Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.

MR-guided focused ultrasound therapy of extra-abdominal desmoid tumors: a multicenter retrospective study of 105 patients.

OBJECTIVE: To assess the safety and efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment extra-abdominal desmoids. METHODS: A total of 105 patients with desmoid fibromatosis (79 females, 26 males; 35 ± 14 years) were treated with MRgFUS between 2011 and 2021 in three centers. Total and viable tumors were evaluated per patient at last follow-up after treatment. Response and progression-free survival (PFS) were assessed with (modified) response evaluation criteria in solid tumors (RECIST v.1.1 and mRECIST). Change in Numerical Rating Scale (NRS) pain and 36-item Short Form Health Survey (SF-36) scores were compared. Treatment-related adverse events were recorded. RESULTS: The median initial tumor volume was 114 mL (IQR 314 mL). After MRgFUS, median total and viable tumor volume decreased to 51 mL (95% CI: 30-71 mL, n = 101, p < 0.0001) and 29 mL (95% CI: 17-57 mL, n = 88, p < 0.0001), respectively, at last follow-up (median: 15 months, 95% CI: 11-20 months). Based on total tumor measurements (RECIST), 86% (95% CI: 75-93%) had at least stable disease or better at last follow-up, but 50% (95% CI: 38-62%) of remaining viable nodules (mRECIST) progressed within the tumor. Median PFS was reached at 17 and 13 months for total and viable tumors, respectively. NRS decreased from 6 (IQR 3) to 3 (IQR 4) (p < 0.001). SF-36 scores improved (physical health (41 (IQR 15) to 46 (IQR 12); p = 0.05, and mental health (49 (IQR 17) to 53 (IQR 9); p = 0.02)). Complications occurred in 36%, most commonly 1st/2nd degree skin burns. CONCLUSION: MRgFUS reduced tumor volume, reduced pain, and improved quality of life in this series of 105 patients with extra-abdominal desmoid fibromatosis. CLINICAL RELEVANCE STATEMENT: Imaging-guided ablation is being increasingly used as an alternative to surgery, radiation, and medical therapy for the treatment of desmoid fibromatosis. MR-guided high-intensity focused ultrasound is an incisionless ablation technique that can be used to reduce tumor burden effectively and safely. KEY POINTS: • Desmoid fibromatosis was treated with MR-guided high-intensity focused ultrasound in 105 patients. • MR-guided focused ultrasound ablation reduced tumor volume and pain and improved quality of life. • MR-guided focused ultrasound is a treatment option for patients with extra-abdominal desmoid tumors.

Cerebral uptake of microvesicles occurs in normocapnic but not hypocapnic passive hyperthermia in young healthy male adults.

Passive hyperthermia causes cerebral hypoperfusion primarily from heat-induced respiratory alkalosis. However, despite the cerebral hypoperfusion, it is possible that the mild alkalosis might help to attenuate cerebral inflammation. In this study, the cerebral exchange of extracellular vesicles (microvesicles), which are known to elicit pro-inflammatory responses when released in conditions of stress, were examined in hyperthermia with and without respiratory alkalosis. Ten healthy male adults were heated passively, using a warm water-perfused suit, up to core temperature + 2°C. Blood samples were taken from the radial artery and internal jugular bulb. Microvesicle concentrations were determined in platelet-poor plasma via cells expressing CD62E (activated endothelial cells), CD31+ /CD42b- (apoptotic endothelial cells), CD14 (monocytes) and CD45 (pan-leucocytes). Cerebral blood flow was measured via duplex ultrasound of the internal carotid and vertebral arteries to determine cerebral exchange kinetics. From baseline to poikilocapnic (alkalotic) hyperthermia, there was no change in microvesicle concentration from any cell origin measured (P-values all >0.05). However, when blood CO2 tension was normalized to baseline levels in hyperthermia, there was a marked increase in cerebral uptake of microvesicles expressing CD62E (P = 0.028), CD31+ /CD42b- (P = 0.003) and CD14 (P = 0.031) compared with baseline, corresponding to large increases in arterial but not jugular venous concentrations. In a subset of seven participants who underwent hypercapnia and hypocapnia in the absence of heating, there was no change in microvesicle concentrations or cerebral exchange, suggesting that hyperthermia potentiated the CO2 /pH-mediated cerebral uptake of microvesicles. These data provide insight into a potential beneficial role of respiratory alkalosis in heat stress. KEY POINTS: The hyperthermia-induced hyperventilatory response is observed in most humans, despite causing potentially harmful reductions in cerebral blood flow. We tested the hypothesis that the respiratory-induced alkalosis is associated with lower circulating microvesicle concentrations, specifically in the brain, despite the reductions in blood flow. At core temperature + 2°C with respiratory alkalosis, microvesicles derived from endothelial cells, monocytes and leucocytes were at concentrations similar to baseline in the arterial and cerebral venous circulation, with no changes in cross-brain microvesicle kinetics. However, when core temperature was increased by 2°C with CO2 /pH normalized to resting levels, there was a marked cerebral uptake of microvesicles derived from endothelial cells and monocytes. The CO2 /pH-mediated alteration in cerebral microvesicle uptake occurred only in hyperthermia. These new findings suggest that the heat-induced hyperventilatory response might serve a beneficial role by preventing potentially inflammatory microvesicle uptake in the brain.

