Bioavailability of dissolved and crushed single tablets of bictegravir, emtricitabine, tenofovir alafenamide in healthy adults: the SOLUBIC randomized crossover study.

BACKGROUND: Crushing or dissolving bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) tablets is not recommended because there are no data supporting this practice. METHODS: A crossover, randomized trial in healthy adults (NCT04244448) investigated the bioavailability of two off-label uses of BIC/TAF/FTC (50/200/25 mg), dissolved in water or crushed in apple compote, compared with the solid tablet. Pharmacokinetic (PK) parameters were estimated from sequential intensive plasma antiretroviral concentrations over a 72 h period post dose. Bioequivalence was met if the 90% CIs of the geometric least-squares means ratios comparing BIC/TAF/FTC exposures (AUC and Cmax) from the experimental phases were within 80%-125% of the reference. RESULTS: Eighteen subjects participated in each of the three phases. Dissolved tablet Cmax geometric mean ratio (90% CI) for BIC/TAF/FTC was 105% (93-119)/97% (87-108)/96% (74-124), respectively. Dissolved tablet AUC geometric mean ratio (90% CI) for BIC/TAF/FTC was 111% (100-122)/100% (94 to 105)/99% (81 to 120), respectively. Crushed tablet Cmax geometric mean ratio (90%) CI for BIC/TAF/FTC was 110% (97 to 124)/70% (63-78)/66% (51-85), respectively. Crushed tablet AUC geometric mean ratio (90%) CI for BIC/TAF/FTC was 107% (96-118)/86% (82-91)/84% (69-103), respectively. CONCLUSIONS: Crushing BIC/TAF/FTC tablets may lead to suboptimal emtricitabine and tenofovir alafenamide drug exposures. Dissolving BIC/TAF/FTC in water may be acceptable if the tablet cannot be swallowed whole.

Medicosurgical management of deep wound infections after thoracolumbar instrumentation: risk factors of poor outcomes.

BACKGROUND: Surgical site infection (SSI) after thoracolumbar osteosynthesis is a common complication. Its management relies on surgical revision and antibiotic therapy, but treatment failure is not uncommon. The aim of our study was to assess the frequency of SSI management failure and its risk factors. METHODS: A retrospective study of patients hospitalized from 2011 to 2019 at the University Hospital of Caen was carried out. The infection rate and the time to onset of failure were assessed over a minimum follow-up of 1 year. Treatment failure was defined as the occurrence of a new intervention in the spine in the year following the end of antibiotic therapy, the establishment of long-term suppressive antibiotic therapy, or death from any cause within 1 year of the end of antibiotic therapy. We compared the treatment failure group with the treatment success group to determine risk factors for treatment failure. RESULTS: A total of 2881 patients underwent surgery during the study period, and 92 developed an SSI, corresponding to an SSI rate of 3.19%. Thirty-six percent of the patients with an SSI presented treatment failure. The median time to failure was 31 days. On multivariate analysis, diabetes mellitus was identified as a risk factor for treatment failure, whereas prolonged postoperative drainage for 4 to 5 days was a protective factor. CONCLUSIONS: The number of failures was significant, and failure occurred mainly during the early phase. To decrease the risk of treatment failure, prolonged duration of postoperative drainage seems to be helpful. Additionally, as diabetes is a risk factor for treatment failure, good control of glycemia in these patients might impact their outcomes.

Vaccination perception and coverage among healthcare students in France in 2019.

BACKGROUND: Vaccine hesitancy in healthcare workers has been increasing especially in France while they are the cornerstone of vaccination programs. Greater understanding of healthcare students (HCS) vaccine knowledge, attitudes and beliefs is necessary to provide an adequate vaccination education to better equip them to promote vaccination in their future careers. The aim of this study was to assess vaccination perception (VP) (perception of benefits and risks of vaccines) and its impact on vaccination coverage (VC) for mandatory and recommended vaccines among HCS. METHODS: A standardized, anonymous self-reporting electronic questionnaire was prospectively sent to HCS (medicine, nursing, pharmacy, midwifery, physiotherapy students and 1st year of health sciences students) of Normandy University in France between 18/03/2019 and 8/04/2019. VP was evaluated with questions regarding vaccination hesitancy, safety of vaccine and the benefit/risk balance of vaccination. Global VC (GVC) was defined as being vaccinated according to the mandatory and/or recommended vaccination schedule by national French law in 2018. RESULTS: 542 HCS took part in this survey. VC was high for mandatory (diphtheriae, poliomyelitis, tetanus 93.5%, hepatitis B virus 88.6%) and even most of recommended vaccinations (measles 95%, pertussis 88.2%). Global VC (40.4%) was not statistically different between HCS except for 1st year health sciences students who were less vaccinated (25.6%). Regarding VP, 97.8% of HCS thought that vaccine are effective. When vaccine safety and level of vaccine hesitancy were assessed (on a 0-10 scale, 0: not safe or not hesitant and 10: completely safe and strongly hesitant for vaccine), 91% of respondents stated that vaccine safety is ≥7 and in 80% the vaccine hesitancy was < 3. There was no difference among student categories. 80.6% of HCS recommended all vaccines but only 52% agreed that flu vaccination should be mandatory for HCS. In the multivariate analysis, being a 1st year health care sciences student was associated with a lower GVC (OR 95% CI = 2 [1.2-3.3], p = 0.004) than being a medical student. CONCLUSION: HCS perceived vaccine as effective and secure. Despite the good perception of vaccines, less than half HCS are well vaccinated.

