Use of actigraphy for monitoring agitation and rest-activity cycles in patients with acute traumatic brain injury in the ICU.

BACKGROUND: In traumatic brain injury patients (TBI) admitted to the intensive care unit (ICU), agitation can lead to accidental removal of catheters, devices as well as self-extubation and falls. Actigraphy could be a potential tool to continuously monitor agitation. The objectives of this study were to assess the feasibility of monitoring agitation with actigraphs and to compare activity levels in agitated and non-agitated critically ill TBI patients. METHODS: Actigraphs were placed on patients' wrists; 24-hour monitoring was continued until ICU discharge or limitation of therapeutic efforts. Feasibility was assessed by actigraphy recording duration and missing activity count per day. RESULTS: Data from 25 patients were analyzed. The mean number of completed day of actigraphy per patient was 6.5 ± 5.1. The mean missing activity count was 20.3 minutes (±81.7) per day. The mean level of activity measured by raw actigraphy counts per minute over 24 hours was higher in participants with agitation than without agitation. CONCLUSIONS: This study supports the feasibility of actigraphy use in TBI patients in the ICU. In the acute phase of TBI, agitated patients have higher levels of activity, confirming the potential of actigraphy to monitor agitation.

Exposure levels and target attainment of piperacillin/tazobactam in adult patients admitted to the intensive care unit: a prospective observational study.

PURPOSE: The objective of this study was to evaluate the exposure and the pharmacodynamic target attainment of piperacillin/tazobactam (PTZ) in adult critically ill patients. METHODS: We conducted a prospective observational study in the intensive care unit (ICU) of the Hôpital du Sacré-Cœur de Montréal (a Level I trauma centre in Montreal, QC, Canada) between January 2021 and June 2022. We included patients aged 18 yr or older admitted to the ICU who received PTZ by intravenous administration. Demographic and clinical characteristics were collected, and clinical scores were calculated. On study day 1 of antimicrobial therapy, three blood samples were collected at the following timepoints: one hour after PTZ dose administration and at the middle and at the end of the dosing interval. The sampling schedule was repeated on days 4 and 7 of therapy if possible. Samples were analyzed by ultra-high performance liquid chromatography with diode array detector to determine the total piperacillin concentration. Middle- and end-of-interval concentrations were used for target attainment analyses, and were defined as a concentration above the minimal inhibitory concentration of 16 mg·L-1, corresponding to the breakpoint of Enterobacteriaceae and Pseudomonas aeruginosa. RESULTS: Forty-three patients were recruited and 202 blood samples were analyzed. The most prevalent dose was 3/0.375 g every six hours (n = 50/73 doses administered, 68%) with a 30-min infusion. We observed marked variability over the three sampling timepoints, and the median [interquartile range] piperacillin concentrations at peak, middle of interval, and end of interval were 109.4 [74.0-152.3], 59.3 [21.1-74.4], and 25.3 [6.8-44.6] mg·L-1, respectively. When assessing target attainment, 37% of patients did not reach the efficacy target of a trough concentration of 16 mg·L-1. The majority of patients who were underexposed were patients with normal to augmented renal clearance. CONCLUSION: In this prospective observational study of adult ICU patients receiving intravenous PTZ, a large proportion had subtherapeutic concentrations of piperacillin. This was most notable in patients with normal to augmented renal clearance. More aggressive dosage regimens may be required for this subpopulation to ensure attainment of efficacy targets.

