Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin.

The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC50) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P = 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment.

Clinical impact of the disposable ventouse iCup® versus a metallic vacuum cup: a multicenter randomized controlled trial.

BACKGROUND: Assisted vaginal delivery by vacuum extraction is frequent. Metallic resterilizible metallic vacuum cups have been routinely used in France. In the last few years a new disposable semi-soft vacuum extraction cup, the iCup, has been introduced. Our objective was to compare maternal and new-born outcomes between this disposable cup and the commonly used Drapier-Faure metallic cup. METHODS: This was a multicenter prospective randomized controlled open clinical trial performed in the maternity units of five university hospitals and one community hospital in France from October 2009 to February 2013. We included consecutive eligible women with a singleton gestation of at least 37 weeks who required vacuum assisted delivery. Women were randomized to vacuum extraction using the iCup or usual Drapier-Faure metallic cup. The primary outcome was a composite criterion including both the risk of cup dysfunction and the most frequent maternal and neonatal harms: the use of other instruments after attempted vacuum extraction, caesarean section after attempted vacuum extraction, three detachments of the cup, caput succedaneum, cephalohaematoma, episiotomy and perineal tears. RESULTS: 335 women were randomized to the disposable cup and 333 to extraction using the metallic cup. There was no significant difference between the two groups for the primary outcome. However, failed instrumental delivery was more frequent in the disposable cup group, mainly due to detachment: 35.6 % vs 7.1 %, p < 0.0001. Conversely, perineal tears were more frequent in the metallic cup group, especially third or fourth grade perineal tears: 1.7 % versus 5.0 %, p = 0.003. There were no significant differences between the two groups concerning post-partum haemorrhage, transfer to a neonatal intensive care unit (NICU) or serious adverse events. CONCLUSIONS: While the disposable cup had more detachments and extraction failures than the standard metallic cup, this innovative disposable device had the advantage of fewer perineal injuries. TRIAL REGISTRATION: www.clinicaltrials.gov : NCT01058200 on Jan. 27 2010.

Impact of information leaflets on behavior of patients with gastroenteritis or tonsillitis: a cluster randomized trial in French primary care.

OBJECTIVE: To assess the impact of four patient information leaflets on patients' behavior in primary care. DESIGN: Cluster randomized multicenter controlled trial between November 2009 and January 2011. PARTICIPANTS: French adults and children consulting a participating primary care physician and diagnosed with gastroenteritis or tonsillitis. Patients were randomized to receive patient information leaflets or not, according to the cluster randomization of their primary care physician. INTERVENTION: Adult patients or adults accompanying a child diagnosed with gastroenteritis or tonsillitis were informed of the study. Physicians in the intervention group gave patients an information leaflet about their condition. Two weeks after the consultation patients (or their accompanying adult) answered a telephone questionnaire on their behavior and knowledge about the condition. MAIN MEASURES: The main and secondary outcomes, mean behavior and knowledge scores respectively, were calculated from the replies to this questionnaire. RESULTS: Twenty-four physicians included 400 patients. Twelve patients were lost to follow-up (3 %). In the group that received the patient information leaflet, patient behavior was closer to that recommended by the guidelines than in the control group (mean behavior score 4.9 versus 4.2, p < 0.01). Knowledge was better for adults receiving the leaflet than in the control group (mean knowledge score 4.2 versus 3.6, p < 0.01). There were fewer visits for the same symptoms by household members of patients given leaflets (23.4 % vs. 56.2 %, p < 0.01). CONCLUSION: Patient information leaflets given by the physician during the consultation significantly modify the patient's behavior and knowledge of the disease, compared with patients not receiving the leaflets, for the conditions studied.

Morbidity and mortality conferences: their place in quality assessments.

PURPOSE: This article aims to analyze morbidity and mortality conferences (M&MCs) in a university-affiliated hospital, notably their format and progression since the 1990s. DESIGN/METHODOLOGY/APPROACH: A cross-sectional study was conducted and M&MC characteristics were collected using three methods: a questionnaire to all department heads to identify past M&MCs; semi-structured interviews with each M&MC leader; and when available, meeting reports were analyzed. FINDINGS: Of 189 questionnaires sent to department heads, 105 were completed and returned (55.6 per cent). A total of 27 M&MCs were identified; five times more than in 1994. The M&MC format varied greatly between departments. In surgical units, cases per conference tended to be higher than in intensive care or medical units and paramedical staff were invited less often. Compared with 1998, head nurses (70.4 vs 27.3 percent, p = 0.03) and paramedical staff (63.0 vs 18.2 percent, p = 0.03) attendance increased significantly. Physicians considered M&MCs important for improving service quality, patient safety and enhancing team cohesion. RESEARCH LIMITATIONS/IMPLICATIONS: Patient outcomes were not assessed. PRACTICAL IMPLICATIONS: Although undefined formats allowed leaders to conduct M&MCs according to their objectives, how these conferences are conducted should impact healthcare quality and safety. ORIGINALITY/VALUE: Results indicate that M&MCs have evolved over the past 20 years, showing them to be valuable quality and safety improvement methods.