In vivo bioluminescence imaging of labile iron in xenograft models and liver using FeAL-1, an iron-activatable form of D-luciferin.

Dysregulated iron homeostasis underlies diverse pathologies, from ischemia-reperfusion injury to epithelial-mesenchymal transition and drug-tolerant "persister" cancer cell states. Here, we introduce ferrous iron-activatable luciferin-1 (FeAL-1), a small-molecule probe for bioluminescent imaging of the labile iron pool (LIP) in luciferase-expressing cells and animals. We find that FeAL-1 detects LIP fluctuations in cells after iron supplementation, depletion, or treatment with hepcidin, the master regulator of systemic iron in mammalian physiology. Utilizing FeAL-1 and a dual-luciferase reporter system, we quantify LIP in mouse liver and three different orthotopic pancreatic ductal adenocarcinoma tumors. We observed up to a 10-fold increase in FeAL-1 bioluminescent signal in xenograft tumors as compared to healthy liver, the major organ of iron storage in mammals. Treating mice with hepcidin further elevated hepatic LIP, as predicted. These studies reveal a therapeutic index between tumoral and hepatic LIP and suggest an approach to sensitize tumors toward LIP-activated therapeutics.

Preventing Suicide: Time to Mobilize the Physical Therapist Workforce.

Each year, approximately 700,000 people, including 46,000 Americans, die by suicide; however, many more people experience suicidal thoughts and behaviors. Historically, the prevention of suicide has largely been the domain of mental health professionals working within specialist mental health care settings. An issue with this approach is that many individuals who experience suicidal ideation never disclose these thoughts to a mental health professional. The nonprofessional and paraprofessional mental health movement aims to bring suicide prevention to the people who need it, rather than wait for them to seek help. The nonprofessional and paraprofessional mental health movement does so by upskilling people who are not recognized as mental health professionals but may have contact with people experiencing suicidal thoughts and behaviors. In this Perspective, we argue that physical therapists are well-positioned to engage in suicide prevention. For example, physical therapists working in pain management are likely to frequently encounter clients experiencing suicidal thoughts and behaviors. Physical therapy is also viewed as a physical health profession, meaning that they may have contact with a broad range of populations at high risk of suicide who may be difficult to reach through traditional channels (eg, men from rural communities). Physical therapists will require training on how to provide crisis support, including how to link clients with appropriate mental health services. However, given the size of the physical therapist workforce globally, the impact of mobilizing the physical therapist workforce could be significant.

A mobile addiction service for community-based overdose prevention.

Mainstays of opioid overdose prevention include medications for opioid use disorder (e.g., methadone or buprenorphine) and naloxone distribution. Inadequate access to buprenorphine limits its uptake, especially in communities of color, and people with opioid use disorders encounter multiple barriers to obtaining necessary medications including insurance, transportation, and consistent availability of telephones. UMass Memorial Medical Center and our community partners sought to alleviate these barriers to treatment through the deployment of a mobile addiction service, called the Road to Care. Using this approach, multidisciplinary and interprofessional providers deliver holistic addiction care by centering our patients' needs with respect to scheduling, location, and convenience. This program also extends access to buprenorphine and naloxone among people experiencing homelessness. Additional systemic and individualized barriers encountered are identified, as well as potential solutions for future mobile addiction service utilization. Over a two-year period, we have cared for 1,121 individuals who have accessed our mobile addiction service in over 4,567 encounters. We prescribed buprenorphine/naloxone (Suboxone®) to 330 individuals (29.4% of all patients). We have distributed nearly 250 naloxone kits directly on-site or and more than 300 kits via prescriptions to local pharmacies. To date, 74 naloxone rescue attempts have been reported back to us. We have demonstrated that a community-based mobile addiction service, anchored within a major medical center, can provide high-volume and high-quality overdose prevention services that facilitate engagement with additional treatment. Our experience is described as a case study below.

