Hôpital Universitaire Dupuytren

BACKGROUND: In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death. METHODS: We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score <25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 microg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected. RESULTS: Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01). CONCLUSIONS: The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.

Importance: The benefits of endovascular revascularization using the contact aspiration technique vs the stent retriever technique in patients with acute ischemic stroke remain uncertain because of lack of evidence from randomized trials. Objective: To compare efficacy and adverse events using the contact aspiration technique vs the standard stent retriever technique as a first-line endovascular treatment for successful revascularization among patients with acute ischemic stroke and large vessel occlusion. Design, Setting, and Participants: The Contact Aspiration vs Stent Retriever for Successful Revascularization (ASTER) study was a randomized, open-label, blinded end-point clinical trial conducted in 8 comprehensive stroke centers in France (October 2015-October 2016). Patients who presented with acute ischemic stroke and a large vessel occlusion in the anterior circulation within 6 hours of symptom onset were included. Interventions: Patients were randomly assigned to first-line contact aspiration (n = 192) or first-line stent retriever (n = 189) immediately prior to mechanical thrombectomy. Main Outcomes and Measures: The primary outcome was the proportion of patients with successful revascularization defined as a modified Thrombolysis in Cerebral Infarction score of 2b or 3 at the end of all endovascular procedures. Secondary outcomes included degree of disability assessed by overall distribution of the modified Rankin Scale (mRS) score at 90 days, change in National Institutes of Health Stroke Scale (NIHSS) score at 24 hours, all-cause mortality at 90 days, and procedure-related serious adverse events. Results: Among 381 patients randomized (mean age, 69.9 years; 174 women [45.7%]), 363 (95.3%) completed the trial. Median time from symptom onset to arterial puncture was 227 minutes (interquartile range, 180-280 minutes). For the primary outcome, the proportion of patients with successful revascularization was 85.4% (n = 164) in the contact aspiration group vs 83.1% (n = 157) in the stent retriever group (odds ratio, 1.20 [95% CI, 0.68-2.10]; P = .53; difference, 2.4% [95% CI, -5.4% to 9.7%]). For the clinical efficacy outcomes (change in NIHSS score at 24 hours, mRS score at 90 days) and adverse events, there were no significant differences between groups. Conclusions and Relevance: Among patients with ischemic stroke in the anterior circulation undergoing thrombectomy, first-line thrombectomy with contact aspiration compared with stent retriever did not result in an increased successful revascularization rate at the end of the procedure. Trial Registration: clinicaltrials.gov Identifier: NCT02523261.

BACKGROUND: The course and prognosis of childhood-onset multiple sclerosis have not been well described. METHODS: We used data from 13 adult neurology departments affiliated with the European Database for Multiple Sclerosis (EDMUS) network to identify a cohort of 394 patients who had multiple sclerosis with an onset at 16 years of age or younger and a comparison group of 1775 patients who had multiple sclerosis with an onset after 16 years of age. We determined the initial clinical features, the dates of disease onset, and the occurrence of outcomes, including relapse, conversion to secondary progression, and irreversible disability as measured by scores of 4 (limited walking ability but ability to walk more than 500 m without aid or rest), 6 (ability to walk with unilateral support no more than 100 m without rest), and 7 (ability to walk no more than 10 m without rest while using a wall or furniture for support) on the Kurtzke Disability Status Scale (range, 0 to 10; higher scores indicate more severe disability). RESULTS: For patients with childhood-onset multiple sclerosis, the estimated median time from onset to secondary progression was 28 years, and the median age at conversion to secondary progression was 41 years. The median times from onset to disability scores of 4, 6, and 7 were 20.0, 28.9, and 37.0 years, respectively, and the corresponding median ages were 34.6, 42.2, and 50.5 years. In comparison with patients with adult-onset disease, those with childhood-onset disease were more likely to be female than male (female:male ratio, 2.8 vs. 1.8), were more likely to have an exacerbating-remitting initial course (98% vs. 84%), took approximately 10 years longer to reach secondary progression and irreversible disability, and reached these landmarks at an age approximately 10 years younger (P<0.001 for all comparisons). CONCLUSIONS: Patients with childhood-onset multiple sclerosis take longer to reach states of irreversible disability but do so at a younger age than patients with adult-onset multiple sclerosis.

