Examination of Cognitive Function, Neurotrophin Concentrations, and both Brain and Systemic Inflammatory Markers Following a Simulated Game of American Football.

ABSTRACT: Hoffman, JR, Ostfeld, I, Zamir, A, Amedi, R, Fonville, TR, Horstemeyer, MF, and Gepner, Y. Examination of cognitive function, neurotrophin concentrations, and both brain and systemic inflammatory markers following a simulated game of American football. J Strength Cond Res 36(3): 686-694, 2022-This investigation examined the effect of a simulated American football game on cognitive function, neurotrophin concentrations, and markers of both systemic and brain inflammation. Members of the Israel national team (6 linemen and 9 skill position players) were examined 1 week before (PRE), immediately post (IP) and 24-hour post (24P) game. Blood was obtained, and cognitive function was measured at each assessment. No head injuries to any of the players participating in the study occurred. Significant (p < 0.001) decreases in acute memory, and a trend (p = 0.066) toward a decrease in delayed memory was noted at IP. Significant negative correlations were observed between playing time (number of plays) and concentration changes from PRE to IP (r = -0.801; p = 0.001) and from PRE to 24P (r = -0.549; p = 0.034). All cognitive function measures returned to PRE levels by 24P. Increases from PRE were noted in tumor necrosis factor-alpha (TNF-α) (p = 0.041) at IP and in brain-derived neurotrophic factor (p = 0.009) and C-reactive protein (CRP) (p = 0.019) concentrations at 24P. Circulating CRP concentrations and the cytokine markers, interleukin (IL)-4, IL-6, IL-10, and TNF-α, were significantly elevated in linemen compared with skill players. Brain inflammatory markers (S100B and glial fibrillary acidic protein) and total tau protein (a marker of brain injury) were not elevated from PRE. No change from PRE was noted in either myoglobin or creatine kinase-MM concentrations. In conclusion, muscle damage and inflammatory marker responses observed from the scrimmage game were consistent with muscle desensitization associated with football participation. In addition, the systemic inflammatory marker results observed in linemen were suggestive of chronic low-grade inflammation.

Self-Rated Frailty and Mortality in Old Men: The Manitoba Follow-up Study.

BACKGROUND: While a multitude of definitions and operationalizations of frailty have been developed, rarely have these considered the perspective of the older adult themselves. This knowledge gap was addressed by examining older adults' self-rating of frailty. OBJECTIVES: To assess the validity of self-rated frailty and to determine whether self-rated frailty relates to mortality. DESIGN: The Manitoba Follow-up Study was initiated in 1948 as a prospective cohort study of 3,983 men. SETTING: Community dwelling older adult men. PARTICIPANTS: Survivors of the original cohort (231 men) were sent a quality of life survey in 2015. A response was received from 186 men, including 146 surveys completed by the participant himself and thus were eligible to include (completion rate of 78.4%). MEASUREMENTS: The quality of life survey is sent out annually to the study participants to ascertain information about mental, physical, and social functioning. In 2015, the Clinical Frailty Scale was adapted and added to the survey as a simple self-rating of frailty. RESULTS: The mean age of the 146 respondents in 2015 was 93.7 years (SD 2.7) Self-ratings of "moderate-severe" frailty, received from 132 men, were associated with worse measures of physical health and functional impairment, thus supporting the significance of self-rated frailty. Adjusted for age, the Hazard Ratio for mortality over the next 3 years was 3.3 (95% CI: 1.5, 7.1) for those who rated themselves as "mildly to severely frail" vs. "very fit or well, with no disease". CONCLUSION: The present study has illustrated that self-rated frailty is associated with other measures of health and that self-rated frailty predicts mortality over a three-year period. These findings support the utilization of older adult's self-ratings of frailty for new avenues of operationalizing frailty.

Cytotoxicity of cobalt chloride in brain cell lines - a comparison between astrocytoma and neuroblastoma cells.

