume recommendation' group (age = 15.6 ± 1.2 years; 50% female; 10.2 ± 3.4 hours/week). A higher proportion of the 'exceeds age/volume recommendation' group agreed with the statement 'youth in my sport play too many games before college' than the 'meets age/volume recommendation' group (33% vs. 16%; p = 0.03). After adjusting for the effect of age, sport specialization level, and weight, exceeding age/volume recommendations was associated with the perception that youth in sports play too many games before college (aOR = 3.24; 95% CI = 1.26, 8.29; p = 0.01), while burnout (aOR = 0.99; 95% CI = 0.94, 1.06; p = 0.93), anxiety (aOR = 0.97; 95% CI = 0.84, 1.11; p = 0.65), and depressive symptoms (aOR = 0.90; 95% CI = 0.74, 1.10; p = 0.30) were not significantly related., Conclusion: Athletes who spend more hours in sport than their age appear to perceive their competition load during youth sports to be excessive. Coaches and providers should monitor athlete's training hours and perceptions of competition load to offer support and potentially prevent burnout development.

Background: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases., Methods: Urinary 11-dehydro-thromboxane B 2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values., Results: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg., Conclusions: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin., (© 2023. The Author(s).)

Objective: To determine the association between academic time loss postconcussion and vision symptoms/impairments among pediatric patients., Design: Cross-sectional., Setting: Sports medicine clinic., Patients: Pediatric patients seen for care in a sports medicine clinic between the ages 6 and 18 years (n = 212; mean age = 14.3, SD = 2.4 years; 48% female) were evaluated within 21 days of concussion (mean = 9.8, SD = 5.7 days)., Independent Variable: Patients were grouped based on academic time loss (missed >5 days vs ≤5 days of school) at their initial postconcussion evaluation., Outcome Measures: Patients rated concussion symptoms using the Health and Behavior Inventory (HBI) and underwent near point of convergence (NPC) testing. We compared groups on specific HBI symptom ratings of dizziness, blurry vision, seeing double, and light sensitivity, as well as NPC break and recovery point distances., Results: Two hundred twelve patients were included; n = 36 (17%) who reported missing >5 days of school. After adjusting for time since injury, parental education level, mechanism of injury, and preinjury anxiety, patients who reported missing >5 days of school had higher ratings of double vision (β = 0.27; 95% confidence interval [CI], 0.01-0.53; P = 0.04) and light sensitivity (β = 0.506; 95% CI, 0.061-0.951; P = 0.02), but not dizziness (β = 0.390; 95% CI, -0.047 to 0.827; P = 0.08) or blurry vision (β = 0.026; 95% CI, -0.352 to 0.404; P = 0.89)., Conclusion: Missing >5 days of school was associated with worse double vision and light sensitivity symptoms. Given the importance of vision in learning, assessing postconcussion vision symptoms may facilitate a successful return to school. Clinicians should assess a wide spectrum of vision-specific symptoms to ensure appropriate support during the return-to-school process., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Clinicians rely on objective concussion assessments that may be influenced by patient characteristics, creating difficulties in isolating the effect of concussion on patient function. The purpose of our study was to identify characteristics associated with performance on the Sport Concussion Assessment Tool 5 th edition (SCAT5) 10-word recall test following adolescent concussion. We evaluated patients seen for care within 14 days of concussion (n=125; 15.2±1.6 years of age, range=11-18 years; 46% female; 6.9±3.4 days post-concussion). Patient demographic (age, sex, medical and concussion history, etc.), injury (timing of presentation, symptom severity, sport-type, etc.), and clinical test (Modified Balance Error Scoring System [mBESS], tandem gait) characteristics were assessed, in addition to SCAT5 immediate and delayed memory testing using the 10-word recall list. Immediate and delayed recall performance was significantly associated with concussion symptom burden and cognitive accuracy during tandem gait, although effect sizes were notably small. Specific variables such as age, sex, diagnosis of ADD/ADHD, and performance on other clinical assessments were not significantly associated with recall performance after controlling for covariates. Further, the 10-word recall list demonstrates specific advantages over previously used 5-word lists by way of decreased ceiling effects and reduced interference of inherent patient characteristics., Competing Interests: Unrelated to this investigation, Dr. Howell has received research support from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R03HD094560, R01HD108133), the National Institute of Neurological Disorders And Stroke (R01NS100952, R43NS108823), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R13AR080451), 59th Medical Wing Department of the Air Force, MINDSOURCE Brain Injury Network, the Tai Foundation, and the Colorado Clinical and Translational Sciences Institute (UL1 TR002535-05) and he serves on the Scientific/Medical Advisory Board of Synaptek, LLC. The remaining authors have no conflicts of interest to declare., (Thieme. All rights reserved.)