Importance: Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option. Objective: To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure. Design, Setting, and Participants: Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19-related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board. Interventions: Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73). Main Outcomes and Measures: The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay. Results: The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, -8.6% [95.48% CI, -24.9% to 7.7%]; P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment. Conclusions and Relevance: In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT02517489.

RATIONALE: Many patients with severe acute respiratory distress syndrome (ARDS) caused by influenza A(H1N1) infection receive extracorporeal membrane oxygenation (ECMO) as a rescue therapy. OBJECTIVES: To analyze factors associated with death in ECMO-treated patients and the influence of ECMO on intensive care unit (ICU) mortality. METHODS: Data from patients admitted for H1N1-associated ARDS to French ICUs were prospectively collected from 2009 to 2011 through the national REVA registry. We analyzed factors associated with in-ICU death in ECMO recipients, and the potential benefit of ECMO using a propensity score-matched (1:1) cohort analysis. MEASUREMENTS AND MAIN RESULTS: A total of 123 patients received ECMO. By multivariate analysis, increasing values of age, lactate, and plateau pressure under ECMO were associated with death. Of 103 patients receiving ECMO during the first week of mechanical ventilation, 52 could be matched to non-ECMO patients of comparable severity, using a one-to-one matching and using control subjects only once. Mortality did not differ between the two matched cohorts (odds ratio, 1.48; 95% confidence interval, 0.68-3.23; P = 0.32). Interestingly, the 51 ECMO patients who could not be matched were younger, had lower Pa(o(2))/Fi(o(2)) ratio, had higher plateau pressure, but also had a lower ICU mortality rate than the 52 matched ECMO patients (22% vs. 50%; P < 0.01). CONCLUSIONS: Under ECMO, an ultraprotective ventilation strategy minimizing plateau pressure may be required to improve outcome. When patients with severe influenza A(H1N1)-related ARDS treated with ECMO were compared with conventionally treated patients, no difference in mortality rates existed. The unmatched, severely hypoxemic, and younger ECMO-treated patients had, however, a lower mortality.

OBJECTIVE: To evaluate the occurrence of malnutrition in patients with ALS, to assess the relation of malnutrition to the neurologic deficit, and to determine the impact of nutritional status on patient survival. BACKGROUND: Although ALS may be associated with significant malnutrition, the relative impact on patient survival has not yet been well established. METHODS: In a prospective 7-month study of 55 ALS patients in a referral neurology practice, nutritional status was assessed by calculating body mass index. Neurologic evaluation includes four functional scores and identifies the form of disease onset. Slow vital capacity (VC) was also measured. RESULTS: Occurrence of malnutrition in patients studied was 16.4%. Survival (using the Kaplan-Meier method) was worse for malnourished patients (p < 0.0001), with a 7.7-fold increased risk of death. Using multivariate analysis, only reduced VC (p < 0.0001) and malnutrition (p < 0.01) were found to have significant independent prognostic value. The degree of malnutrition is independent of neurologic scores and of forms of ALS onset. CONCLUSION: Nutritional surveillance of ALS patients is very important, both in bulbar-onset and spinal-onset patients.

