In-Host Adaptation of Salmonella enterica Serotype Dublin during Prosthetic Hip Joint Infection.

Genome degradation has been central to the adaptation of Salmonella enterica serotypes to their hosts throughout evolution. We witnessed the patho-adaptation of a strain of Salmonella Dublin (a cattle-adapted serotype) to a human host during the course of a recurrent prosthetic hip joint infection evolving over several years.

Trends in survival after cancer diagnosis among HIV-infected individuals between 1992 and 2009. Results from the FHDH-ANRS CO4 cohort.

Although the decline in cancer mortality rates with the advent of combination antiretroviral therapy (cART) in HIV-infected individuals can be mostly explained by a decrease in cancers incidence, we looked here if improved survival after cancer diagnosis could also contribute to this decline. Survival trends were analyzed for most frequent cancers in the HIV-infected population followed in the French Hospital Database on HIV: 979 and 2,760 cases of visceral and non-visceral Kaposi's sarcoma (KS), 2,339 and 461 cases of non-Hodgkin lymphoma (NHL) and Hodgkin's lymphoma (HL), 446 lung, 312 liver and 257 anal cancers. Five-year Kaplan-Meier survival rates were estimated for four periods: 1992-1996, 1997-2000, 2001-2004 and 2005-2009. Cox proportional hazard models were used to compare survival across the periods, after adjustment for confounding factors. For 2001-2004, survival was compared to the general population after standardization on age and sex. Between the pre-cART (1992-1996) and early-cART (1997-2000) periods, survival improved after KS, NHL, HL and anal cancer and remained stable after lung and liver cancers. During the cART era, 5-year survival improved after visceral and non-visceral KS, NHL, HL and liver cancer, being 83, 92, 65, 87 and 19% in 2005-2009, respectively, and remained stable after lung and anal cancers, being 16 and 65%, respectively. Compared with the general population, survival in HIV-infected individuals in 2001-2004 was poorer for hematological malignancies and similar for solid tumors. For hematological malignancies, survival continues to improve after 2004, suggesting that the gap between the HIV-infected and general populations will close in the future.

Risk of AIDS-defining cancers among HIV-1-infected patients in France between 1992 and 2009: results from the FHDH-ANRS CO4 cohort.

BACKGROUND: We examined trends in the incidence of the 3 AIDS-defining cancers (ADCs; Kaposi sarcoma [KS], non-Hodgkin lymphoma [NHL], and cervical cancer) among human immunodeficiency virus (HIV)-infected patients relative to the general population between 1992 and 2009 in France, focusing on age at ADC diagnosis and on patients with controlled viral load and restored immunity on combination antiretroviral therapy (cART). METHODS: Age- and sex-standardized incidence rates were estimated in patients enrolled in the French hospital database on HIV, and in the general population in France during 4 calendar periods (1992-1996, 1997-2000, 2001-2004, and 2005-2009). Standardized incidence ratios (SIRs) were calculated for all periods and separately for patients on cART, with CD4 counts ≥500 cells/µL for at least 2 years and viral load ≤500 copies/mL. RESULTS: Although the incidence of ADCs fell significantly across the calendar periods, the risk remained constantly higher in HIV-infected patients than in the general population. In patients with restored immunity, the relative risk remained significantly elevated for KS (SIR = 35.4; 95% confidence interval [CI], 18.3-61.9), and was similar to that of the general population for NHL (SIR = 1.0; 95% CI, .4-1.8). ADCs were diagnosed at a younger age in HIV-infected patients, with a particularly marked difference for NHL (-11.3 years, P < .0001). CONCLUSIONS: The incidence of all ADCs continued to fall, including cervical cancer, in the cART period, but the risk remained higher than in the general population in 2005-2009. In patients with stably restored immunity, KS remained significantly more frequent than in the general population.

Neuropsychology supervision: A survey of practices in Quebec and a cross-cultural comparison.