Objective: To examine the association between dizziness and neck/shoulder pain after concussion and if differences in postural stability and oculomotor function exist among patients reporting dizziness with or without concurrent neck/shoulder pain., Design: Cross sectional., Setting: Sports medicine clinic., Patients: Pediatric patients ≤14 days post concussion., Interventions: N/A., Outcome Measures: Patients completed the Health and Behavior Inventory (HBI) symptom rating and separately rated neck/shoulder pain (scale 0-3; 0 = no pain). We grouped patients by HBI dizziness rating (0 = not-dizzy; 1-3 = dizzy) and compared neck/shoulder pain ratings between the groups. We then compared oculomotor and postural stability outcomes between dizzy patients with and without neck/shoulder pain., Results: We included 153 patients: dizzy (n = 100; age = 14.6 ± 2.2 years; 48% female) and not-dizzy (n = 53, age = 14.4 ± 3.1 years; 38% female). The dizzy group reported significantly higher neck/shoulder pain (1.4 ± 1.1 vs 0.5 ± 0.9 points, P < 0.001) and total symptom score (25.7 ± 11.2 vs 11.7 ± 9.3 points, P < 0.001) than the not-dizzy group. After adjusting for total symptom score and preinjury anxiety, depression, and migraines, dizziness was associated with higher odds of neck/shoulder pain (odds ratio = 1.9, 95% CI, 1.2-3.0; P = 0.004). No differences were observed between dizzy patients with and without neck/shoulder pain for near point of convergence (10.0 ± 7.5 vs 8.5 ± 6.7 cm, P = 0.43), modified Balance Error Scoring System (8.9 ± 5.5 vs 6.8 ± 4.7 errors, P = 0.09), or tandem gait (single-task: 26.0 ± 12.3 vs 24.2 ± 11.9 seconds, P = 0.56; dual-task: 35.1 ± 14.3 vs 35.6 ± 18.6 seconds, P = 0.90)., Conclusions: In concussion patients experiencing dizziness, evaluating neck/shoulder pain may help identify individuals who would benefit from cervical spine rehabilitation. However, other potential causes of dizziness should also be evaluated to facilitate timely recovery., Competing Interests: The remaining authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To determine if sleep quality, fatigue, anxiety, depressive symptoms, or perceptions of sport participation differ between high-, moderate-, and low-specialized high school athletes with or without prior injuries., Methods: During pre-participation physical examinations (PPE), high school athletes completed questionnaires on sport specialization level, history of time-loss orthopedic injury, perceptions of sport participation, as well as sleep quality (Pittsburgh Sleep Quality Index (PSQI)), fatigue, anxiety, and depressive symptoms (Patient-Reported Outcomes Measurement Information System (PROMIS®)). Athletes were grouped according to sport specialization level and history of prior time-loss orthopedic injury., Results: A total of 186 athletes completed the study: 49% (n = 92; mean age = 15.3 ± 2.0 yrs; 50% female) were low specialized, 34% (n = 64; mean age = 15.3 ± 1.3 yrs; 47% female) were moderately specialized, and 16% (n = 30; mean age = 15.7 ± 1.1 yrs; 57% female) were highly specialized. Groups were similar for demographics, training volume, and injury history. Compared to the moderate-specialization group, highly specialized athletes reported higher levels of fatigue (3.1 ± 3.7 vs. 1.5 ± 2.2; p = 0.02), anxiety (3.6 ± 4.1 vs. 1.8 ± 2.6; p = 0.02), and depressive symptoms (2.4 ± 4.0 vs. 0.8 ± 2.0; p = 0.02). No differences in psychometric ratings, sleep quality, or perceptions of sport participation were observed between the low/moderate- or low/high-specialization groups. We did not observe any significant differences between groups who did and did not report a history of prior time-loss orthopedic injury., Conclusions: Highly specialized high school athletes report higher levels of fatigue, more anxiety symptoms, and more depressive symptoms than their moderately specialized peers, despite no differences in training volume or injury history. Low specialized athletes did not differ from moderately specialized or highly specialized athletes in the aforementioned domains, and there were no differences in sleep quality across specialization groups. These findings add to the current body of literature on early sport specialization by illustrating the distinctive psychosocial implications of sport specialization and demonstrating the need for further prospective research.

Background: While healthcare and health outcome disparities have been studied across a variety of different injuries, their relation to concussion incidence and management are relatively understudied., Aim: The aim of this study was to evaluate the association between history of concussion or musculoskeletal injury, and family affluence and/or school-level measures of socioeconomic status., Methods: We conducted a cross-sectional study of adolescent athletes in a local school district. Adolescent athletes ( n = 192; mean age = 15.3, SD = 1.6 years; 49% female), who presented for a pre-participation physical evaluation reported concussion and injury history, and family affluence scale (FAS) scores. We also examined the percent of students on free/reduced lunch at each school compared to state averages. Independent variables, individual FAS score and school-based marker of socioeconomic status, were compared between those with and without a history of concussion and time-loss musculoskeletal injury., Results: Of the participants, 40 (21%) reported a history of concussion. Athletes with a concussion history had significantly lower FAS scores than athletes without a history of concussion (mean difference = 0.7, 95%CI = 0.1, 1.4; P = 0.027). There was no significant difference in FAS scores between those with and without a history of time-loss musculoskeletal injury (mean difference = 0.0, 95% CI = -0.5, 0.5; P = 0.97). Athletes with a history of concussion had a higher proportion of a prior time-loss musculoskeletal injury (68% vs. 32%; P < 0.001). After adjusting for age, school free-reduced lunch rate, and history of musculoskeletal injury, a lower FAS score was associated with concussion history (adjusted odds ratio = 0.79; 95% CI = 0.64, 0.96; P = 0.019). Concussion and musculoskeletal injury were not associated with school-level markers of socioeconomic status., Conclusion: Lower individual measures, but not school-level measures, of socioeconomic status were associated with a history of concussion in our sample of adolescent athletes., Relevance for Patients: Enhance providers' understanding of how socioeconomic factors may impact concussion history and empower providers to adequately screen for and provide concussion education to mitigate disparities., Competing Interests: The authors have no conflicts of interest relevant to this article to disclose., (Copyright: © 2022 Author(s).)

Background: The Veterans Health Administration COVID-19 (VACO) Index predicts 30-day all-cause mortality in patients with COVID-19 using age, sex and pre-existing comorbidity diagnoses. The VACO Index was initially developed and validated in a nationwide cohort of US veterans-we now assess its accuracy in an academic medical centre and a nationwide US Medicare cohort., Methods: With measures and weights previously derived and validated in US national Veterans Health Administration (VA) inpatients and outpatients (n=13 323), we evaluated the accuracy of the VACO Index for estimating 30-day all-cause mortality using area under the receiver operating characteristic curve (AUC) and calibration plots of predicted versus observed mortality in inpatients at a single US academic medical centre (n=1307) and in Medicare inpatients and outpatients aged 65+ (n=427 224)., Results: 30-day mortality varied by data source: VA 8.5%, academic medical centre 17.5%, Medicare 16.0%. The VACO Index demonstrated similar discrimination in VA (AUC=0.82) and academic medical centre inpatient population (AUC=0.80), and when restricted to patients aged 65+ in VA (AUC=0.69) and Medicare inpatient and outpatient data (AUC=0.67). The Index modestly overestimated risk in VA and Medicare data and underestimated risk in Yale New Haven Hospital data., Conclusions: The VACO Index estimates risk of short-term mortality across a wide variety of patients with COVID-19 using data available prior to or at the time of diagnosis. The VACO Index could help inform primary and booster vaccination prioritisation, and indicate who among outpatients testing positive for SARS-CoV-2 should receive greater clinical attention or scarce treatments., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Existing data suggest that after concussion, athletes experience an increased risk of subsequent injury. Exploring methods that may reduce injury risk after successful postconcussion return to play may lead to new treatment approaches., Purpose: To examine the efficacy of a neuromuscular training (NMT) intervention on acute sports-related time-loss injury over the subsequent year relative to standard of care., Study Design: Randomized clinical trial; Level of evidence, 1., Methods: A total of 27 youth athletes were assessed initially postconcussion (median, 7 days postconcussion; interquartile range [IQR], 5-10) and after return-to-play clearance (median, 40 days postconcussion; IQR, 15-52). After return-to-play clearance, they were randomly assigned to NMT intervention (n = 11; mean ± SD age, 14.7 ± 1.7 years; 36% female) or standard of care (n = 16; mean ± SD age, 15.3 ± 1.8 years; 44% female). The intervention (duration, 8 weeks; frequency, 2 times per week) included guided strength exercises with landing stabilization focus. Standard of care received no recommendations. For the subsequent year, athletes prospectively completed a monthly log of sports-related injuries and organized sports competitions., Results: During the first year after postconcussion return-to-play clearance, sports-related time-loss injuries were more common among standard of care relative to NMT intervention (75% [95% CI, 48%-93%] vs 36% [95% CI, 11%-69%]). After adjusting for age and sex, the hazard of subsequent injury in the standard-of-care group was 3.56 times (95% CI, 1.11-11.49; P = .0334) that of the NMT intervention group. Sports participation was similar between NMT intervention and standard of care during the year-long monitoring period (hours of organized sports per month; median, 12 [IQR, 2.6-32.1] vs 15.6 [IQR, 3.5-105.9]; P = .55). The age- and sex-adjusted incidence of injuries was 10.2 per 1000 competitive exposures (95% CI, 3.7-28.4) in the standard-of-care group as opposed to 3.4 per 1000 (95% CI, 0.9-13.4) in the NMT intervention group. After adjusting for age and sex, incidence of injuries was higher for standard of care vs NMT intervention (rate ratio, 2.96 [95% CI, 0.89-9.85]; P = .076)., Conclusion: Although preliminary, our findings suggest that an NMT intervention initiated after return-to-play clearance may significantly reduce sports-related time-loss injuries over the subsequent year., Registration: NCT03917290 (ClinicalTrials.gov identifier).

