Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis.

Non-canonical lipolysis induced by inflammatory cytokines or Toll-like receptor ligands is required for the regulation of inflammation during endotoxemia and sepsis. Canonical lipolysis induced by catecholamines declines during aging due to factors including an expansion of lymphocytes, pro-inflammatory macrophage polarization, and an increase in chronic low-grade inflammation; however, the extent to which the non-canonical pathway of lipolysis is active and impacted by immune cells during aging remains unclear. Therefore, we aimed to define the extent to which immune cells from old mice influence non-canonical lipolysis during sepsis. We identified age-associated impairments of non-canonical lipolysis and an accumulation of dysfunctional B1 B cells in the visceral white adipose tissue (vWAT) of old mice. Lifelong deficiency of B cells results in restored non-canonical lipolysis and reductions in pro-inflammatory macrophage populations. Our study suggests that targeting the B cell-macrophage signaling axis may resolve metabolic dysfunction in aged vWAT and attenuate septic severity in older individuals.

Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leucocyte transcriptomic subphenotypes.

RATIONALE: Heterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating biomarkers have defined hyper-inflammatory and hypo-inflammatory subphenotypes in ARDS associated with differential treatment response. It is unknown if similar subphenotypes exist in sepsis populations where leucocyte transcriptomic-defined subphenotypes have been reported. OBJECTIVES: We investigated whether inflammatory clusters based on cytokine protein abundance were seen in sepsis, and the relationships with previously described transcriptomic subphenotypes. METHODS: Hierarchical cluster and latent class analysis were applied to an observational study (UK Genomic Advances in Sepsis (GAinS)) (n=124 patients) and two clinical trial datasets (VANISH, n=155 and LeoPARDS, n=484) in which the plasma protein abundance of 65, 21, 11 circulating cytokines, cytokine receptors and regulators were quantified. Clinical features, outcomes, response to trial treatments and assignment to transcriptomic subphenotypes were compared between inflammatory clusters. MEASUREMENTS AND MAIN RESULTS: We identified two (UK GAinS, VANISH) or three (LeoPARDS) inflammatory clusters. A group with high levels of pro-inflammatory and anti-inflammatory cytokines was seen that was associated with worse organ dysfunction and survival. No interaction between inflammatory clusters and trial treatment response was found. We found variable overlap of inflammatory clusters and leucocyte transcriptomic subphenotypes. CONCLUSIONS: These findings demonstrate that differences in response at the level of cytokine biology show clustering related to severity, but not treatment response, and may provide complementary information to transcriptomic sepsis subphenotypes. TRIAL REGISTRATION NUMBER: ISRCTN20769191, ISRCTN12776039.

MADD regulates natural killer cell degranulation through Rab27a activation.

Natural killer (NK) cells have the ability to lyse other cells through the release of lytic granules (LGs). This is in part mediated by the small GTPase Rab27a, which was first identified to play a crucial role in degranulation through the study of individuals harboring mutations in the gene encoding Rab27a. However, the guanine nucleotide exchange factor (GEF) regulating the activation of Rab27a in cytotoxic lymphocytes was unknown. Here, we show that knockout of MADD significantly decreased the levels of GTP-bound Rab27a in both resting and stimulated NK cells, and MADD-deficient NK cells and CD8+ T cells displayed severely reduced degranulation and cytolytic ability, similar to that seen with Rab27a deficiency. Although MADD colocalized with Rab27a on LGs and was enriched at the cytolytic synapse, the loss of MADD did not impact Rab27a association with LGs nor their recruitment to the cytolytic synapse. Together, our results demonstrate an important role for MADD in cytotoxic lymphocyte killing.

The radiology quality assurance process in the Yorkshire Lung Screening Trial, and findings from the baseline round of low dose CT screening for lung cancer.

