Thermococcus kodakarensis TK0353 is a novel AP lyase with a new fold.

Hyperthermophilic organisms thrive in extreme environments prone to high levels of DNA damage. Growth at high temperature stimulates DNA base hydrolysis resulting in apurinic/apyrimidinic (AP) sites that destabilize the genome. Organisms across all domains have evolved enzymes to recognize and repair AP sites to maintain genome stability. The hyperthermophilic archaeon Thermococcus kodakarensis encodes several enzymes to repair AP site damage including the essential AP endonuclease TK endonuclease IV. Recently, using functional genomic screening, we discovered a new family of AP lyases typified by TK0353. Here, using biochemistry, structural analysis, and genetic deletion, we have characterized the TK0353 structure and function. TK0353 lacks glycosylase activity on a variety of damaged bases and is therefore either a monofunctional AP lyase or may be a glycosylase-lyase on a yet unidentified substrate. The crystal structure of TK0353 revealed a novel fold, which does not resemble other known DNA repair enzymes. The TK0353 gene is not essential for T. kodakarensis viability presumably because of redundant base excision repair enzymes involved in AP site processing. In summary, TK0353 is a novel AP lyase unique to hyperthermophiles that provides redundant repair activity necessary for genome maintenance.

Chronic traumatic encephalopathy neuropathologic change in former Australian rugby players.

AIMS: We applied the 2021 consensus criteria for both chronic traumatic encephalopathy neuropathological change and traumatic encephalopathy syndrome in a small case series of six former elite-level Australian rugby code players. METHODS: Neuropathological assessment of these cases was carried out at the Sydney and Victorian Brain Banks. Clinical data were collected via clinical interviews and health questionnaires completed by the participants and/or their next of kin, and neuropsychological testing was conducted with participants who were capable of completing this testing. RESULTS: All cases exhibited progressive cognitive impairment during life. Chronic traumatic encephalopathy neuropathological change was identified in four out of the six cases. However, coexisting neuropathologies were common, with limbic-predominant age-related TDP-43 encephalopathy and ageing-related tau astrogliopathy seen in all cases, intermediate or high Alzheimer's disease neuropathological change seen in four cases and hippocampal sclerosis seen in two of the six cases. CONCLUSION: The presence of multiple neuropathologies in these cases complicates clinical diagnostic efforts for traumatic encephalopathy syndrome. It will be important for further clinicopathological studies on larger groups to report all neuropathological comorbidities found in cases diagnosed with either chronic traumatic encephalopathy neuropathological change and/or traumatic encephalopathy syndrome.

Maximal calf conductance is associated with 6-minute walk distance in participants with and without peripheral artery disease.

INTRODUCTION: The aims were (a) to compare the maximal calf conductance and 6-minute walk distance of participants with and without peripheral artery disease (PAD) and claudication, (b) to determine whether maximal calf conductance was more strongly associated with 6-minute walk distance in participants with PAD than in the controls, and (c) to determine whether this association was significant in participants with PAD after adjusting for ABI, as well as for demographic, anthropometric, and comorbid variables. METHODS: Participants with PAD (n = 633) and without PAD (n = 327) were assessed on maximal calf conductance using venous occlusion plethysmography, and on 6-minute walk distance. Participants were further characterized on ABI, and on demographic, anthropometric, and comorbid variables. RESULTS: The PAD group had lower maximal calf conductance than the control group (0.136 ± 0.071 vs 0.201 ± 0.113 mL/100 mL/min/mmHg, p < 0.001). Additionally, the PAD group had a lower 6-minute walk distance (375 ± 98 m vs 480 ± 107 m, p < 0.001). Maximal calf conductance was positively associated with 6-minute walk distance in both groups (p < 0.001) and was more strongly associated in the PAD group (p < 0.001). In adjusted analyses, maximal calf conductance remained positively associated with 6-minute walk distance in the PAD group (p < 0.001) and in the control group (p < 0.001). CONCLUSIONS: Participants with PAD and claudication had impaired maximal calf conductance and a lower 6-minute walk distance than those without PAD, and maximal calf conductance was positively and independently associated with 6-minute walk distance within each group before and after adjusting for ABI, and for demographic, anthropometric, and comorbid variables.

Survivorship of the dual-mobility construct in elective primary total hip replacement: a systematic review and meta-analysis including registry data.

