Virtual reality for acute pain in outpatient hysteroscopy: a randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of virtual reality as a distraction technique in the management of acute pain and anxiety during outpatient hysteroscopy. DESIGN: Parallel group, prospective randomised controlled trial. SETTING: UK University Hospital. METHODS: Forty consenting, eligible women were randomised to virtual reality intervention (immersive video content as a distraction method) or standard care during outpatient hysteroscopy from August to October 2018. MAIN OUTCOME MEASURES: Pain and anxiety outcomes were measured as a numeric rating score (scale 0-10). RESULTS: Compared with standard care, women with virtual reality intervention experienced less average pain (score 6.0 versus 3.7, mean difference 2.3, 95% CI 0.61-3.99, P = 0.009) and anxiety (score 5.45 versus 3.3, mean difference 2.15, 95% CI 0.38-3.92, P = 0.02). CONCLUSION: Virtual reality was effective in reducing pain and anxiety during outpatient hysteroscopy in a mixed-methods randomised control trial. Its wide potential role in ambulatory gynaecological procedures needs further evaluation. TWEETABLE ABSTRACT: Virtual reality can be used as a part of a multimodal strategy to reduce acute pain and anxiety in patients undergoing outpatient hysteroscopy.

Refining the criteria for immediate total-body CT after severe trauma.

OBJECTIVES: Initial trauma care could potentially be improved when conventional imaging and selective CT scanning is omitted and replaced by immediate total-body CT (iTBCT) scanning. Because of the potentially increased radiation exposure by this diagnostic approach, proper selection of the severely injured patients is mandatory. METHODS: In the REACT-2 trial, severe trauma patients were randomized to iTBCT or conventional imaging and selective CT based on predefined criteria regarding compromised vital parameters, clinical suspicion of severe injuries, or high-risk trauma mechanisms in five trauma centers. By logistic regression analysis with backward selection on the 15 study inclusion criteria, a revised set of criteria was derived and subsequently tested for prediction of severe injury and shifts in radiation exposure. RESULTS: In total, 1083 patients were enrolled with median ISS of 20 (IQR 9-29) and median GCS of 13 (IQR 3-15). Backward logistic regression resulted in a revised set consisting of nine original and one adjusted criteria. Positive predictive value improved from 76% (95% CI 74-79%) to 82% (95% CI 80-85%). Sensitivity decreased by 9% (95% CI 7-11%). The area under the receiver operating characteristics curve remained equal and was 0.80 (95% CI 0.77-0.83), original set 0.80 (95% CI 0.77-0.83). The revised set retains 8.78 mSv (95% CI 6.01-11.56) for 36% of the non-severely injured patients. CONCLUSIONS: Selection criteria for iTBCT can be reduced from 15 to 10 clinically criteria. This improves the positive predictive value for severe injury and reduces radiation exposure for less severely injured patients. KEY POINTS: • Selection criteria for iTBCT can be reduced to 10 clinically useful criteria. • This reduces radiation exposure in 36% of less severely injured patients. • Overall discriminative capacity for selection of severely injured patients remained equal.

Emergency Bleeding Control Interventions After Immediate Total-Body CT Scans in Trauma Patients.

BACKGROUND: Immediate total-body CT (iTBCT) is often used for screening of potential severely injured patients. Patients requiring emergency bleeding control interventions benefit from fast and optimal trauma screening. The aim of this study was to assess whether an initial trauma assessment with iTBCT is associated with lower mortality in patients requiring emergency bleeding control interventions. METHODS: In the REACT-2 trial, patients who sustained major trauma were randomized for iTBCT or for conventional imaging and selective CT scanning (standard workup; STWU) in five trauma centers. Patients who underwent emergency bleeding control interventions following their initial trauma assessment with iTBCT were compared for mortality and clinically relevant time intervals to patients that underwent the initial trauma assessment with the STWU. RESULTS: In the REACT-2 trial, 1083 patients were enrolled of which 172 (15.9%) underwent emergency bleeding control interventions following their initial trauma assessment. Within these 172 patients, 85 (49.4%) underwent iTBCT as primary diagnostic modality during the initial trauma assessment. In trauma patients requiring emergency bleeding control interventions, in-hospital mortality was 12.9% (95% CI 7.2-21.9%) in the iTBCT group compared to 24.1% (95% CI 16.3-34.2%) in the STWU group (p = 0.059). Time to bleeding control intervention was not reduced; 82 min (IQR 5-121) versus 98 min (IQR 62-147), p = 0.108. CONCLUSIONS: Reduction in mortality in trauma patients requiring emergency bleeding control interventions by iTBCT could not be demonstrated in this study. However, a potentially clinically relevant absolute risk reduction of 11.2% (95% CI - 0.3 to 22.7%) in comparison with STWU was observed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01523626.