OBJECTIVE: As lung cancer screening is rolled-out, there is a need to develop an effective quality assurance (QA) framework around radiology reporting to ensure optimal implementation. Here, we report a structured QA process for low-dose CT (LDCT) scans performed in the Yorkshire Lung Screening Trial. METHODS: Negative LDCT scans were single read after using computer-aided detection software. The radiology QA process included reviewing 5% of negative scans selected at random, and all cases with a subsequent diagnosis of extrapulmonary cancer or interval lung cancer not detected on the baseline scan. Radiologists were not informed of the reason for review and original radiology reports were scored as either "satisfactory", "satisfactory with learning points", or "unsatisfactory". RESULTS: From 6650 participants undergoing LDCT screening, 208 negative scans were reviewed alongside 11 cases with subsequent extrapulmonary cancer and 10 cases with interval lung cancer. Overall, only three reports were ultimately judged "unsatisfactory", 1% of randomly selected negative scans (n = 2/208) and one interval lung cancer scan (n = 1/10). Four out of a total of five cases judged "satisfactory with learning points" were related to oesophageal abnormalities where the participant was subsequently diagnosed with oesophageal cancer. CONCLUSION: The described process attempts to minimise bias in retrospective review of screening scans, and may represent a framework for future QA of national screening programmes. ADVANCES IN KNOWLEDGE: This study describes a structured QA process for a lung cancer screening programme, involving blinded second-read of LDCT screening scans to ensure fair, constructive audit of clinical performance.

Measuring spirometry in a lung cancer screening cohort highlights possible underdiagnosis and misdiagnosis of COPD.

Introduction: COPD is underdiagnosed, and measurement of spirometry alongside low-dose computed tomography (LDCT) screening for lung cancer is one strategy to increase earlier diagnosis of this disease. Methods: Ever-smokers at high risk of lung cancer were invited to the Yorkshire Lung Screening Trial for a lung health check (LHC) comprising LDCT screening, pre-bronchodilator spirometry and a smoking cessation service. In this cross-sectional study we present data on participant demographics, respiratory symptoms, lung function, emphysema on imaging and both self-reported and primary care diagnoses of COPD. Multivariable logistic regression analysis identified factors associated with possible underdiagnosis and misdiagnosis of COPD in this population, with airflow obstruction defined as forced expiratory volume in 1 s/forced vital capacity ratio <0.70. Results: Out of 3920 LHC attendees undergoing spirometry, 17% had undiagnosed airflow obstruction with respiratory symptoms, representing potentially undiagnosed COPD. Compared to those with a primary care COPD code, this population had milder symptoms, better lung function and were more likely to be current smokers (p≤0.001 for all comparisons). Out of 836 attendees with a primary care COPD code who underwent spirometry, 19% did not have airflow obstruction, potentially representing misdiagnosed COPD, although symptom burden was high. Discussion: Spirometry offered alongside LDCT screening can potentially identify cases of undiagnosed and misdiagnosed COPD. Future research should assess the downstream impact of these findings to determine whether any meaningful changes to treatment and outcomes occur, and to assess the impact on co-delivering spirometry on other parameters of LDCT screening performance such as participation and adherence. Additionally, work is needed to better understand the aetiology of respiratory symptoms in those with misdiagnosed COPD, to ensure that this highly symptomatic group receive evidence-based interventions.

Diagnoses and treatments for participants with interstitial lung abnormalities detected in the Yorkshire Lung Screening Trial.

