Impact of race and ethnicity on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma.

Non-Hispanic Black patients are disproportionally affected by multiple myeloma (MM) and whether efficacy outcomes after autologous stem cell transplant (ASCT) differ by race and ethnicity remains an area of active investigation. This study included 449 patients enriched with a large proportion of non-Hispanic Black patients and sought to highlight the impact of race and ethnicity on outcomes after HDT-ASCT for patients with newly diagnosed MM. We found induction chemotherapy followed by high-dose therapy-ASCT and maintenance chemotherapy is associated with long-term PFS and OS, regardless of race or ethnicity.

Clopidogrel Administration Impairs Post-Stroke Learning and Memory Recovery in Mice.

Clopidogrel, which is one of the most prescribed antiplatelet medications in the world, is given to stroke survivors for the prevention of secondary cardiovascular events. Clopidogrel exerts its antiplatelet activity via antagonism of the P2Y12 receptor (P2RY12). Although not widely known or considered during the initial clinical trials for clopidogrel, P2RY12 is also expressed on microglia, which are the brain's immune cells, where the receptor facilitates chemotactic migration toward sites of cellular damage. If microglial P2RY12 is blocked, microglia lose the ability to migrate to damaged sites and carry out essential repair processes. We aimed to investigate whether administering clopidogrel to mice post-stroke was associated with (i) impaired motor skills and cognitive recovery; (ii) physiological changes, such as survival rate and body weight; (iii) changes in the neurovascular unit, including blood vessels, microglia, and neurons; and (iv) changes in immune cells. Photothrombotic stroke (or sham surgery) was induced in adult male mice. From 24 h post-stroke, mice were treated daily for 14 days with either clopidogrel or a control. Cognitive performance (memory and learning) was assessed using a mouse touchscreen platform (paired associated learning task), while motor impairment was assessed using the cylinder task for paw asymmetry. On day 15, the mice were euthanized and their brains were collected for immunohistochemistry analysis. Clopidogrel administration significantly impaired learning and memory recovery, reduced mouse survival rates, and reduced body weight post-stroke. Furthermore, clopidogrel significantly increased vascular leakage, significantly increased the number and appearance of microglia, and significantly reduced the number of T cells within the peri-infarct region post-stroke. These data suggest that clopidogrel hampers cognitive performance post-stroke. This effect is potentially mediated by an increase in vascular permeability post-stroke, providing a pathway for clopidogrel to access the central nervous system, and thus, interfere in repair and recovery processes.

Mental fatigue and technical performance in elite rugby league.

The aims of this study were to determine the impact of elite rugby league competition on mental fatigue; and to investigate how mental fatigue influenced in-match technical performance. Twenty elite male rugby league players recorded their pre- and post-game subjective mental fatigue and had their technical performance analysed during matches across one competition season. Metrics were created to assess in-match technical performance and described the percentage of positive, neutral, and negative involvements for each player, while accounting for the context and difficulty of each involvement. Self-reported mental fatigue increased from pre-game to post-game (maximum a posteriori estimation [MAP] = 33.1, 95% high-density interval [HDI] = 26.9-39.8), with backs reporting higher changes in mental fatigue than forwards (MAP = 18.0, 95% HDI = 9.7-26.9). Larger increases in mental fatigue from pre-game to post-game were negatively associated with the adjusted percentage of positive involvements metric (MAP = -2.1, 95% HDI = -5.6 to 1.1). Elite rugby league players reported increased mental fatigue following competitive games, with backs reporting a greater increase than forwards. Mental fatigue impacted technical performance, whereby participants had a lower percentage of positive involvements when they reported being more mentally fatigued.

Remote photobiomodulation targeted at the abdomen or legs provides effective neuroprotection against parkinsonian MPTP insult.

