Efficacy of plasma exchange in patients with anti-MDA5 rapidly progressive interstitial lung disease.

BACKGROUND: Rapidly progressive interstitial lung disease (RP-ILD) is a frequent and severe manifestation of anti-MDA5 dermatomyositis (MDA5-DM) associated with poor outcome. The optimal treatment regimen for MDA5-DM RP-ILD is yet to be determined. Specifically, the value of adding plasma exchange (PLEX) to corticosteroids and immunosuppressants remains unclear. We aimed to evaluate the effect of PLEX on the outcome of patients with MDA5-DM RP-ILD. METHODS: This French nationwide multicentre retrospective study included all MDA5-DM RP-ILD patients from 2012 to 2021 admitted to 18 centres. The primary endpoint was one-year transplant-free survival. RESULTS: 51 patients with MDA5-DM RP-ILD (female 67%; mean age at disease onset: 51 ± 11.6 years) were included. Thirty-two (63%) patients required mechanical ventilation and twenty-five (49%) received PLEX. One-year mortality or lung transplant occurred in 63% cases after a median follow-up of 77 [38-264] days. The Cox proportional hazards multivariable model only retained mechanical ventilation but not PLEX (p = 0.7) as independent predictor of the primary endpoint. One-year transplant-free survival rates in PLEX + vs. PLEX-were 20% vs. 54% (p = 0.01), respectively. The Kaplan-Meier estimated probabilities of one-year transplant-free survival was statistically higher in PLEX-compared to PLEX + patients (p = 0.05). PLEX + compared to PLEX-patients more frequently received mechanical ventilation and immunosuppressants suggesting PLEX + patients had a more severe disease. CONCLUSION: MDA5-DM RP-ILD is associated with poor rate of one-year transplant-free survival. The use of PLEX was not associated with a better outcome albeit they were mainly given to more severe patients. While our study reports the largest series of MDA5-DM RP-ILD given PLEX, these results needs to be interpreted with caution owing the numerous selection, indication and interpretation bias. Further studies are needed to evaluate their efficacy in this setting.

Whole exome sequencing, a hypothesis-free approach to investigate recurrent early miscarriage.

RESEARCH QUESTION: Are there genetic determinants shared by unrelated women with unexplained recurrent early miscarriage (REM)? DESIGN: Thirty REM cases and 30 controls were selected with extreme phenotype among women from Eastern Brittany (France), previously enrolled in an incident case-control study on thrombophilic mutations. Cases and controls were selected based on the number of early miscarriages or live births, respectively. Peripheral blood was collected for DNA extraction at initial visit. The burden of low-frequency variants in the coding part of the genes was compared using whole exome sequencing (WES). RESULTS: Cases had 3 to 17 early miscarriages (20 cases: ≥5 previous losses). Controls had 1 to 4 live births (20 controls: ≥3 previous live births) and no miscarriages. WES data were available for 29 cases and 30 controls. A total of 209,387 variants were found (mean variant per patient: 59,073.05) with no difference between groups (P = 0.68). The top five most significantly associated genes were ABCA4, NFAM1, TCN2, AL078585.1 and EPS15. Previous studies suggest the involvement of vitamin B12 deficiency in REM. TCN2 encodes for vitamin B12 transporter into cells. Therefore, holotranscobalamin (active vitamin B12) was measured for both cases and controls (81.2 ± 32.1 versus 92.9 ± 34.3 pmol/l, respectively, P = 0.186). Five cases but no controls were below 50 pmol/l (P = 0.052). CONCLUSIONS: This study highlights four new genes of interest in REM, some of which belong to known networks of genes involved in embryonic development (clathrin-mediated endocytosis and ciliary pathway). The study also confirms the involvement of TCN2 (vitamin B12 pathway) in the early first trimester of pregnancy.

Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases.

OBJECTIVES: The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease. METHODS: To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data. RESULTS: Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis. CONCLUSION: Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.

Blood anti-Müllerian hormone is a possible determinant of recurrent early miscarriage, yet not conclusive in predicting a further miscarriage.