INTRODUCTION: Dislocation is a common complication associated with total hip replacement (THR). Dual-mobility constructs (DMC-THR) may be used in high-risk patients and have design features that may reduce the risk of dislocation. We aimed to report overall pooled estimates of all-cause construct survival for elective primary DMC-THR. Secondary outcomes included unadjusted dislocation rate, revision for instability, infection and fracture. METHODS: MEDLINE, EMBASE, Web of Science, Cochrane Library and National Joint Registry reports were systematically searched (CRD42020189664). Studies reporting revision (all-cause) survival estimates and confidence intervals by brand and construct including DMC bearings were included. A meta-analysis was performed weighting series by the standard error. RESULTS: Thirty-seven studies reporting 39 case series were identified; nine (10,494 DMC-THR) were included. Fourteen series (23,020 DMC-THR) from five national registries were included. Pooled case series data for all-cause construct survival was 99.7% (95% CI 99.5-100) at 5 years, 95.7% (95% CI 94.9-96.5) at 10 years, 96.1% (95% CI 91.8-100) at 15 years and 77% (95% CI 74.4-82.0) at 20 years. Pooled joint registry data showed an all-cause construct survivorship of 97.8% (95% CI 97.3-98.4) at 5 years and 96.3% (95% CI 95.6-96.9) at 10 years. CONCLUSIONS: Survivorship of DMC-THR in primary THR is acceptable according to the national revision benchmark published by National Institute for Clinical Excellence (NICE).

Microvascular dysfunction and neurovascular uncoupling are exacerbated in peripheral artery disease, increasing the risk of cognitive decline in older adults.

Peripheral artery disease (PAD) is a vascular pathology with high prevalence among the aging population. PAD is associated with decreased cognitive performance, but the underlying mechanisms remain obscure. Normal brain function critically depends on an adequate adjustment of cerebral blood supply to match the needs of active brain regions via neurovascular coupling (NVC). NVC responses depend on healthy microvascular endothelial function. PAD is associated with significant endothelial dysfunction in peripheral arteries, but its effect on NVC responses has not been investigated. This study was designed to test the hypothesis that NVC and peripheral microvascular endothelial function are impaired in PAD. We enrolled 11 symptomatic patients with PAD and 11 age- and sex-matched controls. Participants were evaluated for cognitive performance using the Cambridge Neuropsychological Test Automated Battery and functional near-infrared spectroscopy to assess NVC responses during the cognitive n-back task. Peripheral microvascular endothelial function was evaluated using laser speckle contrast imaging. We found that cognitive performance was compromised in patients with PAD, evidenced by reduced visual memory, short-term memory, and sustained attention. We found that NVC responses and peripheral microvascular endothelial function were significantly impaired in patients with PAD. A positive correlation was observed between microvascular endothelial function, NVC responses, and cognitive performance in the study participants. Our findings support the concept that microvascular endothelial dysfunction and neurovascular uncoupling contribute to the genesis of cognitive impairment in older PAD patients with claudication. Longitudinal studies are warranted to test whether the targeted improvement of NVC responses can prevent or delay the onset of PAD-associated cognitive decline.NEW & NOTEWORTHY Peripheral artery disease (PAD) was associated with significantly decreased cognitive performance, impaired neurovascular coupling (NVC) responses in the prefrontal cortex (PFC), left and right dorsolateral prefrontal cortices (LDLPFC and RDLPFC), and impaired peripheral microvascular endothelial function. A positive correlation between microvascular endothelial function, NVC responses, and cognitive performance may suggest that PAD-related cognitive decrement is mechanistically linked, at least in part, to generalized microvascular endothelial dysfunction and subsequent impairment of NVC responses.

Capillary Electrophoresis-Based Functional Genomics Screening to Discover Novel Archaeal DNA Modifying Enzymes.

