Dynamic modulation of subthalamic nucleus activity facilitates adaptive behavior.

Adapting actions to changing goals and environments is central to intelligent behavior. There is evidence that the basal ganglia play a crucial role in reinforcing or adapting actions depending on their outcome. However, the corresponding electrophysiological correlates in the basal ganglia and the extent to which these causally contribute to action adaptation in humans is unclear. Here, we recorded electrophysiological activity and applied bursts of electrical stimulation to the subthalamic nucleus, a core area of the basal ganglia, in 16 patients with Parkinson's disease (PD) on medication using temporarily externalized deep brain stimulation (DBS) electrodes. Patients as well as 16 age- and gender-matched healthy participants attempted to produce forces as close as possible to a target force to collect a maximum number of points. The target force changed over trials without being explicitly shown on the screen so that participants had to infer target force based on the feedback they received after each movement. Patients and healthy participants were able to adapt their force according to the feedback they received (P < 0.001). At the neural level, decreases in subthalamic beta (13 to 30 Hz) activity reflected poorer outcomes and stronger action adaptation in 2 distinct time windows (Pcluster-corrected < 0.05). Stimulation of the subthalamic nucleus reduced beta activity and led to stronger action adaptation if applied within the time windows when subthalamic activity reflected action outcomes and adaptation (Pcluster-corrected < 0.05). The more the stimulation volume was connected to motor cortex, the stronger was this behavioral effect (Pcorrected = 0.037). These results suggest that dynamic modulation of the subthalamic nucleus and interconnected cortical areas facilitates adaptive behavior.

LINE-1 mRNA 3' end dynamics shape its biology and retrotransposition potential.

LINE-1 (L1) retrotransposons are mobile genetic elements that create new genomic insertions by a copy-paste mechanism involving L1 RNA/RNP intermediates. L1 encodes two ORFs, of which L1-ORF2p nicks genomic DNA and reverse transcribes L1 mRNA using the nicked DNA as a primer which base-pairs with poly(A) tail of L1 mRNA. To better understand the importance of non-templated L1 3' ends' dynamics and the interplay between L1 3' and 5' ends, we investigated the effects of genomic knock-outs and temporal knock-downs of XRN1, DCP2, and other factors. We hypothesized that in the absence of XRN1, the major 5'→3' exoribonuclease, there would be more L1 mRNA and retrotransposition. Conversely, we observed that loss of XRN1 decreased L1 retrotransposition. This occurred despite slight stabilization of L1 mRNA, but with decreased L1 RNP formation. Similarly, loss of DCP2, the catalytic subunit of the decapping complex, lowered retrotransposition despite increased steady-state levels of L1 proteins. In both XRN1 and DCP2 depletions we observed shortening of L1 3' poly(A) tails and their increased uridylation by TUT4/7. We explain the observed reduction of L1 retrotransposition by the changed qualities of non-templated L1 mRNA 3' ends demonstrating the important role of L1 3' end dynamics in L1 biology.

Subthalamic control of impulsive actions: insights from deep brain stimulation in Parkinson's disease.

Control of actions allows adaptive, goal-directed behaviour. The basal ganglia, including the subthalamic nucleus, are thought to play a central role in dynamically controlling actions through recurrent negative feedback loops with the cerebral cortex. Here, we summarize recent translational studies that used deep brain stimulation to record neural activity from and apply electrical stimulation to the subthalamic nucleus in people with Parkinson's disease. These studies have elucidated spatial, spectral and temporal features of the neural mechanisms underlying the controlled delay of actions in cortico-subthalamic networks and demonstrated their causal effects on behaviour in distinct processing windows. While these mechanisms have been conceptualized as control signals for suppressing impulsive response tendencies in conflict tasks and as decision threshold adjustments in value-based and perceptual decisions, we propose a common framework linking decision-making, cognition and movement. Within this framework subthalamic deep brain stimulation can lead to suboptimal choices by reducing the time that patients take for deliberation before committing to an action. However, clinical studies have consistently shown that the occurrence of impulse control disorders is reduced, not increased, after subthalamic deep brain stimulation surgery. This apparent contradiction can be reconciled when recognizing the multifaceted nature of impulsivity, its underlying mechanisms and modulation by treatment. While subthalamic deep brain stimulation renders patients susceptible to making decisions without proper forethought, this can be disentangled from effects related to dopamine comprising sensitivity to benefits vs. costs, reward delay aversion and learning from outcomes. Alterations in these dopamine-mediated mechanisms are thought to underlie the development of impulse control disorders, and can be relatively spared with reduced dopaminergic medication after subthalamic deep brain stimulation. Together, results from studies using deep brain stimulation as an experimental tool have improved our understanding of action control in the human brain and have important implications for treatment of patients with Neurological disorders.