RéSUMé: OBJECTIF: L'objectif de cette étude était d'évaluer l'exposition et l'atteinte des cibles pharmacodynamiques de la pipéracilline/tazobactam (PTZ) chez la patientèle adulte aux soins intensifs. MéTHODES: Nous avons réalisé une étude observationnelle prospective dans l'unité de soins intensifs (USI) de l'Hôpital du Sacré-Cœur de Montréal (un centre de traumatologie de niveau 1 à Montréal, QC, Canada) entre janvier 2021 et juin 2022. Nous avons inclus les patient·es adultes âgé·es de 18 ans ou plus admis·es à l'USI ayant reçu de la PTZ par administration intraveineuse. Les caractéristiques démographiques et cliniques ont été recueillies, et les scores cliniques ont été calculés. Au jour 1 de la thérapie antimicrobienne, trois échantillons sanguins ont été prélevés aux moments suivants : 1 h après l'administration de la dose de PTZ, au milieu et à la fin de l'intervalle d'administration. Le calendrier d'échantillonnage a été répété aux jours 4 et 7 de la thérapie si possible. Les échantillons ont été analysés par chromatographie liquide à ultra-haute performance avec détecteur à diodes pour déterminer la concentration totale de pipéracilline. Les concentrations du milieu et de fin d'intervalle ont été utilisées pour les analyses d'atteinte de cible, définie comme une concentration supérieure à la concentration minimale inhibitrice de 16 mg·L-1, associée aux Enterobacteriaceae et au Pseudomonas aeruginosa. RéSULTATS: Quarante-trois patient·es ont été recruté·es et 202 échantillons sanguins ont été analysés. La dose la plus prévalente était une dose de 3/0,375 g aux 6 h (n = 50/73 doses administrées, 68 %) avec une perfusion sur 30 min. Nous avons observé une variabilité marquée aux trois temps de prélèvement, et les concentrations médianes [intervalle interquartile] de pipéracilline au pic, au milieu et à la fin de l'intervalle étaient respectivement de 109,4 [74,0-152,3], 59,3 [21,1-74,4] et 25,3 [6,8-44,6] mg·L−1. Lors de l'évaluation de l'atteinte de la cible, 37 % des patient·es n'ont pas atteint la cible d'efficacité d'une concentration de 16 mg·L−1 à la fin de l'intervalle posologique. La majorité des patient·es sous-exposé·es étaient des personnes dont la clairance rénale était normale ou augmentée. CONCLUSION: Dans cette étude observationnelle prospective de patient·es adultes aux soins intensifs recevant de la PTZ par voie intraveineuse, une grande proportion de patient·es présentait des concentrations sous-thérapeutiques de pipéracilline. Ceci était plus marqué chez les patient·es ayant une clairance rénale normale ou augmentée. Des schémas posologiques plus agressifs pourraient être nécessaires pour cette sous-population afin de favoriser l'atteinte des cibles d'efficacité.

Neurological Manifestations of SARS-CoV-2 Infection: Protocol for a Sub-analysis of the COVID-19 Critical Care Consortium Observational Study.

Introduction: Neurological manifestations and complications in coronavirus disease-2019 (COVID-19) patients are frequent. Prior studies suggested a possible association between neurological complications and fatal outcome, as well as the existence of potential modifiable risk factors associated to their occurrence. Therefore, more information is needed regarding the incidence and type of neurological complications, risk factors, and associated outcomes in COVID-19. Methods: This is a pre-planned secondary analysis of the international multicenter observational study of the COVID-19 Critical Care Consortium (which collected data both retrospectively and prospectively from the beginning of COVID-19 pandemic) with the aim to describe neurological complications in critically ill COVID-19 patients and to assess the associated risk factors, and outcomes. Adult patients with confirmed COVID-19, admitted to Intensive Care Unit (ICU) will be considered for this analysis. Data collected in the COVID-19 Critical Care Consortium study includes patients' pre-admission characteristics, comorbidities, severity status, and type and severity of neurological complications. In-hospital mortality and neurological outcome were collected at discharge from ICU, and at 28-days. Ethics and Dissemination: The COVID-19 Critical Care Consortium main study and its amendments have been approved by the Regional Ethics Committee of participating sites. No further approval is required for this secondary analysis. Trial Registration Number: ACTRN12620000421932.

The Suitability of Potential Organ Donors Using Real Case-Scenarios; Do we Need to Create a "Donor Board" Process for Donors Perceived as Unlikely Suitable?

Introduction: Despite availability of selection criteria, different interpretations can lead to variability in the appreciation of donor eligibility with possible viable organs missed. Our primary objective was to test the perception of feasibility of potential organ donors through the survey of a small sample of external evaluators. Methods: Clinical scenarios summarizing 66 potential donors managed in the first year of our Organ Recovery Center were sent to four critical care physicians to evaluate the feasibility of the potential donors and the probability of organ procurement. Results: Potential donors procuring at least one organ were identified in 55 of the 66 cases (83%). Unanimity was reached in 38 cases, encompassing 35 out of the 55 converted and 3 of the non-converted donors. The overall agreement was moderate (kappa = 0.60, 95% CI: 0.37-0.82). For the organs finally procured for transplantation, organ donation was predicted for the majority of the cases, but high discrepancy was present with the final outcome of organs not procured (particularly liver and kidney). Conclusion: The assessment of a potential donor is a complex dynamic process. In order to increase organ availability, standardized electronically clinical data, as well a "donor board" structure of decision might inform future systems.