Objectives: To examine kinesiophobia (i.e. fear of movement) among adolescent athletes with concussion compared to controls, and correlations of kinesiophobia with symptoms and reaction time., Design: Prospective cohort study., Methods: We evaluated 49 adolescent athletes twice. The concussion group was assessed within 14 days of injury and at return-to-play clearance. The control group was tested initially and approximately 28 days later. Participants completed Tampa Scale of Kinesiophobia, Post-Concussion Symptom Inventory, and clinical reaction time assessments., Results: We included 32 concussion participants (15 ± 2 years; 50% female) and 17 controls (16 ± 1 years; 47% female). Acutely (<14 days post-injury), the concussion group reported greater Tampa Scale of Kinesiophobia scores (38.5 ± 5.4 vs. 29.4 ± 6.7; p < 0.001; Cohen's d = 1.54), and a greater proportion of "high" (≥37) scores than controls (69% vs. 6%; p < 0.001). At return-to-play, there were no significant between-group differences (33.3 ± 6.5 vs. 30.8 ± 7.4; p = 0.23; Cohen's d = 0.36); 28% of the concussion group reported "high" Tampa Scale of Kinesiophobia scores. At return-to-play, kinesiophobia was significantly/moderately correlated with clinical reaction time for the concussion group (r = 0.50; p = 0.01)., Conclusions: Adolescents recovering from concussion commonly reported high kinesiophobia initially postconcussion, while 28% continued to report high kinesiophobia at return-to-play clearance. Additionally, a correlation between Tampa Scale of Kinesiophobia scores and clinical reaction time was observed for the concussion group. This finding would benefit from further study to determine potential perception-behavior relationships following concussion., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To determine the feasibility of an 8-week neuromuscular training program initiated upon return-to-play clearance following concussion., Design: Feasibility trial., Setting: A single sports medicine center., Participants: We approached n = 54 patients; n = 32 agreed to participate (59%). N = 27 participants returned for their second visit at return-to-play clearance (84%) and were randomized to neuromuscular training (n = 13) or standard-of-care (n = 14)., Main Outcome Measures: Participants completed three assessments: within 14 days post-concussion, immediately after return-to-play clearance, and 8-weeks following return-to-play clearance. The intervention aimed to achieve positive neuromuscular adaptations and occurred 2x/week for 8 weeks under supervision., Results: N = 2 participants randomized to the intervention elected not to participate, both due to schedule conflicts (e.g., time required to meet with the study team). Participants began the intervention an average of 11 days after return-to-play clearance, the majority (91%) completed >75% of training sessions, and training sessions lasted an average of 18.2 ± 4.8 min. One participant stopped the intervention after 7 training sessions due to time availability., Conclusion: It is feasible to initiate a neuromuscular training program for most athletes shortly after returning to play following concussion. Clinicians and researchers may consider this approach to mitigate the increased musculoskeletal injury risk for concussion patients returning to sports., Competing Interests: Declaration of competing interest This study was funded by the Children's Hospital Colorado Research Institute Pilot Award Program. Separate from this study, Dr. Howell has received research support from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R03HD094560), the National Institute of Neurological Disorders And Stroke (R01NS100952, R03HD094560, and R43NS108823), and MINDSOURCE Brain Injury Network. The remaining authors have no conflicts to disclose. We would like to thank Jillian Descoteaux, PhD, ATC, and Scott Long, MS, ATC for their assistance in performing the intervention training., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Real-time process metrics are standard for the majority of fermentation-based industries but have not been widely adopted by the wine industry. In this study, replicate fermentations were conducted with temperature as the main process parameter and assessed via in-line Oxidation Reduction Potential (ORP) probes and at-line profiling of phenolics compounds by UV-Vis spectroscopy. The California and Oregon vineyards used in this study displayed consistent vinification outcomes over five vintages and are representative of sites producing faster- and slower-fermenting musts. The selected sites have been previously characterized by fermentation kinetics, elemental profile, phenolics, and sensory analysis. ORP probes were integrated into individual fermentors to record how ORP changed throughout the fermentation process. The ORP profiles generally followed expected trends with deviations revealing previously undetectable process differences between sites and replicates. Site-specific differences were also observed in phenolic and anthocyanin extraction. Elemental composition was also analyzed for each vineyard, revealing distinctive profiles that correlated with the fermentation kinetics and may influence the redox status of these wines. The rapid ORP responses observed related to winemaking decisions and yeast activity suggest ORP is a useful process parameter that should be tracked in addition to Brix, temperature, and phenolics extraction for monitoring fermentations.