High levels of circulating cobalt ions in blood have been reported to induce systemic reactions in patients with metal-on-metal (MoM) hip implants. We still lack information regarding these adverse effects, which may specifically impact on patients showing adverse neurological symptoms. To investigate this, we used a battery of in vitro viability and proliferation assays to identify toxic cobalt chloride (CoCl2) concentrations in two different brain cell types: SH-SY5Y neuroblastoma and U-373 astrocytoma cells. Cobalt cytotoxicity was characterised by MTT and Neutral Red (NR) assays at concentrations ranging from 0 to 500 µM after 24, 48, and 72 h exposure. MTT and NR showed a dose- and time-dependent toxicity with cobalt decreasing cell viability at high concentrations. IC50s for MTT at 72 h (astrocytes: 333.15 ±â€¯22.88; neurons: 100.01 ±â€¯5.91 µM) and for BrdU proliferation assays (astrocytes: 212.89 ±â€¯9.84; neurons: 88.86 ±â€¯19.03 µM) demonstrate that SH-SY5Y neurons are significantly more vulnerable to cobalt than astrocytes. Increased BrdU and MTT assay sensitivity suggested that DNA synthesis and metabolism disruption were involved in Co toxicity. Intracellular cobalt level measured by ICP-MS was significant after 100 µM treatment. Astrocytes displayed improved resistance to cobalt toxicity and higher uptake, which may reflect their neuroprotective nature. In summary, exposure to high concentrations of extracellular cobalt has deleterious effects in neurons and astrocytes, with neurons showing particular sensitivity.

Corrigendum to: The acute physiological status of white sharks (Carcharodon carcharias) exhibits minimal variation after capture on SMART drumlines.

[This corrects the article DOI: 10.1093/conphys/coz042.].

Personalised treatments for acute whiplash injuries: A pilot study of nested N-of-1 trials in a multiple baseline single-case experimental design.

BACKGROUND: Whiplash associated disorder (WAD), a common and disabling condition, incurs huge burden and costs to Australia. Yet, current treatments for whiplash are not very effective; improved outcomes are urgently needed. Clinical guidelines recommend simple analgesia (paracetamol and non-steroidal anti-inflammatory drugs) but there have been no trials of guideline-recommended drugs. This study will investigate the effectiveness of evidence-based advice (EBA), paracetamol, naproxen, and both paracetamol and naproxen, in reducing daily neck pain and preventing chronic neck pain after whiplash injury. METHODS: This study is a pilot series of multi-cycle, double-blinded, randomised N-of-1 trials, nested in a multiple baseline design. The design will comprise three baselines of 5, 8 or 11 days duration. Post enrolment, participants will be randomly assigned to one of the baselines. Fifteen participants with acute (<2 weeks) Grade II WAD, experiencing at least moderate pain (NRS: ≥ 5/10), and at risk of poor recovery will be recruited from hospitals in Queensland, Australia, and through local physiotherapists. Patients will receive EBA plus a randomised sequence of three cycles of ten day treatment triplets (paracetamol designated as a C phase, naproxen, designated as a D phase, and both paracetamol and naproxen, designated as an E phase). DISCUSSION: We will test the effects of different treatments on the primary outcome of average neck pain intensity collected daily and at 4 and 7 months post-injury. Secondary outcomes, including disability, depression, post-traumatic stress symptoms, pain catastrophizing, and feasibility of study procedures, will also be evaluated. The results of this study will inform a larger trial aiming to strengthen the evidence on EBA and simple analgesics for WAD. TRIAL REGISTRATION: Clinical Trials Primary Registry: Australian and New Zealand Clinical Trials Registry. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12618001291279. DATE OF REGISTRATION: 31/07/2018. PRIMARY TRIAL SPONSOR: The University of Queensland, Brisbane QLD 4072 Australia. FUNDING: The University of Queensland.

The acute physiological status of white sharks (Carcharodon carcharias) exhibits minimal variation after capture on SMART drumlines.

