Improvement of HIV-associated neurocognitive disorders after antiretroviral therapy intensification: the Neuro+3 study.

OBJECTIVES: Despite the effectiveness of antiretroviral (ARV) therapy to control HIV infection, HIV-associated neurocognitive disorders (HAND) remain frequent. The Neuro+3 study assessed the cognitive improvement associated with ARV intensification based on increased CNS penetration effectiveness (CPE) scoring ≥+3 and total CPE score ≥9. METHODS: Thirty-one patients, aged 18-65 years, with confirmed diagnosis of HAND and effective ARV therapy were included. The cognitive improvement was measured using Frascati three-stage classification and global deficit score (GDS) after 48 and 96 weeks of ARV intensification. Ultrasensitive HIV-RNA, neopterin, soluble CD14, CCL2, CXCL10, IL6, IL8 and NF-L were measured in plasma and cerebrospinal fluid at Day 0 (baseline), Week 48 (W48) and W96. RESULTS: The intensified ARV was associated with a median (IQR) CPE score increase from 6 (4-7) at baseline to 10 (9-11). From baseline to W96, the median (IQR) GDS decreased from 1.4 (0.8-2.2) to 1.0 (0.6-2.0) (P = 0.009); HAND classification improved from 2 to 1 HIV-associated dementia, 22 to 8 mild neurocognitive disorders, 7 to 17 asymptomatic neurocognitive impairment and 0 to 5 patients without any neurocognitive alterations (P = 0.001). In multivariable linear regression analysis, GDS improvement at W96 was significantly associated with CPE score ≥9 after intensification (P = 0.014), CD4 lymphocyte increase at W48 (P < 0.001) and plasma CXCL10 decrease at W96 (P = 0.001). CONCLUSIONS: In patients with HAND, a significant cognitive improvement was observed after the ARV intensification strategy, with a higher CPE score. Cognitive improvement was more often observed in the case of a switch of two drug classes, arguing for better control of CNS HIV immune activation.

Relationships between neuropsychological impairments and functional outcome eight years after severe traumatic brain injury: Results from the PariS-TBI study.

BACKGROUND/OBJECTIVES: The objective was to assess the relationships between neuropsychological impairments, functional outcome and life satisfaction in a longitudinal study of patients after a severe traumatic brain injury (TBI) (PariS-TBI study). PATIENTS: Out of 243 survivors, 86 were evaluated 8 years post-injury. They did not significantly differ from patients lost-to-follow up except for the latter being more frequently students or unemployed before the injury. METHODS: Outcome measures included the Glasgow Outcome Scale-Extended (GOS-E), a functional independence questionnaire, employment, mood, fatigue and satisfaction with life. Neuropsychological outcome was assessed by two ways: performance-based outcome measures, using neuropsychological tests and patient and relative-based measures. RESULTS: Neuropsychological measures were not significantly related to initial injury severity nor to gender, but were significantly related to age and education. After statistical correction for multiple comparisons, cognitive testing and cognitive questionnaires were significantly correlated with most outcome measures. By contrast, satisfaction with life was only related with patient-rated questionnaires. A regression analysis showed that the Trail-Making-Test-A was the best predictor of functional outcome, in addition to education duration. CONCLUSIONS: Cognitive measures, particularly slowed information processing speed, were significant indicators of functional outcome at a long-term post-injury, beyond and above demographics or injury severity measures.

Economic model of albumin infusion in septic shock: The EMAISS study.

BACKGROUND: The cost-effectiveness of albumin-based fluid support in patients with septic shock is currently unknown. METHODS: In a simulation study, we compared standard medical practice and systematic 20% albumin infusion. The study population consisted of patients with septic shock admitted to one of the 28 ICUs belonging to the Cub-Réa regional database between 1 January 2014 and 31 December 2016. Cost estimates were based on French diagnosis-related groups and fixed daily prices. Estimation of mortality reduction relied on ALBIOS trial data documenting a Risk Ratio of 0.87 in a non-preplanned subgroup of patients with septic shock. Life expectancy was estimated with follow up data of 184 patients with septic shock admitted in the year 2000 in the same ICUs. Several sensitivity analyses were performed including a one-way Deterministic Sensitivity Analysis (DSA) and a Probabilistic multivariate Sensitivity Analysis (PSA). RESULTS: About 6406 patients were included. In the base-case scenario, the mean live years gained with albumin was 0.49. The mean extra cost of using albumin was €480 per year. The cost per year gained was €974. Sensitivity analyses confirmed the robustness of the results. The probability of albumin being cost-effective was 95% and 97% for a threshold fixed at €20 000 and €30 000 per life-year saved, respectively. CONCLUSION: Based on the risk reduction observed in the septic shock subgroup analysis of the ALBIOS dataset, the application of the ALBIOS trial results to Cub-Réa data may suggest that albumin infusion is likely cost-effective in septic shock.