EXperienceS and aTtitudes towards Agitated behaviours in Traumatic brain injury in the Intensive Care unit patients (EXSTATIC): a protocol for an interprofessional mixed-method study.

INTRODUCTION: Agitation and violent behaviours are common conditions developed by patients with acute traumatic brain injury (TBI) in intensive care units (ICUs). Healthcare professionals caring for these patients have various tools to manage these behaviours, but lack of a formal protocol to assess and manage them makes caring for these patients a challenge. Moreover, safety may often be compromised for both ICU professionals and patients encountering such situations. The EXperienceS and aTtitudes towards Agitated behaviours in Traumatic brain injury in the Intensive Care unit patients (EXSTATIC) study aims to explore the experiences and attitudes of ICU nurses and other ICU healthcare professionals on the management of agitated behaviours in patients with acute TBI. METHODS AND ANALYSIS: EXSTATIC is a multicenter mixed methods convergent study exploring experiences and attitudes of ICU healthcare professionals caring of agitated patients with TBI. The study includes three qualitative methods (observation, semistructured interviews and focus groups) and one quantitative method (retrospective cohort). The integration of the different methods will be done using sequential steps of the research and by the integration of results for each step. Qualitative data will be evaluated following a thematic analysis derived from a grounded theory approach. Quantitative data will be analysed using descriptive statistics. Qualitative and quantitative results will be combined in a convergent interactive interpretative design. Gender and race perspective will be integrated in collection, analysis and interpretation of data. ETHICS AND DISSEMINATION: This study has been approved by the Centre intégré universitaire de santé et de services sociaux du nord de l'île de Montréal (CIUSSS-NÎM) Research Ethics Board. The findings will be disseminated locally with ICU staff and health managers, international peer-reviewed journals, a PhD dissertation, and national and international conferences. The knowledge derived from this study is key in the development of clinical protocols to manage agitation and related behaviours in patients with TBI and designing further interventional studies targeting this specific problematic. TRIAL REGISTRATION NUMBER: NCT04741399.

Validation of the Critical-Care Pain Observation Tool-Neuro in brain-injured adults in the intensive care unit: a prospective cohort study.

BACKGROUND: Pain assessment in brain-injured patients in the intensive care unit (ICU) is challenging and existing scales may not be representative of behavioral reactions expressed by this specific group. This study aimed to validate the French-Canadian and English revised versions of the Critical-Care Pain Observation Tool (CPOT-Neuro) for brain-injured ICU patients. METHODS: A prospective cohort study was conducted in three Canadian and one American sites. Patients with a traumatic or a non-traumatic brain injury were assessed with the CPOT-Neuro by trained raters (i.e., research staff and ICU nurses) before, during, and after nociceptive procedures (i.e., turning and other) and non-nociceptive procedures (i.e., non-invasive blood pressure, soft touch). Patients who were conscious and delirium-free were asked to provide their self-report of pain intensity (0-10). A first data set was completed for all participants (n = 226), and a second data set (n = 87) was obtained when a change in the level of consciousness (LOC) was observed after study enrollment. Three LOC groups were included: (a) unconscious (Glasgow Coma Scale or GCS 4-8); (b) altered LOC (GCS 9-12); and (c) conscious (GCS 13-15). RESULTS: Higher CPOT-Neuro scores were found during nociceptive procedures compared to rest and non-nociceptive procedures in both data sets (p < 0.001). CPOT-Neuro scores were not different across LOC groups. Moderate correlations between CPOT-Neuro and self-reported pain intensity scores were found at rest and during nociceptive procedures (Spearman rho > 0.40 and > 0.60, respectively). CPOT-Neuro cut-off scores ≥ 2 and ≥ 3 were found to adequately classify mild to severe self-reported pain ≥ 1 and moderate to severe self-reported pain ≥ 5, respectively. Interrater reliability of raters' CPOT-Neuro scores was supported with intraclass correlation coefficients > 0.69. CONCLUSIONS: The CPOT-Neuro was found to be valid in this multi-site sample of brain-injured ICU patients at various LOC. Implementation studies are necessary to evaluate the tool's performance in clinical practice.