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.

Cortical beta oscillations help synchronise muscles during static posture holding in healthy motor control.

How cortical oscillations are involved in the coordination of functionally coupled muscles and how this is modulated by different movement contexts (static vs dynamic) remains unclear. Here, this is investigated by recording high-density electroencephalography (EEG) and electromyography (EMG) from different forearm muscles while healthy participants (n = 20) performed movement tasks (static and dynamic posture holding, and reaching) with their dominant hand. When dynamic perturbation was applied, beta band (15-35 Hz) activities in the motor cortex contralateral to the performing hand reduced during the holding phase, comparative to when there was no perturbation. During static posture holding, transient periods of increased cortical beta oscillations (beta bursts) were associated with greater corticomuscular coherence and increased phase synchrony between muscles (intermuscular coherence) in the beta frequency band compared to the no-burst period. This effect was not present when resisting dynamic perturbation. The results suggest that cortical beta bursts assist synchronisation of different muscles during static posture holding in healthy motor control, contributing to the maintenance and stabilisation of functional muscle groups. Theoretically, increased cortical beta oscillations could lead to exaggerated synchronisation in different muscles making the initialisation of movements more difficult, as observed in Parkinson's disease.

Cognition is selectively impaired in males with spinal pain: A retrospective analysis of data from the Longitudinal Study of Ageing Danish Twins.

Cognitive decline and spinal pain (back pain [BP] and neck pain [NP]) represent a major public health challenge, yet the potential relationship between them remains elusive. A retrospective analysis of the Longitudinal Study of Ageing Danish Twins was performed to determine any potential relationships between BP/NP and cognitive function adjusting for age, sex, educational and socioeconomic status. A total of 4731 adults (2788 females/1943 males) aged 78 ± 6 (SD) years were included in the analysis. We observed a 1-month prevalence of 25% with BP, 21% with NP and 11% for combined BP/NP. While there were no differences in cognition scores for males and females reporting combined BP/NP, compared to those without combined BP/NP (34.38 points [95% confidence interval (CI) = 31.88, 36.88] vs. 35.72 points [95% CI = 35.19, 36.26]; P = 0.180; and 35.72 points [95% CI = 35.19, 36.26] vs. 35.85 points [95% CI = 35.39, 36.31]; P = 0.327; for male and females, respectively), an adjusted analysis revealed that males with combined BP/NP presented with lower cognitive scores compared to males without combined BP/NP (81.26 points [95% CI = 73.80, 88.72] vs. 79.48 points [95% CI = 70.31, 88.66]; P = 0.043). The findings of this hypothesis-generating study may highlight a potential sex-specific association between spinal pain and later-life neurodegeneration.

Moving, fast and slow: behavioural insights into bradykinesia in Parkinson's disease.

The debilitating symptoms of Parkinson's disease, including the hallmark slowness of movement, termed bradykinesia, were described more than 100 years ago. Despite significant advances in elucidating the genetic, molecular and neurobiological changes in Parkinson's disease, it remains conceptually unclear exactly why patients with Parkinson's disease move slowly. To address this, we summarize behavioural observations of movement slowness in Parkinson's disease and discuss these findings in a behavioural framework of optimal control. In this framework, agents optimize the time it takes to gather and harvest rewards by adapting their movement vigour according to the reward that is at stake and the effort that needs to be expended. Thus, slow movements can be favourable when the reward is deemed unappealing or the movement very costly. While reduced reward sensitivity, which makes patients less inclined to work for reward, has been reported in Parkinson's disease, this appears to be related mainly to motivational deficits (apathy) rather than bradykinesia. Increased effort sensitivity has been proposed to underlie movement slowness in Parkinson's disease. However, careful behavioural observations of bradykinesia are inconsistent with abnormal computations of effort costs due to accuracy constraints or movement energetic expenditure. These inconsistencies can be resolved when considering that a general disability to switch between stable and dynamic movement states can contribute to an abnormal composite effort cost related to movement in Parkinson's disease. This can account for paradoxical observations such as the abnormally slow relaxation of isometric contractions or difficulties in halting a movement in Parkinson's disease, both of which increase movement energy expenditure. A sound understanding of the abnormal behavioural computations mediating motor impairment in Parkinson's disease will be vital for linking them to their underlying neural dynamics in distributed brain networks and for grounding future experimental studies in well-defined behavioural frameworks.