It has been predicted that 30 to 80% of archaeal genomes remain annotated as hypothetical proteins with no assigned gene function. Further, many archaeal organisms are difficult to grow or are unculturable. To overcome these technical and experimental hurdles, we developed a high-throughput functional genomics screen that utilizes capillary electrophoresis (CE) to identify nucleic acid modifying enzymes based on activity rather than sequence homology. Here, we describe a functional genomics screening workflow to find DNA modifying enzyme activities encoded by the hyperthermophile Thermococcus kodakarensis (T. kodakarensis). Large DNA insert fosmid libraries representing an ∼5-fold average coverage of the T. kodakarensis genome were prepared in Escherichia coli. RNA-seq showed a high fraction (84%) of T. kodakarensis genes were transcribed in E. coli despite differences in promoter structure and translational machinery. Our high-throughput screening workflow used fluorescently labeled DNA substrates directly in heat-treated lysates of fosmid clones with capillary electrophoresis detection of reaction products. Using this method, we identified both a new DNA endonuclease activity for a previously described RNA endonuclease (Nob1) and a novel AP lyase DNA repair enzyme family (termed 'TK0353') that is found only in a small subset of Thermococcales. The screening methodology described provides a fast and efficient way to explore the T. kodakarensis genome for a variety of nucleic acid modifying activities and may have implications for similar exploration of enzymes and pathways that underlie core cellular processes in other Archaea. IMPORTANCE This study provides a rapid, simple, high-throughput method to discover novel archaeal nucleic acid modifying enzymes by utilizing a fosmid genomic library, next-generation sequencing, and capillary electrophoresis. The method described here provides the details necessary to create 384-well fosmid library plates from Thermococcus kodakarensis genomic DNA, sequence 384-well fosmids plates using Illumina next-generation sequencing, and perform high-throughput functional read-out assays using capillary electrophoresis to identify a variety of nucleic acid modifying activities, including DNA cleavage and ligation. We used this approach to identify a new DNA endonuclease activity for a previously described RNA endonuclease (Nob1) and identify a novel AP lyase enzyme (TK0353) that lacks sequence homology to known nucleic acid modifying enzymes.

Light and moderate intensity physical activity are associated with better ambulation, quality of life, and vascular measurements in patients with claudication.

OBJECTIVE: We sought to determine whether patients with claudication who reported performing either light intensity physical activity (LPA) or moderate-to-vigorous intensity physical activity (MVPA) would have higher levels of objectively determined physical activity and better physical function, health-related quality of life (HRQoL), and vascular measures, consisting of exercise time to minimum calf muscle oxygen saturation (StO2) and high-sensitivity C-reactive protein, than patients who reported being physically sedentary. METHODS: A total of 269 patients were assessed using the Johnson Space Center physical activity scale. The patients were grouped according to whether they performed no physical activities (n = 75), LPAs (n = 140), or MVPAs (n = 54). The primary measurements were the total daily steps obtained from a step activity monitor worn for 1 week, peak walking time obtained from a treadmill test, physical function score on the Medical Outcomes Study short-form 36-item survey to assess HRQoL, and high-sensitivity C-reactive protein. RESULTS: The total daily steps was significantly different among the groups. Both the LPA group (mean ± standard deviation, 7878 ± 2808 steps/d) and the MVPA group (mean, 8551 ± 3365 steps/d) had taken more daily steps (P < .01) than had the sedentary group (mean, 3323 ± 986 steps/d). The treadmill peak walking time was significantly different among the three groups. Both the LPA group (433 ± 296 seconds) and the MVPA group (548 ± 300 seconds) had had a greater peak walking time (P < .01) than that of the sedentary group (302 ± 210 seconds). The physical function score was also significantly different among the groups. The LPA group (44% ± 20%) and MVPA group (58% ± 19%) both had had higher scores (P < .01) than the sedentary group (36% ± 20%). In addition, the exercise time to the minimum calf muscle StO2 was significantly different among the groups. Both the LPA group (215 ± 238 seconds) and the MVPA group (377 ± 351 seconds) had had greater values (P < .05 and P < .01, respectively) than the sedentary group (147 ± 172 seconds). Finally, the high-sensitivity C-reactive protein level was significantly different among the groups. Both the LPA group (4.8 ± 5.5 mg/L) and the MVPA group (3.5 ± 3.6 mg/L) had had lower values (P < .01) than the sedentary group (8.6 ± 8.4 mg/L). CONCLUSIONS: Patients with claudication who reported performing LPA had greater amounts of objectively determined physical activity levels and better physical function, HRQoL, and vascular measures than those who reported being physically sedentary. Furthermore, these favorable results associated with LPA were even more pronounced for the patients who performed MVPA compared with those who were sedentary. The clinical significance is that our results have shown that engaging in any physical activity, even at relatively light intensity, is associated with favorable health and vascular measures for patients with claudication.

Minimal clinically important differences in daily physical activity outcomes following supervised and home-based exercise in peripheral artery disease.