Measurement of Serum Anti-staphylococcal Antibodies Increases Positive Predictive Value of Preoperative Aspiration for Hip Prosthetic Joint Infection.

BACKGROUND: Preoperative synovial fluid culture is pivotal in the early diagnosis of prosthetic joint infection (PJI) but may yield false-positive and false-negative results. We evaluated the predictive value of synovial fluid culture results combined with the measurement of serum anti-staphylococcal antibodies (SASA). QUESTIONS/PURPOSES: (1) For hip and knee PJI, does combining positive SASA results with preoperative synovial culture results improve the positive predictive value (PPV) of preoperative synovial fluid culture alone? (2) Does combining preoperative synovial fluid culture results with a positive cell count and differential result increase the PPV of preoperative synovial fluid culture alone? (3) What proportion of isolated organisms exhibit concordance in antibiotic susceptibility: preoperative aspiration versus intraoperative isolates? METHODS: A prospective study was conducted at two French reference centers that manage bone and joint infections and included 481 adult patients who had a revision or resection arthroplasty between June 25, 2012 and June 23, 2014. Exclusion criteria including no serum sample available for immunoassay, the lack of microbiological documentation, and the absence of preoperative aspiration reduced the patient number to 353. Seven patients with an undetermined SASA result were excluded from the analysis. We also excluded patients with PJI involving more than one Staphylococcus species (polystaphylococcal infection) and those in whom more than one Staphylococcus species was recovered from the preoperative synovial fluid culture (polystaphylococcal synovial fluid culture). In total, 340 patients were included in the analysis (no infection, 67% [226 of 340]; staphylococcal infection, 21% [71 of 340]; other infection, 13% [43 of 340]). The preoperative synovial fluid analysis included a cell count and differential and bacterial culture. SASAs were measured using a multiplex immunoassay. The diagnosis of PJI was determined using the Infectious Diseases Society of America (IDSA) criteria [] and intraoperative tissue culture at the time of revision surgery was used as the gold standard (at least one positive intraoperative sample for a "virulent" organism (such as S. aureus) or two positive samples for a "non-virulent" (for example S. epidermidis). RESULTS: SASA increased the PPV compared with synovial fluid culture alone (92% [95% CI 82 to 97] versus 79% [95% CI 68 to 87]; p = 0.04); when stratified by site, an increase in PPV was seen in hip infections (100% [95% CI 89 to 100] versus 77% [95% CI 63 to 88]; p = 0.01) but not in knee infections (84% [95% CI 66 to 95] versus 80% [95% CI 64 to 91]; p = 0.75). A positive cell count and differential result increased the PPV of staphylococcal synovial fluid cultures compared with synovial fluid culture alone (86% [95% CI 70 to 95] versus 79% [95% CI 68 to 87]; p = 0.36); when stratified by site, no difference in hip and knee infections was observed (86% [95% CI 67 to 96] versus 77% [95% CI 63 to 88]; p = 0.42) and 86% [95% CI 70 to 95] versus 80% [95% CI 64 to 91]; p = 0.74). CONCLUSION: SASA measurement improves the predictive value of synovial fluid cultures of the hip for all staphylococcal organisms, including coagulase-negative staphylococci, but the PPV of SASA plus synovial fluid culture it is not superior to the PPV of synovial fluid cell count/differential plus synovial culture for the knee. LEVEL OF EVIDENCE: Level III, diagnostic study.

Sequelae of Congenital Cytomegalovirus Following Maternal Primary Infections Are Limited to Those Acquired in the First Trimester of Pregnancy.

