Multidisciplinary team meeting for complex bone and joint infections diagnosis: The PHICTOS study.

BACKGROUND: In France, the most severe bone and joint infections (BJI), called "complex" (CBJI), are assessed in a multidisciplinary team meeting (MTM) in a reference center. However, the definition of CBJI, drawn up by the Health Ministry, is not consensual between physicians. The objective was to estimate the agreement for CBJI classification. METHODS: Initially, five experts from one MTM classified twice, one-month apart, 24 cases as non-BJI, simple BJI or CBJI, using the complete medical record. Secondly, six MTMs classified the same cases using standardized information. Agreements were estimated using Fleiss and Cohen kappa (κ) coefficients. RESULTS: Inter-expert agreement during one MTM was moderate (κ=0.49), and fair (κ=0.23) when the four non-BJIs were excluded. Intra-expert agreement was moderate (κ=0.50, range 0.27-0.90), not improved with experience. The overall inter-MTM agreement was moderate (κ=0.58), it was better between MTMs with professor (κ=0.65) than without (κ=0.51) and with longer median time per case (κ=0.60) than shorter (κ=0.47). When the four non-BJIs were excluded, the overall agreement decreased (κ=0.40). CONCLUSION: The first step confirmed the heterogeneity of CBJI classification between experts. The seemingly better inter-MTM than inter-expert agreement could be an argument in favour of MTMs, which are moreover a privileged place to enhance expertise. Further studies are needed to assess these results as well as the quality of care and medico-economic outcomes after a MTM.

Diagnostic delay of pyogenic vertebral osteomyelitis and its associated factors.

OBJECTIVES: Pyogenic vertebral osteomyelitis (PVO) is a rare disease with possible severe complications (e.g. sepsis and spinal cord injury). In the 1990s, diagnostic delay (DD) was often extensive as PVO has a non-specific clinical spectrum, mostly afebrile with back pain, and access to magnetic resonance imaging (MRI) was not straightforward. Our aim was to perform a new study focusing on the clinical spectrum and DD of PVO and its associated factors. METHOD: This study examined a prospective cohort of 88 patients having PVO with microbiological identification between 15 November 2006 and 15 November 2010. RESULTS: The 88 patients included in the study (female:male ratio 1:8) had a mean age of 64.1 years. The mean (sd) DD was 45.5 (50.4) days (range 2-280), and 46 patients (52.2%) were febrile at diagnosis. The main microorganism involved was Staphylococcus (n = 45; 51.1%). In univariate and multivariate analyses, age > 75 years, antecedent back pain, involvement of bacteria, topography of PVO, and anti-inflammatory drug intake did not affect the DD, unlike a C-reactive protein (CRP) value > 63 mg/L or a positive blood culture (DD lowered from 73 to 17 days and from 90 to 30 days, respectively). Conversely, X-ray investigation was associated with a longer DD (from 14 to 34.7 days). Severity at diagnosis was not significantly different depending on the intake of anti-inflammatory drugs. CONCLUSIONS: Despite easier access to MRI, the DD for PVO remains long. One shortening factor is a high CRP value, which could be a useful diagnostic tool in case of back pain. Anti-inflammatory drugs seem to have no impact on DD and severity at diagnosis.

Microbiological diagnosis of vertebral osteomyelitis: relevance of second percutaneous biopsy following initial negative biopsy and limited yield of post-biopsy blood cultures.

The purpose of this investigation was to evaluate the microbiological diagnosis yield of post-biopsy blood cultures (PBBCs) and second percutaneous needle biopsy (PNB) following an initial negative biopsy in vertebral osteomyelitis (VO) without bacteremia. A retrospective multicenter study was performed. Patients with VO, pre-biopsy negative blood culture(s), ≥1 PNB, and ≥1 PBBC (0-4 h) were included. One hundred and sixty-nine PNBs (136 first and 33 following initial negative biopsy) were performed for 136 patients (median age = 58 years, sex ratio M/F = 1.9). First and second PNBs had a similar yield: 43.4 % (59/136) versus 39.4 % (13/33), respectively. Only two PBBCs (1.1 %) led to a microbiological diagnosis. The strategy with positive first PNB and second PNB following an initial negative result led to microbiological diagnosis in 79.6 % (74/93) of cases versus 44.1 % (60/136) for the strategy with only one biopsy. In the multivariate analysis, young age (odds ratio, OR [95 % confidence interval (CI)] = 0.98 [0.97; 0.99] per 1 year increase, p = 0.02) and >1 sample (OR = 2.4 ([1.3; 4.4], p = 0.007)) were independently associated with positive PNB. To optimize microbiological diagnosis in vertebral osteomyelitis, performing a second PNB (after an initial negative biopsy) could lead to a microbiological diagnosis in nearly 80 % of patients. PBBC appears to be limited in microbiological diagnosis.

