L’inhumation des immatures in ecclesia à l’époque moderne : l’exemple de la nef de Saint-André-le-Haut (Vienne, Isère, France)

Fondée au VIe siècle, l’abbaye bénédictine féminine de Saint-André-le-Haut (Vienne, Isère) est l’une des plus anciennes fondations monastiques de la ville. À la fin du XVIe siècle, l’église abbatiale devient paroissiale et les paroissiens investissent le sous-sol de la nef comme lieu d’inhumation. Depuis 2003, la nef de Saint-André-le-Haut a été fouillée aux deux tiers et a livré 317 sépultures datées de l’époque moderne, parmi lesquelles 102 sont celles d’individus immatures, dont 30 sont décédés avant l’âge d’un an. La présence de ces derniers au sein de la communauté paroissiale, à plus forte raison dans l’église, semble signifier une intégration à part entière au monde chrétien. Deux rassemblements d’individus immatures se distinguent, le premier autour d’un pilier vers l’entrée de l’église, le second contre le mur gouttereau nord. Il est possible que la présence d’aménagements liturgiques particuliers à ces deux endroits soit en rapport avec le regroupement de ces immatures.The Abbey of Saint-André-le-Haut (Vienne, Isère, France), founded by Benedictine nuns in the 6th century, is one of the city’s oldest monastic buildings. In the 16th century, the abbey church became a parish church and the parishioners consecrated the floor of its nave as a burial site. Since 2003, two-thirds of the nave of Saint-André-le-Haut have been excavated, revealing 317 burials from the early modern period. Of these, 102 are of immature individuals, including 30 in the [0] class. The presence of these individuals within the parish community, particularly inside the church, points to full integration into the Christian world. Two groups of small children stand out: the first around a pillar at the church entrance, the second beside the north lateral wall. It is possible that the presence of distinctive liturgical details in these two places is related to these groups of small children

Linking in vitro lipolysis and microsomal metabolism for the quantitative prediction of oral bioavailability of BCS II drugs administered in lipidic formulations

Lipidic formulations (LFs) are increasingly utilized for the delivery of drugs that belong to class II of the Biopharmaceutics Classification System (BCS). The current work proposes, for the first time, the combination of in vitro lipolysis and microsomal metabolism studies for the quantitative prediction of human oral bioavailability of BCS II drugs administered in LFs. Marinol® and Neoral® were selected as model LFs and their observed oral bioavailabilities (Fobserved) obtained from published clinical studies in humans. Two separate lipolysis buffers, differing in the level of surfactant concentrations, were used for digestion of the LFs. The predicted fraction absorbed (Fabs) was calculated by measuring the drug concentration in the micellar phase after completion of the lipolysis process. To determine first-pass metabolism (Fg∙Fh), drug depletion studies with human microsomes were performed. Clearance values were determined by applying the “in vitro half-life approach”. The estimated Fabs and Fg∙Fh values were combined for the calculation of the predicted oral bioavailability (Fpredicted). Results showed that there was a strong correlation between Fobserved and Fpredicted values only when Fabs was calculated using a buffer with surfactant concentrations closer to physiological conditions. The general accuracy of the predicted values suggests that the novel in vitro lipolysis/metabolism approach could quantitatively predict the oral bioavailability of lipophilic drugs administered in LFs

Australian and New Zealand Pulmonary Rehabilitation Guidelines

Background and objective: The aim of the Pulmonary Rehabilitation Guidelines (Guidelines) is to provide evidence-based recommendations for the practice of pulmonary rehabilitation (PR) specific to Australian and New Zealand healthcare contexts. Methods: The Guideline methodology adhered to the Appraisal of Guidelines for Research and Evaluation (AGREE) II criteria. Nine key questions were constructed in accordance with the PICO (Population, Intervention, Comparator, Outcome) format and reviewed by a COPD consumer group for appropriateness. Systematic reviews were undertaken for each question and recommendations made with the strength of each recommendation based on the GRADE (Gradings of Recommendations, Assessment, Development and Evaluation) criteria. The Guidelines were externally reviewed by a panel of experts. Results: The Guideline panel recommended that patients with mild-to-severe COPD should undergo PR to improve quality of life and exercise capacity and to reduce hospital admissions; that PR could be offered in hospital gyms, community centres or at home and could be provided irrespective of the availability of a structured education programme; that PR should be offered to patients with bronchiectasis, interstitial lung disease and pulmonary hypertension, with the latter in specialized centres. The Guideline panel was unable to make recommendations relating to PR programme length beyond 8 weeks, the optimal model for maintenance after PR, or the use of supplemental oxygen during exercise training. The strength of each recommendation and the quality of the evidence are presented in the summary. Conclusion: The Australian and New Zealand Pulmonary Rehabilitation Guidelines present an evaluation of the evidence for nine PICO questions, with recommendations to provide guidance for clinicians and policymakers