<h3>Background</h3> COVID-19 is a global pandemic caused by the novel coronavirus SARS-CoV-2. Risk factors and prognostic markers of severe disease remain to be fully determined, although some studies have suggested a correlation between abnormal liver function and adverse outcomes. Further studies are needed to investigate this further. <h3>Methods</h3> This retrospective study enrolled patients with a confirmed diagnosis of COVID-19 who were admitted to Kingston Hospital in the UK. Data collected included age, sex, ethnicity, comorbidity profile, biochemical markers of liver function and the acute phase response, and overall outcome. <h3>Results</h3> Between 16 March 2020 and 30 April 2020, a total of 343 patients were admitted to the acute medical team at Kingston Hospital. Excluding those with a history of liver disease, 299 patients had liver function tests performed with abnormalities demonstrated in 44.8% of individuals. Derangement of liver function was associated with greater need for ventilatory support (p&lt;0.001), admission to high dependency unit or intensive care (p&lt;0.001) and increased length of hospital stay (p&lt;0.001). Of note, liver dysfunction was more common in those of non-white ethnicity (p=0.007) and correlated with higher levels of C reactive protein (p=0.01) and ferritin (p&lt;0.001). <h3>Conclusion</h3> Abnormal liver function is associated with a negative outcome among those hospitalised with COVID-19. The cause for this association is unclear, but correlation between abnormal liver function and higher serum levels of acute phase proteins suggest that dysregulation of the immune system in response to SARS-CoV-2 may be contributory.

Conventional karyotypes performed before any treatment in 208 patients with multiple myeloma were reviewed by the Groupe Français de Cytogénétique Hématologique. A total of 138 patients displayed complex chromosomal abnormalities (CCAs). According to the chromosome number pattern, a first group of 75 patients had a hyperdiploid karyotype. A second group of 63 patients referred to as the hypodiploid group had either pseudodiploid, hypodiploid, or near-tetraploid karyotypes. Of 159 treated patients available for survival analysis, 116 had an abnormal karyotype. The comparison of overall survival (OS) between hyperdiploid and hypodiploid patients showed a highly significant difference (median OS 33.8 vs 12.6 months, respectively, P <.001). The presence of 14q32 rearrangements (36 of 116 patients) worsened the prognosis (median OS 17.6 vs 29.9 months, P <.02). The presence of chromosome 13q abnormalities (13qA, 63 patients) did not modify OS in CCA patients (median OS 20.6 vs 27.8 months, P <.59). However, taking into account the whole series including normal karyotypes, 13qA (63 of 159 patients) had a significant impact on OS (median 20.6 vs 37.1 months, P <.04). In the same way, the presence of a hypodiploid karyotype (52 of 159 patients) had a strong prognostic value (OS 12.8 vs 44.5 months, P <.000 01). A multivariate analysis including stage, beta2-microglobulin, bone marrow plasmocytosis, treatment type, 13qA, and hyperdiploidy and hypodiploidy showed that a hypodiploid karyotype was the first independent factor for OS (P <.001), followed by treatment approach. These results confirm that the chromosome number pattern of malignant plasma cells is a very powerful prognostic factor in newly diagnosed multiple myeloma patients.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Patients with severe pulmonary arterial hypertension (PAH) in New York Heart Association (NYHA) functional class (FC) III/IV have a poor prognosis, despite survival benefits being demonstrated with intravenous epoprostenol. In this pilot study, the efficacy and safety of a triple combination therapy regimen in patients with severe PAH was investigated. Data from newly diagnosed NYHA FC III/IV PAH patients (n=19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil) were collected retrospectively from a prospective registry. Significant improvements in 6-min walk distance and haemodynamics were observed after 4 months' triple combination therapy in 18 patients (p<0.01); 17 patients had improved to NYHA FC I or II. One patient was not included in the month 4 assessment (due to an emergency lung transplant in month 3). At the final evaluation (mean ± sd 32 ± 19 months), all 18 patients had sustained clinical and haemodynamic improvement. Overall survival estimates for the triple combination cohort were 100% at 1, 2 and 3 years. Expected survival calculated from the French equation was 75% (95% CI 68-82%), 60% (95% CI 50-70%) and 49% (95% CI 38-60%) at 1, 2 and 3 years, respectively. This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH.

