Individual QT–R‐R Relationship: Average Stability over Time Does Not Rule Out an Individual Residual Variability: Implication for the Assessment of Drug Effect on the QT Interval

Background: Universal QT correction formulae have been shown to under or overcorrect the QT interval duration. Individual QT–R‐R modeling has been proposed as a preferable solution for heart rate correction of QT intervals. However, the QT–R‐R relationship stability over time needs to be evaluated. Methods: The present report is part of randomized, double‐dummy, and placebo‐controlled 4‐way crossover phase 1 study (48 healthy volunteers). Each randomized period included a run‐in placebo day followed the day after by drug administration, with moxifloxacin as a positive control for QT interval measurement. Digital Holter ECG data were analyzed using the “bin” approach. For each period, individual QT–R‐R relationship were calculated using two different models (linear and parabolic log–log models). Results: The mean intrasubject variability for the α coefficient of the linear modeling (SDintra = 0.011 ± 0.005) reached 28.6 ± 10.2%. When the parabolic model was considered, the SDintra was 0.026 ± 0.009 for the α coefficient. The QT–R‐R relationship variability was in part related to long‐term RR changes (R²= 30%, P < 0.05). However, no significant time effect (ANOVA) was evidenced for QT–R‐R coefficients. Moxifloxacin significantly increased the α coefficient of the QT–R‐R relationship from 0.07 ± 0.018 to 0.085 ± 0.019, P < 0.05 (linear model). Conclusions: The individual QT–R‐R relationship shows a residual variability in part related to long‐term autonomic changes. In addition, the QT–R‐R relationship might be modulated by the drug tested. As a consequence, pretherapy QT–R‐R relationship obtained in a given patient cannot be used as a fingerprint throughout a drug trial.     

Comparison of non-invasive liver fibrosis biomarkers in HIV/HCV co-infected patients: the fibrovic study--ANRS HC02

BACKGROUND/AIMS: To compare non-invasive biological liver fibrosis scores, as alternatives to liver biopsy, in HIV/HCV co-infected patients. METHODS: Two hundred and seventy-two HIV/HCV patients, nai ve for HCV treatment, underwent liver biopsy [197 (72%) men, 39.9 years, fibrosis stage (Metavir) F1 (25%), F2 (40%), F3 (25%), F4 (10%), median CD4 486/mm(3) and median HIV viral load 3.5log. Fibrotest (FT), Hepascore (HS), Fibrometer (FM), SHASTA, APRI, Forns index, and Fib-4 were tested in order to differentiate patients with mild to moderate fibrosis (F2) and those with advanced fibrosis (F3). The AUROC and the rate of well-classified patients were compared to liver biopsy. RESULTS: FT, HS, and FM were able to stage liver fibrosis in all patients with AUROCs of 0.78, 0.84 and 0.89 for the diagnosis of F2, respectively. The correlation coefficient indexes were 0.37, 0.46 and 0.48, respectively. The rates of well-classified patients were 62%, 68% and 71%, respectively. Fib-4, APRI and the Forn's index were only able to stage 37-61% of patients and showed lower accuracies. Using a combination of FT, HS and FM did not significantly increase the performance of each test. CONCLUSIONS: In HIV/HCV co-infected patients, Fibrometer, Hepascore and Fibrotest outperformed other non-invasive liver fibrosis biomarkers for the prediction of significant liver fibrosis.     

Bronchoalveolar lavage in amiodarone pneumonitis. Cellular abnormalities and their relevance to pathogenesis

To investigate the contribution of direct cytotoxicity and immune-mediated hypersensitivity to the pathogenesis of amiodarone pneumonitis, we evaluated cells recovered by bronchoalveolar lavage from 13 patients with amiodarone pneumonitis. Alveolar macrophages from all patients contained two types of abnormal inclusions: small clear vacuoles and large phagolysosomes containing phospholipid in lamellar structures, abnormalities previously attributed to direct cytotoxicity from amiodarone. However, these changes were always associated with abnormalities in the numbers and types of immune and inflammatory cells present in the lower respiratory tract, which closely resemble those seen in hypersensitivity pneumonitis associated with inhaled antigens. Following discontinuation of amiodarone and institution of corticosteroid therapy, clinical improvement correlated with a return toward normal in the pattern of inflammatory cells present in the lung, although alveolar macrophages continued to display evidence of drug-induced cytotoxicity. These findings support the possibility that a cell-mediated immune response usually plays a role in the pathogenesis of amiodarone pneumonitis, although direct cytotoxicity may predispose these patients to the development of this abnormal immune response.     