INTRODUCTION: Interstitial lung abnormalities (ILA) are relatively common incidental findings in participants undergoing low-dose CT screening for lung cancer. Some ILA are transient and inconsequential, but others represent interstitial lung disease (ILD). Lung cancer screening therefore offers the opportunity of earlier diagnosis and treatment of ILD for some screening participants. METHODS: The prevalence of ILA in participants in the baseline screening round of the Yorkshire Lung Screening Trial is reported, along with the proportion referred to a regional ILD service, eventual diagnoses, outcomes and treatments. RESULTS: Of 6650 participants undergoing screening, ILA were reported in 169 (2.5%) participants. Following review in a screening review meeting, 56 participants were referred to the ILD service for further evaluation (0.8% of all screening participants). 2 participants declined referral, 1 is currently awaiting review and the remaining 53 were confirmed as having ILD. Eventual diagnoses were idiopathic pulmonary fibrosis (n=14), respiratory bronchiolitis ILD (n=4), chronic hypersensitivity pneumonitis (n=2), connective tissue disease/rheumatoid arthritis-related ILD (n=4), asbestosis (n=1), idiopathic non-specific interstitial pneumonia (n=1), sarcoidosis (n=1) and pleuroparenchymal fibroelastosis (n=1). Twenty five patients had unclassifiable idiopathic interstitial pneumonia. Overall, 10 people received pharmacotherapy (7 antifibrotics and 3 prednisolone) representing 18% of those referred to the ILD service and 0.15% of those undergoing screening. 32 people remain under surveillance in the ILD service, some of whom may require treatment in future. DISCUSSION: Lung cancer screening detects clinically significant cases of ILD allowing early commencement of disease-modifying treatment in a proportion of participants. This is the largest screening cohort to report eventual diagnoses and treatments and provides an estimate of the level of clinical activity to be expected by ILD services as lung cancer screening is implemented. Further research is needed to clarify the optimal management of screen-detected ILD. TRIAL REGISTRATION NUMBER: ISRCTN42704678.

Diagnosis and treatment outcomes from prebronchodilator spirometry performed alongside lung cancer screening in a Lung Health Check programme.

INTRODUCTION: Incorporating spirometry into low-dose CT (LDCT) screening for lung cancer may help identify people with undiagnosed chronic obstructive pulmonary disease (COPD), although the downstream impacts are not well described. METHODS: Participants attending a Lung Health Check (LHC) as part of the Yorkshire Lung Screening Trial were offered spirometry alongside LDCT screening. Results were communicated to the general practitioner (GP), and those with unexplained symptomatic airflow obstruction (AO) fulfilling agreed criteria were referred to the Leeds Community Respiratory Team (CRT) for assessment and treatment. Primary care records were reviewed to determine changes to diagnostic coding and pharmacotherapy. RESULTS: Of 2391 LHC participants undergoing prebronchodilator spirometry, 201 (8.4%) fulfilled the CRT referral criteria of which 151 were invited for further assessment. Ninety seven participants were subsequently reviewed by the CRT, 46 declined assessment and 8 had already been seen by their GP at the time of CRT contact. Overall 70 participants had postbronchodilator spirometry checked, of whom 20 (29%) did not have AO. Considering the whole cohort referred to the CRT (but excluding those without AO postbronchodilation), 59 had a new GP COPD code, 56 commenced new pharmacotherapy and 5 were underwent pulmonary rehabilitation (comprising 2.5%, 2.3% and 0.2% of the 2391 participants undergoing LHC spirometry). CONCLUSIONS: Delivering spirometry alongside lung cancer screening may facilitate earlier diagnosis of COPD. However, this study highlights the importance of confirming AO by postbronchodilator spirometry prior to diagnosing and treating patients with COPD and illustrates some downstream challenges in acting on spirometry collected during an LHC.

Breed distribution of spontaneous chronic corneal epithelial defects in UK dogs.

BACKGROUND: This study aimed to assess the risk of bilateral disease in dogs affected by spontaneous chronic corneal epithelial defects (SCCEDs) and identify any recent changes in the distribution of breeds affected. METHODS: Medical records of dogs assessed at a single ophthalmic centre for the management of SCCEDs between 2007 and 2020 were reviewed, and clinical data were extracted. RESULTS: Three hundred and seven dogs met the inclusion criteria. Boxers (129 dogs), Staffordshire Bull Terriers (37 dogs) and French Bulldogs (20 dogs) were most frequently affected. Overall, the median age at presentation was 8 years (range 1-15 years), but French Bulldogs had a younger median age of 6 years. Boxers, French Bulldogs and Staffordshire Bull Terriers showed higher odds of bilateral ulceration (odds ratio 1.79, 1.65 and 1.64, respectively) compared to the overall study population. The median time between presentations when both eyes were affected was 4 months (range 0-42 months). There was a statistically significant increase in French Bulldogs, a reduction in Boxers and a stable number of Staffordshire Bull Terriers treated for this condition. However, as the effective sample size from each individual breed was small, further studies would be beneficial to confirm these findings. CONCLUSION: The results from this study suggest a shift in breed distribution. The risk of bilateral disease is higher in the three breeds reported here, and owners should be counselled appropriately at the initial examination.