Drumlines incorporating SMART (Shark-Management-Alert-in-Real-Time) technology are a new tool used in several bather protection programmes globally. In New South Wales (NSW), Australia, the white shark (Carcharodon carcharias) is a target species for SMART drumlines because they are often involved in attacks on humans. To understand white shark sensitivity to capture and to establish protocols around acceptable timeframes for responding to alerts, 47 juvenile and subadult white sharks were caught on SMART drumlines at five locations off the east coast of Australia. There was no at-vessel mortality during the sampling period. After capture, blood was sampled from each shark to assess its acute physiological status. Of the 18 metabolites investigated, only lactate and aspartate aminotransferase exhibited significant positive relationships with the capture duration on SMART drumlines. These results indicate that the capture process is relatively benign and that the current response times used here are appropriate to minimize long-term negative impacts on released white sharks. Where white sharks are likely to interact negatively with beachgoers, SMART drumlines can therefore be a useful addition to bather protection programmes that also aim to minimize harm to captured animals. Other shark species captured on SMART drumlines should also be investigated to gain broader understanding of potential physiological consequences of using this new technology.

Etoposide Upregulates Survival Favoring Sphingosine-1-Phosphate in Etoposide-Resistant Retinoblastoma Cells.

Improved knowledge of retinoblastoma chemotherapy resistance is needed to raise treatment efficiency. The objective of this study was to test whether etoposide alters glucosyl-ceramide, ceramide, sphingosine, and sphingosine-1-phosphate (sphingosine-1-P) levels in parental retinoblastoma cells (WERI Rb1) or their etoposide-resistant subclones (WERI EtoR). WERI Rb1 and WERI EtoR were incubated with 400 ng/ml etoposide for 24 h. Levels of glucosyl-ceramides, ceramides, sphingosine, sphingosine-1-P were detected by Q-TOF mass spectrometry. Statistical analysis was done by ANOVA followed by Tukey post-hoc test (p < 0.05). The mRNA expression of sphingolipid pathways enzymes in WERI Rb1, WERI EtoR and four human retinoblastoma tissue samples was analyzed by quantitative real-time PCR. Pathways enzymes mRNA expression confirmed similarities of human sphingolipid metabolism in both cell lines and tissue samples, but different relative expression. Significant up-regulation of sphingosine was seen in both cell lines (p < 0.001). Only sphingosine-1-P up-regulation was significantly increased in WERI EtoR (p < 0.01), but not in WERI Rb1 (p > 0.2). Both cell lines upregulate pro-apoptotic sphingosine after etoposide incubation, but only WERI EtoR produces additional survival favorable sphingosine-1-P. These data may suggest a role of sphingosine-1-P in retinoblastoma chemotherapy resistance, although this seems not to be the only resistance mechanism.

Histone-Complexed DNA Fragments Levels are Associated with Coagulopathy, Endothelial Cell Damage, and Increased Mortality after Severe Pediatric Trauma.

BACKGROUND: The release of damage-associated molecular pattern molecules in the extracellular space secondary to injury has been shown to cause systemic activation of the coagulation system and endothelial cell damage. We hypothesized that pediatric trauma patients with increased levels of histone-complexed DNA fragments (hcDNA) would have evidence of coagulopathy and endothelial damage that would be associated with poor outcomes. METHODS: We conducted a prospective observational study of 149 pediatric trauma patients and 62 control patients at two level 1 pediatric trauma centers from 2013 to 2016. Blood samples were collected upon arrival and at 24 h, analyzed for hcDNA, coagulation abnormalities, endothelial damage, and clinical outcome. Platelet aggregation was assessed with impedance aggregometry (Multiplate) and coagulation parameters were assessed by measuring prothrombin time ratio in plasma and the use of viscoelastic techniques (Rotational Thromboelastometry) in whole blood. RESULTS: The median age was 8.3 years, the median injury severity score (ISS) was 20, and overall mortality was 10%. Significantly higher levels of hcDNA were found on admission in patients with severe injury (ISS > 25), coagulopathy, and/or abnormal platelet aggregation. Patients with high hcDNA levels also had significant elevations in plasma levels of syndecan-1, suggesting damage to the endothelial glycocalyx. Finally, significantly higher hcDNA levels were found in non-survivors. CONCLUSION: hcDNA is released following injury and correlates with coagulopathy, endothelial glycocalyx damage, and poor clinical outcome early after severe pediatric trauma. These results indicate that hcDNA may play an important role in development of coagulation abnormalities and endothelial glycocalyx damage in children following trauma.

Trajectories of Nutritional Risk: The Manitoba Follow-Up Study.