Concussion management has evolved to de-emphasize rest in favor of early introduction of post-injury physical activity. However, the optimal quantity, frequency and intensity of physical activity are unclear. Our objective was to examine the association between objective physical activity metrics and clinical recovery after concussion. We prospectively enrolled a cohort of 32 youth athletes with concussion, evaluated within 14 days of injury and after return-to-play (RTP) clearance. For two weeks after enrollment, we quantified steps/day and exercise frequency, duration, and intensity via wrist-worn actigraphy. We grouped participants by RTP clearance timing (<28 days vs. ≥28 days). Seventeen (53%) participants required ≥28 days post-concussion for RTP clearance. Groups were similar in age (14.9 ± 1.9 vs. 15.4 ± 1.5 years; p = 0.38), proportion of females (47% vs. 40%; p = 0.69), and concussion history (59% vs. 47%; p = 0.49). During the study period, the RTP ≥ 28 days group took fewer steps/day (8158 ± 651 vs. 11,147 ± 4013; p = 0.02), exercised fewer days/week (2.9 ± 2.4 vs. 5.0 ± 1.9 days/week; p = 0.01), and exercised fewer total minutes/week (117 ± 122 vs. 261 ± 219 min/week; p = 0.03). Furthermore, we observed ≥10,251 average steps/day, ≥4 exercise sessions/week, and exercising ≥134 total minutes/week were optimal cutpoints to distinguish between groups. These findings support the benefit of physical activity during concussion recovery.

Significance: Concussions are complex injuries that require a multifaceted testing battery. Vision impairments are common after concussion, but it is unknown exactly how eye tracking may be affected after injury and how it is associated with other clinical concussion assessments., Purpose: This study aimed to (1) examine the relationship between eye tracking performance (BOX score) and other common concussion evaluations, (2) identify if eye tracking adds novel information that augments baseline concussion evaluations, and (3) examine the effect of age, concussion history, and attention-deficit/hyperactivity disorder on eye tracking and other ophthalmological measures., Methods: A total of 102 male high school football athletes (age, 16.0 years; 95% confidence interval, 15.8 to 16.2 years) completed a series of visual and neurocognitive tests during their pre-season baseline assessment. The main outcome measures were BOX score, near point of convergence (NPC) distance, binocular accommodative amplitude (BAA) distance, Standardized Assessment of Concussion score, and Immediate Post-Concussion Assessment and Cognitive Testing composite scores., Results: BOX score was not significantly associated with symptoms, Standardized Assessment of Concussion score, NPC distance, BAA distance, or any Immediate Post-Concussion Assessment and Cognitive Testing composite scores. Age, concussion history, attention-deficit/hyperactivity disorder, and number of prior years playing football were not significantly associated with BOX score or NPC distance, but there was a significant association between concussion history and greater BAA distance (β = 1.60; 95% confidence interval = 0.19 to 3.01; P < .03). The BOX score cutoff of 10 resulted in a 12% false-positive rate., Conclusions: Eye tracking was not significantly associated with the commonly used clinical concussion assessments. These results suggest that an objective eye tracking variable may be a valuable addition to the current concussion battery., Competing Interests: Conflict of Interest Disclosure: The authors declare no conflicts of interest related to this study. WPM receives royalties from (1) ABC-CLIO publishing for the sale of his books, Kids, Sports, and Concussion: A Guide for Coaches and Parents, and Concussions; (2) Springer International for the book Head and Neck Injuries in Young Athlete; and (3) Wolters Kluwer for working as an author for UpToDate. His research is funded, in part, by philanthropic support from the National Hockey League Alumni Association through the Corey C. Griffin Pro-Am Tournament and the National Football League. DRH receives research support from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R03HD094560) and the National Institute of Neurological Disorders and Stroke (R01NS100952 and R41NS103698) of the National Institutes of Health. He has previously received research support from a research contract between Boston Children's Hospital, Cincinnati Children's Hospital Medical Center; ElMindA Ltd.; and the Eastern Athletic Trainers Association, Inc., (Copyright © 2021 American Academy of Optometry.)

Our purpose was to compare the clinical and injury characteristics of concussion patients with a receded near point of convergence (NPC) vs those without a receded NPC. Concussion patients were seen within 14 days of injury. We compared those with receded a NPC (>6 cm) break point distance and those with a normal NPC distance on symptom, behavioral, and clinical assessments. We also compared NPC break points between those who did/did not recover within 28 days of injury. 123 patients completed the assessment. 77/123 (63%) of participants demonstrated a receded NPC when tested within 14 days of injury. Those with receded a NPC break point (n = 77; mean = 14.9, SD = 1.5 years; 47% female) were significantly younger than those with a normal NPC break point (n = 46; mean = 15.7, SD = 1.7 years; 46% female). The receded NPC break point group had a significantly greater proportion of patients reporting headaches (86% vs. 61%), as well as significantly greater cognitive (mean = 13.4, SD = 8.7 vs. mean = 8.8, SD = 8.6), somatic (mean = 10.0, SD = 5.9 vs. mean = 6.9, SD = 6.6), and overall (mean = 23.7, SD = 13.6 vs. mean = 15.8, SD = 14.4) symptom severity. Our multivariable model indicated among all potential predictor variables, more severe somatic symptoms were significantly associated with a greater NPC break point (β = 0.26; 95% CI = 0.01, 0.52). The group who went onto experience persistent symptoms had a significantly greater NPC break point at initial evaluation than those without persistent symptoms (mean = 9.7, SD = 7.5 cm vs. mean = 7.0, SD = 4.0 cm). Those with a receded NPC break point at initial evaluation showed an increased symptom burden, most notable with somatic symptoms, compared with those without a receded NPC break point., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The tandem gait test has gained interest recently for assessment of concussion recovery. The purpose of our study was to determine the prognostic and diagnostic use of the single- and dual-task tandem gait test, alongside other clinical measures, within 10 days of pediatric concussion., Methods: We assessed 126 patients post-concussion (6.3 ± 2.3 days post-injury, mean ± SD) at a pediatric sports medicine clinic and compared them to 58 healthy controls (age: 15.6 ± 1.3 years; 43% female). We also compared the 31 patients with concussion who developed persistent post-concussion symptoms (PPCS) (age = 14.9 ± 2.0 years; 48% female) to the 81 patients with concussion who did not develop PPCS following the initial assessment (age: 14.1 ± 3.0 years; 41% female). All subjects completed a test battery, and concussion patients were monitored until they experienced concussion-symptom resolution. The test battery included tandem gait (single-task, dual-task (performing tandem gait while concurrently completing a cognitive test) conditions), modified Balance Error Scoring System (mBESS), and concussion symptom assessment (Health and Behavior Inventory). We defined PPCS as symptom resolution time > 28 days post-concussion for the concussion group. Measurement outcomes included tandem gait time (single- and dual-task), dual-task cognitive accuracy, mBESS errors (single/double/tandem stances), and symptom severity., Results: The concussion group completed the single-task (mean difference = 9.1 s, 95% confidential interval (95%CI): 6.1-12.1) and dual-task (mean difference = 12.7 s, 95%CI: 8.7-16.8) tandem gait test more slowly than the control group. Compared to those who recovered within 28 days of concussion, the PPCS group had slower dual-task tandem gait test times (mean difference = 7.9 s, 95%CI: 2.0-13.9), made more tandem-stance mBESS errors (mean difference = 1.3 errors, 95%CI: 0.2-2.3), and reported more severe symptoms (mean difference = 26.6 Health and Behavior Inventory rating, 95%CI: 21.1-32.6)., Conclusion: Worse dual-task tandem gait test time and mBESS tandem stance performance predicted PPCS in pediatric patients evaluated within 10 days of concussion. Tandem gait assessments may provide valuable information augmenting common clinical practices for concussion management., (Copyright © 2020. Production and hosting by Elsevier B.V.)