The Incident Feedback Committee (IFC): A Useful Tool to Investigate Errors in Clinical Research.

In clinical practice, an objective of safety management is to identify preventable causes of adverse events to avoid the incidents from recurring. Likewise, in the field of clinical research adequate methods to investigate incidents that impair the quality of a clinical trial are needed. Understanding the causes of errors and undesirable incidents can help guarantee participant safety, improve the practices of research coordinators, investigators, and clinical research assistants and help to minimize research costs. Here, we present the main features of our Incident Feedback Committees (IFC) in clinical research, with outcomes over 5 years. METHODS: The IFC has adapted the ALARM and ORION post-event methods with investigations focused on 'the incidents' occurring during research studies. It sought the root causes contributing to these incidents and proposed corrective actions. RESULTS: Since our IFC was set up in 2015 it has examined 52 incidents from nine studies. The most frequent causes mainly concerned the working environment (54%). Most incidents had two or more causes. Some corrective actions were planned for ongoing or future studies. CONCLUSION: IFCs provide a useful and much-appreciated method of analysing incidents in the performance of clinical research. A multicentre study is needed to evaluate the effect of IFCs on the quality of an establishment's clinical research, at the individual level (patient safety) and also at the system level (changes in the organization of tasks).

A multiplicative hazard regression model to assess the risk of disease transmission at hospital during community epidemics.

BACKGROUND: During community epidemics, infections may be imported within hospital and transmitted to hospitalized patients. Hospital outbreaks of communicable diseases have been increasingly reported during the last decades and have had significant consequences in terms of patient morbidity, mortality, and associated costs. Quantitative studies are thus needed to estimate the risks of communicable diseases among hospital patients, taking into account the epidemiological process outside, hospital and host-related risk factors of infection and the role of other patients and healthcare workers as sources of infection. METHODS: We propose a multiplicative hazard regression model to analyze the risk of acquiring a communicable disease by patients at hospital. This model derives from epidemiological data on communicable disease epidemics in the community, hospital ward, patient susceptibility to infection, and exposure of patients to infection at hospital. The model estimates the relative effect of each of these factors on a patient's risk of communicable disease. RESULTS: Using individual data on patients and health care workers in a teaching hospital during the 2004-2005 influenza season in Lyon (France), we show the ability of the model to assess the risk of influenza-like illness among hospitalized patients. The significant effects on the risk of influenza-like illness were those of old age, exposure to infectious patients or health care workers, and a stay in a medical care unit. CONCLUSIONS: The proposed multiplicative hazard regression model could be an interesting epidemiological tool to quantify the risk of communicable disease at hospital during community epidemics and the uncertainty inherent in such quantification. Furthermore, key epidemiological, environmental, host, or exposure factors that influence this risk can be identified.

Automated drug dispensing system reduces medication errors in an intensive care setting.

OBJECTIVES: We aimed to assess the impact of an automated dispensing system on the incidence of medication errors related to picking, preparation, and administration of drugs in a medical intensive care unit. We also evaluated the clinical significance of such errors and user satisfaction. DESIGN: Preintervention and postintervention study involving a control and an intervention medical intensive care unit. SETTING: Two medical intensive care units in the same department of a 2,000-bed university hospital. PATIENTS: Adult medical intensive care patients. INTERVENTIONS: After a 2-month observation period, we implemented an automated dispensing system in one of the units (study unit) chosen randomly, with the other unit being the control. MEASUREMENTS AND MAIN RESULTS: The overall error rate was expressed as a percentage of total opportunities for error. The severity of errors was classified according to National Coordinating Council for Medication Error Reporting and Prevention categories by an expert committee. User satisfaction was assessed through self-administered questionnaires completed by nurses. A total of 1,476 medications for 115 patients were observed. After automated dispensing system implementation, we observed a reduced percentage of total opportunities for error in the study compared to the control unit (13.5% and 18.6%, respectively; p<.05); however, no significant difference was observed before automated dispensing system implementation (20.4% and 19.3%, respectively; not significant). Before-and-after comparisons in the study unit also showed a significantly reduced percentage of total opportunities for error (20.4% and 13.5%; p<.01). An analysis of detailed opportunities for error showed a significant impact of the automated dispensing system in reducing preparation errors (p<.05). Most errors caused no harm (National Coordinating Council for Medication Error Reporting and Prevention category C). The automated dispensing system did not reduce errors causing harm. Finally, the mean for working conditions improved from 1.0±0.8 to 2.5±0.8 on the four-point Likert scale. CONCLUSIONS: The implementation of an automated dispensing system reduced overall medication errors related to picking, preparation, and administration of drugs in the intensive care unit. Furthermore, most nurses favored the new drug dispensation organization.