Seasonal influenza vaccination coverage and its determinants among nursing homes personnel in western France.

BACKGROUND: Influenza-associated deaths is an important risk for the elderly in nursing homes (NHs) worldwide. Vaccination coverage among residents is high but poorly effective due to immunosenescence. Hence, vaccination of personnel is an efficient way to protect residents. Our objective was to quantify the seasonal influenza vaccination (IV) coverage among NH for elderly workers and identify its determinants in France. METHODS: We conducted a cross-sectional study in March 2016 in a randomized sample of NHs of the Ille-et-Vilaine department of Brittany, in western France. A standardized questionnaire was administered to a randomized sample of NH workers for face-to-face interviews. General data about the establishment was also collected. RESULTS: Among the 33 NHs surveyed, IV coverage for the 2015-2016 season among permanent workers was estimated at 20% (95% Confidence Interval (CI) 15.3%-26.4%) ranging from 0% to 69% depending on the establishments surveyed. Moreover, IV was associated with having previously experienced a "severe" influenza episode in the past (Prevalence Ratio 1.48, 95% CI 1.01-2.17), and varied by professional categories (p < 0.004) with better coverage among administrative staff. Better knowledge about influenza prevention tools was also correlated (p < 0.001) with a higher IV coverage. Individual perceptions of vaccination benefits had a significant influence on the IV coverage (p < 0.001). Although IV coverage did not reach a high rate, our study showed that personnel considered themselves sufficiently informed about IV. CONCLUSIONS: IV coverage remains low in the NH worker population in Ille-et-Vilaine and also possibly in France. Strong variations of IV coverage among NHs suggest that management and working environment play an important role. To overcome vaccine "hesitancy", specific communication tools may be required to be adapted to the various NH professionals to improve influenza prevention.

Reactogenicity among health care workers following a BNT162b2 or mRNA-1273 second dose after priming with a ChAdOx1 nCOV-19 vaccine.

OBJECTIVES: In March 2021, French authorities recommended a heterologous second dose of the mRNA vaccine for persons aged <55 years, with administration 9 to 12 weeks after the first dose of ChAdOx1 nCoV-19. This recommendation was despite a lack of data on the reactogenicity and safety of the regimen. Since then, several studies have shown an acceptable short-term safety profile of ChAdOx1 nCoV-19 and BNT162b2 heterologous vaccination, although some transient increased reactogenicity has been described. METHODS: We performed a single-centre prospective observational cohort study among health care workers (HCWs) at a tertiary care hospital to assess the reactogenicity of the BNT162b2 and mRNA-1273 vaccines administered as a second dose in participants primed with ChAdOx1 nCoV-19. RESULTS: Among 1184 HCWs, 356 (30%) agreed to participate. Of the participants, 32.3% were male, and the mean age was 35 years (standard deviation: 10.1 years). Of the participants, 229 received BNT162b2 and 127 received mRNA-1273. A systemic reaction was observed in 130 of 229 (56.8%) and 100 of 127 (78.7%) HCWs, respectively. Injection site reactions were generally limited (grade 1 or 2 in 163 of 229 (97.6%) and 90 of 127 (85.7 %) HCWs, respectively). After adjustment for age, sex, and HCW role, receiving the mRNA-1273 vaccine was associated with higher reactogenicity with more grade 3 side effects (adjusted OR (aOR): 3.34; 95% CI, 1.91-5.85), more systemic symptoms (aOR: 2.82; 95% CI, 1.69-4.7), and not being able to work (aOR: 8.35; 95% CI, 3.78-18.44) compared with receiving the BNT162b2 vaccine. DISCUSSION: Among patients receiving the mRNA1273 vaccine as a second dose, our study confirms good tolerance of the heterologous schedule with a higher risk of short-term side effects in comparison with patients receiving the BNT162b2 vaccine.