BACKGROUND: The known relationship between the gestational age at maternal primary infection an the outcome of congenital CMV is based on small, retrospective studies conducted between 1980 and 2011. They reported that 32% and 15% of cases had sequelae following a maternal primary infection in the first and second or the third trimester, respectively. We aimed to revisit this relationship prospectively between 2011 and 2017, using accurate virological tools. METHODS: We collected data on women with a primary infection and an infected child aged at least 1 year at the time of analysis. An accurate determination of the timing of the primary infection was based upon serial measurements of immunoglobulin (Ig) M and IgG and on IgG avidity in sera collected at each trimester. The case outcome was assessed according to a structured follow-up between birth and 48 months. RESULTS: We included 255 women and their 260 fetuses/neonates. The dating of the maternal infection was prospective in 86% of cases and retrospective in 14%. At a median follow-up of 24 months, the proportion of sensorineural hearing loss and/or neurologic sequelae were 32.4% (95% confidence interval [CI] 23.72-42.09) after a maternal primary infection in the first trimester, 0 (95% CI 0-6.49) after an infection in the second trimester, and 0 (95% CI 0-11.95) after an infection in the third trimester (P < .0001). CONCLUSIONS: These results suggest that a cytomegalovirus infection can be severe only when the virus hits the fetus in the embryonic or early fetal period. Recent guidelines recommend auditory follow-ups for at least 5 years for all infected children. This raises parental anxiety and generates significant costs. We suggest that auditory and specialized neurologic follow-ups may be recommended only in cases of a maternal infection in the first trimester.

Efficacy of colistin alone and in various combinations for the treatment of experimental osteomyelitis due to carbapenemase-producing Klebsiella pneumoniae.

OBJECTIVES: In a new experimental model of carbapenemase-producing Klebsiella pneumoniae osteomyelitis we evaluated the efficacy of colistin alone and in various combinations and examined the emergence of colistin-resistant strains and cross-resistance to host defence peptides (HDPs). METHODS: KPC-99YC is a clinical strain with intermediate susceptibility to meropenem (MIC = 4 mg/L) and full susceptibility to gentamicin, colistin and tigecycline (MICs = 1 mg/L) and fosfomycin (MIC = 32 mg/L). Time-kill curves were performed at 4× MIC. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu. Treatment started 14 days later for 7 days in seven groups: (i) control; (ii) colistin; (iii) colistin + gentamicin; (iv) colistin + tigecycline; (v) colistin + meropenem; (vi) colistin + meropenem + gentamicin; and (vii) colistin + fosfomycin. RESULTS: In vitro, colistin was rapidly bactericidal, but regrowth occurred after 9 h. Combinations of colistin with meropenem or fosfomycin were synergistic, whereas combination with tigecycline was antagonistic. In vivo, colistin alone was not effective. Combinations of colistin with meropenem or fosfomycin were bactericidal (P < 0.001) and the addition of gentamicin enhanced the efficacy of colistin + meropenem (P = 0.025). Tigecycline reduced the efficacy of colistin (P = 0.007). Colistin-resistant strains emerged in all groups except colistin + fosfomycin and two strains showed cross-resistance to HDP LL-37. CONCLUSIONS: In this model, combinations of colistin plus meropenem, with or without gentamicin, or colistin plus fosfomycin were the only effective therapies. The combination of colistin and tigecycline should be administered with caution, as it may be antagonistic in vitro and in vivo.

Sleep duration, quality of life and depression in adolescents: a school-based survey.

BACKGROUND: The main objective of this study was to assess the link between sleep duration, quality of life and depression in adolescents. The secondary objective was to study the sleeping behavior of a large sample of adolescents from different socioeconomic backgrounds. METHODS: Study subjects were high school students studying in or around Paris with a general, vocational or technological training background. A survey was conducted to evaluate the subject's perception of their own sleep, quality of life and depression. RESULTS: The survey analyzed 855 students between 14 and 19 years of age, with equal numbers of males and females. The average sleep duration was 7 h 14 min ±1 h 20 min and was inversely correlated with age (r=-0.142, P<0.01). Students studying vocational subjects reported significantly more sleep than students studying technological subjects (P=0.02). Univariate analyses revealed a positive relationship between sleep duration and quality of life (r=0.17, P<0.001) and an inverse relationship between sleep duration and depression (r=-0.5, P<0.001). Multivariate analyses identified depression, delayed sleep phase disorder, and medical condition as determinants of sleep duration. CONCLUSIONS: This investigation of a large student cohort has confirmed that the average sleep duration in adolescents is far below what is recommended. Depression significantly influenced sleep duration. We recommend that a quantitative and qualitative evaluation of sleep should be made during the medical examination of any adolescent.

Subjective complaints after acquired brain injury: presentation of the Brain Injury Complaint Questionnaire (BICoQ).