Patient-Reported Outcome Measures (PROMs) for Two Implant Placement Techniques in Sinus Region (Bone Graft versus Computer-Aided Implant Surgery): A Randomized Prospective Trial.

PURPOSE: To assess patient-reported outcomes measures (PROMs) for two implant placement techniques in cases of sinus bone atrophy (bone graft surgery (BGS) versus computer-aided implant surgery (CAIS)), after surgery and one year later, and to evaluate the clinical success of both treatments. METHODS: Sixty patients with bone atrophy in the posterior maxilla and in need of implant placement were randomly assigned to two groups, and in accordance with the case report form (CRF), 30 were treated with BGS and 30 with CAIS. Immediately after treatment and one year later, PROMs were assessed, and the clinical success of both treatments was evaluated. RESULTS: No significant differences were found between BGS and CAIS with regard to the following: loss of implants (p = 492); patient recommendation (p = 210); duration of surgery (p = 987); pain on the intervention day (p = 512); pain in the week after intervention (p = 299); and complications in the stage of surgery (p = 1.00). Similarly, at one year, no differences were found with regard to the following: pain around implant (p = 481); infection of implants (p = 491); abnormal radiographic imaging (p = 226); occurrence of undesirable events (p = 1.00); loss of one of the implants (p = 1.00); plaque detection (p = 1.00); bleeding on probing (p = 236); and presence of keratinized mucosa (p = 226). However, a significant difference was found among BGS and CAIS with regard to the number of consultations (p = 0001); number of implants placed (p = 033); and treatment difficulty (p = 0369). Significant differences were found for peri-implantitis (p = 0481) and radiology of craterization (p = 020) in clinical examination at the first year. CONCLUSION: Treatment difficulty and number of consultations were higher for BGS than for CAIS, as well as peri-implantitis and bone craterization at one year, indicating significant differences between the two treatments. However, there were no statistically significant differences between BGS and CAIS regarding the other PROMs, at placement and after one year.

Biostatistics Disruptive Acculturation Through Serious Gaming: A New Hope.

Biostatistics is one of the transversal subjects that all future doctors must acquire and master. Nonetheless, it is a subject that has the reputation of being difficult, which has not been able to be corrected even with the application of new pedagogical methods such as blended learning. We address this problem with our acculturative and disruptive approach in the form of a serious game scenario in clinical research that integrates biostatistics with our R4Web adapted tools. Our approach was launched in 2008 for the second year of medical school. Here we describe this LOE scenario for serious game including the biostatistics disruptive acculturation task and present its new international version.

Non-invasive fibrosis tests to predict complications in compensated post-hepatitis C cirrhosis.

BACKGROUND AND AIMS: Markers predicting complications of post-hepatitis C cirrhosis are needed. We asked whether changes in noninvasive markers of fibrosis can predict liver-related complications. METHODS: This was a case-controlled study using a prospective national cohort (ANRS-CO12-CIRVIR) of 1323 HCV-infected patients with compensated cirrhosis: 97 patients who developed liver-related complications such as hepatocellular carcinoma or hepatic decompensation (cases) matched in age, sex and follow-up duration were compared with 257 patients without complications (controls). Actitest/Fibrotest™, Inflameter/Fibrometer™, ELF™ and Fibroscan™ were performed at baseline and yearly. Samples based on Propensity score matching were built and mixed linear models performed. Outcomes in a sustained virological response (SVR) negative population and a SVR-positive population were also described. RESULTS: At baseline, all characteristics of patients were similar between the groups. All fibrosis tests were statistically higher for cases compared to controls, Fibroscan™ excepted: Fibrotest™: 0.83±0.13 vs. 0.77±0.16; Fibrometer™: 0.93±0.07 vs. 0.90±0.11; ELF™: 11.4±1.0 vs. 11.0±1.2 (P<0.02). The mean follow-up was 5.7±1.9 years. Over a 3-year period, the significant difference in fibrosis marker values between cases and controls remained constant; with a trend toward a decrease in inflammation markers in controls, independent of SVR status. CONCLUSIONS: Baseline noninvasive serum fibrosis and inflammation markers were significantly higher in patients developing a complication than in controls. During the follow-up only inflammatory markers decreased in controls, but not in cases, and thus could potentially be used to predict the occurrence of complications in cirrhotic patients.

Impact of Cone Beam Computed Tomography Dose in Pre-Surgical Implant Analysis.