Photobiomodulation (PBM)-the irradiation of tissue with low-intensity light-mitigates neuropathology in rodent models of Parkinson's disease (PD) when targeted at the head ('transcranial PBM'). In humans, however, attenuation of light energy by the scalp and skull necessitates a different approach. We have reported that targeting PBM at the body also protects the brain by a mechanism that spreads from the irradiated tissue ('remote PBM'), although the optimal peripheral tissue target for remote PBM is currently unclear. This study compared the neuroprotective efficacy of remote PBM targeting the abdomen or leg with transcranial PBM, in mouse and non-human primate models of PD. In a pilot study, the neurotoxin MPTP was used to induce PD in non-human primates; PBM (670 nm, 50 mW/cm2 , 6 min/day) of the abdomen (n = 1) was associated with fewer clinical signs and more surviving midbrain dopaminergic cells relative to MPTP-injected non-human primates not treated with PBM. Validation studies in MPTP-injected mice (n = 10 per group) revealed a significant rescue of midbrain dopaminergic cells in mice receiving PBM to the abdomen (~80%, p < .0001) or legs (~80%, p < .0001), with comparable rescue of axonal terminals in the striatum. Strikingly, this degree of neuroprotection was at least as, if not more, pronounced than that achieved with transcranial PBM. These findings confirm that remote PBM provides neuroprotection against MPTP-induced destruction of the key circuitry underlying PD, with both the abdomen and legs serving as viable remote targets. This should provide the impetus for a comprehensive investigation of remote PBM-induced neuroprotection in other models of PD and, ultimately, human patients.

The Impact of Cognitive, Physical, and Psychological Stressors on Subsequent Cognitive Performance.

OBJECTIVE: To quantify the impact of performing challenging cognitive, physical and psychological tasks on subsequent cognitive performance, and whether differences in performance are predicted by psychological variables. BACKGROUND: Successful performance in many occupations depends on resilient cognition: the degree to which cognitive functions can withstand, or are resilient to, the effects of stress. Several studies have examined the effect of individual stressors on cognition; however, the capacity to compare different types of stress across studies is limited. METHOD: Fifty-eight participants completed cognitive, physical, psychological and control interventions, immediately preceded, and followed, by a battery of cognitive tasks. Self-efficacy and cognitive appraisal were reported at baseline. Perceived stress was recorded post-intervention. Subjective workload was recorded for each cognitive battery and intervention. RESULTS: Cognitive performance was impaired by the cognitive, physical and psychological interventions, with the greatest effect following the cognitive intervention. The subjective workload reported for the post-intervention cognitive battery was higher following the cognitive and physical interventions. Neither self-efficacy, cognitive appraisal, perceived stress nor subjective workload of the intervention strongly predicted post-intervention performance. CONCLUSION: Given the differences among interventions and cognitive domains, it appears that challenges to resilient cognition are broad and varied, and the mechanism(s) by which impairment occurs is complex. APPLICATION: Considering the increase in subjective workload for the post-intervention cognitive battery, a combination of subjective and objective measures of cognitive performance monitoring should be considered.

The Acute Readiness Monitoring Scale: Assessing Predictive and Concurrent Validation.

To complement and enhance readiness-monitoring capability, the Acute Readiness Monitoring Scale (ARMS) was developed: a widely applicable, simple psychometric measure of perceived readiness. While this tool may have widespread utility in sport and military settings, it remains unknown if the ARMS demonstrates predictive and concurrent validity. Here, we investigated whether the ARMS is: (1) responsive to an acute manipulation of readiness using sleep deprivation, (2) relates to biological markers of readiness [cortisol/heart-rate variability (HRV)], and (3) predicts performance on a cognitive task. Thirty young adults (aged 23 ± 4 years; 18 females) participated. All participants engaged in a 24-h sleep deprivation protocol. Participants completed the ARMS, biological measures of readiness (salivary cortisol, HRV), and cognitive performance measures (psychomotor vigilance task) before, immediately after, 24-, and 48-h post-sleep deprivation. All six of the ARMS subscales changed in response to sleep deprivation: scores on each subscale worsened (indicating reductions in perceived readiness) immediately after sleep deprivation, returning to baseline 24/48 h post. Lower perceived readiness was associated with reduced awakening responses in cortisol and predicted worse cognitive performance (slower reaction time). No relationship was observed between the ARMS and HRV, nor between any biological markers of readiness (cortisol/HRV) and cognitive performance. These data suggest that the ARMS may hold practical utility in detecting, or screening for, the wide range of deleterious effects caused by sleep deprivation; may constitute a quick, cheap, and easily interpreted alternative to biological measures of readiness; and may be used to monitor or mitigate potential underperformance on tasks requiring attention and vigilance.

ɑ-Lactalbumin Improves Sleep and Recovery after Simulated Evening Competition in Female Athletes.