OBJECTIVE: Supervisors in neuropsychology have an ethical responsibility to continuously improve their ability to supervise. Despite a growing interest in the field, there exist little data on the actual practice and few guidelines to help the practitioner through the process of neuropsychology supervision. This study aims to characterize neuropsychology supervisors and their practices in Quebec, Canada and compare these with supervisory practices of supervisors in the United States, with the ultimate aim of offering recommendations to supervisors. METHOD: Seventy-nine neuropsychology supervisors responded to the 20-question online survey of supervisory experience, education, practices, and familiarity with and use of supervision models that was inspired by Shultz and colleagues. RESULTS: Experience in clinical supervision ranged from 0.12 to 35 years and from having supervised 1-150 supervisees. About half of respondents reported having received continuing education in supervision and about two thirds were familiar with at least one type of supervision model. Some supervisory practices were associated with experience, but not with familiarity and utilization of supervision models. Supervisors from Quebec and the U.S. reported a similar frequency of addressing most of the various supervisory competencies with their supervisees. CONCLUSIONS: Based on the competency-based approach we offer a portrait of neuropsychology supervision in Quebec while highlighting some cultural differences with the U.S. Recommendations include focusing more on certain foundational (e.g. reflective practice) and functional competencies (supervision most notably). Neuropsychology supervisors are also encouraged to devote more time to continuing education opportunities in supervision in order to ensure supervisee development and quality care.

Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-controlled trial of efficacy and safety.

OBJECTIVE: The objective of the study was to assess the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) for the treatment of vasomotor symptoms. STUDY DESIGN: This was a 26 week, double-blind, placebo-controlled trial of 567 postmenopausal women (mean age, 53.7 years; time since natural menopause, 4.8 years) experiencing 50 or more hot flushes (HFs) per week, randomly assigned to desvenlafaxine (100 or 150 mg) or placebo. Change from baseline in average daily number of moderate to severe HFs and average daily HF severity were compared with placebo at weeks 4, 12, and 26. RESULTS: A significantly greater decrease from baseline in number of HFs occurred at weeks 4 and 12 with 100 and 150 mg desvenlafaxine compared with placebo (week 12 reductions: 60%, 66%, and 47%, respectively; all P < or = .002). Only the 150 mg dose showed significant improvement from baseline at 26 weeks compared with placebo (week 26 reductions: 61%, 69%, and 51%, respectively), although the study was not powered to demonstrate efficacy beyond the initial 12 weeks of therapy. The average daily severity decreased significantly more at weeks 4 and 12 with desvenlafaxine compared with placebo (all P < or = .002). Significantly more desvenlafaxine-treated subjects than placebo-treated subjects discontinued because of adverse events during week 1 only. CONCLUSION: Desvenlafaxine is an effective treatment for menopausal HFs.

Computer-aided lateral ventricular and brain volume measurements in 3D ultrasound for assessing growth trajectories in newborns and neonates.

For newborns and neonates, ultrasound (US) is the most common imaging modality used for examinations due to its accessibility and ease of use. However, precise volume measurements remain limited in 2D, while MRI in newborns is typically avoided because of immobilization issues which may require sedation. The objective of this study is to assess and validate the lateral ventricular and total brain volumes obtained with an automatic segmentation method using cerebral trans-fontanelle 3D US. Infants aged between 2 and 8.5 months old were recruited, with both MRI and 3D US acquired on the same day was used to validate ventricular and brain volume measurements in comparison to MRI. Lateral ventricles were segmented on both the US (manually and with a proposed automatic fusion-based approach) and MRI, while brain volumes were estimated with an automatic segmentation method. Volumetric 3D US measurements were then evaluated with respect to age distribution. For the comparison between MRI and 3D US, strong inter-class correlations (ICC) were found for the ventricle volumes (manual: 5.9% ± 2.5% difference (ICC = 0.99); automatic: 6.0% ± 2.6% difference (ICC = 0.98)), as well as the total brain size, with a 3.0% ± 1.3% difference (ICC = 0.98). There was no statistically significant difference based on t-test and f-test for the lateral ventricles volume (t-test: p = 0.542) and (f-test: p = 0.738) and for the total brain volume (t-test: p = 0.412) and (f-test: p = 0.685) between MRI and 3D US. This study demonstrates that 3D US can be used to automatically assess lateral ventricular and total brain volumes with no significant difference to the MRI acquisitions. The highest correlations were obtained for infants under 8 months when the fontanelle is open.