OBJECTIVE: To assess the feasibility, safety, and outcome of laparoscopic liver resection for malignant liver tumors. SUMMARY BACKGROUND DATA: The precise role of laparoscopy in resection of liver malignancies (hepatocellular carcinoma [HCC] and liver metastases) remains controversial despite an increasing number of publications reporting laparoscopic resection of benign liver tumors. METHODS: A retrospective study was performed in 11 surgical centers in Europe regarding their experience with laparoscopic resection of liver malignancies. Detailed questionnaires were sent to each surgeon focusing on patient characteristics, clinical data, type and characteristics of the tumor, technical details of the operation, and early and late clinical outcome. All patients had radiologic investigations at follow-up to exclude disease recurrence. RESULTS: From February 1994 to December 2000, 37 patients with malignant liver tumors were included in this study. Ten patients had HCC, including 9 with cirrhotic liver, and 27 patients had liver metastases. The mean tumor size was 3.3 cm, and 89% of the tumors were located in the left lobe or in the anterior segments of the right liver. Liver procedures included 12 wedge resections, 9 segmentectomies, 14 bisegmentectomies (including 13 left lateral segmentectomies), and 2 major hepatectomies. The transfusion rate, the use of pedicular clamping, the conversion rate (13.5% in the whole series), and the complication rate were significantly greater in patients with HCC. There were no deaths. Postoperative complications occurred in eight patients (22%). The surgical margin was less than 1 cm in 30% of the patients. During a mean follow-up of 14 months, the 2-year disease-free survival was 44% for patients with HCC and 53% for patients having hepatic metastases from colorectal cancer. No port-site metastases were observed during follow-up. CONCLUSIONS: In patients with small malignant tumors, located in the left lateral segments or in the anterior segments of the right liver, laparoscopic resection is feasible and safe. The complication rate is low, except in patients with HCC on cirrhotic liver. By using laparoscopic ultrasound, a 1-cm free surgical margin should be routinely obtained. The late outcome needs to be evaluated in expert centers.

Marked phenotypic variation characterizes isolates of Toxoplasma gondii, a ubiquitous zoonotic parasite that serves as an important experimental model for studying apicomplexan parasites. Progress in identifying the heritable basis for clinically and epidemiologically significant differences requires a robust system for describing and interpreting evolutionary subdivisions in this prevalent pathogen. To develop such a system, we have examined more than 950 isolates collected from around the world and genotyped them using three independent sets of polymorphic DNA markers, sampling 30 loci distributed across all nuclear chromosomes as well as the plastid genome. Our studies reveal a biphasic pattern consisting of regions in the Northern Hemisphere where a few, highly clonal and abundant lineages predominate; elsewhere, and especially in portions of South America are characterized by a diverse assemblage of less common genotypes that show greater evidence of recombination. Clustering methods were used to organize the marked genetic diversity of 138 unique genotypes into 15 haplogroups that collectively define six major clades. Analysis of gene flow indicates that a small number of ancestral lineages gave rise to the existing diversity through a process of limited admixture. Identification of reference strains for these major groups should facilitate future studies on comparative genomics and identification of genes that control important biological phenotypes including pathogenesis and transmission.

RATIONALE: Assessment of fluid responsiveness relies on dynamic echocardiographic parameters that have not yet been compared in large cohorts. OBJECTIVES: To determine the diagnostic accuracy of dynamic parameters used to predict fluid responsiveness in ventilated patients with a circulatory failure of any cause. METHODS: In this multicenter prospective study, respiratory variations of superior vena cava diameter (∆SVC) measured using transesophageal echocardiography, of inferior vena cava diameter (∆IVC) measured using transthoracic echocardiography, of the maximal Doppler velocity in left ventricular outflow tract (∆VmaxAo) measured using either approach, and pulse pressure variations (∆PP) were recorded with the patient in the semirecumbent position. In each patient, a passive leg raise was performed and an increase of aortic velocity time integral greater than or equal to 10% defined fluid responsiveness. MEASUREMENTS AND MAIN RESULTS: Among 540 patients (379 men; age, 65 ± 13 yr; Simplified Acute Physiological Score II, 59 ± 18; Sequential Organ Failure Assessment, 10 ± 3), 229 exhibited fluid responsiveness (42%). ∆PP, ∆VmaxAo, ∆SVC, and ∆IVC could be measured in 78.5%, 78.0%, 99.6%, and 78.1% of cases, respectively. ∆SVC greater than or equal to 21%, ∆VmaxAo greater than or equal to 10%, and ∆IVC greater than or equal to 8% had a sensitivity of 61% (95% confidence interval, 57-66%), 79% (75-83%), and 55% (50-59%), respectively, and a specificity of 84% (81-87%), 64% (59-69%), and 70% (66-75%), respectively. The area under the receiver operating characteristic curve of ∆SVC was significantly greater than that of ∆IVC (P = 0.02) and ∆PP (P = 0.01). CONCLUSIONS: ∆VmaxAo had the best sensitivity and ∆SVC the best specificity in predicting fluid responsiveness. ∆SVC had a greater diagnostic accuracy than ∆IVC and ∆PP, but its measurement requires transesophageal echocardiography.

