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Immune-checkpoint-inhibitor (ICI)–associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. Significance: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027

Treatment modalities and reported adverse events by quartile of period of inclusion.

Example of the first severe ICI-myocarditis case treated with abatacept guided by real-time immune-monitoring assessment of CD86RO (CD86 receptor occupancy) on circulating monocytes.

Methods concerning Immune-checkpoint proteins profiling on peripheral blood mononuclear cells and Circulating immune checkpoint agents drug monitoring

Immune-checkpoint-inhibitor (ICI)–associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation.Significance:Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis.See related commentary by Dougan, p. 1040.This article is highlighted in the In This Issue feature, p. 1027

Background Inaccurate diagnosis of encephalitis is a major issue as immunosuppressive treatments can be deleterious in case of viral infection. The European bat lyssavirus type 1 (EBLV-1), a virus related to rabies virus, is endemic in European bats. No human case has yet been reported in Western Europe. A 59-year-old patient without specific past medical history died from encephalitis. A colony of bats lived in an outbuilding of his house. No diagnosis was made using standard procedures. Methods We used a next generation sequencing (NGS) based transcriptomic protocol to search for pathogens in autopsy samples (meninges and brain frontal lobe). Results were confirmed by polymerase chain reaction (PCR) and by antibody testing in serum. Immunochemistry was used to characterize inflammatory cells and viral antigens in brain lesions. Cells and mice were inoculated with brain extracts for virus isolation. Results The patient’s brain lesions were severe and diffuse in white and gray matter. Perivascular inflammatory infiltrates were abundant and rich in plasma cells. NGS identified European bat lyssavirus type 1a in brain, which was confirmed by PCR. A high titer of neutralizing antibodies was found in serum. No viral antigen was detected, and the virus could not be isolated by cell culture or by mouse inoculation. Conclusions The patient died from European bat lyssavirus type 1a infection. NGS was key to identifying this unexpected viral etiology in an epidemiological context that did not suggest rabies. People exposed to bats should be strongly advised to be vaccinated with rabies vaccines, which are effective against EBLV-1.

On the evening of November 13, 2015, the city of Paris and its surroundings was hit by a series of attacks committed by terrorist groups, using firearms and explosives. The final toll was 140 people deceased (130 victims and 10 terrorists or their relatives) and more than 413 injured, making these attacks the worst mass killings ever recorded in Paris in peacetime. This article presents the forensic operations carried out at the Medicolegal Institute of Paris (MLIP) following these attacks. A total of 68 autopsies of bodies or body fragments and 83 external examinations were performed within 7 days, and the overall forensic operations (including formal identification of the latest victims) were completed 10 days after the attacks. Over this period, 156 body presentations (some bodies were presented several times) were provided to families or relatives. Regarding the 130 civilian casualties, 129 died from firearm wounds and one died from blast injuries after an explosion. Of the 10 terrorists or their relatives who were killed, eight died from suicide bombing, one was shot by police and one died from crush injuries due to partial collapse of a building following the police raid against a terrorist’s hideout after the attacks. All mass shootings were perpetrated with AK-47 or Zastava M70 assault rifles using 7.62 mm × 39 mm cartridges. In the case of ballistic injuries, death was most often obviously caused by craniocerebral injuries, extensive organ lacerations and/or massive haemorrhage. Among the terrorists killed by bombing, the lesion patterns were body transection, multiple amputations, extreme organ lacerations and the presence of foreign bodies owing to the shrapnel load (steel nuts, glass fragments) or the explosive charge fastening system of the devices. This discussion highlights the particular difficulties of interpretation encountered within the framework of ballistic injuries, a conclusion that should lead to a modest and realistic approach in these exceptional situations where forensic operations involve a very large number of victims in a constrained time.

Candida spp. myelopathies are very rare. We report a case of subacute longitudinally extensive transverse myelitis in an apparently immunocompetent 55-year-old man. After a negative infectious workup, corticosteroids and plasma exchange were initiated. Although there was a transient initial improvement, symptoms then worsened, and the lumbar puncture was repeated. Candida albicans was isolated in the CSF, and a diagnosis of spinal cord candidiasis was made. Gene panel sequencing for inborn immune deficiencies identified a homozygous disease-causing CARD9 variant. Despite antifungal treatment, necrotic myelitis, meningoencephalitis, and cerebral vasculitis developed. Fungal spinal cord infections can mimic inflammatory myelitis, and beta-D-glucan testing of both serum and CSF may help narrow down the diagnosis. In cases of severe or unexpected invasive Candida spp. infection, even adults and apparently immunocompetent patients should be screened for inborn immune deficiencies and CARD9 deficiency in particular.