Aortic Arch Debranching and Thoracic Endovascular Aortic Repair (TEVAR) for Type B Aortic Dissection.

BACKGROUND: Since its introduction, thoracic endovascular aortic repair (TEVAR) has revolutionized the treatment of type B aortic dissections (TBADs). However, the proximal aspect of the aortic pathology treated may infringe on the origin of the left subclavian artery or even more proximally. Hence, to ensure durable outcomes, the origin of these vessels needs to be covered, but an extra-anatomical bypass is required to perfuse vital branches, known as aortic arch debranching. This series aims to describe and delineate the disparities of aortic arch debranching during TEVAR for TBAD. METHODS: A retrospective review and analysis of a multicenter international database was conducted to identify patients with TBAD treated with TEVAR between 2005 and 2021. Data analyzed included patient demographics, disease characteristics, operative characteristics, and postoperative outcomes with follow-up on mortality and reintervention. All statistical analyses were carried out using IBM SPSS 26. Patient survival was calculated using a Kaplan-Meier survival analysis, and a P value of less than 0.05 was considered statistically significant. RESULTS: A total of 58 patients were included in the analysis, of which 27 (46.6%) presented with complicated disease and 31 were uncomplicated, of which 10 (17.2%) were classed as high risk and 21 (36.2%) low risk. Zone 2 was the most common proximal landing zone for the stent graft. Left subclavian artery bypass was performed selectively (26%), with 1 stroke occurring, likely due to embolic reasons. A further 6 underwent more proximal aortic debranching before TEVAR (10%) and was a significant risk factor for mortality and the number of stents deployed. The overall rates of reintervention and mortality were 17.2% (n = 10) and 29.3% (n = 17). CONCLUSIONS: Aortic arch debranching and TEVAR for TBAD is associated with significant mortality. Future developments to treat aortic arch pathology could incorporate branched graft devices, eliminating the need for debranching, improving stroke rates, and reducing future reinterventions.

Long-Term Survival and Reintervention Following Thoracic Endovascular Aortic Repair in Blunt Traumatic Thoracic Aortic Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Blunt thoracic aortic injury (BTAI) represents one of the most devastating scenarios of vascular trauma. Different management strategies are available with varying clinical outcomes. However, thoracic endovascular aortic repair (TEVAR) has become the first-line option for most BTAI patients, mainly owing to its minimally invasive nature, yielding improved immediate results. This meta-analysis aims to investigate mortality, long-term survival, and reintervention following TEVAR in BTAI. MATERIAL AND METHODS: A systematic review conducted a comprehensive literature search on multiple electronic databases using strict search terms. Twenty-seven studies met the set inclusion/exclusion criteria. A proportional meta-analysis of extracted data was conducted using the Comprehensive Meta-Analysis Software, v.4. RESULTS: 1498 BTAI patients who underwent TEVAR were included. Using the SVS grading system, 2.6% of the population had Grade 1 injuries, 13.6% Grade 2, 62.2% Grade 3, 19.6% Grade 4, and 1.9% unspecific. All-cause mortality did not exceed 20% in all studies except one outlier with a 37% mortality rate. Using the random effects model, the pooled estimate of overall mortality was 12% (95% confidence interval [CI], 5.35-8.55%; I2 = 70.6%). This was 91% (95% CI, 88.6-93.2; I2 = 30.2%) at 6 months, 90.1% (95% CI, 86.7-92.3; I2 = 53.6%) at 1 year, 89.2% (95% CI, 85.2-91.8; I2 = 62.3%) at 2 years, and 88.1% (95% CI, 83.3-90.9; I2 = 69.6%) at 5 years. Moreover, the pooled estimate of reintervention was 6.4% (95% CI, 0.1-0.49%; I2 = 81.7%). CONCLUSIONS: Despite the high morbidity and mortality associated with BTAI, TEVAR has proven to be a safe and effective management strategy with favorable long-term survival and minimal need for reintervention. Nevertheless, diagnosis of BTAI requires a high index of suspicion with appropriate grading and prompt transfer to trauma centers with appropriate TEVAR facilities.