RESEARCH QUESTION: Is blood anti-Müllerian hormone (AMH) concentration a strong determinant of unexplained recurrent early miscarriage (REM)? DESIGN: In the first part of the study, AMH concentrations measured using an Immunotech ELISA Kit were compared between 188 unselected (mostly fertile) women consecutively referred for three or more miscarriages in the first trimester of pregnancy and 376 age-matched parous women without pregnancy loss. Cases and controls were previously enrolled in an incident case-control study on thrombophilic mutations. Blood samples were collected >2 months after any recognized obstetric event or hormonal treatment. In the second part of the study, a prospective 2-year follow-up of cases was performed. RESULTS: When considering all women irrespective of age, AMH concentration did not significantly differ between cases and controls. However, in the subgroup ≥25 years old (176 cases versus 358 controls of ∼33.5 years), the cases had significantly lower AMH concentrations than the controls (median [interquartile range]: 2.8 [1.4-4.7] versus 3.25 [1.7-5.5], P = 0.046) and the proportion of cases with an AMH concentration <1 ng/ml was significantly higher (17.6% versus 10.6%; odds ratio 1.80; 95% confidence interval 1.07-3.00, P = 0.028). With regard to the subsequent pregnancy, AMH concentration was not correlated with either the conception delay or the miscarriage occurrence. However, increased age and number of previous miscarriages were significantly predictive of a subsequent miscarriage (P = 0.046 and 0.03, respectively). CONCLUSION: An altered ovarian reserve is a possible determinant of unexplained REM. However, AMH blood concentration predicts neither the delay nor the outcome of a subsequent pregnancy.

Hydroxychloroquine for prevention of recurrent miscarriage: study protocol for a multicentre randomised placebo-controlled trial BBQ study.

INTRODUCTION: Recurrent miscarriage (RM), defined by three or more consecutive losses during the first trimester of pregnancy, affects 1%-2% of fertile couples. Standard investigations fail to reveal any apparent cause in ~50% of couples. However, on the basis of animal models and clinical studies, several hypotheses have been put forward concerning underlying mechanisms of RM: altered ovarian reserve, progesterone defect, thrombotic and/or endothelial dysfunction and immunological disturbances. Nonetheless, no study has yet reached conclusive beneficial clinical evidence for a potential treatment in unexplained RM. Hydroxychloroquine (HCQ) is a molecule with extensive safety data during pregnancy. The pharmacological properties of HCQ (eg, antithrombotic, vascular protective, immunomodulatory, improved glucose tolerance, lipidlowering and anti-infectious) could be effective against some mechanisms of unexplained RM. Furthermore, eventhough clinical benefit of HCQ is suggested in prevention of thrombotic and late obstetric events in antiphospholipid (APL) syndrome, there are no data suggesting the benefit of HCQ in RM in the presence of APL antibodies. METHODS AND ANALYSIS: Taken all together and given the low cost of HCQ, the aim of this multicentre, randomised, placebo-controlled, double-blind study is to investigate whether HCQ would improve the live birth rate in women with RM, irrespective of maternal thrombophilic status: (1) no known thrombophilia, (2) inherited thrombophilia or (3) APL antibodies. The primary end point is a live and viable birth. After confirming eligibility and obtaining consent, 300 non-pregnant women will be randomised into two parallel groups for a daily oral treatment (HCQ 400 mg or placebo), initiated before conception and stopped at 10 weeks' gestation. If pregnancy does not occur after 1 year, the treatment will be stopped. ETHICS AND DISSEMINATION: Agreement from the French National Public Health and Drug Security Agency (160765A-22) and ethical approval from the Committee for the Protection of Persons of NORD-OUEST I (2016-001330-97) have been obtained. TRIAL REGISTRATION NUMBERS: NCT0316513; Pre-results.

Extra-haematological manifestations related to human parvovirus B19 infection: retrospective study in 25 adults.

BACKGROUND: To describe extra-haematological manifestations associated with human parvovirus B19 (HPV-B19) infection. METHODS: We conducted a nationwide multicentre study to retrospectively describe the characteristics and outcome of extra-haematological manifestations in French adults. RESULTS: Data from 25 patients followed from 2001 to 2016 were analysed. Median age was 37.9 years (range: 22.7-83.4), with a female predominance (sex ratio: 4/1). Only 3 patients had an underlying predisposing condition (hemoglobinopathy or pregnancy). The most common manifestations were joint (80%) and skin (60%) involvement. Four patients (16%) had renal involvement (endocapillary proliferative or membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis). Three patients (12%) had peripheral nervous system involvement (mononeuritis, mononeuritis multiplex, Guillain-Barré syndrome) and 2 (8%) presented muscle involvement. Other manifestations included hemophagocytic lymphohistiocytosis (n = 1), myopericarditis and pleural effusion (n = 1), and lymphadenopathy and splenomegaly mimicking lymphoma with spleen infarcts (n = 1). Immunological abnormalities were frequent (56.5%). At 6 months, all patients were alive, and 54.2% were in complete remission. In 2 patients, joint involvement evolved into rheumatoid arthritis. Six patients (24%) received intravenous immunoglobulin (IVIg), with a good response in the 3 patients with peripheral nervous system involvement. CONCLUSIONS: HPV-B19 infection should be considered in a wide range of clinical manifestations. Although the prognosis is good, IVIg therapy should be discussed in patients with peripheral nerve involvement. However, its efficacy should be further investigated in prospective studies.

Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia Vasculitis.

Circulating mixed cryoglobulins are detected in 40%-60% of patients with hepatitis C virus (HCV) infection, and overt cryoglobulinemia vasculitis (CryoVas) develops in approximately 15% of patients. Remission of vasculitis has been associated with viral clearance, but few studies have reported the effectiveness of direct-acting antiviral drugs in these patients. We performed an open-label, prospective, multicenter study of the effectiveness and tolerance of an all-oral, interferon- and ribavirin-free regimen of sofosbuvir plus daclatasvir in patients with HCV-associated CryoVas. Forty-one consecutive patients with active HCV-associated CryoVas (median age, 56 y; 53.6% women) were recruited from hospitals in Paris, France, from 2014 through 2016. They received sofosbuvir (400 mg/day) plus daclatasvir (60 mg/day) for 12 weeks (n = 32) or 24 weeks (n = 9), and were evaluated every 4 weeks until week 24 and at week 36. Blood samples were analyzed for complete blood count, serum chemistry profile, level of alanine aminotransferase, rheumatoid factor activity, C4 fraction of complement, and cryoglobulin; peripheral blood mononuclear cells were isolated for flow cytometry analysis. Thirty-seven patients (90.2%) had a complete clinical response (defined by improvement of all the affected organs involved at baseline and no clinical relapse) after a median time of 12 weeks of therapy; all had a sustained virologic response (no detectable serum HCV RNA 12 weeks after the end of antiviral therapy). Patients' mean cryoglobulin level decreased from 0.56 ± 0.18 at baseline to 0.21 ± 0.14 g/L at week 36, and no cryoglobulin was detected in 50% of patients at this time point. After antiviral therapy, patients had increased numbers of T-regulatory cells, IgM+CD21-/low-memory B cells, CD4+CXCR5+ interleukin 21+ cells, and T-helper 17 cells, compared with before therapy. After a median follow-up period of 26 months (interquartile range, 20-30 mo), no patients had a serious adverse event or relapse of vasculitis.

Non HCV-related infectious cryoglobulinemia vasculitis: Results from the French nationwide CryoVas survey and systematic review of the literature.

In patients with infectious cryoglobulinemia vasculitis (CryoVas) in the absence of hepatitis C virus infection, data on presentation, therapeutic management and outcome are lacking. We conducted a nationwide survey that included patients with HCV-negative CryoVas. We describe here the presentation, therapeutic management and outcome of 18 patients with non-HCV infectious CryoVas and 27 additional patients identified form a systematic review of the literature. We included 18 patients, mean age 57.9±13.5 years. Infectious causes were viral infections in 8 patients [hepatitis B virus (HBV) in 4, and cytomegalovirus, Epstein Barr virus, parvovirus B19 and human immunodeficiency virus in one case each], pyogenic bacterial infection in 6 patients, parasitic infection in 2 patients, and leprosy and candidiasis in one case each. Baseline manifestations were purpura (78%), glomerulonephritis (28%), arthralgia (28%), peripheral neuropathy (22%), skin necrosis (22%), cutaneous ulcers (17%), and myalgia (11%). Cryoglobulinemia was type II in 2/3 of cases. Most cases received specific anti-infectious therapy as first-line therapy, sometimes associated with corticosteroids, achieving sustained remission in the majority of cases. Refractory or relapsing patients, frequently related to HBV infection, showed a complete remission after rituximab in addition to antiviral therapy. In contrast, corticosteroids and/or immunosuppressive agents used in the absence of anti-infectious agents were frequently associated with refractory CryoVas. Viral and pyogenic bacterial infections represent the main causes of non-HCV infectious CryoVas. Antimicrobial therapy is commonly associated with sustained remission. Immunosuppressive agents should be considered only as a second-line option in patients with refractory vasculitis.

Efficient Detection of Carbapenemase Activity in Enterobacteriaceae by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry in Less Than 30 Minutes.