Neurophysiological evidence against attentional suppression as the source of the same-location cost in spatial cueing.

Spatial cues that mismatch the colour of a subsequent target have been shown to slow responses to targets that share their location. The source of this 'same location cost' (SLC) is currently unknown. Two potential sources are attentional signal suppression and object-file updating. Here, we tested a direct prediction of the suppression account using data from a spatial-cueing study in which we recorded brain activity using electroencephalography (EEG), and focusing on the event-related PD component, which is thought to index attentional signal suppression. Correlating PD amplitude with SLC magnitude, we tested the prediction that if attentional signal suppression is the source of the SLC, then the SLC should be positively correlated with PD amplitude. Across 48 participants, SLC and PD magnitudes were negatively correlated, in direct contradiction to a suppression account of the SLC. These results are compatible with an object-file updating account of the SLC in which updating is facilitated by reactive suppression of the to-be-updated stimulus information.

European Respiratory Society International Congress 2021: highlights from best-abstract awardees.

This article provides an overview of some of the highlights of the @EuroRespSoc Congress 2021 from the perspective of the best-abstract awardees of the ERS Assemblies @EarlyCareerERS @OrphaLung https://bit.ly/3JCjHYS.

Slow-oscillatory tACS does not modulate human motor cortical response to repeated plasticity paradigms.

Previous history of activity and learning modulates synaptic plasticity and can lead to saturation of synaptic connections. According to the synaptic homeostasis hypothesis, neural oscillations during slow-wave sleep play an important role in restoring plasticity within a functional range. However, it is not known whether slow-wave oscillations-without the concomitant requirement of sleep-play a causal role in human synaptic homeostasis. Here, we aimed to answer this question using transcranial alternating current stimulation (tACS) to induce slow-oscillatory activity in awake human participants. tACS was interleaved between two plasticity-inducing interventions: motor learning, and paired associative stimulation (PAS). The hypothesis tested was that slow-oscillatory tACS would prevent homeostatic interference between motor learning and PAS, and facilitate plasticity from these successive interventions. Thirty-six participants received sham and active fronto-motor tACS in two separate sessions, along with electroencephalography (EEG) recordings, while a further 38 participants received tACS through a control montage. Motor evoked potentials (MEPs) were recorded throughout the session to quantify plasticity changes after the different interventions, and the data were analysed with Bayesian statistics. As expected, there was converging evidence that motor training led to excitatory plasticity. Importantly, we found moderate evidence against an effect of active tACS in restoring PAS plasticity, and no evidence of lasting entrainment of slow oscillations in the EEG. This suggests that, under the conditions tested here, slow-oscillatory tACS does not modulate synaptic homeostasis in the motor system of awake humans.

Participation in community-based lung cancer screening: the Yorkshire Lung Screening Trial.