Our objective was to examine the association between participant-reported family affluence and sport specialization level. We conducted a cross-sectional investigation of adolescent athletes. Specifically, participants completed a level of sport specialization (low/moderate/high) questionnaire and the Family Affluence Scale. The majority (52%) of the 195 youth athlete participants reported low, 33% reported moderate, and 15% reported high sport specialization. Sport specialization groups were similar in age (mean = 15.3 ± 1.6 years), proportion of females (49%), and time spent training (mean = 11.9 ± 5.0 hours per week). The high sport specialization group reported significantly greater family affluence than the low sport specialization group (Family Affluence Scale = 10.4 ± 1.7 vs 9.2 ± 1.9; P = .005). After covariate adjustment, higher levels of sport specialization remained significantly associated with greater family affluence (β = 0.48, 95% confidence interval = 0.11-0.86). Understanding the relationship between family affluence and sports specialization affords an opportunity to better identify and monitor populations likely to specialize in a single sport during high school.

Purpose: To examine the effect of age on postural control outcomes among patients being seen during their initial post-concussion clinical visit., Methods: Youth patients were seen≤14 days post-concussion, and completed a series of postural control evaluations: tandem gait, Romberg, and Balance Error Scoring System (BESS) tests., Results: We included 109 children 8-12 years of age (24% female, evaluated median = 7 [interquartile range = 4-10] days post-injury) and 353 adolescents aged 13-18 years (36% female, evaluated median = 7 [4-10] days post-injury). There was a higher proportion of children who demonstrated abnormal tandem gait relative to adolescents (26% vs. 11%; p < 0.001). They also made more BESS errors in single (median = 5 [2-10] vs. 4 [2-6] errors) and tandem (median = 3 [1-6] vs. 2 [0-4]) firm stances. After covariate adjustment, children demonstrated worse tandem gait (adjusted odds ratio = 3.05, 95% CI = 1.68-5.53) and more firm surface BESS errors (double stance β=0.51, 95% CI = 0.22-0.80; single stance β= 1.18, 95% CI = 0.42-1.95; tandem stance β= 0.98, 95% CI = 0.28-1.68) than adolescents., Conclusions: Tandem gait and BESS performance following concussion differ in children compared to adolescents who present within 2 weeks of injury. Clinicians assessing and managing concussion should recognize age differences in postural control performance when assessing those with concussion.

Establishment of the [ GAR + ] prion in Saccharomyces cerevisiae reduces both transcriptional expression of the HXT3 hexose transporter gene and fermentation capacity in high sugar conditions. We evaluated the impact of deletion of the HXT3 gene on the expression of [ GAR + ] prion phenotype in a vineyard isolate, UCD932, and found that changes in fermentation capacity were observable even with complete loss of the Hxt3 transporter, suggesting other cellular functions affecting fermentation rate may be impacted in [ GAR + ] strains. In a comparison of isogenic [ GAR + ] and [ gar - ] strains, localization of the Pma1 plasma membrane ATPase showed differences in distribution within the membrane. In addition, plasma membrane lipid composition varied between the two cell types. Oxygen uptake was decreased in prion induced cells suggesting membrane changes affect plasma membrane functionality beyond glucose transport. Thus, multiple cell surface properties are altered upon induction of the [ GAR + ] prion in addition to changes in expression of the HXT3 gene. We propose a model wherein [ GAR + ] prion establishment within a yeast population is associated with modulation of plasma membrane functionality, fermentation capacity, niche dominance, and cell physiology to facilitate growth and mitigate cytotoxicity under certain environmental conditions. Down-regulation of expression of the HXT3 hexose transporter gene is only one component of a suite of physiological differences. Our data show the [ GAR + ] prion state is accompanied by multiple changes in the yeast cell surface that prioritize population survivability over maximizing metabolic capacity and enable progeny to establish an alternative adaptive state while maintaining reversibility., (Copyright © 2020 Walker, Henderson, Luong, Block and Bisson.)

Objectives: We assessed the association between hours/week of sports participation and psychosocial outcomes among high school athletes. We hypothesized that more hours of participation would be associated with the lower levels of anxiety and depressive symptoms., Methods: Participants completed the Patient-reported Outcomes Measurement Information System (PROMIS) Pediatric Profile 25 quality of life and other questionnaires to assess sports participation, socioeconomic status, and health history. We evaluated the multivariable relationship between hours/week in sport and PROMIS scores while adjusting for the independent effect of age and varsity team status., Results: A total of 230 high school athletes participated in this study (mean=15.4±1.2 years of age). More hours/week playing sports were significantly associated with the lower levels of depressive symptoms (coefficient=-0.073, 95% CI=-0.137, -0.010; P=0.02). Sports participation was not significantly associated with any other psychosocial domain scores on the PROMIS questionnaire., Conclusion: More hours of sports participation were significantly associated with the lower depressive symptoms, but no other psychosocial domain. While our findings are cross-sectional, sport participation may play a role in attenuating symptoms of depression in high school athletes., Relevance for Patients: Sports participation may play a beneficial role in lessening depressive symptoms among healthy high school students., Competing Interests: Dr. Howell reports grants from Eunice Kennedy Shriver National Institute of Child Health and Human Development (R03HD094560), grants from the National Institute of Neurological Disorders and Stroke (R01NS100952 and R41NS103698), from Boston Children’s Hospital, Cincinnati Children’s Hospital Medical Center, and ElMindA Ltd., outside the submitted work. Dr. Albright reports personal fees from Arthrex Inc., personal fees from Wardlow Enterprises, personal fees from Gemini Medical, personal fees from DJO, LLC, outside the submitted work, and Dr. Albright gives 2-3 lectures per year at Arthrex events. No other authors have disclosures., (Copyright: © Whioce Publishing Pte. Ltd.)