Time-Dependent Mechanical Properties in Polyetherimide 3D-Printed Parts Are Dictated by Isotropic Performance Being Accurately Predicted by the Generalized Time Hardening Model.

The Fused-Deposition Modelling (FDM) technique has transformed the manufacturing discipline by simplifying operational processes and costs associated with conventional technologies, with polymeric materials being indispensable for the development of this technology. A lack of quantification of viscoelastic/plastic behavior has been noted when addressing FDM parts with Polyetherimide (PEI), which is currently being investigated as a potential material to produce functional end-products for the aerospace and health industry. Primary and secondary creep along with stress relaxation tests have been conducted on FDM PEI specimens by applying stresses from 10 to 40 MPa for 100 to 1000 min. Specimens were 3D printed by varying the part build orientation, namely XY, YZ, and XZ. Creep results were fitted to the Generalized Time Hardening equation (GTH), and then this model was used to predict stress relaxation behavior. FDM PEI parts presented an isotropic creep and stress relaxation performance. The GTH model was proven to have a significant capacity to fit viscoelastic/plastic performances for each single build orientation (r > 0.907, p < 0.001), as well as a tight prediction of the stress relaxation behavior (r > 0.998, p < 0.001). Averaged-orientation coefficients for GTH were also closely correlated with experimental creep data (r > 0.958, p < 0.001) and relaxation results data (r > 0.999, p < 0.001). FDM PEI parts showed an isotropic time-dependent behavior, which contrasts with previous publications arguing the significant effect of part build orientation on the mechanical properties of FDM parts. These findings are strengthened by the high correlation obtained between the experimental data and the averaged-coefficient GTH model, which has been proven to be a reliable tool to predict time-dependent performance in FDM parts.

Neurotrophins modulate monocyte chemotaxis without affecting macrophage function.

Neurotrophins nerve growth factor (NGF), brain-derived growth factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) and their high-affinity tyrosine protein kinase receptor (Trk) family, TrkA, TrkB, TrkC, and low-affinity p75(NTR) receptor, are key molecules implicated in the development of the central nervous system. Increasing evidence suggests that they also have physiological and pathological roles outside the nervous system. In this study we examined the expression of neurotrophins and their receptors in human activated macrophages and to what extent neurotrophins themselves modulate macrophage activation, in a model of primary adult monocyte-derived macrophage. Our data indicate that macrophages express neurotrophin and neurotrophin receptor genes differentially, and respond to cell stimulation by specific inductions. Neurotrophins did not modify the antigen-presenting capacities of macrophages or their production of proinflammatory cytokines, but somehow skewed their activation phenotype. In contrast, NGF clearly increased CXCR-4 expression in macrophage and their chemotactic response to low CXCL-12 concentration. The differential effect of specific macrophage stimuli on neurotrophin expression, in particular NGF and NT-3, and the specific enhancement of CXCR-4 expression suggest that neurotrophins might participate in tissue-healing mechanisms that should be investigated further in vivo.

Use of telemedicine in the management of infectious diseases.

Communication technologies have invaded our daily lives. Several studies have assessed these technologies in the management of infectious diseases (mainly HIV). Weekly short text messages and real-time compliance monitoring assessed in HIV patients are both associated with higher compliance in low-income countries. Virtual consultations to monitor stable chronic HIV patients or tuberculosis treatment in high-income countries appear to be acceptable and efficient. Although assessed in small studies, virtual monitoring seems to reinforce the doctor-patient relationship and the relation between primary care settings and hospitals in various infectious diseases (endocarditis, urinary tract infection, skin and soft tissue infection, HIV, tuberculosis, hepatitis C). A better prevention of infectious diseases (mainly sexually transmitted infections) seems to be observed with telemedicine tools. As fees for teleconsultation or telemonitoring have yet to be defined, the development and evaluation (cost effectiveness) of these tools are difficult. The regulatory framework will need to be improved to encourage such developments, all the while ensuring the confidentiality of data. The development of new tools will require the collaboration of physicians, users, and healthcare systems.

Key features of bone and joint infections following the implementation of reference centers in France.