An important proportion of patients with aortic stenosis (AS) have a 'low-gradient' AS, i.e. a small aortic valve area (AVA <1.0 cm(2)) consistent with severe AS but a low mean transvalvular gradient (<40 mmHg) consistent with non-severe AS. The management of this subset of patients is particularly challenging because the AVA-gradient discrepancy raises uncertainty about the actual stenosis severity and thus about the indication for aortic valve replacement (AVR) if the patient has symptoms and/or left ventricular (LV) systolic dysfunction. The most frequent cause of low-gradient (LG) AS is the presence of a low LV outflow state, which may occur with reduced left ventricular ejection fraction (LVEF), i.e. classical low-flow, low-gradient (LF-LG), or preserved LVEF, i.e. paradoxical LF-LG. Furthermore, a substantial proportion of patients with AS may have a normal-flow, low-gradient (NF-LG) AS: i.e. a small AVA-low-gradient combination but with a normal flow. One of the most important clinical challenges in these three categories of patients with LG AS (classical LF-LG, paradoxical LF-LG, and NF-LG) is to differentiate a true-severe AS that generally benefits from AVR vs. a pseudo-severe AS that should be managed conservatively. A low-dose dobutamine stress echocardiography may be used for this purpose in patients with classical LF-LG AS, whereas aortic valve calcium scoring by multi-detector computed tomography is the preferred modality in those with paradoxical LF-LG or NF-LG AS. Although patients with LF-LG severe AS have worse outcomes than those with high-gradient AS following AVR, they nonetheless display an important survival benefit with this intervention. Some studies suggest that transcatheter AVR may be superior to surgical AVR in patients with LF-LG AS.

SCOPUS: ar.j

OBJECTIVE: The objective of this study was to evaluate the benefit of an aggressive approach to gallbladder carcinoma on long-term survival. SUMMARY BACKGROUND DATA: Recent studies have shown that an aggressive surgical treatment of bile duct carcinoma can be associated with a surprising long-term survival. However, recent data on gallbladder carcinoma are not available. METHODS: Data were obtained from a questionnaire sent to 73 institutions in France, Europe, and overseas, and they were analyzed retrospectively. The review included an analysis of patient sex and age, associated hepatobiliary diseases, symptoms and signs, diagnostic tests, operative management, pathology reports, and survival. RESULTS: Seventy-eight per cent of the patients were women, and 22% were men (p < 0.001). Gallstones were present in 86% of the cases. Four per cent of the patients had Tis stage lesions, 11% had T1 to T2 stage lesions, and 85% had T3 to T4 stage lesions (p < 0.001). Pain was the most frequent symptom (77%). Twenty-three per cent of the patients underwent curative operations, and 77% had a palliative treatment (25% of the patients underwent exploratory laparotomy). Exploratory laparotomy was followed by the highest mortality rate (66%), and older patients (> 70 years) had a higher operative risk (p < 0.04). The overall median survival was 3 months, and long-term survival correlated with the cancer stage (Tis, > 60 months; T1 to T2, > 22 months, and T3 to T4, 2 to 8 months). No differences were observed among the different surgical procedures adopted. CONCLUSIONS: No progress has been made in the last 10 years in the treatment of gallbladder malignancies.