OBJECTIVES To examine viral diversity and resistance mutations in different brain areas in cases of HIV-encephalopathy. DESIGN Twelve postmortem brain areas from three cases of possible or certain HIV-encephalopathy were analyzed. METHODS After amplification of the reverse transcriptase and the V3 loop region of the gp120 protein, ultradeep sequencing was performed with Illumina technology. Phylogenetic analysis was performed with Fastree v2.1 using the generalized time-reversible (GTR) model. Identification of resistant viral variants was performed on Geneious software, according to HIV-1 genotypic drug resistance interpretation's algorithms, 2018 administered by the French Agency for Research on AIDS and Viral Hepatitis. RESULTS Phylogenetic analysis revealed significant inter-regional and intra-regional diversity reflecting persistent HIV-1 viral replication in the different brain areas. Although some cerebral regions shared HIV-variants, most of them harbored a specific HIV-subpopulation reflecting HIV compartmentalization in the central nervous system. Furthermore, proportion and distribution of resistance mutations to nucleoside and non-nucleoside reverse transcriptase inhibitors differed among different brain areas of the same case suggesting that penetration of antiretroviral treatment may differ from one compartment to another. CONCLUSION This study, performed with a powerful sequencing technique, confirmed HIV compartmentalization in the central nervous system already shown by classical sequencing, suggesting that there are several reservoirs within the brain.

Terrorist attacks have been on the rise. During the recent terrorist attacks in France, terrorists perpetrated their acts using weapons of war, as well as explosive charges. These two modes of action, when combined, can create skin lesions with similar macroscopic appearances, which can sometimes go unnoticed because of body fragmentation. A total of 68 autopsies, 83 external examinations, 140 standard radiographic examinations, and 49 computed tomography (CT) scans were performed over 7 days during the 2015 terrorist attacks in France. Bodies were injured by firearms and shrapnel-like projectiles. We analysed the clinical findings for the secondary blast cutaneous lesions from the explosive devices and compared these lesions with ballistic-related lesions to highlight that patterns can be macroscopically similar on external examination. Secondary blast injuries are characterised by penetrating trauma associated with materials added to explosive systems that are propelled by explosive air movement. These injuries are caused most often by small, shrapnel-like metallic objects, such as nails and bolts. Propulsion causes ballistic-type injuries that must be recognised and distinguished from those caused by firearm projectiles. Differentiating between these lesions is very difficult when using conventional criteria (size, shape, number and distribution on the body) with only external examination of corpses. This is why the particularities of these lesions must be further illustrated and then confirmed by complete autopsies and radiological and anatomopathological examinations.Key pointsWhen occurring simultaneously in terrorist attacks, injuries caused by secondary blasts appear as cutaneous wound patterns that can be macroscopically very similar to those caused by firearm projectiles.The criteria usually found in the literature for distinguishing these two types of projectiles may be difficult to use.It is important in these difficult situations to benefit from systematic postmortem imaging.Systematic autopsy and then anatomopathological analyses of the orifices also help determine the cause of the wounds.

International audience; The immunopathological pulmonary mechanisms leading to Coronavirus Disease (COVID-19)-related death in adults remain poorly understood. Bronchoalveolar lavage (BAL) and peripheral blood sampling were performed in 74 steroid and non-steroid-treated intensive care unit (ICU) patients (23–75 years; 44 survivors). Peripheral effector SARS-CoV-2-specific T cells were detected in 34/58 cases, mainly directed against the S1 portion of the spike protein. The BAL lymphocytosis consisted of T cells, while the mean CD4/CD8 ratio was 1.80 in non-steroid- treated patients and 1.14 in steroid-treated patients. Moreover, strong BAL SARS-CoV-2 specific T-cell responses were detected in 4/4 surviving and 3/3 non-surviving patients. Serum IFN-γ and IL-6 levels were decreased in steroid-treated patients when compared to non-steroid treated patients. In the lung samples from 3 (1 non-ICU and 2 ICU) additional deceased cases, a lymphocytic memory CD4 T-cell angiopathy colocalizing with SARS-CoV-2 was also observed. Taken together, these data show that disease severity occurs despite strong antiviral CD4 T cell-specific responses migrating to the lung, which could suggest a pathogenic role for perivascular memory CD4 T cells upon fatal COVID-19 pneumonia.