Agitation, confusion, and aggression in critically ill traumatic brain injury-a pilot cohort study (ACACIA-PILOT).

BACKGROUND: Agitated behaviors are problematic in intensive care unit (ICU) patients recovering from traumatic brain injury (TBI) as they create substantial risks and challenges for healthcare providers. To date, there have been no studies evaluating their epidemiology and impact in the ICU. Prior to planning a multicenter study, assessment of recruitment, feasibility, and pilot study procedures is needed. In this pilot study, we aimed to evaluate the feasibility of conducting a large multicenter prospective cohort study. METHODS: This feasibility study recruited adult patients admitted to the ICU with TBI and an abnormal cerebral CT scan. In all patients, we documented Richmond Agitation Sedation Score (RASS) and agitated behaviors every 8-h nursing shift using a dedicated tool documenting 14 behaviors. Our feasibility objectives were to obtain consent from at least 2 patients per month; completion of screening logs for agitated behaviors by bedside nurses for more than 90% of 8-h shifts; completion of data collection in an average of 6 h or less; and obtain 6-month follow-up for surviving patients. The main clinical outcome was the incidence of agitation and individual agitated behaviors. RESULTS: In total, 47 eligible patients were approached for inclusion and 30 (64% consent rate) were recruited over a 10-month period (3 patients/month). In total, 794 out of 827 (96%) possible 8-h periods of agitated behavior logs were completed by bedside nurses, with a median of 24 observations (IQR 28.0) per patient. During the ICU stay, 17 of 30 patients developed agitation (56.7%; 95% CI 0.37-0.75) defined as RASS ≥ 2 during at least one observation period and for a median of 4 days (IQR 5.5). At 6 months post-TBI, among the 24 available patients, an unfavorable score (GOS-E < 5 including death) was reported in 12 patients (50%). In the 14 patients who were alive and available at 6 months, the median QOLIBRI score was 74.5 (IQR 18.5). CONCLUSIONS: This study demonstrates the feasibility of conducting a larger cohort study to evaluate the epidemiology and impact of agitated behaviors in critically ill TBI patients. This study also shows that agitated behaviors are frequent and are associated with adverse events.

A Pilot Randomized Controlled Trial Comparing Levothyroxine to Placebo in Neurologically Deceased Donors.

BACKGROUND: Although commonly prescribed, the efficacy of levothyroxine to improve heart function in neurologically deceased donors is unclear. We evaluated the feasibility of a randomized controlled trial to compare levothyroxine to placebo on the variation of left ventricular ejection fraction, in hemodynamically unstable donors. METHODS: We conducted a pilot, double-blinded, randomized controlled trial. Deceased donors with reduced left ventricular ejection fraction or needing vasopressors were included. We randomized participants to a 20 µg bolus followed by a 20 µg/h infusion of levothyroxine or an identically appearing placebo. We report the proportion of recruited participants, the time to the administration of the study drug, and protocol violations. RESULTS: Twenty-four participants (N = 24/104; 23.1%) were eligible. Five of them (N = 5/24; 20.8%) were excluded by the attending physician. Four others were not included, due to family refusal for research (n = 2/24;8.3%) and unavailability of research staff (n = 2/24; 8.3%). Fifteen participants were randomized (N = 15/104; 14.4%). Mean time between the echocardiography and the initiation of the drug was 1.73 hours, and14 (93.3%) of 15 of the participants received the drug within 2 hours after the echocardiography. We report no study violation. The study was stopped prematurely because of low recruitment. CONCLUSION: This pilot trial suggests that the success of a definitive randomized control trial to assess the efficacy of levothyroxine in deceased donors could benefit from a multicenter recruitment and education on the evidence surrounding the pharmacological management of organ donors. The need for consent to research interventions in deceased donors should also be clarified.