Objectives: Since the recognition of borderline ovarian tumors (BOTs) in the 1970s, the management of this subset of epithelial ovarian tumors has presented a challenge to clinicians. The majority present at an early stage, but their diagnosis is often only made following surgery, hence the heterogeneity of surgical management. Borderline ovarian tumors are morphologically diverse, and their behavior is subsequently also heterogeneous. We aimed to assess recurrence rates and the rate of malignant transformation in patients diagnosed with BOT. Secondary objectives included a review of current management and assessment of tumor markers, stage, cyst dimensions, and the presence of micropapillary features as prognostic indicators of recurrence., Methods: This retrospective cohort study included all patients treated with BOT between 2000 and 2015 in the southeast region of Scotland. Clinical, surgicopathological, and follow-up data were collated. Data were analyzed with reference to recurrence and malignant transformation., Results: Two hundred seventy-five patients underwent treatment for BOT in the study period. Surgical management was highly variable. A diagnosis of recurrent/persistent BOT or ovarian malignancy following initial treatment of BOT was rare, with only 12 (4%) of 275 cases. There were 7 cases (3%) of ovarian malignancy. Advanced International Federation of Gynecology and Obstetrics stage was the most prominent prognostic factor. Elevated preoperative serum CA-125 and the presence of micropapillary features correlated with advanced stage at presentation. With a lack of clear guidance, follow-up was highly variable with a median of 43 months (0-136 months)., Conclusions: To our knowledge, this study is the largest BOT cohort in the United Kingdom. Recurrent disease is rare in optimally staged, completely resected, early-stage BOT, without high-risk features. Caution is needed in women electing not to undergo completion staging after diagnosis and in those opting for a fertility-preserving approach. Thorough informed consent and clear plans for surveillance and follow-up are needed with consideration of delayed completion surgery as appropriate.

Aim: Continuous hyperfractionated accelerated radiotherapy (CHART) remains an option to treat non-small cell lung cancer (NSCLC; NICE, 2011). We have previously published treatment outcomes from 1998-2003 across five UK centres. Here we update the UK CHART experience, reporting outcomes and toxicities for patients treated between 2003 and 2009., Materials and Methods: UK CHART centres were invited to participate in a retrospective data analysis of NSCLC patients treated with CHART from 2003 to 2009. Nine (of 14) centres were able to submit their data into a standard database. The Kaplan-Meier method estimated survival and the Log-rank test analysed the significance., Results: In total, 849 patients had CHART treatment, with a median age of 71 years (range 31-91), 534 (63%) were men, 55% had undergone positron emission tomography-computed tomography (PET-CT) and 26% had prior chemotherapy; 839 (99%) patients received all the prescribed treatment. The median overall survival was 22 months with 2 and 3 year survival of 47% and 32%, respectively. Statistically significant differences in survival were noted for stage IA versus IB (33.2 months versus 25 months; P = 0.032) and IIIA versus IIIB (20 months versus 16 months; P = 0.018). Response at 3 months and outcomes were significantly linked; complete response showing survival of 34 months against 19 months, 15 months and 8 months for partial response, stable and progressive disease, respectively (P < 0.001). Age, gender, performance status, prior chemotherapy and PET-CT did not affect the survival outcomes. Treatment was well tolerated with <5% reporting ≥grade 3 toxicity., Conclusion: In routine practice, CHART results for NSCLC remain encouraging and we have been able to show an improvement in survival compared with the original trial cohort. We have confirmed that CHART remains deliverable with low toxicity rates and we are taking a dose-escalated CHART regimen forward in a randomised phase II study of sequential chemoradiotherapy against other accelerated dose-escalated schedules., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

In Saccharomyces cerevisiae the process of transport of sugar substrates into the cell comprises a complex network of transporters and interacting regulatory mechanisms. Members of the large family of hexose (HXT) transporters display uptake efficiencies consistent with their environmental expression and play physiological roles in addition to feeding the glycolytic pathway. Multiple glucose-inducing and glucose-independent mechanisms serve to regulate expression of the sugar transporters in yeast assuring that expression levels and transporter activity are coordinated with cellular metabolism and energy needs. The expression of sugar transport activity is modulated by other nutritional and environmental factors that may override glucose-generated signals. Transporter expression and activity is regulated transcriptionally, post-transcriptionally and post-translationally. Recent studies have expanded upon this suite of regulatory mechanisms to include transcriptional expression fine tuning mediated by antisense RNA and prion-based regulation of transcription. Much remains to be learned about cell biology from the continued analysis of this dynamic process of substrate acquisition.

In experimental science, organisms are usually studied in isolation, but in the wild, they compete and cooperate in complex communities. We report a system for cross-kingdom communication by which bacteria heritably transform yeast metabolism. An ancient biological circuit blocks yeast from using other carbon sources in the presence of glucose. [GAR(+)], a protein-based epigenetic element, allows yeast to circumvent this "glucose repression" and use multiple carbon sources in the presence of glucose. Some bacteria secrete a chemical factor that induces [GAR(+)]. [GAR(+)] is advantageous to bacteria because yeast cells make less ethanol and is advantageous to yeast because their growth and long-term viability is improved in complex carbon sources. This cross-kingdom communication is broadly conserved, providing a compelling argument for its adaptive value. By heritably transforming growth and survival strategies in response to the selective pressures of life in a biological community, [GAR(+)] presents a unique example of Lamarckian inheritance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Incomplete revascularization (ICR) after percutaneous coronary intervention (PCI) is common and is associated with increased rates of rehospitalization, revascularization, and mortality. Adjunctive pharmacotherapy with ranolazine, an inhibitor of the late sodium current with anti-ischemic properties, may be effective in reducing recurrent events after PCI in patients with ICR., Trial Design: RIVER-PCI is a phase 3, randomized, double-blind, placebo-controlled, international event-driven clinical trial evaluating the efficacy of ranolazine in patients with a history of chronic angina and ICR after PCI. Approximately 2,600 participants with ICR post-PCI will be randomized in a 1:1 ratio to ranolazine or matched placebo within 14 days of an index PCI. The primary end point of the trial is time to the first occurrence of ischemia-driven revascularization or ischemia-driven hospitalization without revascularization. Participants will be followed up for a minimum of 1 year and until at least 720 confirmed primary end point events have occurred. Secondary end points include sudden cardiac death, cardiovascular death, myocardial infarction, and measures of quality of life and cost-effectiveness. The evaluation of long-term safety will include all-cause mortality, stroke, transient ischemic attack, and hospitalization for heart failure. Enrollment commenced in November 2011 and was completed in summer 2013., Conclusions: RIVER-PCI is a novel, large-scale, international, randomized, double-blind, placebo-controlled clinical trial evaluating the role of ranolazine in the long-term medical management of patients with ICR post-PCI., (© 2013.)