Introduction: We estimated minimal clinically important differences (MCID) for small, moderate, and large changes in daily step counts and time spent in moderate-to-vigorous physical activity (MVPA) following both supervised and home-based exercise programs in symptomatic patients with peripheral artery disease (PAD). Methods: Patients were randomized to either 12 weeks of a supervised exercise program (n = 60), a home-based exercise program (n = 60), or an attention-control group (n = 60). Results: Using the anchor-based method to determine MCID, the MCID value for a large change in health-related quality of life (HRQoL) was an increase of 1211 total daily steps and an increase in 11 minutes in the time spent in MVPA following 12 weeks of exercise intervention. Using the distribution-based method, the MCID values for small, moderate, and large changes in total daily steps in the home-based exercise group were 558, 1396, and 2233 steps/d, respectively, and the corresponding changes in the time spent in MVPA were 6, 15, and 23 minutes. Similar distribution-based MCID scores were noted for the supervised exercise group. Conclusion: Following 3 months of home-based and supervised exercise programs for patients with PAD and claudication, increases of 11 minutes in time spent in MVPA and 1211 total daily steps were associated with large anchor-based MCID increases in HRQoL. The clinical implication is that patients with PAD and claudication should be encouraged to increase daily steps, particularly by walking an additional 11 minutes each day in MVPA, which is associated with a large meaningful increase in HRQoL.

Novel ribonucleotide discrimination in the RNA polymerase-like two-barrel catalytic core of Family D DNA polymerases.

Family D DNA polymerase (PolD) is the essential replicative DNA polymerase for duplication of most archaeal genomes. PolD contains a unique two-barrel catalytic core absent from all other DNA polymerase families but found in RNA polymerases (RNAPs). While PolD has an ancestral RNA polymerase catalytic core, its active site has evolved the ability to discriminate against ribonucleotides. Until now, the mechanism evolved by PolD to prevent ribonucleotide incorporation was unknown. In all other DNA polymerase families, an active site steric gate residue prevents ribonucleotide incorporation. In this work, we identify two consensus active site acidic (a) and basic (b) motifs shared across the entire two-barrel nucleotide polymerase superfamily, and a nucleotide selectivity (s) motif specific to PolD versus RNAPs. A novel steric gate histidine residue (H931 in Thermococcus sp. 9°N PolD) in the PolD s-motif both prevents ribonucleotide incorporation and promotes efficient dNTP incorporation. Further, a PolD H931A steric gate mutant abolishes ribonucleotide discrimination and readily incorporates a variety of 2' modified nucleotides. Taken together, we construct the first putative nucleotide bound PolD active site model and provide structural and functional evidence for the emergence of DNA replication through the evolution of an ancestral RNAP two-barrel catalytic core.

Incidence of Concussion and Time to Return-to-Play in the National Rugby League.

OBJECTIVES: To examine the rates of concussion and recovery time over the course of 2 seasons of the National Rugby League (NRL). DESIGN: Descriptive cohort study. SETTING: The NRL match play concussion injury surveillance system. PARTICIPANTS: All NRL players who participated in the 2017 and 2018 season. MAIN OUTCOME MEASURES: The (1) frequency of sideline injury surveillance identified head impact events in real-time during the games, (2) frequency of head injury assessments conducted by the medical staff, (3) frequency of medically diagnosed concussions, (4) number of days to medical clearance to return-to-play, and (5) number of games missed after concussion. MAIN RESULTS: There were 472 head injury assessments conducted during the games and 149 medically diagnosed concussions over the course of 2 NRL seasons (1 concussion every 2.70 games). The median number of days until medical clearance was 6 (M = 6.85, SD = 8.03, interquartile range = 4-7; range = 0-79 days). There was a statistically significant difference in the number of days to be medically cleared to return to full contact or match play between seasons (U = 3517.00, P = 0.001), and the percentage of players medically cleared to return-to-play at 5 days after injury was 60.6% in 2017 and 27.6% in 2018. Most players (87.9%) did not miss a game after injury. CONCLUSIONS: There is approximately one concussion sustained for every 3 games in the NRL. Most players are medically cleared to return-to-play in 4 to 7 days.

Association between meeting daily step count goals with ambulatory function and quality of life in patients with claudication.