The Predictive Value of Head Circumference Growth during the First Year of Life on Early Child Traits.

Atypical head circumference (HC) growth has been associated with neurodevelopmental disorders. However, whether it is associated with specific aspects of development in early childhood in the general population is unknown. The objective of this study was to assess the predictive value of HC growth as an early biomarker of behavioral traits. We examined longitudinal associations between HC growth from 0 to 12 months and temperament, cognitive, and motor development at 24 months. A subsample of healthy children (N = 756) was drawn from the 3D (Design, Develop, Discover) cohort study. Early HC growth was modeled with latent growth curve analysis. Greater postnatal HC growth predicted lower temperamental effortful control and lower surgency/extraversion in boys. HC growth did not predict cognitive or fine motor scores, but did predict greater gross motor skills in boys. No significant effect of HC growth was found in girls. This study is the first to demonstrate an association between postnatal HC growth and specific aspects of child development in a healthy population. Results suggest HC growth overshadows brain mechanisms involved in behavioral traits in early infancy. Whether links are maintained throughout development and the mechanisms involved correspond to traits found in atypical populations remains to be studied.

Frequency, determinants and consequences of delayed access to care for HIV infection in France.

BACKGROUND AND OBJECTIVES: We analysed the frequency and predictors of delayed access to care (DAC) for HIV infection, and its influence on survival. METHODS: We studied predictors of DAC among 18,721 patients enrolled between 1997 and 2002 in the French Hospital Database on HIV (FHDH), DAC being defined by a CD4* T-cell count below 200 copies/mm3 and/or AIDS at FHDH enrollment. The association of DAC with the initiation of combined antiretroviral therapy (cART) and of DAC with survival were analysed with Cox multivariable models. RESULTS: The overall prevalence of DAC was 35.7%. Compared with patients under 30 years of age, patients over 60 were 3.5 times more likely to have DAC (P < 10(-4)). Compared with non-migrant women, odds ratios (OR) of DAC were higher among migrant women (1.5), non-migrant men (1.6) and migrant men (1.9; all P < 10(-4)). Compared with men who have sex with men, other transmission groups had an estimated OR for DAC of 1.6 (P < 10(-4)). DAC was more frequent among patients with a recent diagnosis of HIV infection [OR = 1.3, 95% confidence intervals (CI) = (1.2;1.4)]. Patients with DAC received cART earlier than other patients [hazard ratio (HR) = 2.2, 95% CI = (2.1;2.3)]. The DAC/mortality HR was 13.9 in the first 6 months after enrollment in the FHDH, and remained significantly higher than 1 during the subsequent 4 years. CONCLUSION: DAC is common in France and was associated with a higher mortality, despite early initiation of cART. Earlier access to care and specific clinical management of patients with DAC should be considered.

Risk factors for osteonecrosis in HIV-infected patients: impact of treatment with combination antiretroviral therapy.