PURPOSE: This study aimed to determine the efficacy of α-lactalbumin (A-LAC) supplementation for improving sleep and performance recovery after simulated evening competition in female athletes. METHODS: Sixteen trained women (mean ± SD: age, 27 ± 7 yr; mass, 62 ± 10 kg; stature, 167 ± 8 cm) participated in this randomized double-blind three-arm crossover study. Participants completed a simulated evening competition before consuming either an A-LAC whey protein, whey protein placebo (PLA), or water control (CON) beverage. Sleep was monitored via polysomnography, and participants completed a series of physical, cognitive, and perceptual assessments before, and 14 and 24 h after simulated competition. RESULTS: Non-rapid eye movement stage 2 sleep increased after competition in A-LAC (pre, 199 ± 44 min; post, 212 ± 37 min) but decreased in CON (pre, 228 ± 43 min; post, 195 ± 40 min) and PLA (pre, 224 ± 25 min; post, 211 ± 35 min; P = 0.012). In addition, Yo-Yo Intermittent Recovery Test Level 1 distance improved over time in A-LAC (baseline, 664 ± 332 m; 14 h post, 667 ± 326 m; 24 h post, 781 ± 427 m) compared with CON (baseline, 741 ± 366 m; 14 h post, 648 ± 351 m; 24 h post, 720 ± 407 m) and PLA (baseline, 763 ± 394 m; 14 h post, 636 ± 366 m; 24 h post, 720 ± 396 m; P < 0.001). CONCLUSIONS: The findings indicate that A-LAC supplementation may be useful for retaining some sleep characteristics after evening competition, leading to improved physical performance in female athletes.

A 4-week endurance training program improves tolerance to mental exertion in untrained individuals.

OBJECTIVES: The aim of this study was to investigate whether 4 weeks of endurance training could improve tolerance to mental exertion in untrained participants. DESIGN: Longitudinal training study. METHODS: Twenty untrained young adults (14 F, 6 M; 27.6±6.2 years) completed a 4-week training protocol in a randomised and counterbalanced order. Baseline and follow-up assessment were conducted over three sessions in the week preceding and following the training period. During session 1, participants completed an incremental maximal ramp test. During sessions 2 and 3 participants completed a 15min cycling time trial preceded by either a mental exertion or control conditions. Following baseline assessments, participants were randomised into a physical training or placebo group that completed the training intervention thrice weekly over four weeks. RESULTS: The physical training resulted in increase in VO2 peak relative to the placebo group (p=0.003). Linear Mixed Models utilising the control condition time trial performance as a covariate found the physical training group increased their time trial distance following the mental exertion condition to a greater extent than the placebo group (p=0.03). RPE during the time trial and perceptual measures of mental exertion did not significantly change between groups (all p>0.10) although interaction effects were observed when considering the RPE-power output relationship during the time trial. CONCLUSIONS: Four weeks of endurance training increased tolerance to mental exertion in untrained participants during a subsequent physical performance, but not during prolonged cognitive performance. This finding suggests that the ability to tolerate mental exertion is trainable in at least some contexts and highlights the far-reaching benefits of endurance training.

Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.

Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo, including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses.Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.

Critical role for iron accumulation in the pathogenesis of fibrotic lung disease.

Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1+ macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Physiological Factors Which Influence Cognitive Performance in Military Personnel.

OBJECTIVE: To identify and detail physiological factors that influence cognition in military personnel. BACKGROUND: Maintenance of cognitive and task performance is important under several scenarios, none more so than in a military context. Personnel are prepared for and trained to tolerate many of the stressors they encounter; however, consideration of stressors typically extends only as far as the physical, psychological, and environmental requirements of a given task. While considering these factors certainly characterizes the broader picture, several physiological states and traits can influence cognition and thus, should also be considered. METHOD: A systematic review of the electronic databases Medline (PubMed), EMBASE (Scopus), PsycINFO, and Web of Science was conducted from inception up to January 2019. Eligibility criteria included current military personnel, an outcome of cognition, and the assessment of a physiological factor. RESULTS: The search returned 60,564 records, of which 60 were included in the review. Eleven studies examined the impact of demographic factors on cognition, 16 examined fatigue, 10 investigated nutrition, and 24 the impact of biological factors on cognitive performance. CONCLUSION: Factors identified as having a positive impact on cognition include aerobic fitness, nutritional supplementation, and visual acuity. In contrast, factors identified as having a negative impact include fatigue arising from sustained operations, dehydration, undernutrition, and an exaggerated physiological stress response to a cognitive task or a stressor. A further subset of these factors was considered modifiable. APPLICATION: The modifiable factors identified provide avenues for training and preparation to enhance cognition in ways previously unconsidered.