The recognition of carbapenemase-producing Enterobacteriaceae (CPE) isolates is a major laboratory challenge, and their inappropriate or delayed detection may have negative impacts on patient management and on the implementation of infection control measures. We describe here a matrix-assisted laser desorption ionization-time of flight (MALDI-TOF)-based method to detect carbapenemase activity in Enterobacteriaceae. After a 20-min incubation of the isolate with 0.5 mg/ml imipenem at 37°C, supernatants were analyzed by MALDI-TOF in order to identify peaks corresponding to imipenem (300 Da) and an imipenem metabolite (254 Da). A total of 223 strains, 77 CPE (OXA-48 variants, KPC, NDM, VIM, IMI, IMP, and NMC-A) and 146 non-CPE (cephalosporinases, extended-spectrum ß-lactamases [ESBLs], and porin defects), were tested and used to calculate a ratio of imipenem hydrolysis: mass spectrometry [MS] ratio = metabolite/(imipenem + metabolite). An MS ratio cutoff was statistically determined to classify strains as carbapenemase producers (MS ratio of ≥0.82). We validated this method first by testing 30 of our 223 isolates (15 CPE and 15 non-CPE) 10 times to calculate an intraclass correlation coefficient (ICC of 0.98), showing the excellent repeatability of the method. Second, 43 strains (25 CPE and 18 non-CPE) different from the 223 strains used to calculate the ratio cutoff were used as external controls and blind tested. They yielded sensitivity and specificity of 100%. The total cost per test is <0.10 U.S. dollars (USD). This easy-to-perform assay is time-saving, cost-efficient, and highly reliable and might be used in any routine laboratory, given the availability of mass spectrometry, to detect CPE.

Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial.

It is common practice in many centers to offer antithrombotic medications to women with unexplained recurrent miscarriage, in the presence or absence of inherited thrombophilia. Although no benefit of aspirin vs placebo has been clearly demonstrated, a double-blind placebo-controlled trial on the effect of low-molecular-weight heparin is lacking. We enrolled 258 pregnant women with a history of unexplained recurrent miscarriage (≥2 consecutive miscarriages before 15 weeks' gestation) and a negative thrombophilia workup. They were randomly assigned to receive one daily subcutaneous injection of enoxaparin 40 mg or placebo until 35 weeks' gestation. We included 256 women (mean age 32 years, ≥3 miscarriages: 72%; mean gestational age 39 days of amenorrhea) in the intention-to-treat analysis; 66.6% of 138 who received enoxaparin had a live birth vs 72.9% of 118 who received placebo. The absolute difference was -6% (95% CI, -17.1 to 5.1), excluding a 10% increase in the rate of live-birth on enoxaparin (P = .34). In this first randomized, double-blind, placebo-controlled trial, enoxaparin (40 mg once daily) did not improve the chance of a live birth in nonthrombophilic women with unexplained recurrent miscarriage. This trial is registered at www.ClinicalTrials.gov as #NCT00740545 and the French National Health and Drug Safety Agency (EudraCT #2006-003350-18).

Finegoldia magna, not a well-known infectious agent of bacteriemic post-sternotomy mediastinitis.

Post-sternotomy mediastinitis, a nosocomial infection mostly caused by staphylococci, can be life-threatening. A case of mediastinitis due to Finegoldia magna after a coronary artery bypass graft surgery was reviewed. Although this bacterium is difficult to be isolated from routine blood cultures, a F. magna bacteriemia associated with mediastinitis was diagnosed.

Predictors of early relapse in patients with non-infectious mixed cryoglobulinemia vasculitis: results from the French nationwide CryoVas survey.

OBJECTIVE: Although in most patients induction therapy leads to complete or partial remission, relapses in patients with non-infectious mixed cryoglobulinemia vasculitis (CryoVas) remain a major problem. We aimed to identify predictors of early relapses occurring within the first 12months of treatment in such patients. METHODS: Patients included in the French CryoVas survey exhibiting complete/partial clinical remission and followed-up for at least 12months after induction therapy (n=145) were analyzed for predictors of early relapses. RESULTS: Forty out of 145 patients (28%) experienced early relapse. Relapses occurred after a median time of 9.5months after induction therapy (3-12) and involved skin (75%), joints and peripheral nerve (28% each), kidneys (25%) and gastrointestinal tract (5%). Baseline factors associated with an early relapse were purpura [HR 3.35 (1.02-10.97), P=0.046], cutaneous necrosis [HR 4.46 (1.58-12.57), P=0.005] and articular involvement [HR 2.20 (1.00-4.78), P=0.048]. The only factor negatively associated with an early relapse during follow-up was the achievement of complete immunological response [HR 0.07 (0.01-0.51), P=0.009]. The use of corticosteroids plus rituximab or cyclophosphamide tended to be associated negatively with early relapse [HR 0.43 (0.17-1.08), P=0.07]. CONCLUSION: In patients with non-infectious CryoVas, main predictors of early relapses after initial remission are purpura, articular involvement, and cutaneous necrosis. The absence of complete immunological response during follow-up was associated with early relapse. These findings may help in adapting future treatment strategies.