BACKGROUND: Osteonecrosis was increasingly associated with HIV infection in the 1990s. It is unclear whether its risk increases with the duration of HIV infection, the duration of combination antiretroviral therapy (cART) or both. OBJECTIVE: To analyse factors associated with the rate of symptomatic osteonecrosis, particularly the relative impacts of the duration of HIV infection and the duration of cART, using the French Hospital Database on HIV, which comprises a large number of subjects with substantial follow-up. METHODS: Poisson regression model was used to identify factors associated with the rate of osteonecrosis among patients enrolled in 1996-2002. RESULTS: The study involved 56,393 subjects with a total follow-up of 229,031 person-years. Symptomatic osteonecrosis was diagnosed in 104 subjects with an incidence rate of 4.5/10,000 person-years. Multivariate analysis identified three factors associated with the rate of osteonecrosis: prior AIDS-defining illnesses [adjusted relative rate (RR), 3.1; 95% confidence interval (CI), 2.0-4.9], the CD4 cell nadir [RR, 1.6 (95% CI, 0.9-2.9) for CD4 cell count 50-199 cells/microl; RR, 1.8 (95% CI, 1.0-3.3) for CD4 cell count < 50 cells/microl; both relative to CD4 cell count > or = 200 cells/microl] and exposure to cART. Compared with unexposed patients, the RR of osteonecrosis ranged from 2.6 (95% CI, 1.2-5.9) in patients treated with cART for < 12 months to 5.1 (95% CI, 2.1-12.6) in patients treated for > or = 60 months. CONCLUSIONS: Osteonecrosis appears to be a complication of both HIV infection and cART.

Sexually transmitted acute infection with a clustered genotype 4 hepatitis C virus in HIV-1-infected men and inefficacy of early antiviral therapy.

BACKGROUND: Recent studies have suggested an increased risk of acute hepatitis C (HCV) infection in homosexual HIV-infected men and that early treatment with standard or pegylated interferon-alfa, alone or associated with ribavirin, significantly reduces the risk of chronic evolution in HIV-infected patients. METHODS: A retrospective analysis of 12 HIV-infected patients who were consecutively diagnosed as developing acute HCV infection, defined by both seroconversion of anti-HCV antibodies and detection of serum HCV RNA in those with previous negative results. Ten of these patients received early antiviral treatment with standard or pegylated interferon-alfa, alone or associated with ribavirin. RESULTS: The only risk factor in these patients was unprotected sexual intercourse with men. Acute HCV infection was asymptomatic in 10 patients, and the HCV genotype was 4d in 10 patients. The 10 genotype 4d viruses formed a monophylogenetic group and clustered separately from other local sequences of HCV genotype 4d, suggesting a common source of infection. None of the 10 patients who were treated early with antiviral therapy had a sustained virological response, as defined by undetectable HCV RNA 6 months after therapy. CONCLUSIONS: There is a risk of sexual transmission of HCV in HIV-infected men who have sex with men; the cluster of HCV genotype 4d suggested a common source of infection and a failure in prevention counselling. Early treatment with standard interferon-alfa failed to prevent chronic evolution of HCV infection in this particular group of HIV-infected patients who had acquired this peculiar cluster of genotype 4 strains.

Impact of newly available drugs on clinical progression in patients with virological failure after exposure to three classes of antiretrovirals.

OBJECTIVE: To study the prognosis of HIV-infected patients with virological failure after exposure to three classes of antiretroviral drugs (ARVs). DESIGN: Cohort study. SETTING: French Hospital Database on HIV. PATIENTS: Patients previously exposed to at least two nucleoside reverse transcriptase inhibitors (NRTIs), two protease inhibitors and one non-NRTI, with viral load (/L) values of > 5000 copies/ml after the exposure criteria were met and a new treatment initiated between 1998 and 2001 with VL > 5000 copies/ml. MAIN OUTCOME MEASURES: Risk of new AIDS-defining-events (ADEs) or death from first introduction of a drug never used before occurring between 1998 and 2001 defined as baseline. RESULTS: The main baseline characteristics of the 1092 patients were: previous ADE in 49% of cases, median CD4 cell count 181 microl, median VL 4.9 log10 copies/ml, median duration of ARV therapy 5.0 years and previous exposure to a median of nine ARVs. The crude progression rates were 20.1/100 patient-years among patients included in 1998, 15.1 in 1999, 11.1 in 2000 and 8.6 in 2001. After adjustment for baseline characteristics, the calendar year of inclusion was associated with the risk of clinical progression (P < 0.001). When the types of newly available drugs used at baseline or during follow-up were introduced into the model, year of inclusion was no longer associated with the risk of clinical progression (P = 0.42), while exposure to amprenavir/r, lopinavir/r, abacavir or tenofovir was associated with a lower risk. CONCLUSIONS: The clinical prognosis of heavily pretreated patients experiencing virological failure improved between 1998 and 2001, mainly thanks to the use of newly available drugs with more favourable resistance profiles.