We present a case of disseminated congenital toxoplasmosis in a newborn born to a mother who had been immunized against toxoplasmosis before conception. The mother was reinfected, likely by ingestion of imported raw horse meat during pregnancy. This clinical presentation is exceptional in France and raised the possibility of infection by a highly virulent Toxoplasma strain. The strain responsible was isolated from the peripheral blood of the newborn, and when genotyped with microsatellite markers, it exhibited an atypical genotype, one which is very uncommon in Europe but had been described in South America. We tested the hypothesis of a reinfection with a different genotype by using an experimental mouse model, which confirmed that acquired immunity against European Toxoplasma strains may not protect against reinfection by atypical strains acquired during travel outside Europe or by eating imported meat.

OBJECTIVES: The aims were to analyse changes in nutritional parameters from diagnosis of amyotrophic lateral sclerosis (ALS) to death and to assess their relationships with survival at the time of diagnosis and during follow-up. METHODS: 92 ALS patients were included and clinically assessed every 3 months (ALS functional rating scale, manual muscular testing, forced vital capacity, weight, BMI, percentage weight loss). Bioimpedance was performed to evaluate body composition (fat-free mass, fat mass and hydration status) and phase angle. Survival analyses were performed from diagnosis to death or censoring date using a Cox model. RESULTS: The evolution of nutritional parameters in ALS patients was marked by significant decreases in weight, BMI, fat-free mass and phase angle, and increased fat mass. The authors identified an adjusted 30% increased risk of death for a 5% decrease from usual weight at time of diagnosis (RR 1.30; 95% CI 1.08 to 1.56). During follow-up, the authors identified adjusted 34% (95% CI 18% to 51%) and 24% (95% CI 13% to 36%) increased risks of death associated with each 5% decrease in usual weight and each unit decrease in usual BMI, respectively (p<0.0001). Malnutrition during the course was related to a shorter survival (p=0.01), and fat mass level was associated with a better outcome (RR 0.90 for each 2.5 kg fat mass increment). CONCLUSIONS: Nutritional parameters of ALS patients worsened during evolution of the disease, and worse nutritional status (at time of diagnosis or during the course) was associated with a higher mortality. This study offers some justification for studying the use of therapeutic nutritional intervention to modify the survival of ALS patients.

Importance: The natural history and the management of patients with asymptomatic aortic stenosis (AS) have not been fully examined in the current era. Objective: To determine the clinical outcomes of patients with asymptomatic AS using data from the Heart Valve Clinic International Database. Design, Setting, and Participants: This registry was assembled by merging data from prospectively gathered institutional databases from 10 heart valve clinics in Europe, Canada, and the United States. Asymptomatic patients with an aortic valve area of 1.5 cm2 or less and preserved left ventricular ejection fraction (LVEF) greater than 50% at entry were considered for the present analysis. Data were collected from January 2001 to December 2014, and data were analyzed from January 2017 to July 2018. Main Outcomes and Measures: Natural history, need for aortic valve replacement (AVR), and survival of asymptomatic patients with moderate or severe AS at entry followed up in a heart valve clinic. Indications for AVR were based on current guideline recommendations. Results: Of the 1375 patients included in this analysis, 834 (60.7%) were male, and the mean (SD) age was 71 (13) years. A total of 861 patients (62.6%) had severe AS (aortic valve area less than 1.0 cm2). The mean (SD) overall survival during medical management (mean [SD] follow up, 27 [24] months) was 93% (1%), 86% (2%), and 75% (4%) at 2, 4, and 8 years, respectively. A total of 104 patients (7.6%) died under observation, including 57 patients (54.8%) from cardiovascular causes. The crude rate of sudden death was 0.65% over the duration of the study. A total of 542 patients (39.4%) underwent AVR, including 388 patients (71.6%) with severe AS at study entry and 154 (28.4%) with moderate AS at entry who progressed to severe AS. Those with severe AS at entry who underwent AVR did so at a mean (SD) of 14.4 (16.6) months and a median of 8.7 months. The mean (SD) 2-year and 4-year AVR-free survival rates for asymptomatic patients with severe AS at baseline were 54% (2%) and 32% (3%), respectively. In those undergoing AVR, the 30-day postprocedural mortality was 0.9%. In patients with severe AS at entry, peak aortic jet velocity (greater than 5 m/s) and LVEF (less than 60%) were associated with all-cause and cardiovascular mortality without AVR; these factors were also associated with postprocedural mortality in those patients with severe AS at baseline who underwent AVR (surgical AVR in 310 patients; transcatheter AVR in 78 patients). Conclusions and Relevance: In patients with asymptomatic AS followed up in heart valve centers, the risk of sudden death is low, and rates of overall survival are similar to those reported from previous series. Patients with severe AS at baseline and peak aortic jet velocity of 5.0 m/s or greater or LVEF less than 60% have increased risks of all-cause and cardiovascular mortality even after AVR. The potential benefit of early intervention should be considered in these high-risk patients.

