Modulation de la douleur par la contrestimulation nociceptive hétérotopique et l'attention sélective chez des patients atteints de lombalgie chronique non spécifique

La douleur est une expérience subjective qui peut être modulée par des mécanismes neurophysiologiques régulateurs et des facteurs psychologiques. La douleur est un système d’alarme ayant un rôle de protection, mais elle peut parfois persister au-delà du temps requis pour la guérison tissulaire et devenir chronique. Parmi les syndromes douloureux chroniques, la lombalgie chronique non spécifique est une condition très prévalente et incapacitante. Afin de mieux comprendre la physiopathologie de la chronicisation, il s’avère crucial d'évaluer l'intégrité des mécanismes de modulation endogènes de la douleur. Ces derniers peuvent être évalués de manière expérimentale par un paradigme de contrestimulation nociceptive (inhibition d’une douleur par une autre douleur). En premier lieu, nous avons mis au point un protocole expérimental permettant d’évaluer la contribution de l’attention à l’analgésie induite par la contrestimulation nociceptive. Tout d’abord, les participants volontaires sains recevaient une série de stimulations électriques douloureuses appliquées sur le trajet du nerf sural à une intensité ajustée afin d’évoquer le réflexe nociceptif de flexion (RIII). La douleur était modulée dans un premier temps par une stimulation froide non douloureuse sur le bras (contrestimulation non nociceptive) et dans un deuxième temps par l’application d’un coussin de gel congelé provoquant une douleur sur l’avant-bras (contrestimulation nociceptive). La direction de l’attention était manipulée au cours de deux sessions. Tel qu’attendu, la douleur induite par les stimulations électriques a été inhibée par la contrestimulation nociceptive, par rapport au niveau de base (p < 0,01). De plus, l’effet hypoalgésique de la contrestimulation nociceptive était plus important que celui de la contrestimulation non nociceptive (p < 0,01). Également, cette inhibition était plus importante lorsque l’attention était dirigée vers la contrestimulation que vers la stimulation électrique (p = 0,02). Concernant l’inhibition de la transmission spinale nociceptive, le RIII a été significativement inhibé par la contrestimulation par rapport au niveau de base (p < 0,01) et l’effet s’est avéré plus important pour la contrestimulation nociceptive que pour la contrestimulation non nociceptive (p = 0,03). Toutefois, cet effet n’a pas été modulé par la direction de l’attention (p = 0,35). Les résultats de cette étude indiquent que l’attention sélective et la contrestimulation nociceptive produisent une inhibition additive de la douleur. Cette inhibition additive n’ayant pas été observée pour le RIII, cela suggère l'implication d’un mécanisme cérébral indépendant de la transmission spinale nociceptive. En deuxième lieu, nous nous sommes intéressés aux patients atteints de lombalgie chronique non spécifique, dont la physiopathologie n’est pas bien définie. Dans cette étude, nous avons utilisé le paradigme décrit ci-haut en ajoutant une session contrôle, durant laquelle les participants ne recevaient que des stimulations électriques sans aucune contrestimulation. Cela a permis de mesurer et contrôler les effets temporels non spécifiques. En plus de mesurer la douleur et le RIII, les potentiels évoqués par la stimulation électrique ont été enregistrés afin de mesurer la modulation de l'activité cérébrale. L’inhibition de la douleur par la contrestimulation ou l’attention sélective n’était pas significativement différente entre les patients lombalgiques et les contrôles (p = 0,99). Cependant, pour les deux groupes combinés, la contrestimulation nociceptive a produit une inhibition marginale de la douleur (p = 0,06) ainsi qu'une inhibition significative des composantes N100 et N150 des potentiels évoqués (p < 0,001). Quant à l’attention sélective, elle a induit une hypoalgésie (p < 0,01) et a inhibé la composante N100 (p < 0,001). Les résultats de cette étude suggèrent que la lombalgie chronique non spécifique ne repose pas sur un déficit des mécanismes d’inhibition de la douleur évalués dans cette étude.Pain is a subjective experience that can be modulated by regulatory neurophysiological mechanisms and psychological factors. It has alarming and protective functions, but it sometimes persist beyond the time required for tissue healing and becomes chronic. Among chronic pain syndromes, chronic non-specific low back pain is a very prevalent and incapacitating condition. In order to better understand the pathophysiology of chronic non-specific low back pain, it is crucial to evaluate the integrity of endogenous pain modulation mechanisms. The latter can be evaluated experimentally by a nociceptive counterstimulation paradigm (pain-inhibit-pain phenomenon). First, we developed an experimental protocol to assess the contribution of attention to hypoalgesia induced by nociceptive counter-stimulation. Healthy volunteer participants received a series of painful transcutaneous electrical stimulations applied over the sural nerve at an individually-adjusted intensity to evoke the nociceptive flexion reflex (RIII) and moderate pain. Pain was modulated by a cold non-painful stimulation applied on the arm (non-nociceptive counterstimulation) and by a frozen gel pack causing pain on the forearm (nociceptive counterstimulation). The direction of attention was manipulated across two sessions. As expected, pain induced by electrical stimulations was inhibited by nociceptive counterstimulation relative to baseline (p < 0.01). In addition, the hypoalgesic effect of nociceptive counterstimulation was greater than that of non-nociceptive counterstimulation (p < 0.01). Moreover, this inhibition was greater when attention was directed towards counterstimulation than towards electrical stimulation (p = 0.02). As for inhibition of spinal nociceptive transmission, the RIII was significantly inhibited by counterstimulation relative to baseline (p < 0.01) and the effect was significantly greater for nociceptive than for non-nociceptive counterstimulation (p = 0.03). However, this effect was not modulated by the direction of attention (p = 0.35). The results of this study indicate that selective attention and nociceptive counterstimulation produce additive inhibition of pain. This additive effect was not observed for the RIII, which suggests the implication of a cerebral mechanism independent of spinal nociceptive transmission. Secondly, we investigated pain modulation mechanisms in patients with chronic non-specific low back pain, which pathophysiology is not well defined. In this study, we used the experimental paradigm described above to which we added a control session. During this session, participants received electrical stimulation only, without counterstimulation. This allowed measuring and controlling for non-specific temporal effects. In addition to measuring pain and RIII, evoked potentials were recorded in order to measure the modulation of pain-related brain activity. The inhibition of pain by counterstimulation or by selective attention was not significantly different between patients and controls (p = 0.99). However, for both groups combined, nociceptive counterstimulation produced a marginal inhibition of pain (p = 0.06) as well as significant inhibition of the N100 and N150 components of the evoked potentials (p < 0.001). Also, selective attention induced significant hypoalgesia (p < 0.01) and significantly inhibited the N100 component (p < 0.001). The results of this study suggest that nonspecific chronic low back pain does not rely on a deficit of the pain inhibition mechanisms assessed in this study