Continuous monitoring and feedback of quality of recovery indicators for anaesthetists: a qualitative investigation of reported effects on professional behaviour.

BACKGROUND: Research suggests that providing clinicians with feedback on their performance can result in professional behaviour change and improved clinical outcomes. Departments would benefit from understanding which characteristics of feedback support effective quality monitoring, professional behaviour change and service improvement. This study aimed to report the experience of anaesthetists participating in a long-term initiative to provide comprehensive personalized feedback to consultants on patient-reported quality of recovery indicators in a large London teaching hospital. METHODS: Semi-structured interviews were conducted with 13 consultant anaesthetists, six surgical nursing leads, the theatre manager and the clinical coordinator for recovery. Transcripts were qualitatively analysed for themes linked to the perceived value of the initiative, its acceptability and its effects upon professional practice. RESULTS: Analysis of qualitative data from participant interviews suggested that effective quality indicators must address areas that are within the control of the anaesthetist. Graphical data presentation, both longitudinal (personal variation over time) and comparative (peer-group distributions), was found to be preferable to summary statistics and provided useful and complementary perspectives for improvement. Developing trust in the reliability and credibility of the data through co-development of data reports with clinical input into areas such as case-mix adjustment was important for engagement. Making feedback specifically relevant to the recipient supported professional learning within a supportive and open collaborative environment. CONCLUSIONS: This study investigated the requirements for effective feedback on quality of anaesthetic care for anaesthetists, highlighting the mechanisms by which feedback may translate into improvements in practice at the individual and peer-group level.

Immediate total-body CT scanning versus conventional imaging and selective CT scanning in patients with severe trauma (REACT-2): a randomised controlled trial.

BACKGROUND: Published work suggests a survival benefit for patients with trauma who undergo total-body CT scanning during the initial trauma assessment; however, level 1 evidence is absent. We aimed to assess the effect of total-body CT scanning compared with the standard work-up on in-hospital mortality in patients with trauma. METHODS: We undertook an international, multicentre, randomised controlled trial at four hospitals in the Netherlands and one in Switzerland. Patients aged 18 years or older with trauma with compromised vital parameters, clinical suspicion of life-threatening injuries, or severe injury were randomly assigned (1:1) by ALEA randomisation to immediate total-body CT scanning or to a standard work-up with conventional imaging supplemented with selective CT scanning. Neither doctors nor patients were masked to treatment allocation. The primary endpoint was in-hospital mortality, analysed in the intention-to-treat population and in subgroups of patients with polytrauma and those with traumatic brain injury. The χ(2) test was used to assess differences in mortality. This trial is registered with ClinicalTrials.gov, number NCT01523626. FINDINGS: Between April 22, 2011, and Jan 1, 2014, 5475 patients were assessed for eligibility, 1403 of whom were randomly assigned: 702 to immediate total-body CT scanning and 701 to the standard work-up. 541 patients in the immediate total-body CT scanning group and 542 in the standard work-up group were included in the primary analysis. In-hospital mortality did not differ between groups (total-body CT 86 [16%] of 541 vs standard work-up 85 [16%] of 542; p=0.92). In-hospital mortality also did not differ between groups in subgroup analyses in patients with polytrauma (total-body CT 81 [22%] of 362 vs standard work-up 82 [25%] of 331; p=0.46) and traumatic brain injury (68 [38%] of 178 vs 66 [44%] of 151; p=0.31). Three serious adverse events were reported in patients in the total-body CT group (1%), one in the standard work-up group (<1%), and one in a patient who was excluded after random allocation. All five patients died. INTERPRETATION: Diagnosing patients with an immediate total-body CT scan does not reduce in-hospital mortality compared with the standard radiological work-up. Because of the increased radiation dose, future research should focus on the selection of patients who will benefit from immediate total-body CT. FUNDING: ZonMw, the Netherlands Organisation for Health Research and Development.

Surgical swab counting: a qualitative analysis from the perspective of the scrub nurse.