Aims Cardiac involvement of Erdheim–Chester disease (ECD), a rare L group histiocytosis, has been reported to be associated with poor outcomes, but systematic studies are lacking. The present study aimed to investigate the prevalence, clinical features, imaging features, and prognosis of cardiac involvement in ECD in a large series. Methods and results All patients with ECD who underwent cardiac magnetic resonance (CMR) imaging between 2003 and 2019 at a French tertiary center were retrospectively included. Primary outcome was all-cause mortality. Secondary outcomes were pericarditis, cardiac tamponade, conduction disorders, device implantation and coronary artery disease (CAD). A total of 200 patients were included [63 (54–71) years, 30% female, 58% BRAFV600E mutated]. Median follow-up was 5.5 years (3.3–9 years). On CMR, right atrioventricular sulcus infiltration was observed in 37% of patients, and pericardial effusion was seen in 24% of patients. In total, 8 patients (4%) had pericarditis (7 acute, 1 constrictive), 10 patients (5%) had cardiac tamponade, 5 patients (2.5%) had ECD-related high-degree conduction disorders, and 45 patients (23%) had CAD. Overall, cardiac involvement was present in 96 patients (48%) and was associated with BRAFV600E mutation [Odds ratio (OR) = 7.4, 95% confidence interval (CI) (3.5–16.8), P < 0.001] and ECD-related clinical events [OR = 5, 95%CI (1.5–21.2), P = 0.004] but not with lower survival in multivariate analysis [adjusted hazard ratio (HR) = 1.4, 95% CI (0.8–2.5), P = 0.2]. Conclusion Cardiac involvement is present in nearly half of ECD patients and is associated with BRAFV600E mutation and complications (pericarditis, cardiac tamponade, and conduction disorders) but not with lower survival.

Variant CJD in a Laboratory Technician Variant Creutzfeldt–Jakob disease was identified in a technician who had cut her thumb while handling brain sections of mice infected with adapted BSE 7.5 yea...

In cases of terrorist bomb attacks, the issue of victim identification is the principal aim. For investigators and justice, terrorists must also be identified in a timely manner. The fragmentation of bodies caused by explosive devices however makes this operation difficult. The cases presented correspond to six autopsies of perpetrators carrying explosives. Their explosive belts produced different body sections on areas correlated with the location on the body of carrying explosive charges. Indeed, cross-sectional areas are the signature of the level of explosive devices on the body, and some fracture features through the damage of certain areas of constitutional weaknesses are specific elements to consider. These elements can allow a quick distinction between victims and terrorists, in order to assist in the medico-legal process of identification.

Neurological symptoms are frequently observed in COVID-19. Here, we examine the neuroinvasive potential of SARS-CoV-2 and demonstrate infection of neurons in three separate approaches: mouse model, human brain organoid, and autopsy of COVID-19 patients., Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2., Graphical Abstract

We are grateful to Pierre-Olivier Couraud (INSERM, Paris, France) for the gift of hCMEC/D3 cells, Alain Duperray for the gift of CHO-ICAM1 cells, Yoshikazu Takada for the gift of CHO-αvβ3 cells, and Glen Ulett for the gift of the GFP plasmid. We are extremely grateful to Nathalie Strazielle and Jean-François Ghersi-Egea from BIP (CRNL, Lyon, France) for choroid plexus isolation and helpful comments. We thank Matthieu Benard from the animal facility of the Institut Cochin and Marine Gaillard for their help with animal experiments and Thomas Guilbert and Fabienne Regnier for their help with brain slice clarification. We also thank the Imag’IC and HistIM core facilities of the Cochin Institute and Shaynoor Dramsi for anti-Srr1 antibody and for critical reading of the manuscript.; International audience; Group B Streptococcus (GBS) is the major cause of human neonatal infections. A single clone, designated CC17-GBS, accounts for more than 80% of meningitis cases, the most severe form of the infection. However, the events allowing blood-borne GBS to penetrate the brain remain largely elusive. In this study, we identified the host transmembrane receptors α5β1 and αvβ3 integrins as the ligands of Srr2, a major CC17-GBS-specific adhesin. Two motifs located in the binding region of Srr2 were responsible for the interaction between CC17-GBS and these integrins. We demonstrated in a blood-brain-barrier cellular model that both integrins contributed to the adhesion and internalization of CC17-GBS. Strikingly, both integrins were overexpressed during the postnatal period in the brain vessels of the blood-brain barrier and blood-cerebrospinal fluid barrier and contributed to juvenile susceptibility to CC17 meningitis. Finally, blocking these integrins decreased the ability of CC17-GBS to cross into the CNS of juvenile mice in an in vivo model of meningitis. Our study demonstrated that CC17-GBS exploits integrins in order to cross the brain vessels, leading to meningitis. Importantly, it provides host molecular insights into neonate's susceptibility to CC17-GBS meningitis, thereby opening new perspectives for therapeutic and prevention strategies of GBS-elicited meningitis.