Perspectives of Implementation of Closed-Loop Deep Brain Stimulation: From Neurological to Psychiatric Disorders.

BACKGROUND: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy. SUMMARY: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level. KEY MESSAGES: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders.

Association between psoas major muscle mass and CPET performance and long-term survival following major colorectal surgery: A retrospective cohort study.

OBJECTIVES: To evaluate whether computed tomography (CT)-derived psoas major muscle measurements could predict preoperative cardiopulmonary exercise testing (CPET) performance and long-term mortality in patients undergoing major colorectal surgery and to compare predictive performance of psoas muscle measurements using 2D approach and 3D approach. METHODS: A retrospective cohort study compliant with STROCSS standards was conducted. Consecutive patients undergoing major colorectal surgery between January 2011 and January 2017 following CPET as part of their preoperative assessment were included. Regression analyses were modelled to investigate association between the CT-derived psoas major muscle mass variables [total psoas muscle area (TPMA), total psoas muscle volume (TPMV) and psoas muscle index (PMI)] and CPET performance and mortality (1-year and 5-year). Discriminative performances of the variables were evaluated using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: A total of 457 eligible patients were included. The median TPMA and TPMV were 21 â€‹cm2 (IQR: 15-27) and 274 â€‹cm3 (IQR: 201-362), respectively. The median PMI measured via 2D and 3D approaches were 7 â€‹cm2/m2 (IQR: 6-9) and 99 â€‹cm3/m2 (IQR: 76-120), respectively. The risks of 1-year and 5-year mortality were 7.4% and 27.1%, respectively. Regression analyses showed TPMA, TPMV, and PMI can predict preoperative CPET performance and long-term mortality. However, ROC curve analyses showed no significant difference in predictive performance amongst TPMA, TPMV, and PMI. CONCLUSION: Radiologically-measured psoas muscle mass variables may predict preoperative CPET performance and may be helpful with informing more objective selection of patients for preoperative CPET and prehabilitation.

Healing rate of hospital-acquired skin tears using adhesive silicone foam versus meshed silicone interface dressings: A prospective, randomized, non-inferiority pilot study.

BACKGROUND: A skin tear is a traumatic wound that occurs in up to one in five hospitalized patients. Nursing care includes application of a dressing to create a moist wound healing environment. AIM: To compare the effectiveness of two standard dressings (adhesive silicone foam vs. meshed silicone interface) to heal hospital-acquired skin tear. METHODS: An intention-to-treat pilot study was designed using a randomized, non-inferiority trial in an Australian tertiary hospital setting. Consenting participants (n = 52) had acquired a skin tear within the previous 24 h and had agreed to a 3-week follow-up. Data were collected between 2014 and 2020. The primary outcome measure was wound healing at 21 days. RESULTS: Baseline characteristics were similar in both arms. Per protocol, 86% of skin tears were fully healed at 3 weeks in the adhesive silicone foam group, compared to 59% in the meshed silicone interface group. Greater healing was observed across all skin tear categories in the adhesive silicone foam dressing group. In the intention-to-treat sample, healing was 69% and 42%, respectively. CONCLUSIONS: Results suggest the adhesive silicone foam dressing may be superior, as it produced clinically significant healing of skin tears at 3 weeks compared to the meshed silicone interface dressing. Accounting for potential loss to follow-up, a sample of at least 103 participants per arm would be required to power a definitive study.

Lifelong exposure to high-altitude hypoxia in humans is associated with improved redox homeostasis and structural-functional adaptations of the neurovascular unit.