Chromatin-to-nucleoprotamine transition is controlled by the histone H2B variant TH2B

The conversion of male germ cell chromatin to a nucleoprotamine structure is fundamental to the life cycle, yet the underlying molecular details remain obscure. Here we show that an essential step is the genome-wide incorporation of TH2B, a histone H2B variant of hitherto unknown function. Using mouse models in which TH2B is depleted or C-terminally modified, we show that TH2B directs the final transformation of dissociating nucleosomes into protamine-packed structures. Depletion of TH2B induces compensatory mechanisms that permit histone removal by up-regulating H2B and programming nucleosome instability through targeted histone modifications, including lysine crotonylation and arginine methylation. Furthermore, after fertilization, TH2B reassembles onto the male genome during protamine-to-histone exchange. Thus, TH2B is a unique histone variant that plays a key role in the histone-to-protamine packing of the male genome and guides genome-wide chromatin transitions that both precede and follow transmission of the male genome to the egg.     

Postmortem coronary artery calcium score in cases of myocardial infarction

International Journal of Legal Medicine - Sudden cardiac death (SCD) related to atherosclerotic coronary artery disease (ACAD) resulting in myocardial infarction is the most prevalent cause of...     

Household illness is the strongest predictor of upper respiratory tract symptom risk in elite rugby union players

ObjectivesTo identify periods of increased risk for upper respiratory tract symptom (URTS) episodes, and examine whether biomarkers and/or self-reported lifestyle and wellness data can predict URTS risk in elite rugby union players.DesignProspective, longitudinal and repeated-measures study.MethodsSalivary secretory immunoglobulin A (SIgA), salivary cortisol, URTS, internal training load and self-reported lifestyle and wellness data including household illness, stress, mood, fatigue, muscle soreness and sleep quality were repeatedly measured in elite Southern hemisphere rugby union players (n = 28) throughout a season. Univariate frailty model analysis, which included 495 observations, was used to determine predictors of URTS risk.ResultsSurprisingly, the highest incidence of URTS occurred after rest weeks, namely the Christmas break and bye weeks (i.e., no scheduled trainings or matches); whereas URTS risk was reduced during weeks involving international travel (Hazard ratio (HR): 0.43, p < 0.001)). Household illness was the strongest predictor of URTS risk; players were almost three-fold more at risk for an URTS episode when illness in the household was present (HR: 2.90, p = 0.002). A non-significant, but potentially important trend for an inverse association between SIgA concentration and URTS incidence was also observed (HR: 0.99, p = 0.070).ConclusionsRest weeks were identified as periods of increased risk for URTS; while international travel did not appear to increase players risk for URTS. Incidence of household illness and SIgA concentration independently predicted URTS risk, with household illness being the strongest predictor. These findings can assist practitioners monitoring and management of athletes to potentially reduce URTS risk.     

Effect of build orientation on the manufacturing process and the properties of stereolithographic dental ceramics for crown frameworks

Statement of problemStereolithography (SLA) ceramic crown frameworks are suitable for clinical use, but the impact of SLA build orientation has not been identified.PurposeThe purpose of this in vitro study was to investigate the effect of 3 build orientations on the physical and mechanical properties and the microstructure of SLA alumina dental ceramics.Material and methodsThe physical and mechanical properties and microstructures of 3 different oriented SLA alumina ceramics (ZX, ZY, and XY) were evaluated by visual observation, hydrostatic weighing (n=10/group), Weibull analyses (n=30/group), scanning electron microscopy, 3-point flexural strength (n=30/group), fracture toughness (indentation, single-edge-V-notched-beam) (n=4/group), and Vickers hardness (n=15/group) testing. The hydrostatic weighing, 3-point flexural strength, fracture toughness, and Vickers hardness testing data were statistically analyzed (α=.05).ResultsThe minimum resting period of slurries between the polymerization of 2 layers was shorter for the ZY- and ZX-oriented specimens and increased with the layer surface. The density and Vickers hardness of the SLA-manufactured specimens were similar for all groups (P>.05). The 95% confidence intervals of the Weibull moduli of the ZX- and ZY-oriented specimens were higher than that of the XY-oriented specimens, with no overlap fraction. The ZY-oriented specimens displayed significantly higher 3-point flexural strength (P<.05) and fracture toughness as evaluated by the single-edge-V-notched-beam method than the ZX-oriented specimens (P<.05). They also displayed significantly higher 3-point flexural strength than the XY-oriented specimens (P<.05). The microstructural analysis showed that the texturing was heterogeneous and that the major axis of the large grains of alumina ran parallel to the orientation of the layers.ConclusionsThe ZY orientation produced a reliable dental ceramic by SLA, with the shortest general manufacturing time and the highest mechanical strength when the layers were perpendicular to the test load surface.     