OBJECTIVES: Cone-Beam Computed Tomography (CBCT) produces vital information required for the accurate and prudent placement of dental implants. Lack of standardization between CBCT machines may result in unsafe patient exposure to harmful radiation; higher doses are not necessarily associated with improved image quality. AIM: The study aimed to assess the influence of low- and high-dose milliamperage settings on CBCT images for objective and subjective implant planning. METHODS: Two dry skulls (4 hemi-maxillary segments of the maxilla and 4 hemi-maxillary segments of the mandible) were scanned under low (2 mA) and high (6.3 mA) dosage settings using a CBCT (Carestream CS 9300). Cross-sectional slices of both image qualities were evaluated by five expert clinicians, for image quality for implant planning and objective bone measurements. RESULTS: There were no significant differences in bone measurements taken on high or low dose images (p > 0.05). In qualitative image assessments, assessment and image quality for almost all observers were independent of each other. For planning posterior mandibular implant placement, increased dosage improved concordance and kappa values between low and high dose images. CONCLUSION: Reduction in milliamperage did not affect diagnostic image quality for objective bone measurements and produced sufficient intra-rater reliability for qualitative assessment; therefore dose reduction can be achieved without compromising diagnostic decision- making.

Randomised, prospective, medico-economic nationwide French study of islet transplantation in patients with severely unstable type 1 diabetes: the STABILOT study protocol.

INTRODUCTION: Islet transplantation may be an appropriate treatment option for patients with severely unstable type 1 diabetes experiencing major glucose variability with severe hypoglycaemia despite intensive insulin therapy. Few data are available on the costs associated with islet transplantation in relation to its benefits. The STABILOT study proposes to assess the economic impact of islet transplantation in comparison with the current best medical treatment defined as sensor-augmented pump (SAP) therapy. METHODS: The trial will adopt an open-label, randomised, multicentred design. The study will include 30 patients with severely unstable type 1 diabetes. Eligible participants will be 18-65 years old, with type 1 diabetes duration >5 years, a negative basal or stimulated C-peptide, and severe instability defined by persistent, recurrent and disabling severe hypoglycaemia, despite optimised medical treatment. Participants will be randomised into two groups: one group with immediate registration for islet transplantation, and one group with delayed registration for 1 year while patients receive SAP therapy. The primary endpoint will be the incremental cost-utility ratio at 1 year between islet transplantation and SAP therapy. Perspectives of both the French Health Insurance System and the hospitals will be retained. ETHICS AND DISSEMINATION: Ethical approval has been obtained at all sites. The trial has been approved by ClinicalTrials.gov (Trial registration ID NCT02854696). All participants will sign a free and informed consent form before randomisation. Results of the study will be communicated during national and international meetings in the field of diabetes and transplantation. A publication will be sought in journals usually read by physicians involved in diabetes care, transplantation and internal medicine. TRIAL REGISTRATION NUMBER: NCT02854696; Pre-results.

Contribution of the ELFG test in algorithms of non-invasive markers towards the diagnosis of significant fibrosis in chronic hepatitis C.

BACKGROUND AND AIMS: We aimed to determine the best algorithms for the diagnosis of significant fibrosis in chronic hepatitis C (CHC) patients using all available parameters and tests. PATIENTS AND METHODS: We used the database from our study of 507 patients with histologically proven CHC in which fibrosis was evaluated by liver biopsy (Metavir) and tests: Fibrometer®, Fibrotest®, Hepascore®, Apri, ELFG, MP3, Forn's, hyaluronic acid, tissue inhibitor of metalloproteinase-1 (TIMP1), MMP1, collagen IV and when possible Fibroscan™. For the first test we used 90% negative predictive value to exclude patients with F≤1, next an induction algorithm was applied giving the best tests with at least 80% positive predictive value for the diagnosis of F≥2. The algorithms were computed using the R Software C4.5 program to select the best tests and cut-offs. The algorithm was automatically induced without premises on the part of the investigators. We also examined the inter-observer variations after independent review of liver biopsies by two pathologists. A medico-economic analysis compared the screening strategies with liver biopsy. RESULTS: In "intention to diagnose" the best algorithms for F≥2 were Fibrometer ®, Fibrotest®, or Hepascore® in first intention with the ELFG score in second intention for indeterminate cases. The percentage of avoided biopsies varied between 50% (Fibrotest® or Fibrometer®+ELFG) and 51% (Hepascore®+ELFG). In "per-analysis" Fibroscan™+ELFG avoided liver biopsy in 55% of cases. The diagnostic performance of these screening strategies was statistically superior to the usual combinations (Fibrometer® or Fibrotest®+Fibroscan™) and was cost effective. We note that the consensual review of liver biopsies between the two pathologists was mainly in favor of F1 (64-69%). CONCLUSION: The ELFG test could replace Fibroscan in most currently used algorithms for the diagnosis of significant fibrosis including for those patients for whom Fibroscan™ is unusable.