Minimal PaO2 threshold after traumatic brain injury and clinical utility of a novel brain oxygenation ratio.

OBJECTIVE: Avoiding decreases in brain tissue oxygenation (PbtO2) after traumatic brain injury (TBI) is important. How best to adjust PbtO2 remains unclear. The authors investigated the association between partial pressure of oxygen (PaO2) and PbtO2 to determine the minimal PaO2 required to maintain PbtO2 above the hypoxic threshold (> 20 mm Hg), accounting for other determinants of PbtO2 and repeated measurements in the same patient. They also explored the clinical utility of a novel concept, the brain oxygenation ratio (BOx ratio = PbtO2/PaO2) to detect overtreatment with the fraction of inspired oxygen (FiO2). METHODS: A retrospective cohort study at an academic level 1 trauma center included 38 TBI patients who required the insertion of a monitor to measure PbtO2. Various determinants of PbtO2 were collected simultaneously whenever a routine arterial blood gas was drawn. A PbtO2/PaO2 ratio was calculated for each blood gas and plotted over time for each patient. All patients were managed according to a standardized clinical protocol. A mixed effects model was used to account for repeated measurements in the same patient. RESULTS: A total of 1006 data points were collected. The lowest mean PaO2 observed to maintain PbtO2 above the ischemic threshold was 94 mm Hg. Only PaO2 and cerebral perfusion pressure were predictive of PbtO2 in multivariate analysis. The PbtO2/PaO2 ratio was below 0.15 in 41.7% of all measures and normal PbtO2 values present despite an abnormal ratio in 27.1% of measurements. CONCLUSIONS: The authors' results suggest that the minimal PaO2 target to ensure adequate cerebral oxygenation during the first few days after TBI should be higher than that suggested in the Brain Trauma Foundation guidelines. The use of a PbtO2/PaO2 ratio (BOx ratio) may be clinically useful and identifies abnormal O2 delivery mechanisms (cerebral blood flow, diffusion, and cerebral metabolic rate of oxygen) despite normal PbtO2.

Detection of IKKε by immunohistochemistry in primary breast cancer: association with EGFR expression and absence of lymph node metastasis.

BACKGROUND: IKKε is an oncogenic kinase that was found amplified and overexpressed in a substantial percentage of human breast cancer cell lines and primary tumors using genomic and gene expression analyses. Molecular studies have provided the rational for a key implication of IKKε in breast cancer cells proliferation and invasiveness through the phosphorylation of several substrates. METHODS: Here, we performed immunohistochemical detection of IKKε expression on tissue microarrays constituted of 154 characterized human breast cancer tumors. We further determined the association with multiple clinicopathological parameters and 5-years overall, disease-free and distant disease free survival. RESULTS: We observed expression of IKKε in 60.4% of the breast cancer tumors. IKKε expression status showed no association with a panel of markers used for molecular classification of the tumors, including ER/PR/HER2 status, or with the molecular subtypes. However, IKKε expression was inversely associated with lymph node metastasis status (p = 0.0032). Additionally, we identified a novel association between IKKε and EGFR expression (p = 0.0011). CONCLUSIONS: The unexpected observation of an inverse association between IKKε and lymph node metastasis advocates for larger scale immunohistochemical profiling of primary breast tumors to clarify the role of IKKε in metastasis. This study suggests that breast cancer tumors expressing EGFR and IKKε may be potential targets for drugs aiming at inhibiting IKKε activity or expression.

Redox-modulating agents target NOX2-dependent IKKε oncogenic kinase expression and proliferation in human breast cancer cell lines.