BACKGROUND: Screening with low-dose computed tomography (LDCT) reduces lung cancer mortality; however, the most effective strategy for optimising participation is unknown. Here we present data from the Yorkshire Lung Screening Trial, including response to invitation, screening eligibility and uptake of community-based LDCT screening. METHODS: Individuals aged 55-80 years, identified from primary care records as having ever smoked, were randomised prior to consent to invitation to telephone lung cancer risk assessment or usual care. The invitation strategy included general practitioner endorsement, pre-invitation and two reminder invitations. After telephone triage, those at higher risk were invited to a Lung Health Check (LHC) with immediate access to a mobile CT scanner. RESULTS: Of 44 943 individuals invited, 50.8% (n=22 815) responded and underwent telephone-based risk assessment (16.7% and 7.3% following first and second reminders, respectively). A lower response rate was associated with current smoking status (adjusted OR 0.44, 95% CI 0.42-0.46) and socioeconomic deprivation (adjusted OR 0.58, 95% CI 0.54-0.62 for the most versus the least deprived quintile). Of those responding, 34.4% (n=7853) were potentially eligible for screening and offered a LHC, of whom 86.8% (n=6819) attended. Lower uptake was associated with current smoking status (adjusted OR 0.73, 95% CI 0.62-0.87) and socioeconomic deprivation (adjusted OR 0.78, 95% CI 0.62-0.98). In total, 6650 individuals had a baseline LDCT scan, representing 99.7% of eligible LHC attendees. CONCLUSIONS: Telephone risk assessment followed by a community-based LHC is an effective strategy for lung cancer screening implementation. However, lower participation associated with current smoking status and socioeconomic deprivation underlines the importance of research to ensure equitable access to screening.

State-dependent effects of neural stimulation on brain function and cognition.

Invasive and non-invasive brain stimulation methods are widely used in neuroscience to establish causal relationships between distinct brain regions and the sensory, cognitive and motor functions they subserve. When combined with concurrent brain imaging, such stimulation methods can reveal patterns of neuronal activity responsible for regulating simple and complex behaviours at the level of local circuits and across widespread networks. Understanding how fluctuations in physiological states and task demands might influence the effects of brain stimulation on neural activity and behaviour is at the heart of how we use these tools to understand cognition. Here we review the concept of such 'state-dependent' changes in brain activity in response to neural stimulation, and consider examples from research on altered states of consciousness (for example, sleep and anaesthesia) and from task-based manipulations of selective attention and working memory. We relate relevant findings from non-invasive methods used in humans to those obtained from direct electrical and optogenetic stimulation of neuronal ensembles in animal models. Given the widespread use of brain stimulation as a research tool in the laboratory and as a means of augmenting or restoring brain function, consideration of the influence of changing physiological and cognitive states is crucial for increasing the reliability of these interventions.

Prophylactic efficacy of intravenous paracetamol administration to reduce the incidence of post-operative ocular hypertension in dogs undergoing phacoemulsification: A pilot study.

PURPOSE: To determine whether intravenous administration of paracetamol can prevent postoperative ocular hypertension (POH) in dogs following routine phacoemulsification. METHODS: Diabetic and non-diabetic patients (total 54 dogs) undergoing unilateral or bilateral phacoemulsification were recruited to this placebo-controlled, prospective study. The control group received 1 ml/kg saline via intravenous infusion while the treatment group received 10 mg/kg paracetamol via intravenous infusion. Infusions were administered 30 min prior to surgery and repeated 12 h following initial administration. All patients received topical latanoprost at the conclusion of surgery. Intraocular pressure (IOP) was measured before premedication (baseline), and at 1 h, 3 h, 5 h and 18 h following extubation. POH was defined as an IOP above 25 mmHg (POH25). In addition, the number of patients with an IOP exceeding 20 mmHg was analyzed (POH20). RESULTS: POH20 occurred in 33 of 54 animals (61.1%), including 19 of 25 animals (76.0%) in the control group and 14 of 29 animals (55.2%) in the treatment group. POH25 occurred in 23 of 44 animals (52.3%), including 13 of 25 animals (52.0%) in the control group and 10 of 29 animals (34.5%) in the treatment group. Paracetamol administration showed a significant positive effect on reducing the incidence of POH20 (p = .048), but not POH25 (p = .221). CONCLUSIONS: When comparing groups, treatment with paracetamol showed a statistically significant reduction in the incidence of POH20, although no differences were observed in the incidence of POH25 between groups. Further studies are warranted to explore whether alternative drug regimes or routes of administration can provide enhanced efficacy in the prevention of POH25.

Onchocerca lupi in imported dogs in the UK: implications for animal and public health.