Ceramic Wear Particles: Can They Be Retrieved In Vivo and Duplicated In Vitro?

BACKGROUND: Little is known about retrieved zirconia platelet toughened alumina (ZPTA) wear particles from ceramic-on-ceramic (COC) total hip arthroplasty. Our objectives were to evaluate clinically retrieved wear particles from explanted periprosthetic hip tissues and to analyze the characteristics of in vitro-generated ZPTA wear particles. METHODS: Periprosthetic tissue and explants were received for 3 patients who underwent a total hip replacement of ZPTA COC head and liner. Wear particles were isolated and characterized via scanning electron microscopy and energy dispersive spectroscopy. The ZPTA and control (highly cross-linked polyethylene and cobalt chromium alloy) were then generated in vitro using a hip simulator and pin-on-disc testing, respectively. Particles were assessed in accordance with American Society for Testing and Materials F1877. RESULTS: Minimal ceramic particles were identified in the retrieved tissue, consistent with the retrieved components demonstrating minimal abrasive wear with material transfer. Average particle diameter from in vitro studies was 292 nm for ZPTA, 190 nm for highly cross-linked polyethylene, and 201 nm for cobalt chromium alloy. CONCLUSION: The minimal number of in vivo ZPTA wear particles observed is consistent with the successful tribological history of COC total hip arthroplasties. Due to the relatively few ceramic particles located in the retrieved tissue, in part due to implantation times of 3 to 6 years, a statistical comparison was unable to be made between the in vivo particles and the in vitro-generated ZPTA particles. However, the study provided further insight into the size and morphological characteristics of ZPTA particles generated from clinically relevant in vitro test setups.

Post-procedural Antibiotic Use and Associated Outcomes After Common Urologic Procedures Across a National Healthcare System.

OBJECTIVE: To quantify the benefits and harms of post-procedural antibiotic use after common urologic procedures. MATERIALS AND METHODS: This retrospective cohort study included patients who underwent an endoscopic urologic procedure (transurethral resection of bladder tumor, transurethral resection of prostate, or ureteroscopy) within the Veterans Health Administration between January 1, 2017 and June 30, 2021. A post-procedural antibiotic was any qualifying antibiotic prescribed for administration on the day after the procedure. Guidelines generally do not recommend post-procedural antibiotics for surgical prophylaxis. Outcomes included unplanned return visits and Clostridioides difficile infection within 30 days. Log-binomial models with risk-adjustment were used to measure the association between post-procedural antibiotic use and outcomes. Hospital-level observed-to-expected (O:E) ratios were constructed to compare post-procedural antibiotic use. RESULTS: There were 74,629 qualifying procedures across 105 hospitals; 27,422 (36.7%) received post-procedural antibiotics (median 3 days, IQR 3-6). An unplanned return visit occurred in 20.2% of patients who received post-procedural antibiotics vs 17.2% who did not (adjusted RR 1.032, 95% CI 0.999-1.066). C. difficile infection was diagnosed in 0.27% vs 0.10% in those who received and did not receive post-procedural antibiotics (adjusted RR 1.67, 95% CI 1.13-2.45). The O:E ratio for post-procedural antibiotic use ranged from 0.46 among hospitals in the lowest-use quartile to 1.93 in the highest-use quartile. CONCLUSION: Post-procedural antibiotics were frequently prescribed after urologic procedures with large inter-facility variability even after adjusting for case-mix differences. Post-procedural antibiotic use was associated with increased risk for C. difficile infection but not fewer unplanned return visits. Efforts to reduce guideline-discordant use of post-procedural antibiotics are needed.

Sulfidation and Reoxidation of U(VI)-Incorporated Goethite: Implications for U Retention during Sub-Surface Redox Cycling.