The aim of the study was to conduct a qualitative exploration of the sociotechnical processes underlying retained surgical swabs, and to explore the fundamental reasons why the swab count procedure and related protocols fail in practice. Data was collected through a set of 27 semistructured qualitative interviews with scrub nurses from a large, multi-site teaching hospital. Interview transcripts were analysed using established constant comparative methods, moving between inductive and deductive reasoning. Key findings were associated with interprofessional perspectives, team processes and climate and responsibility for the swab count. The analysis of risk factors revealed that perceived social and interprofessional issues played a significant role in the reliability of measures to prevent retained swabs. This work highlights the human, psychological and organisational factors that impact upon the reliability of the process and gives rise to recommendations to address contextual factors and improve perioperative practice and training.

Multidisciplinary cancer team meeting structure and treatment decisions: a prospective correlational study.

BACKGROUND: Anecdotally, organizational factors appear to have an effect on the quality of decision-making in the multidisciplinary team (MDT) meeting. We assess the effect of the number of team-members present, number and order of cases, and the timing of meetings on the process of decision-making in MDT meetings. METHODS: Between December 2009 and January 2010, data were prospectively collected on treatment decisions, meeting characteristics, quality of information, and teamworking for all cases discussed at a London-based MDT meeting. Variables measured using a validated assessment tool (MDT MODe) and correlational analyses were performed. RESULTS: Treatment decisions were reached in 254 of 298 (85%) cases. Cases toward the end of meetings were associated with lower rates of decision-making, information quality, and teamworking (r = -0.15 to -0.37). Increased number of cases per meeting and team members in attendance were associated with better information and teamworking (r = 0.29-0.43). More time per case was associated with improved teamworking (r = 0.16). A positive correlation was obtained between ability to reach decisions and improved information and teamworking (r = 0.36-0.54; all P ≤ 0.001). CONCLUSIONS: Organizational factors related to the structure of the MDT meeting are associated with variation in the likelihood of reaching a treatment decision. Further research is required to establish causation and to modify such factors in order to improve the quality of cancer care.

[Direct total body CT scan in multi-trauma patients]. / Directe 'total body'-CT-scan bij multitraumapatiënten.

BACKGROUND: Immediate total body computed tomography (CT) scanning has become important in the early diagnostic phase of trauma care because of its high diagnostic accuracy. However, literature provides limited evidence whether immediate total body CT leads to better clinical outcome then conventional radiographic imaging supplemented with selective CT scanning in trauma patients. The aim of the REACT-2 trial is to determine the value of immediate total body CT scanning in trauma patients. DESIGN: The REACT-2 trial is an international, multicenter randomized clinical trial. METHODS: All participating trauma centers have a multi-slice CT scanner located in the trauma room or at the Emergency Department (ED). All adult, non-pregnant, severely injured trauma patients according to predefined criteria will be included. The intervention group will receive a contrast-enhanced total body CT scan (head to pelvis) during the primary survey. The control group will be evaluated according to local conventional trauma imaging protocols (based on ATLS guidelines) supplemented with selective CT scanning. Primary outcome will be in-hospital mortality. Secondary outcomes are differences in mortality and morbidity during the first year post trauma, several trauma work-up time intervals, radiation exposure, general health and quality of life at 6 and 12 months post trauma and cost-effectiveness. CONCLUSION: The REACT-2 trial is the first multicenter randomized clinical trial that will provide evidence on the value of immediate total body CT scanning during the primary survey of severely injured trauma patients.

Using quality indicators in anaesthesia: feeding back data to improve care.

After recent UK policy developments, considerable attention has been focused upon how clinical specialties measure and report on the quality of care delivered to patients. Defining the right indicators alone is insufficient to close the feedback loop. This narrative review aims to describe and synthesize a diverse body of research relevant to the question of how information from quality indicators can be fed back and used effectively to improve care. Anaesthesia poses certain challenges in the identification of valid outcome indicators sensitive to variations in anaesthetic care. Metrics collected during the immediate post-anaesthetic recovery period, such as patient temperature, patient-reported quality of recovery, and pain and nausea, provide potentially useful information for the anaesthetist, yet this information is not routinely fed back. Reviews of the effects of feeding back performance data to healthcare providers suggest that this may result in small to moderate positive effects upon outcomes and professional practice, with stronger effects where feedback is integrated within a broader quality improvement strategy. The dominant model for use of data within quality improvement is based upon the industrial process control approach, in which care processes are monitored continuously for process changes which are rapidly detectable for corrective action. From this review and experience of implementing these principles in practice, effective feedback from quality indicators is timely, credible, confidential, tailored to the recipient, and continuous. Considerable further work is needed to understand how information from quality indicators can be fed back in an effective way to clinicians and clinical units, in order to support revalidation and continuous improvement.