Unexplained pregnancy loss: a marker of basal endothelial dysfunction?

OBJECTIVE: To compare the microparticle levels of women referred for unexplained pregnancy loss with those of parous controls. DESIGN: Incident case-control study. SETTING: University medical center. PATIENT(S): 124 women consecutively referred for unexplained pregnancy losses (two or more losses at or before 21 weeks of gestational age, or at least one later loss), and 273 parous women without pregnancy loss. INTERVENTION(S): Numeration of circulating microparticles by flow cytometry after differentiation of subpopulations according to the expression of membrane-specific antigens (CD51, CD144, or CD146 for endothelial, CD41 for platelet, CD45 and CD66b for leukocyte and neutrophil microparticles). MAIN OUTCOME MEASURE(S): Plasma levels of microparticles. RESULTS: A relative hypercoagulable state assessed by thrombin generation test had been previously reported in such cases, so we hypothesized that this could be explained by an excess of procoagulant microparticles. The study women displayed statistically significantly lower platelet and higher endothelial microparticle levels than the controls. The parameters of the thrombin generation test were only correlated with the level of endothelial microparticles, with a low coefficient of Speerman's correlation (r=0.15). CONCLUSION(S): The difference in microparticle levels between the patients and controls does not clearly explain the hypercoagulable state reported in the patients but could reflect chronic endothelium damage.

The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases.

Type I cryoglobulinemia vasculitis (CryoVas) is considered a life-threatening condition; however, data on the characteristics and outcome are scarce. To analyze the presentation, prognosis, and efficacy and safety of treatments of type I CryoVas, we conducted a French nationwide survey that included 64 patients with type I CryoVas between January 1995 and July 2010: 28 patients with monoclonal gammopathy of unknown significance (MGUS) and 36 with hematologic malignancy.Type I monoclonal CryoVas was characterized by severe cutaneous involvement (necrosis and ulcers) in almost half the patients and high serum cryoglobulin levels, contrasting with a lower frequency of glomerulonephritis than expected. The 1-, 3-, 5-, and 10-year survival rates were 97%, 94%, 94%, and 87%, respectively. Compared to MGUS, type I CryoVas related to hematologic malignancy tended to be associated with a poorer prognosis. Therapeutic regimens based on alkylating agents, rituximab, thalidomide or lenalinomide, and bortezomib showed similar efficacy on vasculitis manifestations, with clinical response rates from 80% to 86%.Data from the CryoVas survey show that the prognosis of type I CryoVas does not seem to be as poor as previously suggested. Besides alkylating agents, the use of regimens based on rituximab, thalidomide or lenalinomide, and bortezomib are interesting alternative options, although the exact role of each strategy remains to be defined.

Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey.

BACKGROUND: Data on the prognosis of non-infectious mixed cryoglobulinaemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. METHODS: The French multicentre and retrospective CryoVas survey included 242 patients with non-infectious mixed CryoVas. Causes of death and prognostic factors of survival were assessed and a prognostic score was determined to predict survival at 5 years. RESULTS: After a median follow-up of 35 months, 42 patients (17%) died. Causes of death were mainly serious infections (50%) and vasculitis flare (19%). One-, 2-, 5- and 10-year overall survival rates were 91%, 89%, 79% and 65%, respectively. A prognostic score, the CryoVas score (CVS), for the prediction of survival at 5 years was devised. Pulmonary and gastrointestinal involvement, glomerular filtration rate <60 ml/min and age >65 years were independently associated with death. At 5 years the death rates were 2.6%, 13.1%, 29.6% and 38.5% for a CVS of 0, 1, 2 and ≥3, respectively. At 1 year the death rates were 0%, 3.2%, 18.5% and 30.8% for a CVS of 0, 1, 2 and ≥3, respectively. The CVS was strongly correlated with the Five Factor Score (FFS) 2009, another prognostic score validated in primary necrotising vasculitis (r=0.82; p<0.0001). The area under the curve for the CVS was 0.74 compared with 0.67 for the FFS, indicating a better performance of the CVS (p=0.052). CONCLUSIONS: In patients with non-infectious mixed CryoVas, the main prognostic factors are age >65 years, pulmonary and gastrointestinal involvement and renal failure. A score including these variables is significantly associated with the prognosis.

Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey.

Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.

Diagnostic accuracy of single-photon emission tomography ventilation/perfusion lung scan in the diagnosis of pulmonary embolism.

BACKGROUND: Planar ventilation/perfusion (V/Q) lung scintigraphy is a validated tool for the diagnosis of pulmonary embolism (PE). Nevertheless, given the high rate of nonconclusive V/Q, further investigation is often necessary. V/Q single-photon emission CT (SPECT) scan could improve V/Q performance, but sparse data are available on its accuracy. This study assessed the diagnostic performance of V/Q SPECT scan in a cohort of consecutive patients with suspected PE. METHODS: Three hundred twenty-one consecutive patients with a clinical suspicion of PE were prospectively included. Patients suspected of having PE were managed according to a reference diagnostic strategy validated by a 3-month follow-up. In addition to the reference strategy, patients had a V/Q SPECT scan, the results of which were compared with the initial work-up results. RESULTS: Prevalence of PE was 0 of 41 (0%; 95% CI, 0%-9%), six of 134 (4%; 95% CI, 2%-9%),15 of 36 (42%; 95% CI, 27%-58%), and 28 of 32 (88%; 95% CI, 72%-95%) in the normal, low,intermediate, and high V/Q SPECT scan probability groups, respectively. The combination of V/Q SPECT scan with clinical probability was diagnostic in 88% of patients. CONCLUSIONS: V/Q SPECT scan results show satisfactory accuracy for PE diagnosis. Validation of dedicated interpretation criteria is required, followed by outcome studies that use V/Q SPECT scan as part of a diagnostic strategy to rule out PE. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01183026; URL: www.clinicaltrials.gov

Increased thrombin generation measured in the presence of thrombomodulin in women with early pregnancy loss.

Compared with 537 parous controls with no history of pregnancy loss, a lower thrombomodulin-related inhibition of the endogenous thrombin potential was measured in 264 cases with previous unexplained pregnancy loss, especially when losses occurred between 9 and 12 weeks of gestation. Adjusting age, protein S, factor VIII, factor V Leiden, and prothrombin G20210A did not change the results.

Impact of atazanavir-based HAART regimen on the carotid intima-media thickness of HIV-infected persons: a comparative prospective cohort.

OBJECTIVE: With the advent of highly active antiretroviral therapy regimens, it is crucial to consider their long-term benefits to risk ratios among HIV-infected persons. The impact of protease inhibitors on the cardiovascular risk is controversial. DESIGN: This observational cohort was designed to investigate the cardiovascular impact of boosted atazanavir (ATV/r), a protease inhibitor that does not provide major dyslipidemia or insulin resistance. SETTING: This study was carried out at the University Hospital of Brest (France). PATIENTS: Among the 229 HIV-infected persons of the cohort, 33 cases treated by ATV/r-containing regimen since less than 6 months were compared to 99 age-matched and sex-matched ATV/r naive controls. INTERVENTION: None. MAIN OUTCOME MEASURE: The main outcome measure was carotid intima-media thickness (cIMT) at the baseline, 6, 12, and 18 months. RESULTS: Although the cIMT was not different at inclusion (0.633 ± 0.05 vs. 0.666 ± 0.09, P = 0.07), the cIMT course significantly decreased (P = 0.018) in cases at 18 months. The differences remained significant even after adjustment on the variables that differed between cases and controls (P < 0.1) at inclusion (high-density lipoprotein cholesterol, cardiovascular family history) and the cumulated and current exposure to the nucleosidic reverse transcriptase inhibitor, nonnucleosidic reverse transcriptase inhibitor, and protease inhibitor class. CONCLUSION: Despite similar HIV and cardiovascular characteristics at baseline, cIMT decreased after 6 months of follow-up among the patients exposed to ATV/r, even after adjustment for the exposure to the three antiretroviral classes. Considering the shortcomings of this study, especially the absence of randomization and the heterogeneity of the control group, the benefit of ATV/r treatment in patients with high cardiovascular should be confirmed by randomized trials.