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Adult congenital heart disease training in Europe:current status, disparities and potential solutions

Objectives:This study aimed to determine the status of training of adult congenital heart disease (ACHD) cardiologists in Europe.Methods:A questionnaire was sent to ACHD cardiologists from 34 European countries.Results:Representatives from 31 of 34 countries (91%) responded. ACHD cardiology was recognised by the respective ministry of Health in two countries (7%) as a subspecialty. Two countries (7%) have formally recognised ACHD training programmes, 15 (48%) have informal (neither accredited nor certified) training and 14 (45%) have very limited or no programme. Twenty-five countries (81%) described training ACHD doctors 'on the job'. The median number of ACHD centres per country was 4 (range 0-28), median number of ACHD surgical centres was 3 (0-26) and the median number of ACHD training centres was 2 (range 0-28). An established exit examination in ACHD was conducted in only one country (3%) and formal certification provided by two countries (7%). ACHD cardiologist number versus gross domestic product Pearson correlation coefficient=0.789 (p&lt;0.001).Conclusion: Formal or accredited training in ACHD is rare among European countries. Many countries have very limited or no training and resort to 'train people on the job'. Few countries provide either an exit examination or certification. Efforts to harmonise training and establish standards in exit examination and certification may improve training and consequently promote the alignment of high-quality patient care

COVID-19-Related Thrombotic and Bleeding Events in Adults With Congenital Heart Disease.