BACKGROUND: Onchocerca lupi is a filarial nematode affecting dogs, and occasionally cats and humans, in continental Europe, North Africa, the Middle East, and the USA. Adult worms are usually found in periocular nodules and enucleation is sometimes required if the infection fails to respond to other treatment options. CASE PRESENTATION: Here, we report the presence of O. lupi in the UK for the first time. Of two dogs re-homed from continental Europe, one developed an ocular nodule seven years after arrival from Portugal. The conjunctival perilimbal mass in its left eye was surgically removed but despite anthelminthic treatment, a further nodule developed in the same eye six months later. In the second case - a dog imported from Romania 12 months earlier - a perilimbal mass was excised from the left eye and prior anthelminthic treatment was supplemented with oral prednisolone and doxycycline. However, nodules recurred, and the left globe was subsequently enucleated. Conjunctival hyperaemia then appeared in the right eye and neither additional anthelminthic treatment nor removal of worm masses failed to prevent the further development of lesions. Excised adult worms were identified in both cases as O. lupi based on morphological characteristics, as well as PCR and sequencing of cytochrome c oxidase subunit I and 12S rRNA gene fragments. CONCLUSION: O. lupi parasitosis can apparently remain cryptic in dogs for several years before any clinical signs manifest. Moreover, the progression of infection can be highly aggressive and recalcitrant to both surgical intervention and anthelminthic treatment. Increasingly, former stray dogs of unknown infection status are entering the UK, raising both veterinary and public health concerns.

Transcranial direct current stimulation of 3 cortical targets is no more effective than placebo as treatment for fibromyalgia: a double-blind sham-controlled clinical trial.

ABSTRACT: Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) and the dorsolateral prefrontal cortex seem to improve pain and other symptoms of fibromyalgia (FM), although the evidence on the effectiveness of tDCS and the optimal stimulation target is not robust enough. Our main objective was to establish the optimal area of stimulation, comparing the 2 classical targets and a novel pain-related area, the operculo-insular cortex, in a sham-controlled trial. Using a double-blind design, we randomly assigned 130 women with FM to 4 treatment groups (M1, dorsolateral prefrontal cortex, operculo-insular cortex, and sham), each receiving fifteen 20-minute sessions of 2 mA anodal tDCS over the left hemisphere. Our primary outcome was pain intensity. The secondary outcomes were the other core symptoms of FM (fatigue, mood, cognitive and sleep disorders, and hyperalgesia measured by the pressure pain threshold). We performed the assessment at 3 time points (before, immediately after treatment, and at 6 months follow-up). The linear mixed-model analysis of variances showed significant treatment effects across time for clinical pain and for fatigue, cognitive and sleep disturbances, and experimental pain, irrespective of the group. In mood, the 3 active tDCS groups showed a significantly larger improvement in anxiety and depression than sham. Our findings provide evidence of a placebo effect, support the use of tDCS for the treatment of affective symptoms, and challenge the effectiveness of tDCS as treatment of FM.

The prevalence of uveitis in a population of donkeys in the UK.

BACKGROUND: Uveitis is reported to be a leading cause of blindness in horses. Little work has been undertaken to date to investigate whether donkeys are affected by a similar disease prevalence. OBJECTIVES: To investigate the disease prevalence of uveitis in a population of donkeys in the UK. STUDY DESIGN: Descriptive observational study. METHODS: An ophthalmic examination was performed on each donkey, in a darkened stable. Each donkey underwent slit lamp biomicroscopy, and direct and/or indirect ophthalmoscopy. Fluorescein staining, STT1 and IOPs were measured when deemed clinically necessary. Pharmacological pupillary dilation was achieved using 1% tropicamide. RESULTS: A total of 207 donkeys were examined: 139 males (67.1%) and 68 females (32.9%). Age range was 2-37 years (median: 17 years, interquartile range: 9-25 years). Three donkeys (1.5%) were blind in one eye, and one was monocular at the time of examination. Signs consistent with either previous or current uveitis were identified in eight eyes of six animals (2.9%). Clinical signs included are as follows: miosis (n = 1), corpora nigra atrophy (n = 6), anterior lens capsule pigment (n = 2), cataract (n = 8), posterior synechiae (n = 3), lens subluxation (n = 1), vitreal changes (n = 2), peripapillary scarring (n = 3) and phthisis bulbi (n = 1). Significant ocular pathology precluded fundic examination in three eyes. Three out of eight eyes (37.5%) were blinded by the pathology. The risk of uveitis was found to increase with age (OR 1.1, CI: 1.01-1.25) on univariable analysis (P = .046.). MAIN LIMITATIONS: Fluorescein staining, tonometry and Schirmer tear test measurements were not performed on all donkeys. CONCLUSIONS: The disease prevalence reported here is comparable to that reported for horses in the UK. Larger prospective studies are necessary to determine whether there is a similar trend in disease prevalence in the donkey population worldwide. In addition, further investigations should aim to establish whether uveitis in donkeys is similar to the ERU syndrome seen in horses.