OBJECTIVE: To determine (a) whether patients with peripheral artery disease (PAD) who walked at least 7000 and 10,000 steps/day had better ambulatory function and health-related quality of life (HRQoL) than patients who walked less than 7000 steps/day, and (b) whether differences in ambulatory function and HRQoL in patients grouped according to these daily step count criteria persisted after adjusting for covariates. METHODS: Two hundred forty-eight patients were assessed on their daily ambulatory activity for 1 week with a step activity monitor, and were grouped according to daily step count targets. Patients who took fewer than 7000 steps/day were included in group 1 (n = 153), those who took 7000 to 9999 steps/day were included in group 2 (n = 57), and patients who took at least 10,000 steps/day were included in group 3 (n = 38). Primary outcomes were the 6-minute walk distance (6MWD) and Walking Impairment Questionnaire (WIQ) distance score, which is a disease-specific measurement of HRQoL. Patients were further characterized on demographic variables, comorbid conditions, and cardiovascular risk factors. RESULTS: The groups were significantly different on ankle-brachial index (P = .02), and on the prevalence of hypertension (P = .04), diabetes (P < .01), abdominal obesity (P < .01), arthritis (P = .04), and chronic obstructive pulmonary disease (P < .01). Thus, these variables served as covariates in adjusted analyses, along with age, weight, and sex. The 6MWD (mean ± standard deviation) was significantly different among the groups in unadjusted (P < .01) and adjusted (P < .01) analyses (group 1, 313 ± 90 m; group 2, 378 ± 84 m; and group 3, 414 ± 77 m), with groups 2 and 3 having a higher 6MWD than group 1 (P < .01). The WIQ distance score was significantly different among the groups in unadjusted (P < .01) and adjusted (P < .01) analyses (group 1, 30 ± 30%; group 2, 45 ± 35%; and group 3, 47 ± 34%), with groups 2 and 3 having higher WIQ distance scores than group 1 (P < .01). CONCLUSIONS: Patients with PAD who walked more than 7000 and 10,000 steps/day had greater ambulatory function and HRQoL than patients who walked fewer than 7000 steps/day. Second, the greater ambulatory function and HRQoL associated with walking 7000 and 10,000 steps/day persisted after adjusting for covariates. This study provides preliminary evidence that patients with PAD who walk more than 7000 steps/day have better ambulatory function and HRQoL than patients below this threshold.

Implementation of Supervised Exercise Therapy for Patients With Symptomatic Peripheral Artery Disease: A Science Advisory From the American Heart Association.

Patients with lower-extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, increased rates of mobility loss, and poorer quality of life than people without PAD. Supervised exercise therapy (SET) improves walking ability, overall functional status, and health-related quality of life in patients with symptomatic PAD. In 2017, the Centers for Medicare & Medicaid Services released a National Coverage Determination (CAG-00449N) for SET programs for patients with symptomatic PAD. This advisory provides a practical guide for delivering SET programs to patients with PAD according to Centers for Medicare & Medicaid Services criteria. It summarizes the Centers for Medicare & Medicaid Services process and requirements for referral and coverage of SET and provides guidance on how to implement SET for patients with PAD, including the SET protocol, options for outcome measurement, and transition to home-based exercise. This advisory is based on the guidelines established by the Centers for Medicare & Medicaid Services for Medicare beneficiaries in the United States and is intended to assist clinicians and administrators who are implementing SET programs for patients with PAD.

Association between calf muscle oxygen saturation with ambulatory function and quality of life in symptomatic patients with peripheral artery disease.

OBJECTIVE: The objective of this study was to determine whether calf muscle hemoglobin oxygen saturation (Sto2) obtained during a standardized treadmill test is associated with ambulatory function and health-related quality of life (HRQoL) in patients with symptomatic peripheral artery disease (PAD). We hypothesized that a rapid decline in calf muscle Sto2 during walking is associated with impaired ambulatory function and HRQoL and that these associations are independent of ankle-brachial index (ABI). METHODS: Calf muscle Sto2, peak walking time, and claudication onset time were obtained during a treadmill test in 151 symptomatic men and women with PAD. Patients were further characterized by demographic variables, comorbid conditions, cardiovascular risk factors, ABI, 6-minute walk distance, daily ambulatory activity, Walking Impairment Questionnaire (WIQ) score, and Medical Outcomes Study 36-Item Short Form Health Survey physical function score to assess HRQoL. RESULTS: The median calf muscle Sto2 value at rest was 52%, which declined to 22% after only 1 minute of walking during the treadmill test and reached a minimum value of 9% after a median time of 87 seconds of walking. Of the various calf muscle Sto2 measurements obtained during the treadmill test, the exercise time to the minimum calf muscle Sto2 value (log transformed) had the strongest univariate associations with peak walking time (r = 0.56; P < .001), claudication onset time (r = 0.49; P < .001), 6-minute walk distance (r = 0.31; P < .001), WIQ distance score (r = 0.33; P < .001), WIQ speed score (r = 0.39; P < .001), WIQ stair-climbing score (r = 0.37; P < .001), and Medical Outcomes Study 36-Item Short Form Health Survey physical function score (r = 0.32; P < .001). In adjusted multiple regression models, these associations persisted (P < .001) after adjustment for demographic measures, cardiovascular risk factors, comorbid conditions, and ABI. CONCLUSIONS: More rapid decline in oxygen saturation of the calf musculature during walking, indicative of impaired microcirculation, is predictive of impaired ambulatory function and HRQoL in patients with symptomatic PAD. Of particular importance, these associations are independent of ABI and other common health burdens, highlighting the clinical relevance that the microcirculation has on ambulatory function and HRQoL in patients with symptomatic PAD.