Assessment of evidence for or against contributions of Chlamydia pneumoniae infections to Alzheimer's disease etiology.

Alzheimer's disease, the most common form of dementia, was first formally described in 1907 yet its etiology has remained elusive. Recent proposals that Aß peptide may be part of the brain immune response have revived longstanding contention about the possibility of causal relationships between brain pathogens and Alzheimer's disease. Research has focused on infectious pathogens that may colonize the brain such as herpes simplex type I. Some researchers have proposed the respiratory bacteria Chlamydia pneumoniae may also be implicated in Alzheimer's disease, however this remains controversial. This review aims to provide a balanced overview of the current evidence and its limitations and future approaches that may resolve controversies. We discuss the evidence from in vitro, animal and human studies proposed to implicate Chlamydia pneumoniae in Alzheimer's disease and other neurological conditions, the potential mechanisms by which the bacterium may contribute to pathogenesis and limitations of previous studies that may explain the inconsistencies in the literature.

Photobiomodulation Mitigates Cerebrovascular Leakage Induced by the Parkinsonian Neurotoxin MPTP.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease (PD) as it specifically damages the nigrostriatal dopaminergic pathway. Recent studies in mice have, however, provided evidence that MPTP also compromises the integrity of the brain's vasculature. Photobiomodulation (PBM), the irradiation of tissue with low-intensity red light, mitigates MPTP-induced loss of dopaminergic neurons in the midbrain, but whether PBM also mitigates MPTP-induced damage to the cerebrovasculature has not been investigated. This study aimed to characterize the time course of cerebrovascular disruption following MPTP exposure and to determine whether PBM can mitigate this disruption. Young adult male C57BL/6 mice were injected with 80 mg/kg MPTP or isotonic saline and perfused with fluorescein isothiocyanate FITC-labelled albumin at various time points post-injection. By 7 days post-injection, there was substantial and significant leakage of FITC-labelled albumin into both the substantia nigra pars compacta (SNc; p < 0.0001) and the caudate-putamen complex (CPu; p ≤ 0.0003); this leakage partly subsided by 14 days post-injection. Mice that were injected with MPTP and treated with daily transcranial PBM (670 nm, 50 mW/cm2, 3 min/day), commencing 24 hours after MPTP injection, showed significantly less leakage of FITC-labelled albumin in both the SNc (p < 0.0001) and CPu (p = 0.0003) than sham-treated MPTP mice, with levels of leakage that were not significantly different from saline-injected controls. In summary, this study confirms that MPTP damages the brain's vasculature, delineates the time course of leakage induced by MPTP out to 14 days post-injection, and provides the first direct evidence that PBM can mitigate this leakage. These findings provide new understanding of the use of the MPTP mouse model as an experimental tool and highlight the potential of PBM as a therapeutic tool for reducing vascular dysfunction in neurological conditions.

Are Individuals Who Engage in More Frequent Self-Regulation Less Susceptible to Mental Fatigue?

The aim of this study was to investigate whether individuals who engage in more frequent self-regulation are less susceptible to mental fatigue. Occupational cognitive demand and participation in sports or exercise were quantified as activities requiring self-regulation. Cardiorespiratory fitness was also assessed. On separate occasions, participants either completed 90 min of an incongruent Stroop task (mental exertion condition) or watched a 90-min documentary (control condition). Participants then completed a cycling time-to-exhaustion (physical endurance) test. There was no difference in the mean time to exhaustion between conditions, although individual responses varied. Occupational cognitive demand, participation in sports or exercise, and cardiorespiratory fitness predicted the change in endurance performance (p = .026, adjusted R2 = .279). Only cognitive demand added significantly to the prediction (p = .024). Participants who reported higher levels of occupational cognitive demand better maintained endurance performance following mental exertion.

Effect of acute modafinil ingestion on cognitive and physical performance following mental exertion.