Over 60 years of nuclear activity have resulted in a global legacy of contaminated land and radioactive waste. Uranium (U) is a significant component of this legacy and is present in radioactive wastes and at many contaminated sites. U-incorporated iron (oxyhydr)oxides may provide a long-term barrier to U migration in the environment. However, reductive dissolution of iron (oxyhydr)oxides can occur on reaction with aqueous sulfide (sulfidation), a common environmental species, due to the microbial reduction of sulfate. In this work, U(VI)-goethite was initially reacted with aqueous sulfide, followed by a reoxidation reaction, to further understand the long-term fate of U species under fluctuating environmental conditions. Over the first day of sulfidation, a transient release of aqueous U was observed, likely due to intermediate uranyl(VI)-persulfide species. Despite this, overall U was retained in the solid phase, with the formation of nanocrystalline U(IV)O2 in the sulfidized system along with a persistent U(V) component. On reoxidation, U was associated with an iron (oxyhydr)oxide phase either as an adsorbed uranyl (approximately 65%) or an incorporated U (35%) species. These findings support the overarching concept of iron (oxyhydr)oxides acting as a barrier to U migration in the environment, even under fluctuating redox conditions.

Online Discussions About Tinnitus: What Can We Learn From Natural Language Processing of Reddit Posts?

BACKGROUND: This study was aimed at identifying key topics in online discussions about tinnitus by examining a large data set extracted from Reddit social media using a natural language processing technique. METHOD: A corpus of 113,215 posts about tinnitus was extracted from Reddit's application programming interface. After cleaning the data for duplications and posts without any text information, the sample was reduced to 101,905 posts, which was subjected to cluster analysis using the open-source IRaMuTeQ software to identify main topics based on the co-occurrence of texts. These clusters were named by a panel of tinnitus experts (n = 9) by reading typical text segments within each cluster. RESULTS: The cluster analysis identified 16 unique clusters that belong to two topics, which were named "tinnitus causes and consequences" and "tinnitus management and coping." Based on their characteristics, the clusters were named: tinnitus timeline (10%), tinnitus perception (9.7%), medical triggers and modulators (8.8%), hearing research (8.8%), attention and silence (8.6%), social media posts about tinnitus (7.4%), hearing protection (7.3%), interaction with hearing health care providers (6.7%), mental health and coping (5.8%), music listening (5.7%), hope for a cure (5.6%), interactions with people without tinnitus (5.4%), dietary supplements and alternative therapies (3.2%), sleep (3.9%), dietary effects (1.7%), and writing about tinnitus and being thankful to online community (1.4%). CONCLUSIONS: Despite some limitations, tinnitus posts on Reddit provide rich real-world data to identify various issues and complaints that tinnitus patients and their significant others discuss in online communities. Some of the clusters identified here are novel (e.g., tinnitus timeline, interactions with people without tinnitus) and have not been much discussed in the tinnitus literature. The results suggest that individuals with tinnitus relay on social media for support and highlight the service delivery needs in providing social support through other means (e.g., support groups).

Immune and Epigenetic Pathways Linking Childhood Adversity and Health Across the Lifespan.

Childhood adversity is associated with a host of mental and physical health problems across the lifespan. Individuals who have experienced childhood adversity (e.g., child abuse and neglect, family conflict, poor parent/child relationships, low socioeconomic status or extreme poverty) are at a greater risk for morbidity and premature mortality than those not exposed to childhood adversity. Several mechanisms likely contribute to the relationship between childhood adversity and health across the lifespan (e.g., health behaviors, cardiovascular reactivity). In this paper, we review a large body of research within the field of psychoneuroimmunology, demonstrating the relationship between early life stress and alterations of the immune system. We first review the literature demonstrating that childhood adversity is associated with immune dysregulation across different indices, including proinflammatory cytokine production (and its impact on telomere length), illness and infection susceptibility, latent herpesvirus reactivation, and immune response to a tumor. We then summarize the growing literature on how childhood adversity may alter epigenetic processes. Finally, we propose future directions related to this work that have basic and applied implications.

Evidence for unconventional superconductivity in twisted bilayer graphene.