Oxidative stress is considered a causative factor in carcinogenesis, but also in the development of resistance to current chemotherapies. The appropriate usage of redox-modulating compounds is limited by the lack of knowledge of their impact on specific molecular pathways. Increased levels of the IKKε kinase, as a result of gene amplification or aberrant expression, are observed in a substantial number of breast carcinomas. IKKε not only plays a key role in cell transformation and invasiveness, but also in the development of resistance to tamoxifen. Here, we studied the effect of in vitro treatment with the redox-modulating triphenylmethane dyes, Gentian Violet and Brilliant Green, and nitroxide Tempol on IKKε expression and cell proliferation in the human breast cancer epithelial cell lines exhibiting amplification of IKKε, MCF-7 and ZR75.1. We show that Gentian Violet, Brilliant Green and Tempol significantly decrease intracellular superoxide anion levels and inhibit IKKε expression and cell viability. Treatment with Gentian Violet and Brilliant Green was associated with a reduced cyclin D1 expression and activation of caspase 3 and/or 7. Tempol decreased cyclin D1 expression in both cell lines, while activation of caspase 7 was only observed in MCF-7 cells. Silencing of the superoxide-generating NOX2 NADPH oxidase expressed in breast cancer cells resulted in the significant reduction of IKKε expression. Taken together, our results suggest that redox-modulating compounds targeting NOX2 could present a particular therapeutic interest in combination therapy against breast carcinomas exhibiting IKKε amplification.

Individual interferon regulatory factor-3 thiol residues are not critical for its activation following virus infection.

The interferon regulatory factor (IRF)-3 transcription factor plays a central role in the capacity of the host to mount an efficient innate antiviral immune defense, mainly through the regulation of type I Interferon genes. A tight regulation of IRF-3 is crucial for an adapted intensity and duration of the response. Redox-dependent processes are now well known to regulate signaling cascades. Recent reports have revealed that signaling molecules upstream of IRF-3, including the mitochondrial antiviral-signalling protein (MAVS) and the TNF receptor associated factors (TRAFs) adaptors, are sensitive to redox regulation. In the present study, we assessed whether redox regulation of thiol residues contained in IRF-3, which are priviledged redox sensors, play a role in its regulation following Sendai virus infection, using a combination of mutation of Cysteine (Cys) residues into Alanine and thiols alkylation using N-ethyl maleimide. Alkylation of IRF-3 on Cys289 appears to destabilize IRF-3 dimer in vitro. However, a detailed analysis of IRF-3 phosphorylation, dimerization, nuclear accumulation, and induction of target gene promoter in vivo led us to conclude that IRF-3 specific, individual Cys residues redox status does not play an essential role in its activation in vivo.

Stat1 is a suppressor of ErbB2/Neu-mediated cellular transformation and mouse mammary gland tumor formation.

The anti-tumor function of Stat1 as a regulator of innate immunity and tumor immune surveillance has been long studied and is well understood; however, less clear is its tumor-site specific role. Although Stat1 phosphorylated at tyrosine (Y) 701 and serine (S) 727 is essential for interferon (IFN) signalling, its function in signalling induced in breast cancer cells is not understood. Herein, we show that Stat1 Y701 phosphorylation is increased in human breast tumor cells with elevated levels of ErbB2/HER-2 and in cells transfected with ErbB2/Neu. However, pharmacological inhibition of ErbB2/HER-2 results in the inhibition of Stat1 Y701 phosphorylation indicating an atypical role of phosphorylated Stat1 in the inhibition of ErbB2/HER-2 signalling. Consistent with this notion, we found that Stat1 suppresses tumor development by an activated form of ErbB2/Neu in mouse embryonic fibroblasts in xenograft tumor assays; however, this anti-tumor function of Stat1 does not rely on Y701 and S727 phosphorylation. Experiments with transgenic mice demonstrated that Stat1 acts to suppress Neu-mediated breast tumorigenesis through immune regulatory and tumor-site specific mechanisms. Our data reveal a previous uncharacterized anti-tumor activity of Stat1 in ErbB2/Neu-mediated cell transformation and breast oncogenesis with possible implications in the diagnosis and treatment of ErbB2-positive breast cancers.

Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene.