Association between Following the ESCMID Guidelines for the Management of Candidemia and Mortality: A Retrospective Cohort Study.

OBJECTIVES: The objective of this study was to evaluate the association between ESCMID adherence and 30-day mortality in candidemia. METHODS: We performed a retrospective cohort study in two French tertiary-care hospitals. All patients with at least one positive blood culture (BC) for Candida spp. between January 2013 and December 2019 were included. An adherent case was defined as a candidemia case for which the treatment fulfilled a bundle of defined criteria based on the latest ESCMID recommendations. We explored factors associated with adherence to ESCMID recommendations in an unadjusted model, and we used a propensity score method to address potential channeling biases with regard to 30-day mortality. RESULTS: During the study period, 165 cases of candidemia were included. Among the ESCMID criteria, funduscopic examination was not performed in 45% and neither was echocardiography in 31%, while the ESCMID criteria were fully implemented in 44 cases (27%). In the propensity score analysis, the all-cause 30-day mortality rate was significantly lower among adherent cases (3.4/36.6, 9%) than among nonadherent cases (42.4/119.5, 36%) (OR = 5.3 95% CI [1.6-17.1]). CONCLUSIONS: In our study, adherence to the bundle of criteria for candidemia management was associated with increased survival, supporting additional efforts to implement these recommendations.

Dolutegravir Monotherapy as Maintenance Strategy: A Meta-Analysis of Individual Participant Data From Randomized Controlled Trials.

Background: Dolutegravir monotherapy (DTG-m) results in virological failure (VF) in some people with human immunodeficiency virus (PWH). We sought to identify the independent factors associated with the risk of VF and to explore the effect size heterogeneity between subgroups of PWH enrolled in DTG-m trials. Methods: We searched for randomized clinical trials (RCTs) evaluating DTG-m versus combined antiretroviral therapy (cART) among PWH virologically controlled for at least 6 months on cART. We performed an individual participant data meta-analysis of VF risk factors and quantified their explained heterogeneity in random-effect models. Definition of VF was a confirmed plasma human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) >50 copies/mL by week 48. Results: Among 416 PWH from 4 RCTs, DTG-m significantly increased the risk of VF (16 of 227 [7%] versus 0 of 189 for cART; risk difference 7%; 95% confidence interval [CI], 1%-2%; P = .02; I2 = 51%). Among 272 participants exposed to DTG-m, VF were more likely in participants with the following: first cART initiated ≥90 days from HIV acute infection (adjusted hazard ratio [aHR], 5.16; 95% 95% CI, 1.60-16.65), CD4 T cells nadir <350/mm3 (aHR, 12.10; 95% CI, 3.92-37.40), HIV RNA signal at baseline (aHR, 4.84; 95% CI, 3.68-6.38), and HIV-deoxyribonucleic acid (DNA) copy number at baseline ≥2.7 log/106 peripheral blood mononuclear cells (aHR, 3.81; 95% CI, 1.99-7.30). Among these independent risk factors, the largest effect size heterogeneity was found between HIV DNA subgroups (I2 = 80.2%; P for interaction = .02). Conclusions: Our study supports the importance of a large viral reservoir size for explaining DTG-m simplification strategy failure. Further studies are needed to link size and genetic diversity of the HIV-1 reservoir.

Von Willebrand factor exerts hepatoprotective effects in acute but not chronic cholestatic liver injury in mice.