A multicenter, randomized controlled trial of immediate total-body CT scanning in trauma patients (REACT-2).

BACKGROUND: Computed tomography (CT) scanning has become essential in the early diagnostic phase of trauma care because of its high diagnostic accuracy. The introduction of multi-slice CT scanners and infrastructural improvements made total-body CT scanning technically feasible and its usage is currently becoming common practice in several trauma centers. However, literature provides limited evidence whether immediate total-body CT leads to better clinical outcome then conventional radiographic imaging supplemented with selective CT scanning in trauma patients. The aim of the REACT-2 trial is to determine the value of immediate total-body CT scanning in trauma patients. METHODS/DESIGN: The REACT-2 trial is an international, multicenter randomized clinical trial. All participating trauma centers have a multi-slice CT scanner located in the trauma room or at the Emergency Department (ED). All adult, non-pregnant, severely injured trauma patients according to predefined criteria will be included. Patients in whom direct scanning will hamper necessary cardiopulmonary resuscitation or who require an immediate operation because of imminent death (both as judged by the trauma team leader) are excluded. Randomization will be computer assisted. The intervention group will receive a contrast-enhanced total-body CT scan (head to pelvis) during the primary survey. The control group will be evaluated according to local conventional trauma imaging protocols (based on ATLS guidelines) supplemented with selective CT scanning. Primary outcome will be in-hospital mortality. Secondary outcomes are differences in mortality and morbidity during the first year post trauma, several trauma work-up time intervals, radiation exposure, general health and quality of life at 6 and 12 months post trauma and cost-effectiveness. DISCUSSION: The REACT-2 trial is a multicenter randomized clinical trial that will provide evidence on the value of immediate total-body CT scanning during the primary survey of severely injured trauma patients. If immediate total-body CT scanning is found to be the best imaging strategy in severely injured trauma patients it could replace conventional imaging supplemented with CT in this specific group. TRIAL REGISTRATION: ClinicalTrials.gov: (NCT01523626).

Systematic review of the application of quality improvement methodologies from the manufacturing industry to surgical healthcare.

BACKGROUND: The demand for the highest-quality patient care coupled with pressure on funding has led to the increasing use of quality improvement (QI) methodologies from the manufacturing industry. The aim of this systematic review was to identify and evaluate the application and effectiveness of these QI methodologies to the field of surgery. METHODS: MEDLINE, the Cochrane Database, Allied and Complementary Medicine Database, British Nursing Index, Cumulative Index to Nursing and Allied Health Literature, Embase, Health Business(™) Elite, the Health Management Information Consortium and PsycINFO(®) were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Empirical studies were included that implemented a described QI methodology to surgical care and analysed a named outcome statistically. RESULTS: Some 34 of 1595 articles identified met the inclusion criteria after consensus from two independent investigators. Nine studies described continuous quality improvement (CQI), five Six Sigma, five total quality management (TQM), five plan-do-study-act (PDSA) or plan-do-check-act (PDCA) cycles, five statistical process control (SPC) or statistical quality control (SQC), four Lean and one Lean Six Sigma; 20 of the studies were undertaken in the USA. The most common aims were to reduce complications or improve outcomes (11), to reduce infection (7), and to reduce theatre delays (7). There was one randomized controlled trial. CONCLUSION: QI methodologies from industry can have significant effects on improving surgical care, from reducing infection rates to increasing operating room efficiency. The evidence is generally of suboptimal quality, and rigorous randomized multicentre studies are needed to bring evidence-based management into the same league as evidence-based medicine.

Feedback from incident reporting: information and action to improve patient safety.