The objective of the present study was to present a new complaint questionnaire designed to assess a wide range of difficulties commonly reported by patients with acquired brain injury. Patients (n = 619) had been referred to a community re-entry service at a chronic stage after brain injury, mainly traumatic brain injury (TBI). The Brain Injury Complaint Questionnaire (BICoQ) includes 25 questions in the following domains: cognition, behavior, fatigue and sleep, mood, and somatic problems. A self and a proxy questionnaire were given. An additional question was given to the relative, about the patient's awareness of his difficulties. The questionnaires had a good internal coherence, as measured with Cronbach's alpha. The most frequent complaints were, in decreasing order, mental slowness, memory troubles, fatigue, concentration difficulties, anxiety, and dual tasking problems. Principal component analysis with varimax rotation yielded six underlying factors explaining 50.5% of total variance: somatic concerns, cognition, and lack of drive, lack of control, psycholinguistic disorders, mood, and mental fatigue/slowness. About 52% of patients reported fewer complaints than their proxy, suggesting lack of awareness. The total complaint scores were not significantly correlated with any injury severity measure, but were significantly correlated with disability and poorer quality of life (Note: only factor 2 [cognition/lack of drive] was significantly related to disability.) The BICoQ is a simple scale that can be used in addition to traditional clinical and cognitive assessment measures, and to assess awareness of everyday life problems.

In vivo daptomycin efficacy against experimental vancomycin-resistant Enterococcus faecium endocarditis.

Objectives: Daptomycin has become a first-line therapeutic option for vancomycin-resistant Enterococcus faecium infective endocarditis (IE). Although high doses (≥8 mg/kg) are often recommended, optimal doses, particularly for strains with MICs close to the susceptibility breakpoint (4 mg/L), are still debated. Methods: Daptomycin efficacy at doses equivalent to 8 mg/kg daptomycin (DAP8) and 12 mg/kg daptomycin (DAP12) in humans was evaluated in a rabbit model of aortic valve IE induced by 108 cfu of E. faecium reference strain Aus0004 (daptomycin MIC = 2 mg/L) or its in vitro mutant strain Mut4 (daptomycin MIC = 4 mg/L). Treatment began 48 h post-inoculation and lasted 5 days. Results: With Aus0004, the median log10 cfu/g of vegetations was significantly lower after DAP8 and DAP12 versus controls [6.05 (n = 12) and 2.15 (n = 10) versus 9.14 (n = 11), respectively; P < 0.001], with DAP12 being more effective than DAP8 concerning vegetation bacterial load (P < 0.001) and percentages of sterile vegetations (100% versus 0%, respectively; P < 0.001). Daptomycin-resistant Aus0004 mutants were detected in 8.3% of DAP8-treated vegetations. With Mut4, the median log10 cfu/g of vegetations was significantly lower after DAP8 and DAP12 versus controls [7.7 (n = 11) and 6.95 (n = 10) versus 9.59 (n = 11), respectively; P = 0.001 and P = 0.002], without any between-dose difference, but no vegetation was sterile. Moreover, 7 of 11 (63.6%) and 7 of 9 (77.8%) vegetations contained resistant mutants after DAP8 and DAP12, respectively. Conclusions: DAP12 was the most successful strategy against IE due to a WT E. faecium strain (daptomycin MIC = 2 mg/L). To treat IE strains with MIC = 4 mg/L, DAP8 or DAP12 monotherapy was poorly effective with the risk of resistant mutant emergence. Reassessment of the daptomycin susceptibility breakpoint for enterococci seems necessary.

Self-awareness four years after severe traumatic brain injury: discordance between the patient's and relative's complaints. Results from the PariS-TBI study.

OBJECTIVE: To evaluate the patient's awareness of his or her difficulties in the chronic phase of severe traumatic brain injury (TBI) and to determine the factors related to poor awareness. DESIGN/SETTING/SUBJECTS: This study was part of a larger prospective inception cohort study of patients with severe TBI in the Parisian region (PariS-TBI study). Intervention/Main measures: Evaluation was carried out at four years and included the Brain Injury Complaint Questionnaire (BICoQ) completed by the patient and his or her relative as well as the evaluation of impairments, disability and quality of life. RESULTS: A total of 90 patient-relative pairs were included. Lack of awareness was measured using the unawareness index that corresponded to the number of discordant results between the patient and relative in the direction of under evaluation of difficulties by the patient. The only significant relationship found with lack of awareness was the subjective burden perceived by the relative (Zarit Burden Inventory) ( r = 0.5; P < 0.00001). There was no significant relationship between lack of awareness and injury severity, pre-injury socio-demographic data, cognitive impairments, mood disorders, functional independence (Barthel index), global disability (Glasgow Outcome Scale), return to work at four years or quality of life (Quality Of Life after Brain Injury scale (QOLIBRI)). CONCLUSION: Lack of awareness four years post severe TBI was not related to the severity of the initial trauma, sociodemographic data, the severity of impairments, limitations of activity and participation, or the patient's quality of life. However, poor awareness did significantly influence the weight of the burden perceived by the relative.