OBJECTIVES: To identify patterns of nutritional risk among older men over a four-year period and to project their survival rates over the next two and a half years. DESIGN: A prospective longitudinal study. SETTING: Canada. PARTICIPANTS: Three hundred and thirty-six male survivors of the Manitoba Follow-up Study (MFUS) cohort with an average age of 90 years in 2011. MEASUREMENTS: Four years of nutritional risk SCREEN II scores (five waves) from the male survivors of the MFUS cohort. The semi-parametric group-based trajectory approach and survival analysis were used to investigate the trajectories of nutritional risk. RESULTS: Of the participants, 30% lived alone. Five distinct developmental trajectory groups for nutritional risk score were identified. Significant statistical differences were found among the five trajectory groups for SF-36 mental health (p=.02), SF-36 physical health (p=<.001), perception of aging successfully (p=.04) and living alone (p=<.001). Among the five groups, the most pairwise differences were found in appetite, intake of meat and alternatives, and vegetables and fruit, weight change, skipping meals and eating with others. Men in the poorest nutritional risk trajectory group were two times more likely to die within a 2 1/2 year period compared to men in the best nutritional risk trajectory group (hazard rate = 2.33, p=.07). CONCLUSION: Distinct nutritional risk trajectories were found for older men over a four year period. Poor nutritional risk trajectories are associated with higher risk of mortality for very old men over a short period of time. Timely nutritional assessments by health professionals are needed to identify older men at nutritional risk. Subsequent nutrition education and follow-up may be important in preventing further decline.

Language disparities in patients transported by emergency medical services.

BACKGROUND: The population of the United States continues to diversify with an increasing percentage of residents with limited English proficiency (LEP). A major concern facing emergency medical services (EMS) providers is increasing scene and transport times. We hypothesized that there would be a significant difference in EMS scene and transport times when comparing LEP and English-speaking (ES) patients and there would be a difference in care, both in and out of hospital. METHODS: This is a retrospective case-control study with patient data extracted from hospital records and EMS run reports from a 911 emergency ambulance service. Patients were only included if they were transported to our level I trauma center. Inclusion in the LEP group was based on a field in EMS run reports that claimed language barrier as the sole reason for no patient signature. All LEP patients from July 1, 2012, to November 1, 2012, were reviewed. A random comparison sampling of ES patients from the same period was evaluated. The patients' demographic data, pain scores, interventions, medications, transport times, and scene times were analyzed. Patients were followed up from emergency department (ED) management through to disposition. Percentages were compared using 95% confidence intervals (CIs). Bivariate analysis used the Student t test and χ(2) test. A multivariable logistic regression model was created to determine predictive variables. A 5% random sampling was compared by 2 investigators for interrater agreement. RESULTS: Data were collected from a total of 101 ES and 100 LEP patients. Interrater agreement was 94% between extractors. Limited English proficiency patients were significantly older (56 ± 20 years old) than ES patients (41 ± 21 years old) and more likely to be female (odds ratio [OR], 2; 95% CI, 1.1-3.3). Limited English proficiency patients had a greater mean EMS transport time of 2.2 minutes (95% CI, 0.04-4.0). The odds of LEP patients receiving electrocardiograms were greater both in the ambulance (OR, 3.7; 95% CI, 1.7-8.1) and in the ED (OR, 2.0; 95% CI, 1.1-3.3) compared to ES patients. There were no differences in additional interventions, medications administered, or pain scores obtained between the 2 groups. In a multivariable logistic regression model corrected for age, type of call, smoking history, and sex, there was no difference in transport times in LEP patients. CONCLUSION: Compared to ES patients, LEP patients are older and more likely to be female. When corrected for differences in age, type of call, smoking history, and sex, we found no difference in scene or transport time for LEP patients. Results of this study indicate that EMS providers should be prepared for a different patient encounter when responding to 911 calls involving LEP patients rather than language variations alone.

A novel autoregulatory loop between the Gcn2-Atf4 pathway and (L)-Proline [corrected] metabolism controls stem cell identity.

