Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Contrôler la plasticité du cortex cérébral adulte à travers l'action non-autonome de l'homéoprotéine Otx2

During postnatal development, extracellular Otx2 homeoprotein is preferentially internalized by parvalbumin (PV) interneurons of the visual cortex and regulates the critical period for ocular dominance plasticity. The specificity of Otx2 internalization is mediated by chondroitin sulfate type E (CS-E) which is a component of the extracellular matrix enriched in glycosaminoglycans that condenses around PV cells during the critical period. The continuous supply of Otx2 in adults is necessary to maintain a non-plastic state of the cerebral cortex. Thus, a reopening of plasticity is possible by disrupting Otx2 transfer. We developed a transgenic mouse line with inducible secretion of single chain antibodies directed against Otx2 to separate the autonomous and non-autonomous activity in order to study its role in the maturation of cortical PV cells. We found that this maturation involves direct regulation of Gadd45b/g genes by Otx2 and that Gadd45b may control plasticity by influencing the methylation state of DNA and thus the epigenetic status of PV cells. We have also developed easily synthesizable peptides that mimic CS-E and are able to interact in vivo with Otx2 to block its transfer. Tools for neutralizing extracellular Otx2 have significant therapeutic potential for critical period pathologies.Durant le développement postnatal, l'homéoprotéine Otx2 est préférentiellement internalisée par les interneurones parvalbumine (PV) du cortex visuel et régule la période critique de plasticité de dominance oculaire. La spécificité d'internalisation d'Otx2 est médié par la chondroïtine sulfate de type E (CS-E) qui est un composant de la matrice extracellulaire enrichie en glycosaminoglycanes condensé autour des cellules PV durant la période critique. L'apport constant d'Otx2 chez l'adulte est nécessaire au maintien de l'état non-plastique du cortex. Une réouverture de plasticité est possible en perturbant le transfert d'Otx2. Nous avons développé une lignée de souris transgénique à sécrétion inductible d'anticorps simple chaine dirigés contre Otx2 pour séparer son activité autonome et non-autonome et pour étudier son rôle dans la maturation des cellules PV. Nous avons démontré que cette maturation est possible par une régulation directe des gènes Gadd45b/g par Otx2. Gadd45b contrôle la plasticité et pourrait avoir une influence sur l'état de méthylation de l'ADN et ainsi sur le statut épigénétique des cellules PV. Nous avons aussi développé des peptides, facilement synthétisable, mimant le CS-E et pouvant perturber in vivo le transfert d'Otx2. Les outils de neutralisation d'Otx2 dans le milieu extracellulaire pourraient avoir un pouvoir thérapeutique important

Controlling visual cortex plasticity through the non-autonomous activity of Otx2 homeoprotein

Durant le développement postnatal, l'homéoprotéine Otx2 est préférentiellement internalisée par les interneurones parvalbumine (PV) du cortex visuel et régule la période critique de plasticité de dominance oculaire. La spécificité d'internalisation d'Otx2 est médié par la chondroïtine sulfate de type E (CS-E) qui est un composant de la matrice extracellulaire enrichie en glycosaminoglycanes condensé autour des cellules PV durant la période critique. L'apport constant d'Otx2 chez l'adulte est nécessaire au maintien de l'état non-plastique du cortex. Une réouverture de plasticité est possible en perturbant le transfert d'Otx2. Nous avons développé une lignée de souris transgénique à sécrétion inductible d'anticorps simple chaine dirigés contre Otx2 pour séparer son activité autonome et non-autonome et pour étudier son rôle dans la maturation des cellules PV. Nous avons démontré que cette maturation est possible par une régulation directe des gènes Gadd45b/g par Otx2. Gadd45b contrôle la plasticité et pourrait avoir une influence sur l'état de méthylation de l'ADN et ainsi sur le statut épigénétique des cellules PV. Nous avons aussi développé des peptides, facilement synthétisable, mimant le CS-E et pouvant perturber in vivo le transfert d'Otx2. Les outils de neutralisation d'Otx2 dans le milieu extracellulaire pourraient avoir un pouvoir thérapeutique important.During postnatal development, extracellular Otx2 homeoprotein is preferentially internalized by parvalbumin (PV) interneurons of the visual cortex and regulates the critical period for ocular dominance plasticity. The specificity of Otx2 internalization is mediated by chondroitin sulfate type E (CS-E) which is a component of the extracellular matrix enriched in glycosaminoglycans that condenses around PV cells during the critical period. The continuous supply of Otx2 in adults is necessary to maintain a non-plastic state of the cerebral cortex. Thus, a reopening of plasticity is possible by disrupting Otx2 transfer. We developed a transgenic mouse line with inducible secretion of single chain antibodies directed against Otx2 to separate the autonomous and non-autonomous activity in order to study its role in the maturation of cortical PV cells. We found that this maturation involves direct regulation of Gadd45b/g genes by Otx2 and that Gadd45b may control plasticity by influencing the methylation state of DNA and thus the epigenetic status of PV cells. We have also developed easily synthesizable peptides that mimic CS-E and are able to interact in vivo with Otx2 to block its transfer. Tools for neutralizing extracellular Otx2 have significant therapeutic potential for critical period pathologies