Risk Factors for Congenital Cytomegalovirus Infection Following Primary and Nonprimary Maternal Infection: A Prospective Neonatal Screening Study Using Polymerase Chain Reaction in Saliva.

BACKGROUND: The design of diagnostic and preventive strategies have been prevented by gaps in knowledge of the epidemiology of congenital cytomegalovirus (cCMV) with the type of maternal infection as well as the lack of large-scale neonatal screening tools. METHODS: In sum, 11715 consecutive newborns were screened for cCMV by polymerase chain reaction (PCR) in saliva. Prevalence, type of maternal infection, sociodemographic, obstetrical, and serological data were analyzed. RESULTS: Positive predictive value of CMV PCR in saliva was 59%; false positive results were associated with lower viral loads (P < .001). Maternal seroprevalence was 61%, birth prevalence was 0.37%, resulting from primary and nonprimary infections in 52% and 47.7% of cases, respectively. The risk to deliver an infected baby after primary infection was increased in younger (OD = 7.9), parous (OD = 4.1) women born in high resources countries (OD = 5.2) and from higher income groups (P = .019). The only 2 risk factors to deliver an infected baby after nonprimary infection were to be young (OD = 4.6) and unemployed (OD = 5.8). The risk to deliver an infected baby was 4-fold higher in women seronegative before their pregnancy (P = .021). CONCLUSIONS: A positive CMV PCR in newborns' saliva should always be confirmed in a repeat-sample. Sociodemographic characteristics of women giving birth to an infected baby after primary and nonprimary infection are different. Seronegative, parous women represent the highest risk population for cCMV in countries with low to intermediate seroprevalence. Urgent action is needed to stop the cCMV's epidemic, particularly in this population easily identifiable by maternal serology and amenable to prevention messages. CLINICAL TRIALS REGISTRATION: NCT01923636.

Translation, cross-cultural adaptation, and validation of the french version of the 15-item Myasthenia Gravis Quality Of life scale.

INTRODUCTION: Evaluation of quality of life (QOL) has become essential in healthcare. Currently no MG-specific QOL measure exists in French. The aim of this study was to translate, culturally adapt, and evaluate the psychometric properties of the French version of the 15-Item Myasthenia Gravis Quality of Life Scale (MG-QOL15) scale for French myasthenia patients. METHODS: Translation and cross-cultural adaption of the MG-QOL15 was performed, followed by reliability and validity evaluations. RESULTS: One hundred and twenty-five patients were included. Internal consistency was excellent (Cronbach α = 0.92) as was test-retest reliability (ICC = 0.92, 95% CI 0.86-0.96). Concurrent validity was good for both clinical scores (myasthenic muscle score: ρ = -0.52, P < 0.001; Myasthenia Gravis-Activities of Daily Living scale score: ρ = 0.62, P < 0.001). Correlations were strongest for overall QOL (ρ = 0.62, P < 0.001) and physical health (ρ = 0.67, P < 0.001) on the World Health Organization Quality of Life short score (WHO-QOL BREF). CONCLUSION: The French version of the MG-QOL15 is valid and reliable and is now available for use with French-speaking patients. Muscle Nerve, 2016 Muscle Nerve 55: 639-645, 2017.

Impact of extended monitoring-guided intensive care on outcome after severe traumatic brain injury: A prospective multicentre cohort study (PariS-TBI study).

OBJECTIVE: We evaluated whether an integrated monitoring with systemic and specific monitoring affect mortality and disability in adults with severe traumatic brain injury (sTBI). METHODS: Adults with severeTBI (Glasgow Coma Scale [GCS] ≤ 8) admitted alive in intensive care units (ICUs) were prospectively included. Primary endpoints were in-hospital 30-day mortality and extended Glasgow outcome score (GOSE) at 3 years. Association with the intensity of monitoring and outcome was studied by comparing a high level of monitoring (HLM) (systemic and ≥3 specific monitoring) and low level of monitoring (LLM) (systemic and 0-2 specific monitoring) and using inverse probability weighting procedure. RESULTS: 476 patients were included and IPW was used to improve the balance between the two groups of treatments (HLM/LMM). Overall hospital mortality (at 30 days) was 43%, being significantly lower in HLM than LLM group (27% vs. 53%: RR, 1.63: 95% CI: 1.23-2.15). The 14-day hospital mortality was also lower in the HLM group than expected, based upon the CRASH prediction model (35%). At 3 years, disability was not significantly different between the monitoring groups. CONCLUSIONS: After adjustment, HLM group improved short-term mortality but did not show any improvement in the 3-year outcome compared with LLM.

Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial.

BACKGROUND: Duration of treatment for patients with vertebral osteomyelitis is mainly based on expert recommendation rather than evidence. We aimed to establish whether 6 weeks of antibiotic treatment is non-inferior to 12 weeks in patients with pyogenic vertebral osteomyelitis. METHODS: In this open-label, non-inferiority, randomised controlled trial, we enrolled patients aged 18 years or older with microbiologically confirmed pyogenic vertebral osteomyelitis and typical radiological features from 71 medical care centres across France. Patients were randomly assigned to either 6 weeks or 12 weeks of antibiotic treatment (physician's choice in accordance with French guidelines) by a computer-generated randomisation list of permuted blocks, stratified by centre. The primary endpoint was the proportion of patients who were classified as cured at 1 year by a masked independent validation committee, analysed by intention to treat. Non-inferiority would be declared if the proportion of cured patients assigned to 6 weeks of treatment was not less than the proportion of cured patients assigned to 12 weeks of treatment, within statistical variability, by an absolute margin of 10%. This trial is registered with EudraCT, number 2006-000951-18, and Clinical Trials.gov, number NCT00764114. FINDINGS: Between Nov 15, 2006, and March 15, 2011, 359 patients were randomly assigned, of whom six in the 6-week group and two in the 12-week group were excluded after randomisation. 176 patients assigned to the 6-week treatment regimen and 175 to the 12-week treatment regimen were analysed by intention to treat. 160 (90·9%) of 176 patients in the 6-week group and 159 (90·9%) of 175 of those in the 12-week group met the criteria for clinical cure. The difference between the groups (0·05%, 95% CI -6·2 to 6·3) showed the non-inferiority of the 6-week regimen when compared with the 12-week regimen. 50 patients in the 6-week group and 51 in the 12-week group had adverse events, the most common being death (14 [8%] in the 6-week group vs 12 [7%] in the 12-week group), antibiotic intolerance (12 [7%] vs 9 [5%]), cardiorespiratory failure (7 [4%] vs 12 [7%]), and neurological complications (7 [4%] vs 3 [2%]). INTERPRETATION: 6 weeks of antibiotic treatment is not inferior to 12 weeks of antibiotic treatment with respect to the proportion of patients with pyogenic vertebral osteomyelitis cured at 1 year, which suggests that the standard antibiotic treatment duration for patients with this disease could be reduced to 6 weeks. FUNDING: French Ministry of Health.

Multiplex Antibody Detection for Noninvasive Genus-Level Diagnosis of Prosthetic Joint Infection.

We developed and evaluated a multiplex antibody detection-based immunoassay for the diagnosis of prosthetic joint infections (PJIs). Sixteen protein antigens from three Staphylococcusspecies (Staphylococcus aureus,Staphylococcus epidermidis, and Staphylococcus lugdunensis) (8 antigens),Streptococcus agalactiae(4 antigens), and Propionibacterium acnes(4 antigens) were selected by comparative immune proteomics using serum samples from PJI cases versus controls. A bead-based multiplex immunoassay that measured serum IgG against purified, recombinant forms of each of the 16 antigens was developed. We conducted a prospective study to evaluate the performance of the assay. A PJI was defined by the presence of a sinus tract and/or positive intraoperative sample cultures (at least one sample yielding a virulent organism or at least two samples yielding the same organism). A total of 455 consecutive patients undergoing revision or resection arthroplasty (hip, 66.3%; knee, 29.7%; shoulder, 4%) at two French reference centers for the management of PJI were included: 176 patients (38.7%) were infected and 279 (61.3%) were not. About 60% of the infections involved at least one of the species targeted by the assay. The sensitivity/specificity values were 72.3%/80.7% for targeted staphylococci, 75%/92.6% forS. agalactiae, and 38.5%/84.8% forP. acnes The assay was more sensitive for infections occurring >3 months after arthroplasty and for patients with an elevated C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR). However, it detected 64.3% and 58.3% of targeted staphylococcal infections associated with normal CRP and ESR values, respectively. This new multiplex immunoassay approach is a novel noninvasive tool to evaluate patients suspected of having PJIs and provides information complementary to that from inflammatory marker values.

In utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter, open-label, phase II study.