Increasing evidence indicates that metabolism is implicated in the control of stem cell identity. Here, we demonstrate that embryonic stem cell (ESC) behaviour relies on a feedback loop that involves the non-essential amino acid L-Proline (L-Pro) in the modulation of the Gcn2-Eif2α-Atf4 amino acid starvation response (AAR) pathway that in turn regulates L-Pro biosynthesis. This regulatory loop generates a highly specific intrinsic shortage of L-Pro that restricts proliferation of tightly packed domed-like ESC colonies and safeguards ESC identity. Indeed, alleviation of this nutrient stress condition by exogenously provided L-Pro induces proliferation and modifies the ESC phenotypic and molecular identity towards that of mesenchymal-like, invasive pluripotent stem cells. Either pharmacological inhibition of the prolyl-tRNA synthetase by halofuginone or forced expression of Atf4 antagonises the effects of exogenous L-Pro. Our data provide unprecedented evidence that L-Pro metabolism and the nutrient stress response are functionally integrated to maintain ESC identity.

Toxicity of cobalt-chromium nanoparticles released from a resurfacing hip implant and cobalt ions on primary human lymphocytes in vitro.

Adverse tissue responses to prostheses wear particles and released ions are important contributors to hip implant failure. In implant-related adverse reactions T-lymphocytes play a prominent role in sustaining the chronic inflammatory response. To further understand the involvement of lymphocytes in metal-on-metal (MoM) implant failure, primary human lymphocytes were isolated and treated with cobalt-chromium (Co-Cr) wear debris and Co ions, individually, and in combination, for 24, 48 and 120 h. There was a significant increase in cell number where debris was present, as measured by the Neutral Red assay. Interleukin-6 (IL-6), interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) secretion levels significantly decreased in the presence of metal particles, as measured by ELISA. Interleukin-2 (IL-2) secretion levels were significantly decreased by both debris and Co ions. Flow cytometry analysis showed that the metal nanoparticles induced a significant increase in apoptosis after 48-h exposure. This investigation showed that prolonged exposure (120 h) to metal debris induces lymphocyte proliferation, suggesting that activation of resting lymphocytes may have occurred. Although cytokine production was affected mainly by metal debris, cobalt toxicity may also modulate IL-2 secretion, and even Co ion concentrations below the MHRA guideline levels (7 ppb) may contribute to the impairment of immune regulation in vivo in patients with MoM implants.

Routine utilization of single-incision pediatric endosurgery (SIPES): a 5-year institutional experience.

BACKGROUND: Single-incision pediatric endosurgery (SIPES) allows operation through one access site, eliminating the multiple sites traditionally used. There are few large series evaluating the versatility of SIPES. The purpose of this study is to review a 5-year single-institution experience with routine SIPES use. PATIENTS AND METHODS: This is an Institutional Review Board-approved retrospective analysis of prospectively collected data. All SIPES cases from March 2009 to December 2013 were included. Our database contains demographics, procedure type, operative duration, estimated blood loss, instance of added ports or conversion to open, complications, and follow-up duration. RESULTS: Of 1322 SIPES operations performed, most (82.1%) were appendectomies and cholecystectomies. Of 871 (66%) patients seen in follow-up, with a median duration of 26 days, 53 (6.1%) experienced postoperative complications. Forty-two cases (4.8%) were surgical-site infections, of which 4 required drainage. Less frequent complications that required operative intervention include recurrent inguinal hernia (n=4), umbilical hernia (n=3), intraabdominal abscess (n=1), bleeding (n=1), abdominal compartment syndrome (n=1), bowel obstruction (n=1), stitch granuloma (n=1), and persistent postoperative pain (n=1). CONCLUSIONS: Operative times and complication rates are comparable to those in prior reported multiport laparoscopic series, allowing safe integration of SIPES into the routine of a surgical practice for most common procedures.

Oral versus intravenous tranexamic acid in enhanced-recovery primary total hip and knee replacement: results of 3000 procedures.