International audience; Aim: Coronary artery disease (CAD) has recently been emphasized as a major cause of sudden cardiac arrest (SCA) in young adults. We aim to assess the rate of immediate coronary angiography performance in young patients resuscitated from SCA.Methods: From May 2011 to May 2017, all cases of out-of-hospital SCA aged 18-40 years alive at hospital admission were prospectively included in 48 hospitals of the Great Paris area. Cardiovascular causes of SCA were centrally adjudicated, and management including immediate coronary angiography performance was assessed.Results: Out of 3579 SCA admitted alive, 409 (11.4%) patients were under 40 years of age (32.3 ± 6.2 years, 69.7% males), with 244 patients having a definite cause identified. Among those, CAD accounted for 72 (29.5%) cases, of which 64 (88.9%) were acute coronary syndromes. The rate of immediate coronary angiography was only 41.7% compared to 65.1% among those ≥40-years (P < 0.001). During the study period, while the rate of immediate coronary angiography increased from 60.5% to 70.3% (P < 0.001) in patients aged ≥40 years, the rate in patients aged less than 40 years remained stable (43.5% to 45.3%, P = 0.795). Patients younger than 40 years were significantly less likely to undergo immediate coronary angiography (OR = 0.34, 95% CI: 0.25-0.47), although early angiography was associated with survival at hospital discharge (OR = 2.68, 95% CI: 1.21-6.00).Conclusion: CAD is the first cause of SCA in young adults aged less than 40 years. The observed low rates of immediate coronary angiography suggest a missed opportunity for early intervention.

Background Human encephalitis represents a medical challenge from a diagnostic and therapeutic point of view. We investigated the cause of 2 fatal cases of encephalitis of unknown origin in immunocompromised patients. Methods Untargeted metatranscriptomics was applied on the brain tissue of 2 patients to search for pathogens (viruses, bacteria, fungi, or protozoans) without a prior hypothesis. Results Umbre arbovirus, an orthobunyavirus never previously identified in humans, was found in 2 patients. In situ hybridization and reverse transcriptase–quantitative polymerase chain reaction (RT-qPCR) showed that Umbre virus infected neurons and replicated at high titers. The virus was not detected in cerebrospinal fluid by RT-qPCR. Viral sequences related to Koongol virus, another orthobunyavirus close to Umbre virus, were found in Culex pipiens mosquitoes captured in the south of France where the patients had spent some time before the onset of symptoms, demonstrating the presence of the same clade of arboviruses in Europe and their potential public health impact. A serological survey conducted in the same area did not identify individuals positive for Umbre virus. The absence of seropositivity in the population may not reflect the actual risk of disease transmission in immunocompromised individuals. Conclusions Umbre arbovirus can cause encephalitis in immunocompromised humans and is present in Europe.

International audience; Granulovacuolar degeneration (GVD) is usually found in Alzheimer's disease (AD) cases or in elderly individuals. Its severity correlates positively with the density of neurofibrillary tangles (NFTs). Mechanisms underlying GVD formation are unknown. We assessed the prevalence and distribution of GVD in cases with TDP-43-related frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS-TDP). Consecutively autopsied cases with FTLD/ALS-TDP and C9orf72 mutations (FTLD/ALS-C9; N = 29), cases with FTLD/ALS-TDP without C9orf72 mutations (FTLD/ALS-nonC9; N = 46), and age-matched healthy controls (N = 40) were studied. The prevalence of GVD was significantly higher in the FTLD/ALS-C9 cases (26/29 cases) than in the FTLD/ALS-nonC9 cases (15/46 cases; Fisher exact test; p

Introduction Since a large proportion of patients resuscitated from out-of-hospital sudden cardiac arrest (SCA) die in the intensive care unit (ICU), early systematic investigation towards identifying etiology may be crucial to ensure targeted therapy and appropriate future prevention among relatives, especially when the index case is young. Purpose We hypothesized that etiologic investigations were not initiated in a timely manner in a significant proportion of young SCA patients, alive at ICU admission, prior to death. Methods In this prospective, ongoing, multicenter, population-based registry (6.7 million inhabitants), data from all SCA over a 5-year period were analyzed, in collaboration with all the 48 hospitals of the area, with a specific focus on young patients ( Results Of the 18,622 out-of-hospital cardiac arrests from May 2011 to May 2016, 3,028 were admitted alive to ICU. Among them, 2,190 (72.3%) died in ICU, including 367 (16.8%) young cases ( Conclusion More than half of young SCA cases who died in ICU remained unexplained. There was significant underuse of core cardiac investigations. Efforts to promote prompt and systematic investigation through better collaboration between intensivist and cardiologist may improve both acute management and future targeted preventive strategies for family members.