Perineuronal nets in brain physiology and disease

International audiencePerineuronal nets (PNNs) in the brain are condensed glycosaminoglycan-rich extracellular matrix structures with heterogeneous composition yet specific organization. They typically assemble around a subset of fast-spiking interneurons that are implicated in learning and memory. Owing to their unique structural organization, PNNs have neuroprotective capacities but also participate in signal transduction and in controlling neuronal activity and plasticity. In this review, we define PNN structure in detail and describe its various biochemical and physiological functions. We further discuss the role of PNNs in brain disorders such as schizophrenia, bipolar disorder , Alzheimer disease and addictions. Lastly, we describe therapeutic approaches that target PNNs to alter brain physiology and counter brain dysfunction

Unsupervised clustering analysis of data from an online community to identify lupus patient profiles with regards to treatment preferences

International audienceObjective: Lupus is a chronic complex autoimmune disease. Non-adherence to treatment can affect patient outcomes. Considering patients' preferences into medical decisions may increase acceptance to their medication. The PREFERLUP study used unsupervised clustering analysis to identify profiles of patients with similar treatment preferences in an online community of French lupus patients. Methods: An online survey was conducted in adult lupus patients from the Carenity community between August 2018 and April 2019. Multiple Correspondence Analysis (MCA) was used with three unsupervised clustering methods (hierarchical, kmeans and partitioning around medoids). Several indicators (measure of connectivity, Dunn index and Silhouette width) were used to select the best clustering algorithm and choose the number of clusters. Results: The 268 participants were mostly female (96%), with a mean age of 44.3 years 83% fulfilled the American College of Rheumatology (ACR) self-reported diagnostic criteria for systemic lupus erythematosus. Overall, the preferred route of administration was oral (62%) and the most important feature of an ideal drug was a low risk of side-effects (32%). Hierarchical clustering identified three clusters. Cluster 1 (59%) comprised patients with few comorbidities and a poor ability to identify oncoming flares; 84% of these patients desired oral treatments with limited side-effects. Cluster 2 (13%) comprised younger patients, who had already participated in a clinical trial, were willing to use implants and valued the compatibility of treatments with pregnancy. Cluster 3 (28%) comprised patients with a longer lupus duration, poorer control of the disease and more comorbidities; these patients mainly valued implants and injections and expected a reduction of corticosteroid intake. Conclusions: Different profiles of lupus patients were identified according to their drug preferences. These clusters could help physicians tailor their therapeutic proposals to take into account individual patient preferences, which could have a positive impact on treatment acceptance and then adherence. The study highlights the value of data acquired directly from patient communities

Immune-mediated inflammatory diseases and nutrition: results from an online survey on patients’ practices and perceptions

International audienceBackground: The central role of microbiota and the contribution of diet in immune-mediated inflammatory diseases (IMID) are increasingly examined. However, patients' perspectives on nutrition and its impact on their disease has not received a lot of attention. We aimed to directly collect information from patients with IMID about their dietary behaviors and their perceptions of the influence of nutrition on their disease. Methods: Adult patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis or psoriasis registered in an online patient community were invited to participate in the study and complete an online self-administered questionnaire. We assessed patients' dietary knowledge and choices by collecting information on the diet regimens they were following or recommended and their perceptions of the diet and its consequences on their disease. Results: Fifty patients per target disease were included with a mean age of 48.1 years (95%CI 46.7-49.6). Other sociodemographic and clinical characteristics varied across the diseases. Since diagnosis, 44% of the patients changed their eating habits, mainly patients with inflammatory bowel disease with 69% of these making the change on their own initiative. Patients who did not change their diet habits reported not having received nutritional advice from their healthcare professionals (HCP) in 69% of the cases. The perceived impact of nutrition on their symptoms was mixed (overall 74% of the patients reported positive consequences and 60% negative ones) and varied across the diseases. Patients with psoriasis only experienced positive consequences from changing their diet, such as reduction of stress and improved mental health, while patients with Crohn's disease reported more negative effects such as increased fatigue and disturbed sleep. Patients with rheumatic diseases and ulcerative colitis reported weight loss and better physical fitness, but also increased fatigue. Conclusions: Even if differences exist across diseases, the importance of nutrition and its potential positive role in symptom management is acknowledged by the majority of the patients. However, there is a need and a demand from patients to receive more dietary advice. Developing therapeutic education tools on nutrition for people with IMID and involving patients' organizations would provide useful information and encourage communication between HCP and patients

Symptom severity is a major determinant of cannabis‐based products use among people with multiple sclerosis