Researching COVID to Enhance Recovery (RECOVER) Adult Study Protocol: Rationale, Objectives, and Design

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Art for reward's sake: Visual art recruits the ventral striatum

A recent study showed that people evaluate products more positively when they are physically associated with art images than similar non-art images. Neuroimaging studies of visual art have investigated artistic style and esthetic preference but not brain responses attributable specifically to the artistic status of images. Here we tested the hypothesis that the artistic status of images engages reward circuitry, using event-related functional magnetic resonance imaging (fMRI) during viewing of art and non-art images matched for content. Subjects made animacy judgments in response to each image. Relative to non-art images, art images activated, on both subject- and item-wise analyses, reward-related regions: the ventral striatum, hypothalamus and orbitofrontal cortex. Neither response times nor ratings of familiarity or esthetic preference for art images correlated significantly with activity that was selective for art images, suggesting that these variables were not responsible for the art-selective activations. Investigation of effective connectivity, using time-varying, wavelet-based, correlation-purged Granger causality analyses, further showed that the ventral striatum was driven by visual cortical regions when viewing art images but not non-art images, and was not driven by regions that correlated with esthetic preference for either art or non -art images. These findings are consistent with our hypothesis, leading us to propose that the appeal of visual art involves activation of reward circuitry based on artistic status alone and independently of its hedonic value

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Study of neutrophil netosis in two models of allergic reactions : NMBA anaphylaxis and asthma

La nétose du polynucléaire neutrophile (PN) correspond à la libération de filaments d’ADN recouverts de protéines appelés Neutrophil Extracellular Trap (NETs). Outre leur rôle anti-infectieux, les NETs représentent des acteurs émergents de nombreuses pathologies inflammatoires et nous avons souhaité évaluer leur implication au cours de réactions allergiques.Au cours d’une étude clinique multicentrique notre équipe a mis en évidence un mécanisme alternatif de l’anaphylaxie aux curares, impliquant les PN. La phase aiguë de ces réactions s’accompagne d’une libération de NETs dont la concentration est corrélée avec la sévérité et avec une diminution de l’expression des récepteurs activateurs des IgG à la surface des PN (FcγRs) ; ceci suggère un rôle des complexes immuns (CI) IgG/curares dans la formation des NETs au cours de ces réactions anaphylactiques.Pour confirmer cette hypothèse, la capacité d’activation de la nétose par les CI IgG a été étudiée, via la mise au point d’un modèle de stimulation in vitro des PN humains purifiés.Ce travail montre que 2 récepteurs aux IgG du PN (FcγRIIa et FcγRIIIB) contribuent à la libération de NETs en réponse à différents types de CI.En parallèle, la formation des NETs a été explorée dans un modèle de réaction allergique chronique, l’asthme. Au niveau systémique, la concentration de NETs est associée à la présence d’un asthme sévère mal contrôlé et d’une obstruction bronchique peu réversible. Inversement, la concentration de NETs dans le lavage broncho-alvéolaire est plus élevée au cours de l’asthme modéré et semble traduire un recrutement pulmonaire et une activation des PN en réponse à une colonisation microbienne.Au total nous montrons que les NETs sont libérés au cours des deux modèles de réactions allergiques choisis, aiguë (anaphylaxie aux curares) et chronique (asthme) et qu’ils pourraient représenter des biomarqueurs de sévérité. Des travaux complémentaires sont nécessaires pour déterminer dans quelle mesure les NETs contribuent à la physiopathologie des allergies.Neutrophil netosis consists in the release of extracellular DNA filaments bound to granular proteins, called Neutrophil extracellular traps (NETs). In addition to their anti-infectious role, NETs are emerging actors of many inflammatory diseases and we decided to investigate their involvement during allergy.In a multicenter clinical study, our team highlighted an alternative mechanism of anaphylaxis to neuromuscular blocking agents (NMBA) involving neutrophils (PN). The acute phase of these reactions is characterized by NETs release which level is correlated with severity and with a decrease in IgG activating receptors (FcγRs) expression on PN; this suggests a role of immune complexes (IC) IgG / NMBA in NETs formation during these anaphylactic reactionsTo confirm this hypothesis, the ability of IgG ICs to activate netosis was studied through the development of an in vitro stimulation model of purified human PNs.This work shows that two PN IgG receptors (FcγRIIa and FcγRIIIB) contribute to NET release upon cellular activation by different ICsIn parallel, NETs formation has been explored in a model of chronic allergic reactions, asthma. At systemic level, NETs levels are associated with severe and poorly controlled asthma as well with the presence of low reversible bronchial obstruction. Conversely, NETs levels in bronchoalveolar lavage are higher in moderate asthma and appear to reflect pulmonary recruitment and activation of PN in response to microbial colonization.Taking together these results show that NETs are released during the two selected models of allergic reactions : acute (NMBA anaphylaxis) and chronic (asthma) and could be used as biomarkers of severity. Furthers works are needed to determine to what extent NETs contribute to the pathophysiology of allergy