INTRODUCTION: Effective feedback from incident reporting systems in healthcare is essential if organisations are to learn from failures in the delivery of care. Despite the wide-scale development and implementation of incident reporting in healthcare, studies in the UK suggest that information concerning system vulnerabilities could be better applied to improve operational safety within organisations. In this article, the findings and implications of research to identify forms of effective feedback from incident reporting are discussed, to promote best practices in this area. METHODS: The research comprised a mixed methods review to investigate mechanisms of effective feedback for healthcare, drawing upon experience within established reporting programmes in high-risk industry and transport domains. Systematic searches of published literature were undertaken, and 23 case studies describing incident reporting programmes with feedback were identified for analysis from the international healthcare literature. Semistructured interviews were undertaken with 19 subject matter experts across a range of domains, including: civil aviation, maritime, energy, rail, offshore production and healthcare. RESULTS: In analysis, qualitative information from several sources was synthesised into practical requirements for developing effective feedback in healthcare. Both action and information feedback mechanisms were identified, serving safety awareness, improvement and motivational functions. The provision of actionable feedback that visibly improved systems was highlighted as important in promoting future reporting. Fifteen requirements for the design of effective feedback systems were identified, concerning: the role of leadership, the credibility and content of information, effective dissemination channels, the capacity for rapid action and the need for feedback at all levels of the organisation, among others. Above all, the safety-feedback cycle must be closed by ensuring that reporting, analysis and investigation result in timely corrective actions that effectively address vulnerabilities in existing work systems. CONCLUSIONS: Limited research evidence exists concerning the issue of effective forms of safety feedback within healthcare. Much valuable operational knowledge resides in safety management communities within high-risk industries. Multiple means of feeding back recommended actions and safety information may be usefully employed to promote safety awareness, improve clinical processes and promote future reporting. Further work is needed to establish best practices for feedback systems in healthcare that effectively close the safety loop.

Plantar pressure in off-loading devices used in diabetic ulcer treatment.

Four off-loading devices used for the treatment of diabetic forefoot ulcers were compared: a custom-molded insole shoe, a cast MABAL shoe, a prefabricated pneumatic walking brace, and a bivalved total contact cast (BTCC). It was anticipated that all devices would significantly reduce forefoot plantar pressure compared with a control shoe. Sixteen healthy volunteers participated. Plantar pressures were evaluated using the Pedar system, while walking speed was determined using an optoelectric timer. Peak pressure (PP) of ten plantar areas and pressure-time integral for the first metatarsal area were analyzed statistically using a repeated measures analysis of variance. Forefoot pressures were significantly reduced compared with the control shoe for all devices (p<0.001). PP was most reduced (by 65.8%) for the BTCC, and pressure-time integral was most reduced for the BTCC and cast MABAL shoe. Small but significant differences between devices in walking speed (p<0.05) could not explain the substantial PP differences between the different devices. Although all off-loading devices resulted in a significant reduction of forefoot plantar pressure, devices differed significantly in the magnitude of pressure reduction. Further research will have to reveal the level of off-loading sufficient for effective treatment of diabetic ulcers.

Negative association between erythrocyte reduced glutathione concentration and diabetic complications.

1. Multiple logistic regression analysis of biochemical and clinical variables in diabetic patients was performed to identify those associated with the presence of diabetic complications (retinopathy, neuropathy and nephropathy). 2. The presence of diabetic complications correlated positively with duration of diabetes and patients age and negatively with the concentration of reduced glutathione in erythrocytes. Individually, retinopathy, neuropathy and nephropathy correlated with duration of diabetes, but retinopathy also correlated positively with haemoglobin A1C in diabetic patients. In insulin-dependent patients, the concentration of methylglyoxal was also in the logistic model for retinopathy and diabetic complications, but the logistic regression coefficient was not significant. 3. Multiple linear regression analysis indicated that erythrocyte reduced glutathione concentration correlated negatively with D-lactate concentration and positively with duration of diabetes in insulin-dependent patients and correlated negatively with glucose concentration in non-insulin-dependent diabetic patients. 4. In non-diabetic subjects, erythrocyte glyoxalase I activity correlated positively with methylglyoxal concentration. There was no similar correlation in diabetic patients. In insulin-dependent patients, methylglyoxal concentration correlated positively with duration of diabetes. 5. Glyoxal and methylglyoxal are detoxified by the glyoxalase system with reduced glutathione as co-factor. The concentration of reduced glutathione may be decreased by oxidative stress and by decreased in situ glutathione reductase activity in diabetes mellitus. A reduced concentration of reduced glutathione may predispose diabetic patients to oxidative damage and to alpha-oxoaldehydemediated glycation by decreasing the in situ glyoxalase I activity. Recent studies of vascular endothelial cells in vitro have suggested that alpha-oxoaldehydes detoxified by glyoxalase I are the major precursors of advanced glycation end products implicated in the development of diabetic complications. The role of these factors in the development of diabetic complications and the prospective prevention of diabetic complications by supplementation of reduced glutathione and/or alpha-oxoaldehyde-scavenging agents now deserve investigation.

Measurement of glucose metabolism and insulin secretion during normal pregnancy and pregnancy complicated by gestational diabetes.