UNLABELLED: DEFINITION OF THE DISEASE: AL amyloidosis results from extra-cellular deposition of fibril-forming monoclonal immunoglobulin (Ig) light chains (LC) (most commonly of lambda isotype) usually secreted by a small plasma cell clone. Most patients have evidence of isolated monoclonal gammopathy or smoldering myeloma, and the occurrence of AL amyloidosis in patients with symptomatic multiple myeloma or other B-cell lymphoproliferative disorders is unusual. The key event in the development of AL amyloidosis is the change in the secondary or tertiary structure of an abnormal monoclonal LC, which results in instable conformation. This conformational change is responsible for abnormal folding of the LC, rich in β leaves, which assemble into monomers that stack together to form amyloid fibrils. EPIDEMIOLOGY: AL amyloidosis is the most common type of systemic amyloidois in developed countries with an estimated incidence of 9 cases/million inhabitant/year. The average age of diagnosed patients is 65 years and less than 10% of patients are under 50. CLINICAL DESCRIPTION: The clinical presentation is protean, because of the wide number of tissues or organs that may be affected. The most common presenting symptoms are asthenia and dyspnoea, which are poorly specific and may account for delayed diagnosis. Renal manifestations are the most frequent, affecting two thirds of patients at presentation. They are characterized by heavy proteinuria, with nephrotic syndrome and impaired renal function in half of the patients. Heart involvement, which is present at diagnosis in more than 50% of patients, leading to restrictive cardiopathy, is the most serious complication and engages prognosis. DIAGNOSTIC METHODS: The diagnosis relies on pathological examination of an involved site showing Congo red-positive amyloid deposits, with typical apple-green birefringence under polarized light, that stain positive with an anti-LC antibody by immunohistochemistry and/or immunofluorescence. Due to the systemic nature of the disease, non-invasive biopsies such as abdominal fat aspiration should be considered before taking biopsies from involved organs, in order to reduce the risk of bleeding complications. DIFFERENTIAL DIAGNOSIS: Systemic AL amyloidosis should be distinguished from other diseases related to deposition of monoclonal LC, and from other forms of systemic amyloidosis. When pathological studies have failed to identify the nature of amyloid deposits, genetic studies should be performed to diagnose hereditary amyloidosis. MANAGEMENT: Treatment of AL amyloidosis is based on chemotherapy, aimed at controlling the underlying plasma clone that produces amyloidogenic LC. The hematological response should be carefully checked by serial measurements of serum free LC. The association of an alkylating agent with high-dose dexamethasone has proven to be effective in two thirds of patients and is considered as the current reference treatment. New agents used in the treatment of multiple myeloma are under investigation and appear to increase hematological response rates. Symptomatic measures and supportive care is necessary in patients with organ failure. Noticeably, usual treatments for cardiac failure (i.e. calcium inhibitors, β-blockers, angiotensin converting enzyme inhibitors) are inefficient or even dangerous in patients with amyloid heart disease, that should be managed using diuretics. Amiodarone and pace maker implantation should be considered in patients with rhythm or conduction abnormalities. In selected cases, heart and kidney transplantation may be associated with prolonged patient and graft survival. PROGNOSIS: Survival in AL amyloidosis depends on the spectrum of organ involvement (amyloid heart disease being the main prognosis factor), the severity of individual organs involved and haematological response to treatment.