Diet is associated with ankle-brachial index, inflammation, and ambulation in patients with intermittent claudication.

OBJECTIVE: The aims of this investigation were to determine whether the daily dietary intake of nutrients by patients with peripheral artery disease (PAD) and intermittent claudication (IC) met recommended levels for adults older than 50 years and to determine whether meeting recommended levels of nutrients was associated with ankle-brachial index (ABI), inflammation, and ambulation of patients with PAD and IC. METHODS: A total of 48 patients were assessed on their dietary intake of 20 nutrients during a 3-day period. Patients were further characterized on demographic variables, comorbid conditions, cardiovascular risk factors, ABI, 6-minute walk distance (6MWD), and high-sensitivity C-reactive protein (hsCRP) concentration. RESULTS: Few patients met the daily recommended intakes for calcium (4%), fiber (6%), vitamin E (6%), trans fatty acids (13%), vitamin A (15%), total sugars (19%), potassium (23%), sodium (29%), saturated fat (29%), and vitamin C (31%), and none of the patients met the daily recommended intake of vitamin D (0%). Overall, patients met few of the 20 dietary recommendations as the median score was seven recommendations. Only 17 of 48 patients met more than seven of the recommendations. For the ABI regression model adjusted for age, sex, race, smoking, hypertension, dyslipidemia, body mass index, and percentage body fat, the only significant predictor was total sugars (P < .001); patients who did not meet the recommendation had lower ABI values. For the hsCRP-adjusted regression model, the strongest significant predictor was omega-3 polyunsaturated fatty acids (P = .001), indicating that those who did not meet the recommendation had higher hsCRP values. Finally, for the 6MWD-adjusted regression model, folate (P = .011) and dietary score index (P = .014) were significant predictors; those who did not meet the recommendation for folate and those who met 5 or fewer of the 20 recommendations had shorter 6MWD. CONCLUSIONS: Patients with PAD and IC consume a low-nutrient-dense diet that is deficient in many vitamins, calcium, fruits, and vegetables and contains too much added sugar, saturated and trans fats, and processed foods. In addition, more severe PAD, greater inflammation, and ambulatory dysfunction are independently associated with aspects of a low-nutrient-dense diet, such as too much intake of added sugars, low intake of omega-3 polyunsaturated fatty acids and folate, and meeting the recommended intakes of only five or fewer nutrients.

Risk of Misdiagnosing Chronic Traumatic Encephalopathy in Men With Depression.

OBJECTIVE: In recent years, it has been proposed that depression represents one clinical subtype of chronic traumatic encephalopathy (CTE). This is the first study to examine the specificity of the research criteria for the clinical diagnosis of CTE in men with depression from the general population. METHODS: Data from the National Comorbidity Survey Replication, an in-person survey that examined the prevalence and correlates of mental disorders in the United States, were used for this study. Men diagnosed as having a major depressive episode in the past 30 days were included (N=101; mean age=39.4 years, SD=12.9, range=18-71). They were deemed to meet research criteriafor CTE if they presented with the purported supportive clinical features of CTE (e.g., impulsivity and substance abuse, anxiety, apathy, suicidality, and headache). RESULTS: Approximately half of the sample (52.5%) met the proposed research criteria for CTE (i.e., traumatic encephalopathy syndrome). If one accepts the delayed-onset criterion as being present, meaning that the men in the sample were presenting with depression years after retirement from sports or the military, then 83.2% of this sample would meet the research criteria for diagnosis. CONCLUSIONS: The clinical problems attributed to CTE, such as depression, suicidality, anxiety, anger control problems, and headaches, co-occurred in this sample of men with depression from the general population-illustrating that these problems are not specific or unique to CTE. More research is needed to determine whether depression is, in fact, a clinical subtype of CTE.