Co-infection and superinfection of hepatitis B virus (HBV) with hepatitis delta virus (HDV) leads to suppression of HBV replication both in patients and in animal and cellular models. The mechanisms behind this inhibition have not previously been explored fully. HBV replication is governed by four promoters and two enhancers, Enh1 and Enh2. Repression of these enhancers has been reported to be one of the main mechanisms of HBV inhibition. Moreover, in a previous study, it has been demonstrated that alpha interferon (IFN-alpha)-inducible MxA protein inhibits HBV replication. HDV encodes two proteins, p24 and p27. p27 was shown to activate several heterologous promoters, including HBV promoters. In an attempt to analyse the mechanisms of HBV inhibition by HDV, the question was raised whether HDV proteins could act directly by repressing HBV enhancers, and/or indirectly by activating the MxA gene. This issue was addressed in a co-transfection model in Huh-7 cells, using p24- or p27-expressing plasmids along with Enh1, Enh2, HBV and MxA promoter-luciferase constructs. Enh1 and Enh2 were strongly repressed, by 60 and 80 % and 40 and 60 %, by p24 and p27, respectively. In addition, p27 was responsible for threefold activation of the MxA promoter and potentiation of IFN-alpha on this promoter. MxA mRNA quantification and a virus yield reduction assay confirmed these results. In conclusion, this study shows that HDV proteins inhibit HBV replication by trans-repressing its enhancers and by trans-activating the IFN-alpha-inducible MxA gene.

Immunological efficacy of a three-dose schedule of hepatitis A vaccine in HIV-infected adults: HEPAVAC study.

BACKGROUND: The immunogenicity of vaccines, including vaccine against hepatitis A virus (HAV), is impaired in patients with HIV infection, requiring revised immunization regimens. METHODS: We evaluated the immunological efficacy and safety of a 3-dose schedule of hepatitis A vaccine in HIV-infected adults. HAV-seronegative HIV-infected adults were randomized to receive either 3 doses of 1440 UI of hepatitis A vaccine (HAVRIX; GlaxoSmithKline, Marly le Roi, France) at weeks 0, 4, and 24 (46 patients) or 2 doses 24 weeks apart (49 patients). RESULTS: At week 28, seroconversion, defined as an anti-HAV antibody >or=20 mIU/mL, occurred in 82.6% and 69.4% of patients in the 3-dose and the 2-dose group, respectively (P = 0.13, intent-to-treat analysis, missing data = nonresponder), and in 88.4% and 72.3% of patients in the 3-dose and the 2-dose group, respectively (P = 0.06, observed analysis). Only 37.9% of patients experienced seroconversion after 1 vaccine dose (intent-to-treat analysis). Anti-HAV antibody geometric mean titers were 323 and 132 mIU/mL in the 3-dose group and 138 and 67 mIU/mL in the 2-dose group, respectively, 28 (P = 0.03) and 72 weeks (P = 0.05) after the first vaccine dose. There were no serious adverse events associated with the vaccine. Multivariate analysis showed no treatment group effect but indicated that absence of tobacco smoking (odds ratio = 2.92, 95% confidence interval: 1.07 to 7.97; P = 0.04) was an independent predictor of response to HAV vaccine. CONCLUSIONS: In HIV-infected adults, immunogenicity of hepatitis A vaccine is poor. Three doses of vaccine were safe and increased antibody titers.

Significance of hepatitis B virus genotypes A to E in a cohort of patients with chronic hepatitis B in the Seine Saint Denis District of Paris (France).

The aim of this study was to examine the genetic variability of the hepatitis B virus (HBV) and its significance. HBV genotypes, core promoter and precore mutants were characterized in 109 consecutive patients with biopsy-proven HBV chronic hepatitis. Genotypes A (26.6%), B (12.8%), C (18.3%), D (18.3%), and E (14.7%) indicate a wide genotypic distribution. Patients were from Asia (30.3%), Europe (28.4%), Sub Saharan Africa (23.9%), the Caribbean (10.1%), North Africa (5.5%), and Madagascar (1.8%). HBV genotypes A and D (HBV/A and /D) infected all subgroups except Asian patients. HBV/B or /C were found in 97% of Asian patients, whereas HBV/E only infected sub-Saharan African and Caribbean patients. Differences according to genotypes were: an increased prevalence of anti-HBe antibodies in patients infected with HBV/D (P = 0.003), higher serum transaminases in patients infected with HBV/A and/D (P = 0.043), more severe liver fibrosis in patients infected with HBV/A, /C and/D (P = 0.02). Precore and core promoter mutants were found in 87% of anti-HBe positive patients, and were associated with HBV/D (P = 0.04) and severe liver fibrosis (P = 0.002). It is concluded that HBV genotypes A, B, C, D, and E circulate in the Seine Saint Denis District, reflecting the geographical origin of patients. HBV/A, /C and/D seem to be associated with more severe hepatic disease.