Risk of non-AIDS-defining cancers among HIV-1-infected individuals in France between 1997 and 2009: results from a French cohort.

OBJECTIVES: Improved survival among HIV-infected individuals after the advent of combination antiretroviral therapy (cART) had drawn attention on non-AIDS-defining cancers. We evaluated the incidence and risk trends of lung cancer, Hodgkin's lymphoma, liver and anal cancers, focusing on patients with CD4 cell recovery and age at diagnosis, by comparison with the general population. DESIGN: Cohort study. METHODS: Standardized incidence rates were calculated in the HIV-infected individuals followed in the FHDH and the general population in France in 1997-2000, 2001-2004, and 2005-2009. We estimated standardized incidence ratios for each period and for patients with CD4 cell count at least 500 cells/µl for at least 2 years on cART. RESULTS: Among the 84,504 HIV-infected individuals, the risk of lung and anal cancers fell during the cART era, whereas that of Hodgkin's lymphoma and liver cancer remained stable. In 2005-2009, the standardized incidence ratios for lung cancer, Hodgkin's lymphoma, liver and anal cancers were, respectively, 2.8 [95% confidence interval (CI) 2.5-3.1], 26.5 (95% CI 23.2-30.1), 10.9 (95% CI 9.6-12.3) and 79.3 (95% CI 69.5-90.1). Among patients with CD4 cell recovery on cART, the risk was close to that of the general population for lung cancer, nine-fold higher for Hodgkin's lymphoma, and 2.4-fold higher for liver cancer. Age at diagnosis was significantly younger among HIV-infected individuals for lung cancer (-3.3 years), Hodgkin's lymphoma (-1 year) and liver cancer (-10.1 years). CONCLUSION: HIV-infected patients were at a higher risk for the four cancers over 1997-2009. CD4 cell recovery appears to control the excess risk of lung cancer. For liver cancer and Hodgkin's lymphoma, our results suggest that CD4 should never drop below 500/µl 500 cells/µl to avoid the excess risk.

[Aging and HIV infection: 4 years follow-up of 149 HIV infected patients older than 60 years in West Paris agglomeration (COREVIH Île-de-France Ouest)]. / Vieillissement et infection par le VIH: suivi de 149 patients âgés de plus de 60ans infectés par le VIH (COREVIH Île-de-France Ouest).

UNLABELLED: In France, patients over 50 years represent more than 23.6% of all registered cases in the French Hospital Database for HIV (FHDH), and 18% of newly HIV-diagnosed patients. OBJECTIVE: To describe the long-term evolution after 4 years of a cohort of HIV infected patients older than 60 years recruited in COREVIH Île-de-France Ouest. RESULTS: One hundred and forty-nine participants, 115 men (77%) and 34 women (23%), were included in the cohort analysis in 2004, and baseline characteristics were: median age 65.4 years (60.3-86.3), CDC stage C: 36%, HBV and HCV co-infections: four (2.7%) and eight (5.4%) patients, median time from first HIV infection diagnosis: 8.5 years (0.25-19.5), ongoing HAART regimen: 88%, median duration of ARV treatment: 7.5 years (0.2-15.5), baseline CD4 cells count: 372/mm(3) (18-1860), HIV viral load less than 200 c/ml: 104 (70%). After a 4-year follow-up, 111 patients were alive, all but one treated with HAART, 17/149 (11.5%) were lost for follow-up, and 21/149 were deceased (14%). Causes of death were acute cardiovascular disease (4/21), neoplasia (11/21), neurological disease 1/21, end stage liver disease 3/21, unknown 2/21. The prevalence of co-morbidities after 4 years of follow-up were: arterial hypertension 40/111 (36%), hypercholesterolemia 48/111 (43%), diabetes 23/111 (21%), kidney disease with renal insufficiency (creatinine clairance<60 ml/min): 36/111 (32%). At the end of follow-up, median CD4 cells count was 494/mm(3), and viral load was undetectable less than 200 c/ml in 107/111 patients (96%). No new opportunistic infection occurred during the 4-year follow-up, but 24 patients had a new diagnosis of neoplasia (incidence 40/1000 person-year). Cancer was the cause of death in 11/24. CONCLUSION: Clinical and immunological improvement was continuous under HAART in these aged HIV infected patients, but co-morbidities are frequently observed in this population, with high incidence of cardiovascular disease and neoplasia, and related mortality. A multidisciplinary approach, with preventive consultations, oncology and cardiovascular screening, as done in geriatrics, is warranted in the aging HIV population.