Introduction Since a large proportion of patients resuscitated from out-of-hospital sudden cardiac arrest (SCA) die in the intensive care unit (ICU), early systematic investigation towards identifying etiology may be crucial to ensure appropriate future prevention among relatives, especially when the index case is young. Purpose We hypothesized that etiologic investigations were not initiated in a timely manner in a significant proportion of young SCA patients prior to death. Methods In this prospective ongoing multicenter, population-based registry (6.7 million inhabitants), data from all SCA over a 5-year period were analyzed with a specific focus on young patients ( Results Of the 18,622 out-of-hospital cardiac arrests from May 2011 to May 2016, 3,028 were admitted alive to ICU. Among them, 2,190 (72.3%) died in ICU, including 367 (16.8%) young cases ( Conclusion More than half of young SCA cases who died in ICU remained unexplained. Efforts to promote early systematic investigation through better collaboration between intensivist and cardiologist may improve future targeted preventive strategies for family members.

International audience; Specific extracellular deposits, glial or neuronal inclusions help defining an ever increasing number of neurodegenerative diseases. Deposits or inclusions are aggregates of proteins: Aβ peptide and tau proteins in Alzheimer disease, a-synuclein in Parkinson disease, for instance. The protein that specifically accumulates in a given disease may be modified by a mutation that can increase its aggregability. Most often the sequence of the protein is normal. Misfolding, despite the protein normal sequence, is then considered the cause of the aggregation. The ubiquitin-proteasome system detects and eliminates misfolded proteins from the cell. Almost all the inclusions are indeed labeled by anti-ubiquitin antibodies, but, in neurodegenerative diseases, the system is unable to get rid of them. The large protein aggregates constituting the inclusions are poorly reactive. Their formation has been consi- dered a defense mechanism, protecting the cell against the toxic action of soluble oligomers that are, in that hypothesis, the real toxic agent, neutralized through aggregation. Soluble oligomers of Aβ peptide, tau or a-synuclein,for instance, have indeed been isolated and were shown to be toxic. In the prion hypothesis, the misfolded configuration may be passed from the misfolded to the normal protein by simple contact. There are indeed experimental evidences suggesting that this prion-like mechanism does occur in transgenic rodent models of Aβ, tau or a-synuclein pathology. This might be the explanation of thepropagation of the pathology through connections, observed in many neurodegenerative diseases. There is currently no epidemiological data suggesting a transmission of neurodegenerative diseases, comparable to the transmission of Creutzfeldt-Jakob or other prion diseases. The prion-like mechanisms of protein aggregation observed in the experimental animals or suspected through human neuropathology make that possibility not as remote as previously thought.

Specific extracellular deposits, glial or neuronal inclusions help defining an ever increasing number of neurodegenerative diseases. Deposits or inclusions are aggregates of proteins: Aβ peptide and tau proteins in Alzheimer disease, a-synuclein in Parkinson disease, for instance. The protein that specifically accumulates in a given disease may be modified by a mutation that can increase its aggregability. Most often the sequence of the protein is normal. Misfolding, despite the protein normal sequence, is then considered the cause of the aggregation. The ubiquitin-proteasome system detects and eliminates misfolded proteins from the cell. Almost all the inclusions are indeed labeled by anti-ubiquitin antibodies, but, in neurodegenerative diseases, the system is unable to get rid of them. The large protein aggregates constituting the inclusions are poorly reactive. Their formation has been consi- dered a defense mechanism, protecting the cell against the toxic action of soluble oligomers that are, in that hypothesis, the real toxic agent, neutralized through aggregation. Soluble oligomers of Aβ peptide, tau or a-synuclein,for instance, have indeed been isolated and were shown to be toxic. In the prion hypothesis, the misfolded configuration may be passed from the misfolded to the normal protein by simple contact. There are indeed experimental evidences suggesting that this prion-like mechanism does occur in transgenic rodent models of Aβ, tau or a-synuclein pathology. This might be the explanation of thepropagation of the pathology through connections, observed in many neurodegenerative diseases. There is currently no epidemiological data suggesting a transmission of neurodegenerative diseases, comparable to the transmission of Creutzfeldt-Jakob or other prion diseases. The prion-like mechanisms of protein aggregation observed in the experimental animals or suspected through human neuropathology make that possibility not as remote as previously thought.