OBJECTIVES: French reference centers for bone and joint infections (BJI) were implemented from 2009 onwards to improve the management of complex BJIs. This study compared BJI burden before and after the implementation of these reference centers. PATIENTS AND METHODS: BJI hospital stays were selected from the 2008 and 2013 national hospital discharge database using a validated algorithm, adding the new complex BJI code created in 2011. Epidemiology and economic burden were assessed. RESULTS: BJI prevalence increased in 2013 (70 vs. 54/100,000 in 2008). Characteristics of BJI remained similar between 2008 and 2013: septic arthritis (50%), increasing prevalence with age and sex, case fatality 5%, mean length of stay 17.5 days, rehospitalization 20%. However, device-associated BJIs increased (34 vs. 26%) as well as costs (€421 million vs. €259 in 2008). Similar device-associated BJI characteristics between 2008 and 2013 were: septic arthritis (70%), case fatality (3%), but with more hospitalizations in reference centers (34 vs. 30%) and a higher cost per stay. Among the 7% of coded complex BJIs, the mean length of stay was 22.2 days and mean cost was €11,960. CONCLUSIONS: BJI prevalence highly increased in France. Complex BJI prevalence assessment is complicated by the absence of clinical consensus and probable undercoding. A validation of clinical case definition of complex BJI is required.

[Acute renal failure with acyclovir in a 42-year-old patient without previous renal dysfunction]. / Insuffisance rénale aiguë sous aciclovir chez un patient de 42 ans sans atteinte rénale préalable.

INTRODUCTION: Herpetic meningoencephalitis is treated with acyclovir (15 mg/kg/8 h). This higher dosage enhance the risk of acute renal failure. CASE REPORT: We report the case of a previously healthy 42 years old man treated by intravenous aciclovir 1g/8 h for a herpetic meningoencephalitis. He presented an acute renal failure and an acute confusional state at the end of the treatment. Renal function and neurologic status improved rapidly with increased hydration and stop of the antiviral therapy. CONCLUSION: If acyclovir is usually well tolerated, there is also a risk of acute nephropathy, especially dose-dependent. We point out the need to monitor renal function when high dosage of acyclovir is indicated.

[Legionella pneumonia in an immunocompetent child]. / La légionellose chez l'enfant immunocompétent: a propos d'un cas.

We report a case of Legionella pneumonia in an immunocompetent child. Legionella pneumonia is a rare pathology among children, and even rarer when they are immuno-competent; a few cases have been reported in the literature. This is explained by the fact that infection occurs primarily to immuno-suppressed patients. Legionella bacteria are not systematically sought for in front of child's atypical pneumonia, contrary to Mycoplasma or Chlamydiae. In addition, a number of cases are probably not even noticed because either not serious (Pontiac fever), spontaneously cured, or cured with macrolides prescribed in the case of suspected pneumonia with Mycoplasma.

Rapid HIV test in family practice.

BACKGROUND: The 2010-2014 HIV/AIDS French program recommends using HIV rapid diagnostic tests in family practice. Our aim was to assess the acceptability and feasibility of the RDT in family practice in France. METHODS: The first part of this study was to determine the opinions of family practitioners (FPs) concerning the news guidelines for screening and the possible use of rapid HIV tests in their practice. The second part was a feasibility study of the actual use of rapid HIV tests given to FPs during six months. The third part was a qualitative analysis of experience feedback to determine the impediments to using rapid HIV tests. RESULTS: Seventy-seven percent of the 352 FPs interviewed were favorable to rapid HIV tests use. The three main impediments were: misinterpretation of test result, complexity of quality control, and lack of training: 23 of the 112 FPs having volunteered to evaluate the rapid HIV tests followed the required training session. Sixty-nine tests were handed out, and three rapid HIV tests were used; the qualitative study involved 12 FPs. The participants all agreed on the difficult use of rapid HIV tests in daily practice. The main reasons were: too few opportunities or requests for use, complex handling, difficulties in proposing the test, fear of having to announce seropositivity, significantly longer consultation. CONCLUSION: Although FPs are generally favorable to rapid HIV tests use in daily practice, the feasibility and contribution of rapid HIV tests are limited in family practice.

Clearance of HIV infection in 12 perinatally infected children: clinical, virological and immunological data.