Acute and chronic liver disease are associated with substantial alterations in the hemostatic system, including elevated levels of the platelet-adhesive protein von Willebrand factor (VWF). Carbon tetrachloride-induced liver fibrosis is reduced in VWF-deficient mice, but it is unclear if VWF plays a pathologic role in all settings of liver fibrosis. Indeed, several studies suggest an anti-fibrotic role for components of the hemostatic system, including platelets, in experimental settings of bile duct fibrosis. However, the role of VWF in this specific pathology has not been examined. We tested the hypothesis that VWF exerts hepatoprotective effects in experimental bile duct injury. Wild-type and VWF-deficient (VWF-/-) mice were challenged with the bile duct toxicant alpha-naphthylisothiocyanate (ANIT) and the impact of VWF deficiency on acute cholestatic liver injury and chronic liver fibrosis was determined. Acute ANIT (60 mg/kg, po)-induced cholestatic liver injury was associated with increased VWF plasma antigen and activity levels. VWF deficiency enhanced ANIT-induced hepatocellular injury, evidenced by increased plasma ALT activity and area of hepatocellular necrosis. Surprisingly, platelet accumulation within necrotic areas was increased in ANIT-challenged VWF-/- mice compared to wild-type mice. Compared to acute ANIT challenge, hepatic platelet accumulation was modest and appeared to be VWF-dependent in mice exposed to ANIT diet (0.05 %) for 6 weeks. However, contrasting the role of VWF after acute ANIT challenge, VWF deficiency did not impact biliary fibrosis induced by chronic ANIT exposure. The results suggest that VWF plays dichotomous roles in experimental acute and chronic ANIT-induced cholestatic liver injury.

Case Report: Leishmania and HIV Co-Diagnosis: How to Understand Medical History?

We report a case of a severe visceral leishmaniasis revealing an HIV-1 infection presenting as an acute primary infection. A young French man living in Paris with history of unprotected sex with a recent male partner and recent travel in Greece was admitted in our Infectious Diseases Department, presenting with acute febrile psychotic disorder, and positive HIV-1 serology with high viral load, very low CD4+ T-cells count and a western blot pattern suggesting an acute infection. The psychotic disorder was finally related to hemophagocytic lymphohistiocytosis diagnosed on bone marrow aspiration, supposedly secondary to HIV acute primary infection. The progressive worsening of pancytopenia despite antiretroviral treatment and the persistence of fever, chills and sweat led to the diagnosis of visceral leishmaniasis through bone marrow biopsy and leishmanial serology. He was treated with intravenous liposomal amphotericin B with quick improvement. We discuss the way HIV infection and visceral leishmaniasis may have interact to lead to the clinical presentation of our patient.

Effect of Tenofovir Disoproxil Fumarate and Emtricitabine on nasopharyngeal SARS-CoV-2 viral load burden amongst outpatients with COVID-19: A pilot, randomized, open-label phase 2 trial.

BACKGROUND: Tenofovir and emtricitabine interfere with the SARS CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). Several cohorts reported that people treated by tenofovir disoproxil fumarate and emtricitabine are less likely to develop SARS CoV-2 infection and related severe COVID-19. METHODS: We conducted a pilot randomized, open-label, controlled, phase 2 trial at two hospitals in France. Eligible patients were consecutive outpatients (aged ≥18 years) with RT-PCR-confirmed SARS-CoV-2 infection and an interval from symptom onset to enrolment of 7 days or less. Patients were randomly assigned in a 1:1 ratio to receive oral tenofovir disoproxil fumarate and emtricitabine (2 pills on day 1 followed by 1 pill per day on days 2-7) or the standard of care. The primary and secondary endpoints were SARS-CoV-2 viral clearance from baseline assessed by cycle threshold (Ct) RT-PCR on nasopharyngeal swab collected at day 4 and day 7, respectively. A higher Ct corresponds to a lower SARS CoV-2 viral burden. Other endpoints were the time to recovery and the number of adverse events. This trial is registered with ClinicalTrials.gov, NCT04685512. FINDINGS: From November, 20th 2020 to March, 19th 2021, 60 patients were enrolled and randomly assigned to a treatment group (30 to tenofovir disoproxil fumarate and emtricitabine and 30 to standard of care). The median number of days from symptom onset to inclusion was 4 days (IQR 3-5) in both groups. Amongst patients who received tenofovir disoproxil fumarate, the difference from standard of care in the increase in Ct RT-PCR from baseline was 2.3 (95% confidence interval [-0.6 to 5.2], p = 0.13) at day 4 and 2.9 (95% CI [0.1 to 5.2], p = 0.044) at day 7. At day 7, 6/30 in the tenofovir disoproxil fumarate and emtricitabine group and 3/30 in the standard of care group reported no COVID-related symptoms. Adverse events included 11 cases of gastrointestinal side effects (grade ≤ 2), three of which leaded to drug discontinuation. Three patients had COVID-19 related hospitalisation, no participant died. INTERPRETATION: In this pilot study of outpatients adult with recent non-severe COVID-19, tenofovir disoproxil fumarate plus emtricitabine appeared to accelerate the natural clearance of nasopharyngeal SARS-CoV-2 viral burden. These findings support the conduct of larger trials of tenofovir-based therapies for the prevention and early treatment of COVID-19. FUNDING: No external funding.