BACKGROUND: Congenital infection with human cytomegalovirus is a major cause of morbidity and mortality. A randomized controlled trial showed that high-dosage valacyclovir prevents cytomegalovirus disease in transplant recipients. Fetuses showing ultrasound features of infection are at high risk of being symptomatic at or before birth. In a pilot study, oral administration of high-dosage valacyclovir to mothers significantly decreased viral load and produced therapeutic concentrations in the blood of infected fetuses. A randomized controlled trial comparing prenatal treatment with valacyclovir against placebo in infected fetuses failed to recruit because women declined randomization. Randomized controlled trials in fetal medicine have often proven unacceptable by women who decline termination of pregnancy and are not prepared to resign themselves to the odds of the natural history of the disease. OBJECTIVE: We evaluated the efficacy of oral valacyclovir, 8 g daily, for pregnant women carrying a symptomatic cytomegalovirus-infected fetus, targeting a high-risk group for developing both neurosensory and neurological impairment. STUDY DESIGN: We designed a multicenter, open-label, phase II study with 1 arm, using one of Simon's optimal 2-stage designs. Symptomatic fetuses were defined by the presence of measurable extracerebral or mild cerebral ultrasound symptoms. They were treated in utero from prenatal diagnosis at a median of 25.9 weeks' gestation until delivery or termination of pregnancy. Fetuses with severe brain anomalies on ultrasound were not included as were cases completely asymptomatic at presentation, because treatment was unlikely to modify either outcome. The primary endpoint was the proportion of asymptomatic neonates born to treated mothers. RESULTS: At the interim analysis, 8 of 11 women delivered an asymptomatic neonate (required: ≥7). In step 2, 32 additional cases were included for a total of 43; the final number of asymptomatic neonates was 34, more than the 31 required to indicate efficacy according to the Simon 2-stage design. They remained asymptomatic at 12 months. High-dosage valacyclovir given for a median of 89 days to pregnant women carrying a moderately infected fetus was efficient at giving birth to asymptomatic neonates. Fetal blood viral loads decreased and platelet counts increased, both significantly (P = .01 and P < .001, respectively), between treatment initiation and birth after treatment completion, regardless of duration of fetal infection. Compared with a historical cohort obtained by a metaanalysis of the literature, the use of valacyclovir (8 g daily) significantly increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment. Although the pill burden was high (16 pills a day) adherence to treatment was >90%. Finally, valacyclovir at this high dosage was extremely well tolerated. CONCLUSION: Our results indicate that high-dosage valacyclovir given in pregnancy is effective for improving the outcome of moderately symptomatic infected fetuses. Although this study is not a randomized controlled trial, this is the first study reporting the efficacy of an antiviral drug to treat cytomegalovirus-infected fetuses. Moreover, this first study will allow new trials to be conducted, using valacyclovir as a baseline safe and effective treatment in pregnancy, to be compared to the new emerging and more potent anticytomegalovirus drugs that have not currently been tested in pregnancy.

Objective and Subjective Burden of Informal Caregivers 4 Years After a Severe Traumatic Brain Injury: Results From the PariS-TBI Study.

OBJECTIVE: Prospective assessment of informal caregiver (IC) burden 4 years after the traumatic brain injury of a relative. SETTING: Longitudinal cohort study (metropolitan Paris, France). PARTICIPANTS: Home dwelling adults (N = 98) with initially severe traumatic brain injury and their primary ICs. MAIN OUTCOME MEASURES: Informal caregiver objective burden (Resource Utilization in Dementia measuring Informal Care Time [ICT]), subjective burden (Zarit Burden Inventory), monetary self-valuation of ICT (Willingness-to-pay, Willingness-to-accept). RESULTS: Informal caregivers were women (81%) assisting men (80%) of mean age of 37 years. Fifty-five ICs reported no objective burden (ICT = 0) and no/low subjective burden (average Zarit Burden Inventory = 12.1). Forty-three ICs reported a major objective burden (average ICT = 5.6 h/d) and a moderate/severe subjective burden (average Zarit Burden Inventory = 30.3). In multivariate analyses, higher objective burden was associated with poorer Glasgow Outcome Scale-Extended scores, with more severe cognitive disorders (Neurobehavioral Rating Scale-revised) and with no coresidency status; higher subjective burden was associated with poorer Glasgow Outcome Scale-Extended scores, more Neurobehavioral Rating Scale-revised disorders, drug-alcohol abuse, and involvement in litigation. Economic valuation showed that on average, ICs did not value their ICT as free and preferred to pay a mean Willingness-to-pay = &OV0556;17 per hour to be replaced instead of being paid for providing care themselves (Willingness-to-accept = &OV0556;12). CONCLUSION: Four years after a severe traumatic brain injury, 44% of ICs experienced a heavy multidimensional burden.