OBJECTIVE: A case of HIV infection clearance in a perinatally infected infant has been recently reported. We report here on the molecular, biological and clinical features of such virus clearance in 12 children. DESIGN AND METHODS: We performed a retrospective analysis of the diagnosis in our 6-year cohort of 188 children born to HIV-seropositive mothers. HIV-1 was detected by coculture of infant peripheral blood mononuclear cells (PBMC) with cord blood cells, direct culture of infant cells, and DNA polymerase chain reaction (PCR). The children were diagnosed three times during the first 3 months of life and then followed up over a postnatal period of 18-36 months. RESULTS: The 12 reverted children had at least two positive PCR in at least two amplified regions. Among them, six were tested positive in culture/coculture assay, and five were treated long-term with zidovudine. Thus, seven out of 12 reversions cannot be attributed to antiretroviral therapy. All the virological results became negative during the first year of life, and serology lowered to negative values between 9 and 23 months. We could not find any correlation between either neutralizing or antibody-dependent cellular cytotoxicity-mediating antibodies and HIV clearance. CONCLUSION: In our cohort, we showed that an unexpected number of children born to HIV-seropositive mothers (6.7%) cleared HIV infection during the first year of life, and subsequently became seronegative. Interestingly, most of these children exhibited unspecified clinical signs during the first months of life. Five of these children were tested positive only by PCR, which suggests a low virus load and could, at least partly, explain spontaneous clearance. However, 4 years later, among the seven remaining infants, two seronegative children presented recurrent hepatosplenomegaly, which may indicate the presence of hidden virus not detectable by peripheral blood testing.

Mechanisms of opsonized HIV entry in normal B lymphocytes.

Using our in vitro model of normal B cell infection that functions with low doses of HIV but requires virus opsonization by seropositive patient serum, and complement, we analyzed what receptors allowed virus entry. Here, we show that HIV infection of B cells occurs through 2 major receptors: the CD4 antigen and the CR1/CR2 complex. These 2 pathways work independently since a complete inhibition of virus entry requires both CD4 and CD21/CD35 blockade on CD4dim tonsillar B cells whereas only the latter is critical on CD4-negative B cells.

Quantitative study of beta1-integrin expression and fibronectin interaction profile of T lymphocytes in vitro infected with HIV.

Cell-extracellular matrix interactions, regulated in part by beta1-integrins, play a key role in the recirculation of T lymphocytes and tissue infiltration in inflammatory and immune responses. HIV infection may affect CD4+ T cell adhesion, and the trafficking and migration of these cells, which are crucial for foreign antigen recognition. We investigated this by studying the expression of the beta1-integrin chains CD29 and CD49c, -d, -e, and -f, on in vitro HIV-infected primary T cells. We also assessed fibronectin binding and production by CD4+ lymphocytes. X4 (HIV-1/LAI), R5 (HIV-1/Ba-L), and X4R5 (HIV-2/ROD) strains, and X4R5 primary isolates (HIV-1/DAS, HIV-1/THI), with different cytopathogenicity and replication kinetics, were used. Beta1-integrin expression on CD4+ and CD4- T cell subpopulations was regulated by cell activation with phytohemagglutinin-P and interleukin 2, but was unaffected by HIV infection, even at the peak of viral replication and CD4+ cell depletion. Similarly, fibronectin binding to CD4+ lymphocytes was not affected by HIV infection. This suggests that infected lymphocytes may be able to extravasate, migrate, and recirculate within the body until their death.

B cell-driven HIV type 1 expression in T cells: an essential role of CD86 costimulatory molecule.

During HIV-1 infection, HIV-1 is sequestered and actively replicates within lymphoid organs, mainly in areas essential for antigen-specific T-B interactions. We investigated whether cognate T-B interactions not only drive humoral response to HIV-1 but also enhance viral replication. Costimulation of in vitro HIV-1-infected tonsillar T cells with autologous or allogeneic activated B cells increased both viral replication and T cell proliferation. Addition of CD86 MAb to cocultures inhibited most p24 (84 +/- 12%, n = 13) and IL-2 (99 +/- 2%, n = 6) production, decreased T cell proliferation by 46 +/- 15% (n = 13), and decreased TNF-alpha and IFN-gamma production by 67 +/- 17% (n = 6) and 53 +/- 6% (n = 6), respectively. In contrast, CD80 MAb, which strongly inhibited IL-2 production (77 +/- 10%, n = 6), moderately downregulated p24 and TNF-alpha production (29 +/- 21%, n = 13 and 34 +/- 10%, n = 6, respectively) and did not decrease T cell proliferation (8 +/- 10%, n = 13) or IFN-gamma production (14 +/- 13%, n = 6). We thus showed that B cells deliver a potent CD86/CD28 costimulatory signal that induces T cell proliferation and simultaneously enhances HIV-1 replication. CD86+ B cells, mainly localized within the light zone of germinal centers, might thus favor active in situ replication of HIV-1 in response to each new challenge by T-dependent antigens.