BACKGROUND Altered coagulation is a striking feature of COVID-19. Adult patients with congenital heart disease (ACHD) are prone to thromboembolic (TE) and bleeding complications. OBJECTIVES The purpose of this study was to investigate the prevalence and risk factors for COVID-19 TE/bleeding complications in ACHD patients. METHODS COVID-19-positive ACHD patients were included between May 2020 and November 2021. TE events included ischemic cerebrovascular accident, systemic and pulmonary embolism, deep venous thrombosis, myocardial infarction, and intracardiac thrombosis. Major bleeding included cases with hemoglobin drop >2 g/dl, involvement of critical sites, or fatal bleeding. Severe infection was defined as need for intensive care unit, endotracheal intubation, renal replacement therapy, extracorporeal membrane oxygenation, or death. Patients with TE/bleeding were compared to those without events. Factors associated with TE/bleeding were determined using logistic regression. RESULTS Of 1,988 patients (age 32 [IQR: 25-42] years, 47% male, 59 ACHD centers), 30 (1.5%) had significant TE/bleeding: 12 TE events, 12 major bleeds, and 6 with both TE and bleeding. Patients with TE/bleeding had higher in-hospital mortality compared to the remainder cohort (33% vs 1.7%; P < 0.0001) and were in more advanced physiological stage (P = 0.032) and NYHA functional class (P = 0.01), had lower baseline oxygen saturation (P = 0.0001), and more frequently had a history of atrial arrhythmia (P < 0.0001), previous hospitalization for heart failure (P < 0.0007), and were more likely hospitalized for COVID-19 (P < 0.0001). By multivariable logistic regression, prior anticoagulation (OR: 4.92; 95% CI: 2-11.76; P = 0.0003), cardiac injury (OR: 5.34; 95% CI: 1.98-14.76; P = 0.0009), and severe COVID-19 (OR: 17.39; 95% CI: 6.67-45.32; P < 0.0001) were independently associated with increased risk of TE/bleeding complications. CONCLUSIONS ACHD patients with TE/bleeding during COVID-19 infection have a higher in-hospital mortality from the illness. Risk of coagulation disorders is related to severe COVID-19, cardiac injury during infection, and use of anticoagulants

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Unprecedented strongly panchromic absorption from proton switchable iridium(III) azoimidazolate complexes

Two novel heteroleptic iridium(III) complexes bearing an aryldiazoimidazole ligand are reported. These complexes differ structurally with respect to the protonation state of the imidazole ring, but can be independently accessed by varying the synthetic conditions. Their structures have been unequivocally confirmed by X-ray crystal structure analysis, with surprising differences in the structural parameters of the two complexes. The strongly absorbing nature of the free diazoimidazole ligand is enhanced in these iridium complexes, with the protonated cationic complex demonstrating extraordinarily strong panchromic absorption up to 700 nm. The absorption profile of the deprotonated neutral complex is blue-shifted by about 100 nm and thus the interconversion between the two complexes as a function of the acidity/basicity of the environment can be readily monitored by absorption spectroscopy. Theoretical calculations reveal the origins of these markedly different absorption properties. Finally, the protonated analogue has been targeted as an acceptor material for organic photovoltaic (OPV) applications and preliminary results are reported.Publisher PDFPeer reviewe

Modulation de la douleur par la contrestimulation nociceptive hétérotopique et l'attention sélective chez des patients atteints de lombalgie chronique non spécifique