Loss to Follow-Up and Social Background in an Inception Cohort of Patients With Severe Traumatic Brain Injury: Results From the PariS-TBI Study.

OBJECTIVES: To assess determinants of loss to follow-up (FU) at 2 time points of an inception traumatic brain injury (TBI) cohort. DESIGN AND PARTICIPANTS: The PariS-TBI study consecutively included 504 adults with severe TBI on the accident scene (76% male, mean age 42 years, mean Glasgow Coma Scale 5). No exclusion criteria were used. MAIN MEASURE: Loss to FU at 1 and 4 years was defined among survivors as having no outcome data other than survival status. RESULTS: Among 257 1-year survivors, 118 (47%) were lost to FU at 1 year and 98 (40%) at 4 years. Main reasons for loss to FU were impossibility to achieve contact (109 at 1 year, 52 at 4 years) and refusal to participate (respectively 5 and 24). At 1 year, individuals not working preinjury or with nonaccidental traumas were more often lost to FU in univariate and multivariable analyses. At 4 years, loss to FU was significantly associated with preinjury alcohol abuse and unemployment. Relationship with injury severity was not significant. CONCLUSIONS: Socially disadvantaged persons are underrepresented in TBI outcome research. It could result in overestimation of outcome and biased estimates of sociodemographic characteristics' effects. These persons, particularly unemployed individuals, require special attention in clinical practice.

Disability and health-related quality-of-life 4 years after a severe traumatic brain injury: A structural equation modelling analysis.

OBJECTIVES: To assess predictors and indicators of disability and quality-of-life 4 years after severe traumatic brain injury (TBI), using structural equation modelling (SEM). METHODS: The PariS-TBI study is a longitudinal multi-centre inception cohort study of 504 patients with severe TBI. Among 245 survivors, 147 patients were evaluated upon 4-year follow-up, and 85 completed the full assessment. Two outcome measures were analysed separately using SEM: the Glasgow Outcome Scale-extended (GOS-E), to measure disability, and the QOLIBRI, to assess quality-of-life. Four groups of variables were entered in the model: demographics; injury severity; mood and cognitive impairments; somatic impairments. RESULTS: The GOS-E was directly significantly related to mood and cognition, injury severity, and somatic impairments. Age and education had an indirect effect, mediated by mood/cognition or somatic deficiencies. In contrast, the only direct predictor of QOLIBRI was mood and cognition. Age and somatic impairments had an indirect influence on the QOLIBRI. CONCLUSION: Although this study should be considered as explorative, it suggests that disability and quality-of-life were directly influenced by different factors. While disability appeared to result from an interaction of a wide range of factors, quality-of-life was solely directly related to psycho-cognitive factors.

Susceptibility Pattern of Microorganisms Isolated by Percutaneous Needle Biopsy in Nonbacteremic Pyogenic Vertebral Osteomyelitis.

Pyogenic vertebral osteomyelitis (VO) is diagnosed according to several lines of evidence: clinical, biological, radiological, and histological. Definitive diagnosis requires the isolation of a causative pathogen or histological confirmation. The aim of our study was to describe the microorganisms isolated by percutaneous needle biopsy (PNB) and to analyze their susceptibility patterns, in order to assess the possibility of empirical combination therapy for the treatment of nonbacteremic patients without resorting to PNB. Based on a French prospective multicenter study of 351 patients with VO, we compiled clinical, biological, and radiological findings for 101 patients with microbiologically confirmed VO. Based on antibiotic susceptibility testing of PNB isolated pathogens, the suitabilities of four antibiotic combinations were analyzed: ofloxacin plus rifampin, levofloxacin plus rifampin, ciprofloxacin plus clindamycin, and ciprofloxacin plus amoxicillin-clavulanate. The main causative pathogens identified were coagulase-negative Staphylococcus spp. (26% of isolates), followed by Staphylococcus aureus (21%), Streptoccocus spp. (13%), and enterobacteria (21%). Empirical antibiotic combination therapy was effective in nearly 75% of cases, and the different combinations gave similar results, except for ofloxacin-rifampin, which was effective in only 58% of cases. A "perfect" empirical antibiotic therapy does not exist. If PNB is not possible, a combination of a fluoroquinolone with clindamycin or rifampin can be used, but the high risk of microbiological failure does not allow the exclusion of PNB. (This study has been registered with EudraCT, number 2006-000951-18, and ClinicalTrials.gov, number NCT00764114.).