Forgiveness of Dolutegravir-Based Triple Therapy Compared With Older Antiretroviral Regimens: A Prospective Multicenter Cohort of Adherence Patterns and HIV-RNA Replication.

BACKGROUND: For many people with HIV (PWH), taking antiretroviral therapy (ARV) every day is difficult. METHODS: Average adherence (Av-Adh) and log-transformed treatment interruption (TI) to ARV were prospectively measured over 6 months using electronic drug monitoring (EDM) in several cohorts of PWH. Multivariate linear regression models including baseline confounders explored the influence of EDM-defined adherence (R 2) on 6-month log10 HIV-RNA. Multivariate logistic regression models were used to compare the risk of HIV-RNA detection (VR) within subgroups stratified by lower (≤95%) and higher (>95%) Av-Adh. RESULTS: Three hundred ninety-nine PWH were analyzed with different ARVs: dolutegravir (n = 102), raltegravir (n = 90), boosted PI (bPI; n = 107), and NNRTI (n = 100). In the dolutegravir group, the influence of adherence pattern measures on R 2 for HIV-RNA levels was marginal (+2%). Av-Adh, TI, and Av-Adh × TI increased the R 2 for HIV-RNA levels by 54% and 40% in the raltegravir and bPI treatment groups, respectively. TI increased the R 2 for HIV-RNA levels by 36% in the NNRTI treatment group. Compared with the dolutegravir-based regimen, the risk of VR was significantly increased for raltegravir (adjusted odds ratio [aOR], 45.6; 95% CI, 4.5-462.1; P = .001), NNRTIs (aOR, 24.8; 95% CI, 2.7-228.4; P = .005), and bPIs (aOR, 28.3; 95% CI, 3.4-239.4; P = .002) in PWH with Av-Adh ≤95%. Among PWH with >95% Av-Adh, there were no significant differences in the risk of VR among the different ARVs. CONCLUSIONS: These findings support the concept that dolutegravir in combination with 2 other active ARVs achieves greater virological suppression than older ARVs, including raltegravir, NNRTI, and bPI, among PWH with lower adherence.

Incidence and risk factors for medical care interruption in people living with HIV in a French provincial city.

OBJECTIVES: The aim of our study was to identify HIV-positive patients at risk of medical care interruption (MCI) in a provincial city of a high-income country. METHODS: We estimated the incidence rate of MCI in 989 individuals followed in an HIV clinic in Caen University Hospital, Normandy, France, between January 2010 and May 2016. We enrolled patients over 18 years old who were seen at the clinic at least twice after HIV diagnosis. Patients were considered to be in MCI if they did not attend care in or outside the clinic for at least 18 months, regardless of whether or not they came back after interruption. We investigated sociodemographic, clinical and immunovirological characteristics at HIV diagnosis and during follow-up through a Cox model analysis. RESULTS: The incidence rate of MCI was estimated to be 3.0 per 100 persons-years (95% confidence interval [CI] = 2.6-3.5). The independent risk factors for MCI were a linkage to care >6 months after HIV diagnosis (hazard ratio [HR] = 1.14; 95% CI = 1.08-1.21), a hepatitis C coinfection (HR = 1.76; 95% CI = 1.07-2.88), being born in Sub-Saharan Africa (HR = 2.18; 95% CI = 1.42-3.34 vs. in France) and not having a mailing address reported in the file (HR = 1.73; 95% CI = 1.07-2.80). During follow-up, the risk of MCI decreased when the patient was older (HR = 0.28; 95% CI = 0.15-0.51 when >45 vs. ≤ 30 years old) and increased when the patient was not on antiretroviral therapy (HR = 2.78; 95% CI = 1.66-4.63). CONCLUSIONS: Our findings show that it is important to link HIV-positive individuals to care quickly after diagnosis and initiate antiretroviral therapy as soon as possible to retain them in care.

Incidence of and risk factors for medical care interruption in people living with HIV in recent years.