OBJECTIVE: Modafinil is a psychostimulant that has been shown to enhance cognitive and physical performance. Given its long half-life, it may provide operational advantages if it can improve tolerance to the deleterious effects of prolonged mental exertion. METHODS: Physically active males (n = 13, 23 ± 4 years, peak oxygen consumption 45.3 ± 3.2 ml kg-1  min-1 ) took part in a placebo controlled, double-blind randomised crossover study to investigate if modafinil could improve cognitive and physical performance following a prolonged period of mental exertion. RESULTS: Overall modafinil improved performance on a task of executive function over time (p = .023; η2  = 0.376) but did not improve subsequent physical endurance performance (mean difference 2.3 ± 11.5%, p = .50), despite improvement in 10 out of the 13 participants. Task demand was reported as lower with modafinil, although perceptual measures of fatigue and motivation did not consistently improve. Heart rate during submaximal exercise was higher (134 ± 11 vs. 119 ± 14 bpm, p < .001), and sleep was reduced (5.5 ± 1.4 vs. 7.5 ± 1.4 hr, p < .001) and less efficient (64 ± 13 vs. 83 ± 9%, p < .001) compared with placebo. CONCLUSIONS: Operationally, modafinil may offer advantages given the established longer half-life than other psychostimulants, despite the variable response. The impact of higher heart rates and disrupted sleep on performance must also be considered.

The Impact of Environmental Stress on Cognitive Performance: A Systematic Review.

OBJECTIVE: In this review, we detail the impact of environmental stress on cognitive and military task performance and highlight any individual characteristics or interventions which may mitigate any negative effect. BACKGROUND: Military personnel are often deployed in regions markedly different from their own, experiencing hot days, cold nights, and trips both above and below sea level. In spite of these stressors, high-level cognitive and operational performance must be maintained. METHOD: A systematic review of the electronic databases Medline (PubMed), EMBASE (Scopus), PsycINFO, and Web of Science was conducted from inception up to September 2018. Eligibility criteria included a healthy human cohort, an outcome of cognition or military task performance and assessment of an environmental condition. RESULTS: The search returned 113,850 records, of which 124 were included in the systematic review. Thirty-one studies examined the impact of heat stress on cognition; 20 of cold stress; 59 of altitude exposure; and 18 of being below sea level. CONCLUSION: The severity and duration of exposure to the environmental stressor affects the degree to which cognitive performance can be impaired, as does the complexity of the cognitive task and the skill or familiarity of the individual performing the task. APPLICATION: Strategies to improve cognitive performance in extreme environmental conditions should focus on reducing the magnitude of the physiological and perceptual disturbance caused by the stressor. Strategies may include acclimatization and habituation, being well skilled on the task, and reducing sensations of thermal stress with approaches such as head and neck cooling.

Mental Fatigue Impairs Endurance Performance: A Physiological Explanation.

Mental fatigue reflects a change in psychobiological state, caused by prolonged periods of demanding cognitive activity. It has been well documented that mental fatigue impairs cognitive performance; however, more recently, it has been demonstrated that endurance performance is also impaired by mental fatigue. The mechanism behind the detrimental effect of mental fatigue on endurance performance is poorly understood. Variables traditionally believed to limit endurance performance, such as heart rate, lactate accumulation and neuromuscular function, are unaffected by mental fatigue. Rather, it has been suggested that the negative impact of mental fatigue on endurance performance is primarily mediated by the greater perception of effort experienced by mentally fatigued participants. Pageaux et al. (Eur J Appl Physiol 114(5):1095-1105, 2014) first proposed that prolonged performance of a demanding cognitive task increases cerebral adenosine accumulation and that this accumulation may lead to the higher perception of effort experienced during subsequent endurance performance. This theoretical review looks at evidence to support and extend this hypothesis.

Role of iron in the pathogenesis of respiratory disease.

Iron is essential for many biological processes, however, too much or too little iron can result in a wide variety of pathological consequences, depending on the organ system, tissue or cell type affected. In order to reduce pathogenesis, iron levels are tightly controlled in throughout the body by regulatory systems that control iron absorption, systemic transport and cellular uptake and storage. Altered iron levels and/or dysregulated homeostasis have been associated with several lung diseases, including chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. However, the mechanisms that underpin these associations and whether iron plays a key role in the pathogenesis of lung disease are yet to be fully elucidated. Furthermore, in order to survive and replicate, pathogenic micro-organisms have evolved strategies to source host iron, including freeing iron from cells and proteins that store and transport iron. To counter these microbial strategies, mammals have evolved immune-mediated defence mechanisms that reduce iron availability to pathogens. This interplay between iron, infection and immunity has important ramifications for the pathogenesis and management of human respiratory infections and diseases. An increased understanding of the role that iron plays in the pathogenesis of lung disease and respiratory infections may help inform novel therapeutic strategies. Here we review the clinical and experimental evidence that highlights the potential importance of iron in respiratory diseases and infections.