New procedure of high-frequency repetitive transcranial magnetic stimulation for central neuropathic pain: a placebo-controlled randomized crossover study.

Repetitive transcranial magnetic stimulation (rTMS) is a procedure increasingly used to treat patients with central neuropathic pain, but its efficacy is still under debate. Patients with medically refractory chronic central neuropathic pain were included in 2 randomized phases (active/sham), separated by a wash-out period of 8 weeks. Each phase consisted of 4 consecutive rTMS sessions and a final evaluation session, all separated from one another by 3 weeks. High-frequency (20 Hz) rTMS was delivered over the primary motor cortex (M1) contralateral to the patient's pain using a neuronavigated robotic system. Patients and clinicians assessing outcomes were blinded to treatment allocation during the trial. The primary outcome measured the percentage of pain relief (%R) from baseline. Secondary outcomes were VAS score, Neuropathic Pain Symptom Inventory, analgesic drug consumption, and quality of life (EQ-5D). Thirty-six patients performed the entire study with no adverse effects. The analgesic effect for the main criterion (%R) was significantly higher in the active (33.8% confidence interval [CI]: [23.88-43.74]) than in the sham phase (13.02% CI: [6.64-19.76]). This was also the case for the secondary outcome VAS (-19.34% CI: [14.31-25.27] vs -4.83% CI: [1.96-8.18]). No difference was observed for quality of life or analgesic drug consumption. Seventeen patients (47%) were identified as responders, but no significant interaction was found between clinical and technical factors considered here and the analgesic response. These results provide strong evidence that 3 weeks spaced high-frequency rTMS of M1 results in a sustained analgesic effect and support the clinical interest of this stimulation paradigm to treat refractory chronic pain.

Self-reported tolerance of the intensity of exercise influences affective responses to and intentions to engage with high-intensity interval exercise.

This study investigated the effect of self-reported tolerance of the intensity of exercise on affective responses to, self-efficacy for and intention to repeat low-volume high-intensity interval exercise (HIIE). Thirty-six healthy participants (mean age 21 ± 2 years) were split into high tolerance (HT; n = 19), low tolerance (LT; n = 9), and very low tolerance (VLT; n = 8) of exercise intensity groups. Participants completed 10 × 6 s cycle sprints with 60 s recovery. Affective valence and perceived activation were measured before exercise, after sprints 2, 4, 6, 8, 10, and 20 min post-HIIE. Intention and self-efficacy were assessed 20 min post-HIIE. Affective valence was significantly lower in VLT vs. LT (P = 0.034, d = 1.01-1.14) and HT (P = 0.018, d = 1.34-1.70). Circumplex profiles showed a negative affective state in VLT only. The VLT group had lower intentions to repeat HIIE once and three times per week than HT (P < 0.001, d = 1.87 and 1.81, respectively) and LT (P = 0.107, d = 0.85; P = 0.295, d = 0.53, respectively). Self-efficacy was not influenced by tolerance. Self-reported tolerance of exercise intensity influences affective responses to and intentions to engage with HIIE.