Recent studies have shown that in more than half of apparently unexplained sudden cardiac arrests (SCA), a specific aetiology can be unmasked by a careful evaluation. The characteristics and the extent to which such cases undergo a systematic thorough investigation in real-life practice are unknown.Data were analysed from an ongoing study, collecting all cases of out-of-hospital cardiac arrest in Paris area. Investigations performed during the index hospitalization or planned after discharge were gathered to evaluate the completeness of assessment of unexplained SCA. Between 2011 and 2016, among the 18 622 out-of-hospital cardiac arrests, 717 survivors (at hospital discharge) fulfilled the definition of cardiac SCA. Of those, 88 (12.3%) remained unexplained after electrocardiogram, echocardiography, and coronary angiography. Cardiac magnetic resonance imaging yielded the diagnosis in 25 (3.5%) cases, other investigations accounted for 14 (2.4%) additional diagnoses, and 49 (6.8%) patients were labelled as idiopathic ventricular fibrillation (IVF) (48.7 ± 15 years, 69.4% male). Among those labelled IVF, only 8 (16.3%) cases benefited from a complete workup (including pharmacological testing). Younger patients [odds ratio (OR) 6.00, 95% confidence interval (CI) 1.80-22.26] and those admitted to university centres (OR 3.60, 95% CI 1.12-12.45) were more thoroughly investigated. Genetic testing and family screening were initiated in only 9 (18.4%) and 12 (24.5%) cases, respectively.Our findings suggest that complete investigations are carried out in a very low proportion of unexplained SCA. Standardized, systematic approaches need to be implemented to ensure that opportunities for specific therapies and preventive strategies (including relatives) are not missed.

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group including both sporadic and familial diseases, characterized by a macroscopic alteration. It may correspond to various cognitive syndromes: behavioral variant of frontotemporal dementia (bvFTD), progressive nonfluent aphasia, and semantic dementia. The neuropathologic classification is now based on identification of the protein that accumulates in neurons and glia: Tau, TAR DNA Binding Protein 43 (TDP-43), and FUsed in Sarcoma (FUS). The disorders in which the corresponding proteins accumulate have been named FTLD-Tau, FTLD-TDP, and FTLD-FUS. FTLD-Tau includes sporadic cases (e.g. Pick's disease) and Tau mutations. FTLD-TDP are subdivided within four types (A, B, C, D) according to the shape and distribution of TDP-43 positive lesions within the associative frontal cortex. The FTLD-FUS group includes atypical FTLD with ubiquitinated lesions (FTLD-U), Neuronal Intermediate Filament Inclusion Disease (NIFID) and Basophilic Inclusion Body Disease (BIBD).

A 43-year-old full-term pregnant woman (gravida 2, para 1, medical history of gestational diabetes mellitus) developed a sudden and malignant hypertension with hemoptysis, sweat, and tachycardia during a scheduled C-section. A dead newborn was delivered and was successfully resuscitated. The mother died after resistant cardiac arrest. Autopsy and pathological analyses revealed an acute pulmonary edema and a necrotic and hemorrhagic voluminous tumor of the left adrenal gland, which was a pheochromocytoma. Pheochromocytoma is a rare tumor of the adrenal glands which secretes catecholamines. In pregnant women, its symptoms can mimic gestational hypertension, preeclampsia or eclampsia, and gestational diabetes mellitus. The gestational diabetes mellitus was presumed to be a symptom of the pheochromocytoma, and cardiopulmonary failure the result from the necrosis of the tumor provoked by gravid uterus compression. From a medico-legal point of view, the tumor could not have been suspected during the pregnancy.

RESUME La signification des inclusions intracellulaires est tres variable : marqueurs de certaines des maladies de la proteolyse, qu'elles contribuent a identifier, elles peuvent relever de multiples autres mecanismes, souvent intriques. A titre d'exemples, les donnees actuelles sur la morphologie et la signification des lipofuscines du vieillissement cellulaire, des degenerescences neurofibrillaires et des corps de Lewy et sur celles des granules de Birbeck de l'histiocytose langherhansienne sont analysees. Certaines de ces inclusions peuvent resulter de la mise en jeu a la fois des systemes d'endocytose, de production, de malconformation et d'agregation proteique et de ceux de proteolyse intracellulaire. D'autres constituants cellulaires sont souvent aussi impliques. Enfin les systemes de proteolyse ne paraissent pas essentiellement en cause dans le cas des granules de Birbeck, considerees comme des domaines sous-membranaires du recyclage endosomial. Ils jouerent un role decisif dans l'identification de l'origine langerhansienne de l'histiocytose X.

Forensic examination is often requested when skeletal remains are discovered. Detailed visual observation can provide much information, such as the human or animal origin, sex, age, stature, and ancestry, and approximate time since death. New three-dimensional imaging techniques can provide further information (osteometry, facial reconstruction). Bone chemistry, and particularly measurement of stable or unstable carbon and nitrogen isotopes, yields information on diet and time since death, respectively. Genetic analyses of ancient DNA are also developing rapidly. Although seldom used in a judicial context, these modern anthropologic techniques are nevertheless available for the most complex cases.