Background: Fever in patients can provide an important clue to the etiology of a patient's symptoms. Non-invasive temperature sites (oral, axillary, temporal) may be insensitive due to a variety of factors. This has not been well studied in adult emergency department patients. To determine whether emergency department triage temperatures detected fever adequately when compared to a rectal temperature., Methods: A retrospective chart review was made of 27 130 adult patients in a high volume, urban emergency department over an eight-year period who received first a non-rectal triage temperature and then a subsequent rectal temperature., Results: The mean difference in temperatures between the initial temperature and the rectal temperature was 1.3 °F (P<0.001), with 25.9% of the patients having higher rectal temperatures ≥2 °F, and 5.0% having higher rectal temperatures ≥4 °F. The mean difference among the patients who received oral, axillary, and temporal temperatures was 1.2 °F (P<0.001), 1.8 °F (P<0.001), and 1.2 °F (P<0.001) respectively. About 18.1% of the patients were initially afebrile and found to be febrile by rectal temperature, with an average difference of 2.5 °F (P<0.001). These patients had a higher rate of admission (61.4%, P<0.005), and were more likely to be admitted to the hospital for a higher level of care, such as an intensive care unit, when compared with the full cohort (12.5% vs. 5.8%, P<0.005)., Conclusions: There are significant differences between rectal temperatures and non-invasive triage temperatures in this emergency department cohort. In almost one in five patients, fever was missed by triage temperature.

Background: There are limited data on the safety of periprocedural heparin in acute ischemic stroke endovascular therapy., Methods: A post hoc analysis was performed on patients enrolled in the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial to compare baseline characteristics and clinical outcomes between patients who received periprocedural heparin (HEP(+)) with patients who did not receive periprocedural heparin (HEP(-)). Data on periprocedural heparin use or nonuse was collected on patients enrolled between February 1, 2006 and July 31, 2006., Results: Of 51 patients included in the analysis cohort, 24 (47%) received periprocedural heparin with a median dose of 3000 U. Baseline and procedural characteristics were similar between the 2 groups, although HEP(+) patients were more likely to have vertebral or basilar occlusion than HEP(-) patients (16.7% v 0%; P = .04). There was no significant difference in rates of hemorrhage, procedural complications, or 90-day mortality between the 2 groups. In multivariable analysis, a 90-day good outcome (modified Rankin scale score of 0-2) was associated with age (odds ratio [OR] 0.92; 95% confidence interval [CI] 0.86-0.98; P = .0104), final revascularization success (OR 6.86; 95% CI 1.39-33.81; P = .0179), and periprocedural heparin use (OR 5.89; 95% CI 1.34-25.92; P = .0189)., Conclusions: In this small subgroup of the Multi MERCI trial, periprocedural heparin use in acute ischemic stroke endovascular therapy was not associated with increased rates of intracerebral hemorrhage or 90-day mortality. The improved 90-day good outcome among patients undergoing mechanical thrombectomy combined with periprocedural heparin warrants further study in a larger cohort., (Copyright © 2012 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Present mechanical devices are unable to achieve recanalisation in up to 20-40% of large vessel occlusion strokes. We compared efficacy and safety of the Trevo Retriever, a new stent-like device, with its US Food and Drug Administration-cleared predecessor, the Merci Retriever., Methods: In this open-label randomised controlled trial, we recruited patients at 26 sites in the USA and one in Spain. We included adults aged 18-85 years with angiographically confirmed large vessel occlusion strokes and US National Institutes of Health Stroke Scale (NIHSS) scores of 8-29 within 8 h of symptom onset. We randomly assigned patients (1:1) with sequentially numbered sealed envelopes to thrombectomy with Trevo or Merci devices. Randomisation was stratified by age (≤68 years vs 69-85 years) and NIHSS scores (≤18 vs 19-29) with alternating blocks of various sizes. The primary efficacy endpoint, assessed by an unmasked core laboratory, was thrombolysis in cerebral infarction (TICI) scores of 2 or greater reperfusion with the assigned device alone. The primary safety endpoint was a composite of procedure-related adverse events. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01270867., Findings: Between Feb 3, 2011, and Dec 1, 2011, we randomly assigned 88 patients to the Trevo Retriever group and 90 patients to Merci Retriever group. 76 (86%) patients in the Trevo group and 54 (60%) in the Merci group met the primary endpoint after the assigned device was used (odds ratio 4·22, 95% CI 1·92-9·69; p(superiority)<0·0001). Incidence of the primary safety endpoint did not differ between groups (13 [15%] patients in the Trevo group vs 21 [23%] in the Merci group; p=0·1826)., Interpretation: Patients who have had large vessel occlusion strokes but are ineligible for (or refractory to) intravenous tissue plasminogen activator should be treated with the Trevo Retriever in preference to the Merci Retriever., Funding: Stryker Neurovascular., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Partly as a result of screening, increasing numbers of older patients are presenting with 'low risk' breast cancer: tumours from which the likelihood of breast cancer death is minute; even so, these patients have a measurable risk of local recurrence if conservative surgery is not followed by some form of adjuvant treatment. However, it must be acknowledged that any such treatment has no detectable impact upon survival, and the value of all such interventions must be considered in the context of the individual patient's non-cancer life expectancy and the complex psychosocial factors that affect older patients. If no impact on survival can be expected and the risk of local recurrence is high enough to warrant some post-operative treatment, the most powerful agent in this respect is radiotherapy. Whilst adjuvant endocrine treatment is becoming increasingly accepted as monotherapy in low risk patients, we propose that radiotherapy should not be forgotten as an alternative which, with its attendant benefits of shorter duration and high compliance, may be more suitable for a number of patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: To determine whether atrial fibrillation (AF) patients with mental health conditions (MHCs) were less likely than AF patients without MHCs to be prescribed warfarin and, if receiving warfarin, to maintain an International Normalized Ratio (INR) within the therapeutic range., Study Design: Detailed chart review of AF patients using a Veterans Health Administration (VHA) facility in 2003., Methods: For a random sample of 296 AF patients, records identified clinician-diagnosed MHCs (independent variable) and AF-related care in 2003 (dependent variables), receipt of warfarin, INR values below/above key thresholds, and time spent within the therapeutic range (2.0-3.0) or highly out of range. Differences between the MHC and comparison groups were examined using X2 tests and logistic regression controlling for age and comorbidity., Results: Among warfarin-eligible AF patients (n = 246), 48.5% of those with MHCs versus 28.9% of those without MHCs were not treated with warfarin (P = .004). Among those receiving warfarin and monitored in VHA, highly supratherapeutic INRs were more common in the MHC group; for example, 27.3% versus 1.6% had any INR >5.0 (P <.001). Differences persisted after adjusting for age and comorbidity., Conclusions: MHC patients with AF were less likely than those without MHC to have adequate management of their AF care. Interventions directed at AF patients with MHC may help to optimize their outcomes.