OBJECTIVES: With HIV treatment as a prevention strategy, retention in care remains a key for sustained viral suppression. We sought to identify HIV-infected patients at risk for medical care interruption (MCI) in a high-income country. METHODS: The HIV-infected patients enrolled had to attend the clinic at least twice between January 2010 and October 2014 and were followed up until May 2016. MCI was defined as patients not seeking care in or outside the clinic for at least 18 months, regardless of whether they returned to care after the interruption. The association between MCI and sociodemographic, clinical, and immuno-virological characteristics at HIV diagnosis and during follow-up was assessed using Cox models. RESULTS: The incidence rate of MCI was 2.5 per 100 persons-years (95% confidence interval [CI] = 2.3-2.7). MCI was more likely in patients who accessed care >6 months after diagnosis (hazard ratio [HR] = 1.30, 95% CI = 1.10-1.54 vs. ≤6 months) or did not report a primary care physician (HR = 2.40; 95% CI = 2.03-2.84). MCI was less likely in patients born in sub-Saharan Africa (HR = 0.75, 95% CI = 0.62-0.91 vs. born in France). During follow-up, the risk of MCI increased when the last CD4 count was ≤350 (HR = 2.85, 95% CI = 2.02-4.04 vs. >500 cells/mm3) and when the patient was not on antiretroviral therapy (HR = 3.67, 95% CI = 2.90-4.66). CONCLUSIONS: The incidence of MCI is low in this hospital that serves a large proportion of migrants. Low or no recorded CD4 counts for a medical visit could alert of a higher risk of MCI, even more in patients who accessed HIV care late or did not report a primary care physician.

Immune Reconstitution Inflammatory Syndrome Unmasking or Worsening AIDS-Related Progressive Multifocal Leukoencephalopathy: A Literature Review.

Incidence of progressive multifocal leukoencephalopathy (PML) in HIV-infected patients has declined in the combined antiretroviral therapy (cART) era although a growing number of acquired immunodeficiency syndrome (AIDS)-related PML-immune reconstitution inflammatory syndromes (PML-IRIS) have been published during the same period. Therapeutic management of PML-IRIS is not consensual and mainly relies on corticosteroids. Our main aim was, in addition to provide a thoughtful analysis of published PML-IRIS cases, to assess the benefit of corticosteroids in the management of PML-IRIS, focusing on confirmed cases. We performed a literature review of the 46 confirmed cases of PML-IRIS cases occurring in HIV-infected patients from 1998 to September 2016 (21 unmasking and 25 paradoxical PML-IRIS). AIDS-related PML-IRIS patients were mostly men (sex ratio 4/1) with a median age of 40.5 years (range 12-66). Median CD4 T cell count before cART and at PML-IRIS onset was 45/µl (0-301) and 101/µl (20-610), respectively. After cART initiation, PML-IRIS occurred within a median timescale of 38 days (18-120). Clinical signs were motor deficits (69%), speech disorders (36%), cognitive disorders (33%), cerebellar ataxia (28%), and visual disturbances (23%). Brain MRI revealed hyperintense areas on T2-weighted sequences and FLAIR images (76%) and suggestive contrast enhancement (87%). PCR for John Cunningham virus (JCV) in cerebrospinal fluid (CSF) was positive in only 84% of cases; however, when performed, brain biopsy confirmed diagnosis of PML in 90% of cases and demonstrated histological signs of IRIS in 95% of cases. Clinical worsening related to PML-IRIS and leading to death was observed in 28% of cases. Corticosteroids were prescribed in 63% of cases and maraviroc in one case. Statistical analysis failed to demonstrate significant benefit from steroid treatment, despite spectacular improvement in certain cases. Diagnosis of PML-IRIS should be considered in HIV-infected patients with worsening neurological symptoms after initiation or resumption of effective cART, independently of CD4 cell count prior to cART. If PCR for JCV is negative in CSF, brain biopsy should be discussed. Only large multicentric randomized trials could potentially demonstrate the possible efficacy of corticosteroids and/or CCR5 antagonists in the management of PML-IRIS.

Analysis of the dynamic co-expression network of heart regeneration in the zebrafish.

The zebrafish has the capacity to regenerate its heart after severe injury. While the function of a few genes during this process has been studied, we are far from fully understanding how genes interact to coordinate heart regeneration. To enable systematic insights into this phenomenon, we generated and integrated a dynamic co-expression network of heart regeneration in the zebrafish and linked systems-level properties to the underlying molecular events. Across multiple post-injury time points, the network displays topological attributes of biological relevance. We show that regeneration steps are mediated by modules of transcriptionally coordinated genes, and by genes acting as network hubs. We also established direct associations between hubs and validated drivers of heart regeneration with murine and human orthologs. The resulting models and interactive analysis tools are available at http://infused.vital-it.ch. Using a worked example, we demonstrate the usefulness of this unique open resource for hypothesis generation and in silico screening for genes involved in heart regeneration.