Aims and objectives: We aimed to identify correlates of cannabinoid-based products (CBP) use in patients with multiple sclerosis (MS) in France and Spain.Background: MS is responsible for a wide range of symptoms, including pain. Access to CBP differs according to local legislation. The French context is more restrictive than the Spanish one, and no data regarding cannabis use among MS patients has yet been published. Characterizing MS patients who use CBP constitutes a first step toward identifying persons most likely to benefit from them.Design: An online cross-sectional survey was submitted to MS patients who were members of a social network for people living with chronic diseases and were living in France or Spain.Methods: Two study outcomes measured therapeutic CBP use and daily therapeutic CBP use. Seemingly unrelated bivariate probit regression models were used to test for associations between the outcomes and patients' characteristics while accounting for country-related differences. STROBE guidelines were followed in reporting this study.Results: Among 641 study participants (70% from France), the prevalence of CBP use was similar in both countries (23.3% in France vs. 20.1% in Spain). MS-related disability was associated with both outcomes, with a gradient observed between different degrees of disability. MS-related pain level was associated with CBP use only.Conclusions: CBP use is common in MS patients from both countries. The more severe the MS, the more participants turned to CBP to alleviate their symptoms. Easier access to CBP should be ensured for MS patients in need of relief, especially from pain.Relevance to clinical practice: This study highlights the characteristics of MS patients using CBP. Such practices should be discussed by healthcare professional with MS patients

Consistency in quality correction factors for ionization chamber dosimetry in scanned proton beam therapy

PURPOSE: The IAEA TRS-398 code of practice details the reference conditions for reference dosimetry of proton beams using ionization chambers and the required beam quality correction factors (kQ ). Pencil beam scanning (PBS) systems cannot approximate reference conditions using a single spot. However, dose distributions requested in TRS-398 can be reproduced with PBS using a combination of spots. This study aims to demonstrate, using Monte Carlo (MC) simulations, that kQ factors computed/measured for broad beams can be used with scanned beams for similar reference dose distributions with no additional significant uncertainty. METHODS: We consider the Alfonso formalism13 usually employed for nonstandard photon beams. To approach reference conditions similar as IAEA TRS-398 and the associated dose distributions, PBS must combine many pencil beams with range or energy modulation and shaping techniques that differ from those used in passive systems (broad beams). In order to evaluate the impact of these differences on kQ factors, ionization chamber responses are computed with MC (Geant4 9.6) in three different proton beams, with their corresponding quality factors (Q), producing a 10 × 10 cm2 field with a flat dose distribution for (a) a dedicated scanned pencil beam (Qpbs ), (b) a hypothetical proton source (Qhyp ), and (c) a double-scattering beam (Qds ). The tested ionization chamber cavities are a 2 × 2 × 0.2 mm³ air cavity, a Roos-type ionization chamber, and a Farmer-type ionization chamber. RESULTS AND DISCUSSION: Ranges of Qpbs , Qhyp , and Qds are consistent within 0.4 mm. Flatnesses of dose distributions are better than 0.5%. Calculated kQpbs,Qhypfpbs,fref is 0.999 ± 0.002 for the air cavity and the Farmer-type ionization chamber and 1.001 ± 0.002 for the Roos-type ionization chamber. The quality correction factors kQpbs,Qdsfpbs,fref is 0.999 ± 0.002 for the Farmer-type and Roos-type ionization chambers and 1.001 ± 0.001 for the Roos-type ionization chamber. CONCLUSION: The Alfonso formalism was applied to scanned proton beams. In our MC simulations, neither the difference in the beam profiles (scanned beam vs hypothetical beam) nor the different incident beam energies influenced significantly the beam correction factors. This suggests that ionization chamber quality correction factors in scanned or broad proton beams are indistinguishable within the calculation uncertainties provided dose distributions achieved by both modalities are similar and compliant with the TRS-398 reference conditions

A Mouse Model for Conditional Secretion of Specific Single-Chain Antibodies Provides Genetic Evidence for Regulation of Cortical Plasticity by a Non-cell Autonomous Homeoprotein Transcription Factor

International audienceDuring postnatal life the cerebral cortex passes through critical periods of plasticity allowing its physiological adaptation to the environment. In the visual cortex, critical period onset and closure are influenced by the non-cell autonomous activity of the Otx2 homeoprotein transcription factor, which regulates the maturation of parvalbumin-expressing inhibitory interneurons (PV cells). In adult mice, the maintenance of a non-plastic adult state requires continuous Otx2 import by PV cells. An important source of extra-cortical Otx2 is the choroid plexus, which secretes Otx2 into the cerebrospinal fluid. Otx2 secretion and internalization requires two small peptidic domains that are part of the DNA-binding domain. Thus, mutating these "transfer" sequences also modifies cell autonomous transcription, precluding this approach to obtain a cell autonomous-only mouse. Here, we develop a mouse model with inducible secretion of an anti-Otx2 single-chain antibody to trap Otx2 in the extracellular milieu. Postnatal secretion of this single-chain antibody by PV cells delays PV maturation and reduces plasticity gene expression. Induced adult expression of this single-chain antibody in cerebrospinal fluid decreases Otx2 internalization by PV cells, strongly induces plasticity gene expression and reopens physiological plasticity. We provide the first mammalian genetic evidence for a signaling mechanism involving intercellular transfer of a homeoprotein transcription factor. Our single-chain antibody mouse model is a valid strategy for extracellular neutralization that could be applied to other homeoproteins and signaling molecules within and beyond the nervous system