Gestational diabetes affects 2-3% of pregnant women and is associated with foetal complications including macrosomia and an increased likelihood of developing diabetes in later life. We have therefore studied seven women with gestational diabetes and five control women both during the third trimester of pregnancy and again 2-3 months post-partum, using the minimal model analysis of the frequently sampled labelled ([6,6-2H2]-glucose) intravenous glucose tolerance test. Glucose tolerance (glucose Kd) was significantly reduced in the women with gestational diabetes compared with the normal pregnant women both in pregnancy (1.16 +/- 0.11 vs 1.78 +/- 0.23%/min; p < 0.05) and post-partum (1.47 +/- 0.22 vs 2.59 +/- 0.43%/min; p < 0.05) and increased significantly in the control women after delivery (p < 0.05). Glucose effectiveness was not significantly different between the women with gestational diabetes and the control group either during or after pregnancy. Insulin sensitivity was significantly lower during pregnancy than after delivery in the women with gestational diabetes (p < 0.05). There was no significant difference in basal insulin secretion in the two groups during pregnancy or post-partum. However, during pregnancy the control subjects significantly increased (p < 0.001) their insulin secretion over a period of 20 min in response to an intravenous glucose tolerance test (96.2 +/- 42.7 pmol/kg) compared with post-partum values (58.3 +/- 25.2 pmol/kg) while in the women with gestational diabetes insulin secretion was similar in pregnancy (65.5 +/- 9.3 pmol/kg) and after delivery (57.7 +/- 15.7 pmol/kg). These data suggest that the glucose intolerance in gestational diabetes compared to normal pregnancy is due to reduced insulin sensitivity and an impaired ability in gestational diabetes to increase insulin secretion in response to glucose.

Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases.

The HBx protein of hepatitis B virus is a dual-specificity activator of transcription, stimulating signal transduction pathways in the cytoplasm and transcription factors in the nucleus, when expressed in cell lines in culture. In the cytoplasm, HBx was shown to stimulate the Ras-Raf-mitogen-activated protein kinase (MAP kinase) cascade, which is essential for activation of transcription factor AP-1. Here we show that HBx protein stimulates two independently regulated members of the MAP kinase family when expressed transiently in cells. HBx protein stimulates the extracellular signal-regulated kinases (ERKs) and the c-Jun N-terminal kinases (JNKs). HBx activation of ERKs and JNKs leads to induction and activation of AP-1 DNA binding activity involving transient de novo synthesis of c-Fos protein and prolonged synthesis of c-Jun, mediated by N-terminal phosphorylation of c-Jun carried out by HBx-activated JNK. New c-Jun synthesis was blocked by coexpression with a dominant-negative MAP kinase kinase (MEK kinase, MEKK-1), confirming that HBx stimulates the prolonged synthesis of c-Jun by activating JNK signalling pathways. Activation of the c-fos gene was blocked by coexpression with a Raf-C4 catalytic mutant, confirming that HBx induces c-Fos by acting on Ras-Raf linked pathways. HBx activation of ERK and JNK pathways resulted in prolonged accumulation of AP-1-c-Jun dimer complexes. HBx activation of JNK and sustained activation of c-jun, should they occur in the context of hepatitis B virus infection, might play a role in viral transformation and pathogenesis.

Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls.

The human hepatitis B virus (HBV) HBx protein is a small transcriptional activator that is essential for virus infection. HBx is thought to be involved in viral hepatocarcinogenesis because it promotes tumorigenesis in transgenic mice. HBx activates the RAS-RAF-mitogen-activated protein (MAP) kinase signaling cascade, through which it activates transcription factors AP-1 and NF-kappa B, and stimulates cell DNA synthesis. We show that HBx stimulates cell cycle progression, shortening the emergence of cells from quiescence (G0) and entry into S phase by at least 12 h, and accelerating transit through checkpoint controls at G0/G1 and G2/M. Compared with serum stimulation, HBx was found to strongly increase the rate and level of activation of the cyclin-dependent kinases CDK2 and CDC2, and their respective active association with cyclins E and A or cyclin B. HBx is also shown to override or greatly reduce serum dependence for cell cycle activation. Both HBx and serum were found to require activation of RAS to stimulate cell cycling, but only HBx could shorten checkpoint intervals. HBx therefore stimulates cell proliferation by activating RAS and a second unknown effector, which may be related to its reported ability to induce prolonged activation of JUN or to interact with cellular p53 protein. These data suggest a molecular mechanism by which HBx likely contributes to viral carcinogenesis. By deregulating checkpoint controls, HBx could participate in the selection of cells that are genetically unstable, some of which would accumulate unrepaired transforming mutations.