A subpopulation of malignant CD34+CD138+B7-H1+ plasma cells is present in multiple myeloma patients.

OBJECTIVE: It is generally assumed that plasma cells from multiple myeloma (MM) patients do not express the stem cell marker CD34. This assumption has led to several clinical trials based on autologous CD34(+) cell transplantation. However, the results of these trials have been disappointing. MATERIALS AND METHODS: We investigated the presence of CD34(+) cell populations in RPMI 8226, KARPAS 417, and U266 MM cell lines in vitro and during their growth as plasmacytoma tumors in nonobese diabetic severe combined immunodeficient mice, and in plasma cells isolated from the bone marrow of 38 MM patients. RESULTS: We showed that in both patients and cell lines, a small population of plasma cells expresses CD34. These cells display morphological characteristics of MM plasma cells, are CD19-negative, and express B7-H1 (PD-L1), a T-cell inhibitory molecule. In patients, CD34(+)CD138(+) cells expressed Ki67, a marker for proliferation. Moreover, when cells from the human myeloma cell line U266 were injected into nonobese diabetic severe combined immunodeficient mice, the U266-derived plasmacytoma tumors showed a large CD34(+)CD138(+) Ki67(+) cell population, indicating that these cells were not quiescent in vivo. CONCLUSIONS: MM patients carry a small subpopulation of cycling CD34(+)CD138(+)B7-H1(+) plasma cells. Their presence may limit the clinical benefits of autologous CD34(+) cell transplantation.

Indoleamine 2,3-dioxygenase activity of acute myeloid leukemia cells can be measured from patients' sera by HPLC and is inducible by IFN-gamma.

The enzyme indoleamine 2,3-dioxygenase (IDO) converts tryptophan to kynurenine, blocking T-cell activation and inducing immunosuppression. In patients with acute myeloid leukemia (AML), the serum kynurenine/tryptophan ratio (Kyn/Trp) was raised, suggesting a higher IDO activity than in healthy people. Patients with higher Kyn/Trp ratios showed lower survival. IDO activity was also detected in AML cells after exposure to IFN-gammain vitro, suggesting that the higher Kyn/Trp ratio in serum of AML patients might have resulted from stimulated leukemic blast cells. Thus, in AML, the activity of IDO can be easily monitored, providing a tool for future clinical testing of IDO-blocking drugs.

Underexpression of RhoH in Hairy Cell Leukemia.

The cause of hairy cell leukemia (HCL) is unknown. Current treatments seem effective only for a limited period of time. In addition, a significant proportion of patients remain refractive to all treatment options. These considerations indicate the need to develop alternative therapeutic strategies for HCL. Here, we report that HCL is characterized by underexpression of RhoH. In vitro reconstitution of RhoH expression inhibits the aberrant adhesion and transendothelial migration that drives disease pathogenesis. In an in vivo model of HCL, RhoH reconstitution limits malignant progression and protects against mortality. These findings provide the proof of principle that RhoH reconstitution represents a potential new approach to the treatment of HCL.