Etude de la nétose du polynucléaire neutrophile dans deux modèles de réactions allergiques : le choc anaphylactique aux curares et l’asthme

Neutrophil netosis consists in the release of extracellular DNA filaments bound to granular proteins, called Neutrophil extracellular traps (NETs). In addition to their anti-infectious role, NETs are emerging actors of many inflammatory diseases and we decided to investigate their involvement during allergy.In a multicenter clinical study, our team highlighted an alternative mechanism of anaphylaxis to neuromuscular blocking agents (NMBA) involving neutrophils (PN). The acute phase of these reactions is characterized by NETs release which level is correlated with severity and with a decrease in IgG activating receptors (FcγRs) expression on PN; this suggests a role of immune complexes (IC) IgG / NMBA in NETs formation during these anaphylactic reactionsTo confirm this hypothesis, the ability of IgG ICs to activate netosis was studied through the development of an in vitro stimulation model of purified human PNs.This work shows that two PN IgG receptors (FcγRIIa and FcγRIIIB) contribute to NET release upon cellular activation by different ICsIn parallel, NETs formation has been explored in a model of chronic allergic reactions, asthma. At systemic level, NETs levels are associated with severe and poorly controlled asthma as well with the presence of low reversible bronchial obstruction. Conversely, NETs levels in bronchoalveolar lavage are higher in moderate asthma and appear to reflect pulmonary recruitment and activation of PN in response to microbial colonization.Taking together these results show that NETs are released during the two selected models of allergic reactions : acute (NMBA anaphylaxis) and chronic (asthma) and could be used as biomarkers of severity. Furthers works are needed to determine to what extent NETs contribute to the pathophysiology of allergy.La nétose du polynucléaire neutrophile (PN) correspond à la libération de filaments d’ADN recouverts de protéines appelés Neutrophil Extracellular Trap (NETs). Outre leur rôle anti-infectieux, les NETs représentent des acteurs émergents de nombreuses pathologies inflammatoires et nous avons souhaité évaluer leur implication au cours de réactions allergiques.Au cours d’une étude clinique multicentrique notre équipe a mis en évidence un mécanisme alternatif de l’anaphylaxie aux curares, impliquant les PN. La phase aiguë de ces réactions s’accompagne d’une libération de NETs dont la concentration est corrélée avec la sévérité et avec une diminution de l’expression des récepteurs activateurs des IgG à la surface des PN (FcγRs) ; ceci suggère un rôle des complexes immuns (CI) IgG/curares dans la formation des NETs au cours de ces réactions anaphylactiques.Pour confirmer cette hypothèse, la capacité d’activation de la nétose par les CI IgG a été étudiée, via la mise au point d’un modèle de stimulation in vitro des PN humains purifiés.Ce travail montre que 2 récepteurs aux IgG du PN (FcγRIIa et FcγRIIIB) contribuent à la libération de NETs en réponse à différents types de CI.En parallèle, la formation des NETs a été explorée dans un modèle de réaction allergique chronique, l’asthme. Au niveau systémique, la concentration de NETs est associée à la présence d’un asthme sévère mal contrôlé et d’une obstruction bronchique peu réversible. Inversement, la concentration de NETs dans le lavage broncho-alvéolaire est plus élevée au cours de l’asthme modéré et semble traduire un recrutement pulmonaire et une activation des PN en réponse à une colonisation microbienne.Au total nous montrons que les NETs sont libérés au cours des deux modèles de réactions allergiques choisis, aiguë (anaphylaxie aux curares) et chronique (asthme) et qu’ils pourraient représenter des biomarqueurs de sévérité. Des travaux complémentaires sont nécessaires pour déterminer dans quelle mesure les NETs contribuent à la physiopathologie des allergies

La pêche miraculeuse des filets du neutrophile

De découverte récente, les neutrophil extracellular traps (NET) constituent une nouvelle facette de l’immunité innée anti-infectieuse, qui est également susceptible d’entraîner des dommages tissulaires importants. En effet, un nombre croissant d’études démontrent la participation des NET dans des pathologies humaines aussi variées que les maladies auto-immunes, les thrombopathies ou certaines maladies inflammatoires. Après une brève description des mécanismes moléculaires de la « nétose » et de son rôle anti-infectieux, nous ferons la synthèse des connaissances sur les effets délétères des NET sur l’organisme. Nous examinerons ensuite les pistes thérapeutiques permettant de moduler une nétose excessive ou inappropriée, afin de limiter les dommages tissulaires