L’assurance maladie a lance debut 2009 un programme dit de paiement a la performance pour les medecins generalistes : le contrat d’amelioration des pratiques individuelles (CAPI). Il propose aux medecins adherents de majorer leur remuneration en echange d’une meilleure qualite de leur pratique, mesuree a partir d’une batterie d’indicateurs. L’article cherche a mettre en evidence les facteurs qui determinent un medecin a y adherer ou non, a partir d’entretiens collectifs de type focus group, avec des medecins adherents, d’une part, et non-adherents, d’autre part. A partir d’une grille construite par une equipe multidisciplinaire, ce travail montre que c’est d’abord le type de positionnement vis-a-vis de l’assurance maladie qui permet de predire leur choix, mais qu’un second facteur a aussi un role propre : le jugement a priori qu’ils portent sur la capacite des indicateurs du CAPI a donner une image valide de la pratique de medecine generale. Les limites de ces resultats sont discutees tout en montrant comment ils permettent d’envisager de coupler au CAPI des incitations non monetaires susceptibles de permettre a des non-adherents d’ameliorer leur pratique.

AIMS OF THE STUDY: To describe the management of extremely preterm newborns at the threshold of viability before 24weeks of gestation in the delivery room when the decision has been made not to provide intensive care; to assess the role of palliative care (PC); to report the problems encountered. METHOD: A prospective qualitative study was conducted using semi-structured interviews from November 2009 to June 2010 in two level III French maternity hospitals (A and B). In each center, four midwives, two obstetricians, two pediatricians, two anesthetists, and one chief midwife were interviewed. RESULTS: In maternity hospital A, a protocol was in place that proposed PC derived from developmental care (noise limitation, drying, warming) provided by parents or staff. The problems reported were related to former euthanasia practices rather than new procedures. In maternity hospital B, no palliative care protocol had been set up. Euthanasia was practiced and accepted fatalistically because the only currently existing alternative (letting the infant die) was considered inhumane. Few problems were reported. The reluctance to carry out PC is conceptual and organizational (the ratio of births per midwife in maternity hospital B was twice that of maternity hospital A). Lexical analysis showed preferential use of the words "fetus" and "expulsion" versus "child" and "delivery" in maternity hospital B (p

Resume Une decision du tribunal administratif de Nimes du 2 juin 2009 est venue condamner l’hopital d’Orange a indemnisation pour obstination deraisonnable apres la reanimation d’un enfant, desormais lourdement handicape, ne en etat de mort apparente apres une periode de souffrance fœtale d’environ 30 minutes suivie de 25 minutes de reanimation. Le tribunal n’a retenu aucune faute a l’encontre de l’hopital lors de la prise en charge maternelle. Mais il condamne l’hopital pour obstination deraisonnable, l’equipe medicale ne pouvant ignorer les consequences neurologiques nefastes d’une souffrance fœtale prolongee et la reanimation ayant ete d’une duree excessive. Nous developperons sur le plan medico-legal et ethique les questions sur : la reanimation de cet enfant consideree comme d’une duree excessive alors que sa seule mise en œuvre n’a pas ete remise en cause ; l’information erronee sur le deces de l’enfant qui n’a pas ete reconnue comme fautive ; l’obligation pour l’hopital d’indemniser le couple et l’enfant ce qui revient a indemniser l’enfant de sa survie, rappelant en certains points l’affaire Perruche ; le risque que l’indemnisation porte sur l’ensemble du handicap de l’enfant, compte tenu des difficultes pour l’expert a individualiser les consequences relevant uniquement de l’obstination a reanimer cet enfant, tout en tenant compte de son etat anterieur. En conclusion, il serait dommageable qu’en reaction a cette menace judiciaire, les reanimateurs preferent s’abstenir de reanimer un nouveau-ne qui aura deja ete victime d’une hypoxie antenatale afin de ne pas etre mis en cause dans la survenue d’un handicap eventuel dont ils ne seraient pas responsables mais avec le risque d’etre accuses de non-assistance a personne en danger.

A february-2008 rule about > stressed that > could be registered at the General Register Office. This rule, which was followed in 2009 by the implementation of new procedures to deal with dead fetuses, highlighted that this topic is more and more becoming an important public issue. The rights for parents to choose has now been recognized, bringing about new questions for health professionals. Another point is which symbolism is to be given to dead fetuses to alleviate couples' suffering, without being too ideological, i.e. seeing fetuses as persons. This change also makes professionals reconsider public health system priorities, and this at a very particular time. Indeed, as parent mourning has now been made easier through registration at the General Register Office, there has not been any rule yet linking national epidemiological registration and fetal death in France. double dagger.