High-altitude (HA) hypoxia may alter the structural-functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex-, age- and body mass index-matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were consistently lower and cognition comparable to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.

Selective elevation in external carotid artery flow during acute gravitational transition to microgravity during parabolic flight.

This study sought to determine to what extent acute exposure to microgravity (0 G) and related increases in central blood volume (CBV) during parabolic flight influence the regional redistribution of intra and extra cranial cerebral blood flow (CBF). Eleven healthy participants performed during two parabolic flights campaigns aboard the Airbus A310-ZERO G aircraft. The response of select variables for each of the 15 parabolas involving exposure to both 0 G and hypergravity (1.8 G) were assessed in the seated position. Mean arterial blood pressure (MAP) and heart rate (HR) were continuously monitored and used to calculate stroke volume (SV), cardiac output ([Formula: see text]), and systemic vascular resistance (SVR). Changes in CBV were measured using an impedance monitor. Extracranial flow through the internal carotid, external carotid, and vertebral artery ([Formula: see text]ICA, [Formula: see text]ECA, and [Formula: see text]VA), and intracranial blood velocity was measured by duplex ultrasound. When compared with 1-G baseline condition, 0 G increased CBV (+375 ± 98 mL, P = 0.004) and [Formula: see text] (+16 ± 14%, P = 0.024) and decreased SVR (-7.3 ± 5 mmHg·min·L-1, P = 0.002) and MAP (-13 ± 4 mmHg, P = 0.001). [Formula: see text]ECA increased by 43 ± 46% in 0 G (P = 0.030), whereas no change was observed for CBF, [Formula: see text]ICA, or [Formula: see text]VA (P = 0.102, P = 0.637, and P = 0.095, respectively).NEW & NOTEWORTHY Our findings demonstrate that in microgravity there is a selective increase in external carotid artery blood flow whereas global and regional cerebral blood flow remained preserved. To what extent this reflects an adaptive, neuroprotective response to counter overperfusion remains to be established.

The development of inducible bronchus-associated lymphoid tissue depends on IL-17.

Ectopic or tertiary lymphoid tissues, such as inducible bronchus-associated lymphoid tissue (iBALT), form in nonlymphoid organs after local infection or inflammation. However, the initial events that promote this process remain unknown. Here we show that iBALT formed in mouse lungs as a consequence of pulmonary inflammation during the neonatal period. Although we found CD4(+)CD3(-) lymphoid tissue-inducer cells (LTi cells) in neonatal lungs, particularly after inflammation, iBALT was formed in mice that lacked LTi cells. Instead, we found that interleukin 17 (IL-17) produced by CD4(+) T cells was essential for the formation of iBALT. IL-17 acted by promoting lymphotoxin-α-independent expression of the chemokine CXCL13, which was important for follicle formation. Our results suggest that IL-17-producing T cells are critical for the development of ectopic lymphoid tissues.

Personal protective equipment-induced systemic hypercapnic hypoxaemia: translational implications for impaired cognitive-clinical functional performance.

BACKGROUND: Personal protective equipment (PPE) adversely affects pulmonary gas exchange and may result in systemic hypercapnic hypoxaemia and headache. This study aimed to determine what extent PPE affects cerebral symptoms, global cerebral blood flow, and cognitive functional performance. METHODS: Higher surgical trainees participated in a randomized, repeated-measures, crossover study, completing 60 min of laparoscopic surgical simulation in both standard operating attire and type 3 PPE. Measurements were collected at baseline and after 60 min of simulation. The primary outcome measure was headache. Headache was examined using the validated visual analogue scale (VAS) and Environmental Symptoms Questionnaire C (ESQ-C), global cerebral blood flow with duplex ultrasonography, and visuospatial and executive gross/fine motor function with grooved peg board (GPB) and laparoscopic bead (LSB) board tasks. RESULTS: Thirty-one higher surgical trainees (20 men, 11 women) completed the study. Compared with standard operating attire, PPE increased headache assessment scores (mean(s.d.) VAS score 3.5(5.6) versus 13.0(3.7), P < 0.001; ESQ-C score 1.3(2.0) versus 5.9(5.1), P < 0.001) and was associated with poorer completion times for GPB-D (61.4(12.0) versus 71.1(12.4) s; P = 0.034) and LSB (192.5(66.9) versus 270.7(135.3) s; P = 0.025) tasks. Wearing PPE increased heart rate (82.5(13.6) versus 93.5(13.0) beats/min; P = 0.022) and skin temperature (36.6(0.4) versus 37.1(0.5)°C; P < 0.001), but decreased peripheral oxygen saturation (97.9(0.8) versus 96.8(1.0) per cent; P < 0.001). Female higher surgical trainees exhibited higher peripheral oxygen saturation across all conditions. No differences were observed in global cerebral blood flow as a function of attire, time or sex. CONCLUSION: Despite no marked changes in global cerebral blood flow, type 3 PPE was associated with increased headache scores and cerebral symptoms (VAS and ESQ-C) alongside impaired executive motor function highlighting the clinical implications of PPE-induced impairment for cognitive-clinical performance.