Consequences of gamma-irradiation on inflammatory cytokine regulation in human monocytes/macrophages.

Inflammation is a frequent result of radiation damage, especially after therapeutic irradiation. Monocytes and macrophages play an important role in inflammatory cytokine secretion. However, knowledge of monocyte/ macrophage involvement in the pathogenesis of inflammation is still incomplete. In this study, we investigated the inflammatory cytokine regulation after in vitro gamma-irradiation of monocytes/macrophages. Semiquantitative RT-PCR after irradiation revealed no significant induction of interleukin 1 beta or tumour necrosis factor-alpha mRNA expression. When induction was observed, for only two donors out of seven, only interleukin 6 gene expression was affected by irradiation, with a 5-14-fold increase in level according to the donor, 2h after irradiation compared with sham-irradiated cells. For only one of seven donors tested, monocytes/macrophages responded to 10-Gy gamma-rays by releasing inflammatory cytokines.

Influence of Irradiation on the Risk of Transmission of HIV in Bone Grafts Obtained from Appropriately Screened Donors and Followed by Radiation Sterilization.

We studied the effects of radiation (electrons of 6.2 MeV) at different temperatures with respect to the inactivation of the human immunodeficiency virus to determine the radiosensitivity of the virus. Using a mathematical model describing the dependence on radiation dose of the proportion of sterile items in a population of bone allografts contaminated by HIV, and subjected to irradiation, we have commented on and explained the calculation of the sterility assurance level in bone transplantation according to different doses of irradiation at different temperatures. Simultaneous application of heat and radiation increases inactivation of HIV. Given the relative imprecision of viral sensitivity curves and the impossibility of knowing the number of viral particles in a patient at a given moment of the disease, irradiation does not authorize bone transplantation without screening. However, irradiation can be considered as a serious adjuvent to decrease the risk of contamination after screening.

[Role of neutralizing antibodies in protection of the fetal from an HIV positive mother]. / Rôle des anticorps neutralisants dans la protection du foetus de mère VIH positive.

The goal of this study is to compare serum Titers of Neutralizing antibodies in HIV 1 infected mothers to the virological status of their newborns. 38 infant-mothers couples were tested. Serum Neutralizing antibodies Titers of the mothers were tested the day of birth. Virological status of new borns was determined by peripheric blood mononuclear cells culture and PCR. 18 Newborns were HIV 1 infected. In 9 cases mothers had no neutralizing antibodies: 7 newborns were HIV 1 infected. In 4 cases mothers had high level of neutralizing antibodies (< 640): none of the newborns was infected. In 25 cases mothers had intermediate value of neutralizing antibodies (between 80 and 320): 11 newborns were HIV 1 infected. Women with neutralizing antibodies to HIV 1, were less likely to transmit HIV 1 to their infants than pregnant women without neutralizing antibodies. Serum neutralizing antibodies titers of pregnant women might be of predictive value in vertical transmission of HIV 1. Further investigations are needed.

Hospital and ambulatory management, and compliance to treatment in HIV infection: regional health insurance agency analysis.

OBJECTIVE: We had for objective to study HIV management (hospital, ambulatory, and mixed) and assess compliance with health insurance database. METHOD: We conducted a retrospective study using the French Social Security (CPAM) database. The inclusion criteria were: age>18years of age, at least 2 prescriptions of antiretroviral therapy. RESULTS: Five hundred and seventy-five patients were included: extra-hospital (12), hospital (162), mixed (401). The prescriptions were exclusively hospital issued for 76.2% of the patients. Among the mixed group patients, 91% of treatments were delivered at least once in the community, and 45.6% of biological tests were performed in private laboratories at least once. The sex ratio (2.1 vs. 1.3), the number of patients having switched antiretroviral therapy (36.7% vs. 27.8%), and the frequency of biological tests (3.1 vs. 2.6) were significantly higher in the mixed group compared to the hospital group. The mean compliance was 90% in the hospital group and 91.8% in the mixed group. The compliance was<80% for 104 patients (21.8%). Patients with≥80% compliance were older (46.1years of age vs. 42.7years of age), with more frequent biological tests (3 per year vs. 2.5 per year), and more frequent switches in treatment (35.4% vs. 26.0%). CONCLUSION: Prescriptions of ARV were almost exclusively hospital issued. Their dispensation and biological tests were split between hospital and extra-hospital settings. Most patients demonstrated an optimal compliance. The CPAM database allows describing HIV management and assessing compliance.