Chronic traumatic encephalopathy neuropathology might not be inexorably progressive or unique to repetitive neurotrauma.

In the 20th century, chronic traumatic encephalopathy (CTE) was conceptualized as a neurological disorder affecting some active and retired boxers who had tremendous exposure to neurotrauma. In recent years, the two research groups in the USA who have led the field have asserted definitively that CTE is a delayed-onset and progressive neurodegenerative disease, with symptoms appearing in midlife or decades after exposure. Between 2005 and 2012 autopsy cases of former boxers and American football players described neuropathology attributed to CTE that was broad and diverse. This pathology, resulting from multiple causes, was aggregated and referred to, in toto, as the pathology 'characteristic' of CTE. Preliminary consensus criteria for defining the neuropathology of CTE were forged in 2015 and published in 2016. Most of the macroscopic and microscopic neuropathological findings described as characteristic of CTE, in studies published before 2016, were not included in the new criteria for defining the pathology. In the past few years, there has been steadily emerging evidence that the neuropathology described as unique to CTE may not be unique. CTE pathology has been described in individuals with no known participation in collision or contact sports and no known exposure to repetitive neurotrauma. This pathology has been reported in individuals with substance abuse, temporal lobe epilepsy, amyotrophic lateral sclerosis, multiple system atrophy, and other neurodegenerative diseases. Moreover, throughout history, some clinical cases have been described as not being progressive, and there is now evidence that CTE neuropathology might not be progressive in some individuals. Considering the current state of knowledge, including the absence of a series of validated sensitive and specific biomarkers, CTE pathology might not be inexorably progressive or specific to those who have experienced repetitive neurotrauma.

The association between multiple prior concussions, cognitive test scores, and symptom reporting in youth rugby league players.

Objective: To examine the effect of prior concussion history on cognitive test performance and concussion symptom reporting among adolescent youth rugby league athletes.Participants: Participants were male elite level youth rugby league players (N = 73; Mean Age = 15.8; SD = 0.9; range = 14-18 years).Main Outcome Measure: CogSport performance based on participants group; those who reported no previous concussions (n = 30),1-2 previous concussions (n = 19), and ≥3 previous concussions (n = 29).Results: 73 participants with valid CogSport scores were included in the cognitive analyses. All participants were included in the symptom analyses. There were no differences between the groups with 0,1-2, or ≥3 previous concussions for processing speed, attention, learning, or working memory. There was atrend for those with multiple prior concussions to report more baseline preseason symptoms.Conclusions: There were no differences in scores on the CogSport test among those with ahistory of 0,1-2, or ≥3 prior concussions. Consistent with prior studies, youth with ahistory of multiple past concussions are more likely to endorse baseline preseason symptoms.

Effects of Exercise on Sport Concussion Assessment Tool-Third Edition Performance in Women.

OBJECTIVE: The purpose of this study was to examine the influence of a brief exercise protocol on Sport Concussion Assessment Tool-Third Edition (SCAT3) performance in amateur women athletes. DESIGN: Cross-over repeated-measures design. SETTING: Off-season, uninjured community amateur athletes. PARTICIPANTS: We examined 87 amateur women athlete volunteers (age = 29.9, SD = 6.9 years). INDEPENDENT VARIABLES: Participants were assessed using the SCAT3 under 2 conditions: at rest and after a 5-minute physical exertion protocol, completed in a counterbalanced order. MAIN OUTCOME MEASURES: Participants' performance on the various components of the SCAT3 under the 2 conditions: at rest and after a 5-minute physical exertion protocol. RESULTS: No significant differences were detected between at-rest and postexercise conditions for the balance, orientation, or cognitive components of the SCAT3. There were no significant differences in the proportion of participants who endorsed specific symptoms at rest compared with the postexercise condition (P > 0.05). However, women athletes who rated their exertion after exercise as "hard" or greater (Borg scale rating 13-20) reported significantly greater blurred vision (M = 0.25, SD = 0.62 vs M = 0.00, SD = 0.00; P = 0.006) and fatigue/low energy (M = 1.38, SD = 1.17 vs M = 0.66, SD = 0.91; P = 0.002) symptoms after exercise than those who rated their exertion as "light" or lower (Borg scale rating 6-12). CONCLUSIONS: In this study of women athletes, a brief bout of exercise did not seem to adversely affect SCAT3 performance and had only small effects on self-reported symptoms. There were differences in symptom reporting, however, in the subgroup of women who rated their exertion levels as "hard" or greater; they reported more blurred vision and fatigue/low energy.