Assessing cardiorespiratory fitness relative to sex improves surgical risk stratification.

BACKGROUND: To what extent sex-related differences in cardiorespiratory fitness (CRF) impact postoperative patient mortality and corresponding implications for surgical risk stratification remains to be established. METHODS: To examine this, we recruited 640 patients (366 males vs. 274 females) who underwent cardiopulmonary exercise testing prior to elective colorectal surgery. Patients were defined high risk if peak oxygen uptake was <14.3 mL kg-1  min-1 and ventilatory equivalent for carbon dioxide at 'anaerobic threshold' >34. Between-sex CRF and mortality was assessed, and sex-specific CRF thresholds predictive of mortality was calculated. RESULTS: Seventeen percent of deaths were attributed to sub-threshold CRF, which was higher than established risk factors for cardiovascular disease (CVD). The group (independent of sex) exhibited a 5-fold higher mortality (high vs. low risk patients hazard ratio = 4.80, 95% confidence interval 2.73-8.45, p < 0.001). Females exhibited 39% lower CRF (p < 0.001) with more classified high risk than males (36 vs. 23%, p = 0.001), yet mortality was not different (p = 0.544). Upon reformulation of sex-specific CRF thresholds, lower cut-offs for mortality were observed in females, and consequently, fewer (20%) were stratified with sub-threshold CRF compared to the original 36% (p < 0.001). CONCLUSIONS: Low CRF accounted for more deaths than traditional CVD risk factors, and when CRF was considered relative to sex, the disproportionate number of females stratified unfit was corrected. These findings support clinical consideration of 'sex-specific' CRF thresholds to better inform postoperative mortality and improve surgical risk stratification.

Acute hypoxia impairs posterior cerebral bioenergetics and memory in man.

Hypoxia has the potential to impair cognitive function; however, it is still uncertain which cognitive domains are adversely affected. We examined the effects of acute hypoxia (∼7 h) on central executive (Go/No-Go) and non-executive (memory) tasks and the extent to which impairment was potentially related to regional cerebral blood flow and oxygen delivery (CDO2 ). Twelve male participants performed cognitive tasks following 0, 2, 4 and 6 h of passive exposure to both normoxia and hypoxia (12% O2 ), in a randomized block cross-over single-blinded design. Middle cerebral artery (MCA) and posterior cerebral artery (PCA) blood velocities and corresponding CDO2 were determined using bilateral transcranial Doppler ultrasound. In hypoxia, MCA DO2 was reduced during the Go/No-Go task (P = 0.010 vs. normoxia, main effect), and PCA DO2 was attenuated during memorization (P = 0.005 vs. normoxia) and recall components (P = 0.002 vs. normoxia) in the memory task. The accuracy of the memory task was also impaired in hypoxia (P = 0.049 vs. normoxia). In contrast, hypoxia failed to alter reaction time (P = 0.19 vs. normoxia) or accuracy (P = 0.20 vs. normoxia) during the Go/No-Go task, indicating that selective attention and response inhibition were preserved. Hypoxia did not affect cerebral blood flow or corresponding CDO2 responses to cognitive activity (P > 0.05 vs. normoxia). Collectively, these findings highlight the differential sensitivity of cognitive domains, with memory being selectively vulnerable in hypoxia. NEW FINDINGS: What is the central question of this study? We sought to examine the effects of acute hypoxia on central executive (selective attention and response inhibition) and non-executive (memory) performance and the extent to which impairments are potentially related to reductions in regional cerebral blood flow and oxygen delivery. What is the main finding and its importance? Memory was impaired in acute hypoxia, and this was accompanied by a selective reduction in posterior cerebral artery oxygen delivery. In contrast, selective attention and response inhibition remained well preserved. These findings suggest that memory is selectively vulnerable to hypoxia.