How to Avoid Nontherapeutic Laparotomy in Patients With Multiple Organ Failure of Unknown Origin. The Role of CT Scan Revisited

Diagnosis of intra-abdominal diseases in critically ill patients remains a clinical challenge. Physical examination is unreliable whereas exploratory laparotomy may aggravate patient''s condition and delay further evaluation. Only a few studies have investigated the place of computed tomography (CT) on this hazardous situation. We aimed to evaluate the ability of CT to prevent unnecessary laparotomy during the management of critically ill patients. Charts of all consecutive patients who had undergone an emergency nontherapeutic laparotomy from 1996 to 2013 were retrospectively studied and patient''s demographic, clinical characteristics, and surgical findings were collected. During this period 59 patients had an unnecessary laparotomy. Fifty-one patients had at least one preoperative imaging and 36 had a CT scan. CT scans were interpreted to be normal (n = 12), with minor anomalies (n = 10), or major anomalies (pneumoperitoneum, portal venous gas/pneumatosis intestinalis, thickened gallbladder wall, and small bowel obstruction signs). Surgical exploration was performed through laparotomy (n = 55) or laparoscopy. Overall mortality was 37% with a median survival after surgery of 7 days. In univariate analysis, hospitalization in ICU before surgical exploration was the only factor related to death. In our series CT scans, objectively interpreted, helped avoid unnecessary surgical exploration in 61% of our patients.Key words: Laparotomy, Critical care, Abnormalities, Digestive system, CT scansEarly diagnosis of acute nontraumatic life-threatening intra-abdominal diseases remains a clinical challenge. In critically ill patients, pathologies such as mesenteric ischemia, intestinal perforation, pancreatitis and biliary diseases carry a high mortality rate ranging from 50% to 100%.^1,2 For these patients, physical examination can be unreliable due to deep sedation and absence of acute abdomen symptoms, and use of imaging studies may therefore be necessary to identify intra-abdominal pathologies and prevent delay in diagnosis. Also, imaging studies may help avoiding unnecessary laparotomy which can be associated with a morbidity rate up to 22%.³ Ultrasonography (US) can be performed at the bedside and is a good alternative for the diagnosis of biliary tract disease; however, it is highly operator dependent, made difficult by abdominal distension,⁴ and not effective for bowel perforation or ischemia.⁵ Computed tomography (CT) scans are increasingly used for emergency patients with acute nontraumatic abdominal pain and tenderness, however, misinterpretation or overinterpretation of CT findings are not rare.^6,7 Despite the large use of imaging procedures in the evaluation of intra-abdominal pathologies, few studies have attempted to assess their impact on the management of critically ill patients.^8,9 The aim of this observational work was to evaluate the results of preoperative imaging procedures, especially CT, in a consecutive series of nontraumatic critically ill patients who underwent nontherapeutic surgical abdominal exploration in a French university tertiary care hospital.     

Rectal biopsy and precancer in ulcerative colitis

Forty-seven patients with ulcerative colitis subjected to elective proctocolectomy were investigated with regard to the occurrence of precancerous changes in the rectal biopsy and the operation specimen. In the rectal biopsy from seven patients precancerous lesions were found and in the operation specimens from these patients precancer was also found in other parts of the colon. In five of these patients the precancer was associated with carcinoma and in four of the patients the tumour had not been detected before operation. It is concluded that rectal biopsy is of great value in patients with ulcerative colitis for detection of early cancer and patients at risk of developing a colitis carcinoma.