The emergence of superconductivity and correlated insulators in magic-angle twisted bilayer graphene (MATBG) has raised the intriguing possibility that its pairing mechanism is distinct from that of conventional superconductors1-4, as described by the Bardeen-Cooper-Schrieffer (BCS) theory. However, recent studies have shown that superconductivity persists even when Coulomb interactions are partially screened5,6. This suggests that pairing in MATBG might be conventional in nature and a consequence of the large density of states of its flat bands. Here we combine tunnelling and Andreev reflection spectroscopy with a scanning tunnelling microscope to observe several key experimental signatures of unconventional superconductivity in MATBG. We show that the tunnelling spectra below the transition temperature Tc are inconsistent with those of a conventional s-wave superconductor, but rather resemble those of a nodal superconductor with an anisotropic pairing mechanism. We observe a large discrepancy between the tunnelling gap ΔT, which far exceeds the mean-field BCS ratio (with 2ΔT/kBTc ~ 25), and the gap ΔAR extracted from Andreev reflection spectroscopy (2ΔAR/kBTc ~ 6). The tunnelling gap persists even when superconductivity is suppressed, indicating its emergence from a pseudogap phase. Moreover, the pseudogap and superconductivity are both absent when MATBG is aligned with hexagonal boron nitride. These findings and other observations reported here provide a preponderance of evidence for a non-BCS mechanism for superconductivity in MATBG.

Generation of H2S from Thiol-Dependent NO Reactivity of Model [4Fe-4S] Cluster and Roussin's Black Anion.

Iron-sulfur clusters (Fe-S) have been well established as a target for nitric oxide (NO) in biological systems. Complementary to protein-bound studies, synthetic models have provided a platform to study what iron nitrosylated products and byproducts are produced depending on a controlled reaction environment. We have previously shown a model [2Fe-2S] system that produced a dinitrosyl iron complex (DNIC) upon nitrosylation along with hydrogen sulfide (H2S), another important gasotransmitter, in the presence of thiol, and hypothesized a similar reactivity pattern with [4Fe-4S] clusters which have largely produced inconsistent reaction products across biological and synthetic systems. Roussin's black anion (RBA), [Fe4(µ3-S)3(NO)7]-, is a previously established reaction product from synthetic [4Fe-4S] clusters with NO. Here, we present a new reactivity for the nitrosylation of a synthetic [4Fe-4S] cluster in the presence of thiol and thiolate. [Et4N]2[Fe4S4(SPh)4] (1) was nitrosylated in the presence of excess PhSH to generate H2S and an "RBA-like" intermediate that when further reacted with [NEt4][SPh] produced a {Fe(NO)2}9 DNIC, [Et4N][Fe(NO)2(SPh)2] (2). This "RBA-like" intermediate proved difficult to isolate but shares striking similarities to RBA in the presence of thiol based on IR υ(NO) stretching frequencies. Surprisingly, the same reaction products were produced when the reaction started with RBA and thiol. Similar to 1/NO, RBA in the presence of thiol and thiolate generates stoichiometric amounts of DNIC while releasing its bridging sulfides as H2S. These results suggest not only that RBA may not be the final product of [4Fe-4S] + NO but also that RBA has unprecedented reactivity with thiols and thiolates which may explain current challenges around identifying biological nitrosylated Fe-S clusters.

Longitudinal study of knee load avoidant movement behavior after total knee arthroplasty with recommendations for future retraining interventions.

BACKGROUND: This study aimed to evaluate clinical and biomechanical changes in self-report survey, quadriceps strength and gait analysis over 3- and 6-months post-total knee arthroplasty (TKA) and confirm the immediate effects of two forms of kinetic biofeedback on improving inter-limb biomechanics during a physically demanding decline walking task. METHODS: Thirty patients with unilateral TKA underwent testing at 3- and 6-months following surgery. All underwent self-report survey, quadriceps strength and gait analysis testing. Patients were assigned to one of two types of biofeedback [vertical ground reaction force (vGRF), knee extensor moment (KEM)]. RESULTS: No decrease in gait asymmetry was observed in non-biofeedback trials over time (p > 0.05), despite significant improvements in self-report physical function (p < 0.01, Cohen d = 0.44), pain interference (p = 0.01, Cohen d = 0.68), numeric knee pain (p = 0.01, Cohen d = 0.74) and quadriceps strength (p = 0.01, Cohen d = 0.49) outcomes. KEM biofeedback induced significant decrease in total support moment (p = 0.05, Cohen f2 = 0.14) and knee extensor moment (p = 0.05, Cohen f2 = 0.21) asymmetry compared to using vGRF biofeedback at 6-months. vGRF biofeedback demonstrated significant decrease in hip flexion kinematic asymmetry compared to KEM biofeedback (p = 0.05, Cohen f2 = 0.18) at 6-months. CONCLUSION: Gait compensation remained similar from 3- to 6-months during a task requiring greater knee demand compared to overground walking post-TKA, despite improvements in self-report survey and quadriceps strength. Single session gait symmetry training at 6-month supports findings at 3-month testing that motor learning is possible. KEM biofeedback is more effective at immediately improving joint kinetic loading compared to vGRF biofeedback post-TKA.