Changes in vascular and inflammatory biomarkers after exercise rehabilitation in patients with symptomatic peripheral artery disease.

OBJECTIVE: Home-based exercise is an alternative exercise mode to a structured supervised program to improve symptoms in patients with peripheral artery disease (PAD), but little is known about whether the slow-paced and less intense home program also elicits changes in vascular and inflammatory biomarkers. In an exploratory analysis from a randomized controlled trial, we compared changes in vascular and inflammatory biomarkers in patients with symptomatic PAD (typical and atypical of claudication) after home-based exercise and supervised exercise programs and in an attention-control group. METHODS: A total of 114 patients were randomized into one of the three groups (n = 38 per group). Two groups performed exercise interventions, consisting of home-based and supervised programs of intermittent walking to mild to moderate claudication pain for 12 weeks; a third group performed light resistance training as a nonwalking attention-control group. Before and after intervention, patients were characterized on treadmill performance and endothelial effects of circulating factors present in sera by a cell culture-based bioassay on primary human arterial endothelial cells, and they were further evaluated on circulating vascular and inflammatory biomarkers. RESULTS: Treadmill peak walking time increased (P = .008) in the two exercise groups but not in the control group (P > .05). Cultured endothelial cell apoptosis decreased after home-based exercise (P < .001) and supervised exercise (P = .007), and the change in the exercise groups combined was different from that in the control group (P = .005). For circulating biomarkers, increases were found in hydroxyl radical antioxidant capacity (P = .003) and vascular endothelial growth factor A (P = .037), and decreases were observed in E-selectin (P = .007) and blood glucose concentration (P = .012) after home-based exercise only. The changes in hydroxyl radical antioxidant capacity (P = .005), vascular endothelial growth factor A (P = .008), and E-selectin (P = .034) in the exercise groups combined were different from those in the control group. CONCLUSIONS: This exploratory analysis found that both home-based and supervised exercise programs are efficacious to decrease cultured endothelial cell apoptosis in patients with symptomatic PAD. Furthermore, a monitored home-based exercise program elicits additional vascular benefits by improving circulating markers of endogenous antioxidant capacity, angiogenesis, endothelium-derived inflammation, and blood glucose concentration in patients with symptomatic PAD. The novel clinical significance is that important trends were found in this exploratory analysis that a contemporary home-based exercise program and a traditional supervised exercise program may favorably improve vascular and inflammatory biomarkers in addition to the well-described ambulatory improvements in symptomatic patients with PAD.

Anger and Depression in Middle-Aged Men: Implications for a Clinical Diagnosis of Chronic Traumatic Encephalopathy.

OBJECTIVE: In recent years, it has been proposed that problems with anger control and depression define clinical features of chronic traumatic encephalopathy (CTE). The authors examined anger problems and depression in middle-aged men from the general population and related those findings to the proposed clinical criteria for CTE. METHODS: A sample of 166 community-dwelling men ages 40-60 was extracted from the normative database of the National Institutes of Health Toolbox. All participants denied prior head injury or traumatic brain injury (TBI). Participants completed scales assessing anger, hostility, aggression, anxiety, and depression. RESULTS: In response to the item "I felt angry," 21.1% of men reported "sometimes," and 4.8% reported "often." When asked "If I am provoked enough I may hit another person," 11.4% endorsed the statement as true. There were moderate correlations between anger and anxiety (Spearman's ρ=0.61) and between depression and affective anger (ρ=0.51), hostility (ρ=0.56), and perceived hostility (ρ=0.35). Participants were dichotomized into a possible depression group (N=49) and a no-depression group (N=117) on the basis of the question "I feel depressed," specific to the past 7 days. The possible depression group reported higher anxiety (p<0.001, Cohen's d=1.51), anger (p<0.001, Cohen's d=0.96), and hostility (p<0.001, Cohen's d=0.95). CONCLUSIONS: Some degree of anger and aggression are reported by a sizable minority of middle-aged men in the general population with no known history of TBI. Anger and hostility are correlated with depression and anxiety, indicating that all tend to co-occur. The base rates and comorbidity of affective dysregulation in men in the general population is important to consider when conceptualizing CTE phenotypes.