Myths and methodologies: Cardiopulmonary exercise testing for surgical risk stratification in patients with an abdominal aortic aneurysm; balancing risk over benefit.

The extent to which patients with an abdominal aortic aneurysm (AAA) should exercise remains unclear, given theoretical concerns over the perceived risk of blood pressure-induced rupture, which is often catastrophic. This is especially pertinent during cardiopulmonary exercise testing, when patients are required to perform incremental exercise to symptom-limited exhaustion for the determination of cardiorespiratory fitness. This multimodal metric is being used increasingly as a complementary diagnostic tool to inform risk stratification and subsequent management of patients undergoing AAA surgery. In this review, we bring together a multidisciplinary group of physiologists, exercise scientists, anaesthetists, radiologists and surgeons to challenge the enduring 'myth' that AAA patients should be fearful of and avoid rigorous exercise. On the contrary, by appraising fundamental vascular mechanobiological forces associated with exercise, in conjunction with 'methodological' recommendations for risk mitigation specific to this patient population, we highlight that the benefits conferred by cardiopulmonary exercise testing and exercise training across the continuum of intensity far outweigh the short-term risks posed by potential AAA rupture.

Lower systemic nitric oxide bioactivity, cerebral hypoperfusion and accelerated cognitive decline in formerly concussed retired rugby union players.

NEW FINDINGS: What is the central question of this study? What are the molecular, cerebrovascular and cognitive biomarkers of retired rugby union players with concussion history? What is the main finding and its importance? Retired rugby players compared with matched controls exhibited lower systemic nitric oxide bioavailability accompanied by lower middle cerebral artery velocity and mild cognitive impairment. Retired rugby players are more susceptible to accelerated cognitive decline. ABSTRACT: Following retirement from sport, the chronic consequences of prior-recurrent contact are evident and retired rugby union players may be especially prone to accelerated cognitive decline. The present study sought to integrate molecular, cerebrovascular and cognitive biomarkers in retired rugby players with concussion history. Twenty retired rugby players aged 64 ± 5 years with three (interquartile range (IQR), 3) concussions incurred over 22 (IQR, 6) years were compared to 21 sex-, age-, cardiorespiratory fitness- and education-matched controls with no prior concussion history. Concussion symptoms and severity were assessed using the Sport Concussion Assessment Tool. Plasma/serum nitric oxide (NO) metabolites (reductive ozone-based chemiluminescence), neuron specific enolase, glial fibrillary acidic protein and neurofilament light-chain (ELISA and single molecule array) were assessed. Middle cerebral artery blood velocity (MCAv, doppler ultrasound) and reactivity to hyper/hypocapnia ( CVR CO 2 hyper ${\mathrm{CVR}}_{{\mathrm{CO}}_{\mathrm{2}}{\mathrm{hyper}}}$ / CVR CO 2 hypo ${\mathrm{CVR}}_{{\mathrm{CO}}_{\mathrm{2}}{\mathrm{hypo}}}$ ) were assessed. Cognition was determined using the Grooved Pegboard Test and Montreal Cognitive Assessment. Players exhibited persistent neurological symptoms of concussion (U = 109(41) , P = 0.007), with increased severity compared to controls (U = 77(41) , P < 0.001). Lower total NO bioactivity (U = 135(41) , P = 0.049) and lower basal MCAv were apparent in players (F2,39  = 9.344, P = 0.004). This was accompanied by mild cognitive impairment (P = 0.020, 95% CI, -3.95 to -0.34), including impaired fine-motor coordination (U = 141(41) , P = 0.021). Retired rugby union players with history of multiple concussions may be characterised by impaired molecular, cerebral haemodynamic and cognitive function compared to non-concussed, non-contact controls.