Negligible influence of moderate to severe hyperthermia on blood-brain barrier permeability and neuronal parenchymal integrity in healthy men.

With growing use for hyperthermia as a cardiovascular therapeutic, there is surprisingly little information regarding the acute effects it may have on the integrity of the neurovascular unit (NVU). Indeed, relying on animal data would suggest hyperthermia comparable to levels attained in thermal therapy will disrupt the blood-brain barrier (BBB) and damage the cerebral parenchymal cells. We sought to address the hypothesis that controlled passive hyperthermia is not sufficient to damage the NVU in healthy humans. Young men (n = 11) underwent acute passive heating until +2°C or absolute esophageal temperature of 39.5°C. The presence of BBB opening was determined by trans-cerebral exchange kinetics (radial-arterial and jugular venous cannulation) of S100B. Neuronal parenchymal damage was determined by the trans-cerebral exchange of tau protein, neuron-specific enolase (NSE), and neurofilament-light protein (NF-L). Cerebral blood flow to calculate exchange kinetics was measured by duplex ultrasound of the right internal carotid and left vertebral artery. Passive heating was performed via a warm-water perfused suit. In hyperthermia, there was no increase in the cerebral exchange of S100B (P = 0.327), tau protein (P = 0.626), NF-L (P = 0.447), or NSE (P = 0.908) suggesting the +2°C core temperature is not sufficient to acutely stress the NVU in healthy men. However, there was a significant condition effect (P = 0.028) of NSE, corresponding to a significant increase in arterial (P = 0.023) but not venous (P = 0.173) concentrations in hyperthermia, potentially indicating extra-cerebral release of NSE. Collectively, results from the present study support the notion that in young men there is little concern for NVU damage with acute hyperthermia of +2 °C.NEW & NOTEWORTHY The acute effects of passive whole-body hyperthermia on the integrity of the neurovascular unit (NVU) in humans have remained unclear. We demonstrate that passive heating for ∼1 h until an increase of +2°C esophageal temperature in healthy men does not increase the cerebral release of neuronal parenchymal stress biomarkers, suggesting the NVU integrity is maintained. This preliminary study indicates passive heating is safe for the brain, at least in young healthy men.

An Examination of a Novel Weight Loss Supplement on Anthropometry and Indices of Cardiovascular Disease Risk.

PURPOSE: This study examined whether adding Dichrostachys glomerata (DG; 300 mg/d) to thermogenic supplements with (DG + C) and without (DG) caffeine and other nutrients affects weight loss, changes in body composition, and/or markers of health. METHODS: Sixty-eight participants (female, 54%) were grouped in a double-blind, parallel, stratified random, placebo-controlled manner to supplement their diet with a placebo, DG, or DG + C for 12 weeks while maintaining their normal diet and physical activity. Diet, physical activity, body weight, body composition, anthropometric measures, resting energy expenditure, fasting blood samples, and questionnaires were obtained at 0, 4, 8, and 12 weeks and analyzed using general linear models with repeated measures. Data are reported as mean (±SD) and change from baseline (mean, 95% confidence interval) for weeks 4, 8, and 12, respectively, with p values showing changes from baseline. RESULTS: DG treatment promoted significant but minor reductions in fat mass (-0.56 [-1.02, -0.14], p = 0.01; -0.63 [-1.23, -0.02], p = 0.04; -0.71 [-1.47, 0.09] kg, p = 0.08) and percent body fat (-0.46 [-0.96, -0.04], p = 0.07; -0.63 [-1.16, -0.10], p = 0.02; -0.78 [-1.45, 0.07] %, p = 0.03). There was some evidence that DG + C increased resting energy expenditure, decreased hunger, increased satiety, and improved sleep quality (diminished in DG + C). No other significant effects were observed. CONCLUSIONS: Ingestion of thermogenic supplements containing DG (300 mg/d) with and without caffeine and other nutrients in overweight but otherwise healthy participants who did not alter diet or physical activity promoted clinically insignificant changes in body weight and composition.