La douleur est une expérience subjective qui peut être modulée par des mécanismes neurophysiologiques régulateurs et des facteurs psychologiques. La douleur est un système d’alarme ayant un rôle de protection, mais elle peut parfois persister au-delà du temps requis pour la guérison tissulaire et devenir chronique. Parmi les syndromes douloureux chroniques, la lombalgie chronique non spécifique est une condition très prévalente et incapacitante. Afin de mieux comprendre la physiopathologie de la chronicisation, il s’avère crucial d'évaluer l'intégrité des mécanismes de modulation endogènes de la douleur. Ces derniers peuvent être évalués de manière expérimentale par un paradigme de contrestimulation nociceptive (inhibition d’une douleur par une autre douleur). En premier lieu, nous avons mis au point un protocole expérimental permettant d’évaluer la contribution de l’attention à l’analgésie induite par la contrestimulation nociceptive. Tout d’abord, les participants volontaires sains recevaient une série de stimulations électriques douloureuses appliquées sur le trajet du nerf sural à une intensité ajustée afin d’évoquer le réflexe nociceptif de flexion (RIII). La douleur était modulée dans un premier temps par une stimulation froide non douloureuse sur le bras (contrestimulation non nociceptive) et dans un deuxième temps par l’application d’un coussin de gel congelé provoquant une douleur sur l’avant-bras (contrestimulation nociceptive). La direction de l’attention était manipulée au cours de deux sessions. Tel qu’attendu, la douleur induite par les stimulations électriques a été inhibée par la contrestimulation nociceptive, par rapport au niveau de base (p < 0,01). De plus, l’effet hypoalgésique de la contrestimulation nociceptive était plus important que celui de la contrestimulation non nociceptive (p < 0,01). Également, cette inhibition était plus importante lorsque l’attention était dirigée vers la contrestimulation que vers la stimulation électrique (p = 0,02). Concernant l’inhibition de la transmission spinale nociceptive, le RIII a été significativement inhibé par la contrestimulation par rapport au niveau de base (p < 0,01) et l’effet s’est avéré plus important pour la contrestimulation nociceptive que pour la contrestimulation non nociceptive (p = 0,03). Toutefois, cet effet n’a pas été modulé par la direction de l’attention (p = 0,35). Les résultats de cette étude indiquent que l’attention sélective et la contrestimulation nociceptive produisent une inhibition additive de la douleur. Cette inhibition additive n’ayant pas été observée pour le RIII, cela suggère l'implication d’un mécanisme cérébral indépendant de la transmission spinale nociceptive. En deuxième lieu, nous nous sommes intéressés aux patients atteints de lombalgie chronique non spécifique, dont la physiopathologie n’est pas bien définie. Dans cette étude, nous avons utilisé le paradigme décrit ci-haut en ajoutant une session contrôle, durant laquelle les participants ne recevaient que des stimulations électriques sans aucune contrestimulation. Cela a permis de mesurer et contrôler les effets temporels non spécifiques. En plus de mesurer la douleur et le RIII, les potentiels évoqués par la stimulation électrique ont été enregistrés afin de mesurer la modulation de l'activité cérébrale. L’inhibition de la douleur par la contrestimulation ou l’attention sélective n’était pas significativement différente entre les patients lombalgiques et les contrôles (p = 0,99). Cependant, pour les deux groupes combinés, la contrestimulation nociceptive a produit une inhibition marginale de la douleur (p = 0,06) ainsi qu'une inhibition significative des composantes N100 et N150 des potentiels évoqués (p < 0,001). Quant à l’attention sélective, elle a induit une hypoalgésie (p < 0,01) et a inhibé la composante N100 (p < 0,001). Les résultats de cette étude suggèrent que la lombalgie chronique non spécifique ne repose pas sur un déficit des mécanismes d’inhibition de la douleur évalués dans cette étude.Pain is a subjective experience that can be modulated by regulatory neurophysiological mechanisms and psychological factors. It has alarming and protective functions, but it sometimes persist beyond the time required for tissue healing and becomes chronic. Among chronic pain syndromes, chronic non-specific low back pain is a very prevalent and incapacitating condition. In order to better understand the pathophysiology of chronic non-specific low back pain, it is crucial to evaluate the integrity of endogenous pain modulation mechanisms. The latter can be evaluated experimentally by a nociceptive counterstimulation paradigm (pain-inhibit-pain phenomenon). First, we developed an experimental protocol to assess the contribution of attention to hypoalgesia induced by nociceptive counter-stimulation. Healthy volunteer participants received a series of painful transcutaneous electrical stimulations applied over the sural nerve at an individually-adjusted intensity to evoke the nociceptive flexion reflex (RIII) and moderate pain. Pain was modulated by a cold non-painful stimulation applied on the arm (non-nociceptive counterstimulation) and by a frozen gel pack causing pain on the forearm (nociceptive counterstimulation). The direction of attention was manipulated across two sessions. As expected, pain induced by electrical stimulations was inhibited by nociceptive counterstimulation relative to baseline (p < 0.01). In addition, the hypoalgesic effect of nociceptive counterstimulation was greater than that of non-nociceptive counterstimulation (p < 0.01). Moreover, this inhibition was greater when attention was directed towards counterstimulation than towards electrical stimulation (p = 0.02). As for inhibition of spinal nociceptive transmission, the RIII was significantly inhibited by counterstimulation relative to baseline (p < 0.01) and the effect was significantly greater for nociceptive than for non-nociceptive counterstimulation (p = 0.03). However, this effect was not modulated by the direction of attention (p = 0.35). The results of this study indicate that selective attention and nociceptive counterstimulation produce additive inhibition of pain. This additive effect was not observed for the RIII, which suggests the implication of a cerebral mechanism independent of spinal nociceptive transmission. Secondly, we investigated pain modulation mechanisms in patients with chronic non-specific low back pain, which pathophysiology is not well defined. In this study, we used the experimental paradigm described above to which we added a control session. During this session, participants received electrical stimulation only, without counterstimulation. This allowed measuring and controlling for non-specific temporal effects. In addition to measuring pain and RIII, evoked potentials were recorded in order to measure the modulation of pain-related brain activity. The inhibition of pain by counterstimulation or by selective attention was not significantly different between patients and controls (p = 0.99). However, for both groups combined, nociceptive counterstimulation produced a marginal inhibition of pain (p = 0.06) as well as significant inhibition of the N100 and N150 components of the evoked potentials (p < 0.001). Also, selective attention induced significant hypoalgesia (p < 0.01) and significantly inhibited the N100 component (p < 0.001). The results of this study suggest that nonspecific chronic low back pain does not rely on a deficit of the pain inhibition mechanisms assessed in this study