Healthcare networks which purpose is to manage patients through better coordination of the care, need to develop a communication strategy to be recognized by the public and by healthcare professionals and to be inserted in the healthcare landscape. We firstly will present legal requirements related to external communication of healthcare networks. Then, we will describe the different tools which can be used to communicate about healthcare networks in its area, with the example from a healthcare network for health services accessibility. In the French Public health code, the legal status and the ethical charter of the healthcare network have to be delivered to the healthcare professionals in its area and to the patients. Moreover, the example healthcare network informed collectively and individually the healthcare professionals of its area about its activities. It made it known to the public by the way of departmental prevention manifestations and health education sessions in community social associations. From these examples, we will conduct an ethical reflection on the modalities and stakes of the external communication of healthcare networks.

Introduction Les anticorps (Ac) anti-RI, sont des Ac antinucleaires neuronaux associes a des syndromes paraneoplasiques (SP) du systeme nerveux central. Ils sont responsables d’une d’atteinte du tronc cerebral et plus rarement d’encephalite limbique (EL). Observation Nous rapportons le cas d’une patiente de 80 ans suivie de novembre 2002 a juin 2009 pour une EL liee a des Ac anti-RI, fortement positifs dans le serum. L’IRM initiale montrait un hypersignal temporal interne gauche. Les electroencephalogrammes (EEG) montraient des crises partielles temporales. Apres deux ans d’evolution, un adenocarcinome mammaire a ete identifie. Le tableau s’est aggrave malgre l’exerese de l’adenocarcinome pour evoluer vers un etat de mal partiel non convulsif permanent. Le taux de CA-125 positif dans le serum initialement, a augmente progressivement en depit d’une annexectomie bilaterale. Il existait une correlation entre le point de depart des crises d’epilepsies partielles qui etait de plus en plus frontales et l’extension des lesions sur l’IRM vers les regions insulaires et frontales. De nombreux medicaments antiepileptiques ont ete essayes sans succes. L’etude neuropathologique complete du cerveau a confirme le diagnostic d’encephalite temporale gauche avec la presence d’un important infiltrat perivasculaire de lymphocytes T CD3+ associe a une gliose astrocytaire massive et un aspect cavitaire des zones atteintes. Il n’y avait pas de tumeur des sereuses retrouvee. Discussion Seuls trois cas d’EL liee a des Ac anti-RI ont ete rapportes dans la litterature. Le profil evolutif des patients et les tumeurs identifiees etaient differents. Seul notre cas a montre une atteinte limbique lentement progressive avec des lesions extensives sur l’IRM, des crises repetees et un etat de mal refractaire sur l’EEG et une reaction lymphoide T associee a une perte neuronale massive. Conclusion A notre connaissance, notre etude est la premiere a rapporter le cas d’une EL liee a des Ac anti-RI responsable d’un etat de mal partiel prolonge durant des mois, de lesions progressives et atrophiantes sur l’IRM, associees a une infiltration inflammatoire majeure.

Resume Les reseaux de sante visent a ameliorer la prise en charge des patients grâce a une meilleure coordination des soins. Pour se faire connaitre du grand public et des professionnels de sante, ils doivent developper une strategie de communication sur ce qu’ils sont et ce qu’ils font. La mise en place d’une campagne de communication, par les reseaux eux-memes, fait craindre un glissement d’une logique de transparence, reposant sur une evaluation et une publication des bilans d’activite, vers une logique publicitaire et commerciale avec mise en competition des reseaux entre eux. La communication des reseaux de sante en direction du grand public et des professionnels de sante, doit donc etre portee aussi par les pouvoirs publics, dans le cadre plus global d’une politique de sante publique d’optimisation de l’acces aux soins des populations.

Forensic examination is often requested when skeletal remains are discovered. Detailed visual observation can provide much information, such as the human or animal origin, sex, age, stature, and ancestry, and approximate time since death. New three-dimensional imaging techniques can provide further information (osteometry, facial reconstruction). Bone chemistry, and particularly measurement of stable or unstable carbon and nitrogen isotopes, yields information on diet and time since death, respectively. Genetic analyses of ancient DNA are also developing rapidly. Although seldom used in a judicial context, these modern anthropologic techniques are nevertheless available for the most complex cases.

Migrants form a heterogeneous population which requires specific medical-social care. Networks providing access to healthcare are one of the solutions enabling migrants to benefit from curative and preventative primary care.