Bereavement among widowed Latinos in the United States: A systematic review of methodology and findings.

This study systematically reviewed the methodology and findings of 19 peer-reviewed studies on the experience of bereavement among widowed Latinos, including risk and protective factors to the health of this vulnerable population. Of these studies, 10 included quantitative data, 3 were qualitative studies, and 6 were narrative reviews. Results emphasized the relevance of cultural beliefs about death, rituals, religion, and Latino values (i.e., familismo, respeto, simpatía, personalismo) as common themes in the included studies, along with expressions of grief (e.g., Ataque de nervios, somatization) that vary by gender and acculturation. Risk factors associated with diminished well-being in this population included being a male, financial strain, cultural stressors, having an undocumented legal status, experiencing widowhood at a younger age, and having poor physical health. Effective coping strategies identified included having adequate social support primarily from family, religion and religious practices, the use of folk medicine, volunteering, and the use of emotional release strategies. Moreover, the results highlight that researches informing the health needs of widowed Latinos in the US is limited, and studies with enhanced methodological rigor are needed to better understand the complex needs of this vulnerable population.

Long Chain Omega-3 Fatty Acid Intervention in Ageing Adults at Risk of Dementia Following Repeated Head Trauma. Low-level Support or an Opportunity for an Unanswered Question?

Emerging evidence of brain injury on risk of neurodegenerative diseases such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) have resulted in interest in therapeutic potential of omega-3 fatty acids (n-3FA). We conducted a systematic review of n-3FA therapeutic efficacy for ageing adults at risk of AD/CTE following a history of repeated head trauma. Databases for articles between 1980-June 2020 were examined for studies reporting on n-3 FAs in adults (≥ 45 years) with a history of repeated brain injury. Following an initial screen of 175 articles, 12 studies were considered but were eventually rejected, as they did not meet inclusion criteria. Our review could find no evidence to support, or disprove, effectiveness of n-3FA intervention in older adults with a history of head trauma. With animal studies showing neuro-restorative potential of n-3FA following brain injury, this review highlights the urgent need for human research in this area.

Fractal auditory stimulation has greater benefit for people with Parkinson's disease showing more random gait pattern.

BACKGROUND: Healthy gait dynamics are characterized by the presence of fractal, persistent stride-to-stride variations, which become more random with Parkinson's disease (PD). Rhythmic auditory stimulation with fractal beat-to-beat variations can change gait dynamics in people with PD toward more persistence. RESEARCH QUESTION: How does gait in people with PD change when synchronizing steps with fractal melodic metronomes with different step-to-beat ratios, and which stimulus do they prefer? METHODS: In this cross-sectional study, 15 people with PD and 15 healthy older adults walked over-ground in three conditions: self-paced, paced by a fractal auditory stimulus with a 1:1 step-to-beat ratio ('metronome'), and fractal auditory stimulus with a 1:2 step-to-beat ratio ('music'). Gait dynamics were recorded with instrumented insoles, and detrended fluctuation analysis (DFA) was applied to the series of stride time intervals. Stimuli preference was assessed using Likert-like scales and open-ended questions. ANOVAs were used to compare mean, coefficient of variation, α-DFA, and the responses from the continuous Likert scales. Pearson correlations were used to assess the relationship between 'music' and 'metronome' enjoyment or difficulty with gait outcomes, and to determine the association between baseline α-DFA and changes due to the stimuli. RESULTS: Our major findings are that (i) stride-to-stride variations were more persistent with the 'metronome' compared to baseline for both groups, (ii) the effect was greater for people with lower α-DFA at baseline (i.e., more random stride-to-stride variations), and (iii) both groups found the 'metronome' less difficult to synchronize with. SIGNIFICANCE: This study showed that people with PD and healthy older adults walk with higher statistical persistence in their stride-to-stride variations when instructed to synchronize their steps with a fractal stimulus. Participants with lower persistence at baseline benefited the most from the fractal 'metronome', highlighting the importance to develop patient-centered tests and interventions.