In our department we use an enhanced recovery protocol for joint replacement of the lower limb. This incorporates the use of intravenous tranexamic acid (IVTA; 15 mg/kg) at the induction of anaesthesia. Recently there was a national shortage of IVTA for 18 weeks; during this period all patients received an oral preparation of tranexamic acid (OTA; 25 mg/kg). This retrospective study compares the safety (surgical and medical complications) and efficacy (reduction of transfusion requirements) of OTA and IVTA. During the study period a total of 2698 patients received IVTA and 302 received OTA. After adjusting for a range of patient and surgical factors, the odds ratio (OR) of receiving a blood transfusion was significantly higher with IVTA than with OTA (OR 0.48 (95% confidence interval 0.26 to 0.89), p = 0.019), whereas the safety profile was similar, based on length of stay, rate of readmission, return to theatre, deep infection, stroke, gastrointestinal bleeding, myocardial infarction, pneumonia, deep-vein thrombosis and pulmonary embolism. The financial benefit of OTA is £2.04 for a 70 kg patient; this is amplified when the cost saving associated with significantly fewer blood transfusions is considered. Although the number of patients in the study is modest, this work supports the use of OTA, and we recommend that a randomised trial be undertaken to compare the different methods of administering tranexamic acid.

A randomised controlled trial evaluating a brief intervention for deficits in recognising emotional prosody following severe ABI.

Many adults with acquired brain injuries, including traumatic brain injuries (TBI) have impaired emotion perception. Impaired perception of emotion in voice can occur independently to facial expression and represents a specific target for remediation. No research to date has addressed this. The current study used a randomised controlled trial to examine the efficacy of a short treatment (three x two-hour sessions) for improving the ability to recognise emotional prosody for people with acquired brain injury, mostly TBI. Ten participants were allocated to treatment and 10 to waitlist. All participants remained involved for the duration of the study in the groups to which they were allocated. There were no significant treatment effects for group, but analyses of individual performances indicated that six of the treated participants made demonstrable improvements on objective measures of prosody recognition. The reasons why some participants showed improvements while others did not, was not obvious. Improvements on objective lab-based measures did not generalise to relative reports of improvements in everyday communicative ability. Nor was there clear evidence of long-term effects. In conclusion, treatment of emotional prosody was effective in the short-term for half of the participants. Further research is required to determine what conditions are required to optimise generalisability and longer-term gains.

Changes in food group consumption and associations with self-rated diet, health, life satisfaction, and mental and physical functioning over 5 years in very old Canadian men: the Manitoba Follow-Up Study.

OBJECTIVE: To identify longitudinal food group consumption trends and the relationship to perceived changes in diet, health, and functioning. DESIGN: A prospective longitudinal study. SETTING: Canada. PARTICIPANTS: Seven hundred and thirty-six community-dwelling Canadian men (mean age: 2000=79.4 yrs; 2005=84.5 yrs) participating in the Manitoba Follow-up Study. MEASUREMENTS: Self-reported food consumption, self-rated diet and health, life satisfaction, physical and mental functioning from questionnaires completed in 2000 and 2005. RESULTS: The majority of participants did not consume from all four food groups daily, based on Canada's Food Guide recommendations, with only 8% in 2000 and up to 15% in 2005. However, over a five year period, more men improved their consumption in each food group than declined. An association was found between change in the self-rating of the healthiness of their diet and change in consumption of vegetables and fruit, or grain products. Men whose self-rating of the healthiness of their diet remained high or improved between 2000 and 2005, were 2.15 times more likely (95% CI=1.45, 3.17) to also have increased consumption of vegetables and fruit, and 1.71 times more likely (95% CI=1.51, 2.54) to have increased consumption of grain products, relative to men whose self-rating of the healthiness of their diet declined between 2000 and 2005. Men who consumed more food groups daily had better mental and physical component scores. CONCLUSION: Dietary improvements are possible in very old men. Greater daily food group consumption is associated with better mental and physical functioning. Given these positive findings, there is still a need to identify older men who require support to improve their dietary habits as nearly half of the participants consumed two or fewer groups daily.

The efficacy of student-centered instruction in supporting science learning.

Transforming science learning through student-centered instruction that engages students in a variety of scientific practices is central to national science-teaching reform efforts. Our study employed a large-scale, randomized-cluster experimental design to compare the effects of student-centered and teacher-centered approaches on elementary school students' understanding of space-science concepts. Data included measures of student characteristics and learning and teacher characteristics and fidelity to the instructional approach. Results reveal that learning outcomes were higher for students enrolled in classrooms engaging in scientific practices through a student-centered approach; two moderators were identified. A statistical search for potential causal mechanisms for the observed outcomes uncovered two potential mediators: students' understanding of models and evidence and the self-efficacy of teachers.