Ambrisentan is an endothelin type A (ET(A))-selective receptor antagonist that is metabolized primarily by glucuronidation but also undergoes oxidative metabolism by CYP3A4. The potential for ketoconazole, the archetypal strong inhibitor of CYP3A4, to alter the pharmacokinetic profile of ambrisentan and its oxidative metabolite, 4-hydroxymethyl ambrisentan, was assessed in an open-label, nonrandomized, 2-period, single-sequence study in 16 healthy men. Participants received a single dose of ambrisentan 10 mg alone and after 4 days of ketoconazole 400 mg administered once daily. In the presence of multiple doses of ketoconazole, single-dose ambrisentan AUC(0-infinity) estimate was increased by 35.3%, whereas C(max) was increased by 20.0%. For the 4-hydroxymethyl ambrisentan metabolite, AUC(0-infinity) estimate was decreased by 4.0%, whereas C(max) was decreased by 16.5%. Concomitant administration of ambrisentan and ketoconazole was well tolerated. In summary, ketoconazole had no clinically significant effect on the pharmacokinetics or safety profile of ambrisentan; therefore, no changes in ambrisentan dose should be necessary when the drug is administered concomitantly with known CYP3A4 inhibitors.

The superoxide radical (O(2)(-)) has long been considered a major cause of aging. O(2)(-) in cytosolic, extracellular, and mitochondrial pools is detoxified by dedicated superoxide dismutase (SOD) isoforms. We tested the impact of each SOD isoform in Caenorhabditis elegans by manipulating its five sod genes and saw no major effects on life span. sod genes are not required for daf-2 insulin/IGF-1 receptor mutant longevity. However, loss of the extracellular Cu/ZnSOD sod-4 enhances daf-2 longevity and constitutive diapause, suggesting a signaling role for sod-4. Overall, these findings imply that O(2)(-) is not a major determinant of aging in C. elegans.

In Caenorhabditis elegans, several manipulations that affect nutrition slow development, reduce fecundity, and increase life span. These are viewed as dietary restriction (DR) and include culture in semidefined, nutrient-rich liquid medium that is axenic (i.e., there is no microbial food source). Here we describe convenient ways to exert DR by culture on agar plates containing axenic medium. We used these to explore whether effects of axenic culture really reflect DR. Our results imply that major nutrient components of axenic medium, and overall caloric content, are not limiting for life span. However, adding growth-arrested Escherichia coli as an additional food source rescued the effects of axenic culture. We then sought to identify the component of E. coli that is critical for normal C. elegans nutrition using add-back experiments. Our results suggest that C. elegans has a nutritional requirement for live, metabolically active microbes or, possibly, an unidentified, heat-labile, nonsoluble component present in live microbes.

To investigate whether alterations in mitochondrial metabolism affect longevity in Drosophila melanogaster, we studied lifespan in various single gene mutants, using inbred and outbred genetic backgrounds. As positive controls we included the two most intensively studied mutants of Indy, which encodes a Drosophila Krebs cycle intermediate transporter. It has been reported that flies heterozygous for these Indy mutations, which lie outside the coding region, show almost a doubling of lifespan. We report that only one of the two mutants lowers mRNA levels, implying that the lifespan extension observed is not attributable to the Indy mutations themselves. Moreover, neither Indy mutation extended lifespan in female flies in any genetic background tested. In the original genetic background, only the Indy mutation associated with altered RNA expression extended lifespan in male flies. However, this effect was abolished by backcrossing into standard outbred genetic backgrounds, and was associated with an unidentified locus on the X chromosome. The original Indy line with long-lived males is infected by the cytoplasmic symbiont Wolbachia, and the longevity of Indy males disappeared after tetracycline clearance of this endosymbiont. These findings underscore the critical importance of standardisation of genetic background and of cytoplasm in genetic studies of lifespan, and show that the lifespan extension previously claimed for Indy mutants was entirely attributable to confounding variation from these two sources. In addition, we saw no effects on lifespan of expression knockdown of the Indy orthologues nac-2 and nac-3 in the nematode Caenorhabditis elegans., Competing Interests: Competing interests. The authors have declared that no competing interests exist.

A molecular mechanics study of small saturated hydrocarbons (up to C-6) substituted by up to six fluorines has been carried out with the MM4 force field. A parameter set has been developed for use in the calculation of bond lengths, bond angles, torsion angles, conformational energies, barriers to rotation, dipole moments, moments of inertia, and vibrational frequencies for these compounds. The results are mostly in fair to good agreement with experiment and ab initio calculations. The high electronegativity of fluorine leads to serious geometric consequences in these compounds, but these consequences can be dealt with adequately by suitable cross-terms in the force constant matrix, and by recognizing that some of the reference bond lengths and angles (l(0), theta(0)) and the corresponding stretching and bending constant parameters (k(s), k(theta)) that are usually thought of as constants must in fact be treated as functions of the electronegativity of the substituents. Additionally, the heavy mass of the fluorine (relative to the mass of hydrogen in alkanes) leads to large values for other cross-terms that were found to be unimportant in hydrocarbons. Conformational equilibria for polyfluorinated compounds are affected by the delta-two effect well-known in carbohydrates. A few larger fluorinated and polyfluorinated alkanes, including perfluoropropane, perfluorobutane, and Teflon, have also been studied.