Performance of Three Estimation Methods in Repeated Time-to-Event Modeling

It is not uncommon that the outcome measurements, symptoms or side effects, of a clinical trial belong to the family of event type data, e.g., bleeding episodes or emesis events. Event data is often low in information content and the mixed-effects modeling software NONMEM has previously been shown to perform poorly with low information ordered categorical data. The aim of this investigation was to assess the performance of the Laplace method, the stochastic approximation expectation-maximization (SAEM) method, and the importance sampling method when modeling repeated time-to-event data. The Laplace method already existed, whereas the two latter methods have recently become available in NONMEM 7. A stochastic simulation and estimation study was performed to assess the performance of the three estimation methods when applied to a repeated time-to-event model with a constant hazard associated with an exponential interindividual variability. Various conditions were investigated, ranging from rare to frequent events and from low to high interindividual variability. The method performance was assessed by parameter bias and precision. Due to the lack of information content under conditions where very few events were observed, all three methods exhibit parameter bias and imprecision, however most pronounced by the Laplace method. The performance of the SAEM and importance sampling were generally higher than Laplace when the frequency of individuals with events was less than 43%, while at frequencies above that all methods were equal in performance.     

Prophylactic antithrombotic therapy after orthopedic surgery with bemiparin, a second-generation low molecular weight heparin]

OBJECTIVE: Bemiparin is a new second generation low molecular weight heparin with a molecular weight of 3,600 daltons and an anti-Xa/anti-IIa ratio greater than 8. The aim of this study was to evaluate the efficacy and safety of bemiparin administered at a daily dose of 3,500 IU anti-Xa (40 mg), with prophylaxis beginning 6 hours after total hip replacement surgery. PATIENTS AND METHODS: Fifty-seven consecutive patients were evaluated by bilateral phlebography of the lower limbs 10 days after surgery. The patients were recruited at two centers specializing in orthopedic surgery. RESULTS: The incidence of deep venous thrombosis (DVT) in the series was 7% (95% CI: 0.4-13.7). In three patients (5%) DVT was proximal (95% CI 0-11.1). These results are consistent with those reported by Kakkar for bemiparin at the same dose begun two hours before surgery (incidence of DVT: 7.2%).No episodes of major bleeding were observed with this new protocol for postoperative administration. The incidence of wound hematoma was low and no patient required further surgery. The rate of post-operative bleeding was similar to that usually reported when low molecular weight heparin is used in hip surgery. CONCLUSIONS: Thromboprophylaxis in orthopaedic surgery with bemiparin beginning 6 hours after surgery appears to be safe and effective.     

A study of hospital discharges for venous thromboembolism in the south of Spain. An analysis of 19,170 cases from a regional database from 1998 to 2001

BACKGROUND: Our objective was to learn about the incidence of hospitalization for venous thromboembolism (VTE) in the public health care system in Andalusia and to define the profile of the patients, with special reference to the Department of Internal Medicine. METHODS: We analyzed the discharged data set of 32 hospitals in the Andalusian Health Care Service between 1998 and 2001, identifying the cases in whom the diagnosis was VTE. The age, sex, length of stay, outcome, number of diagnoses, diagnosis-related group (DRG), and coded procedures were studied. RESULTS: During the period studied, there were 2,228,894 discharges, 19,170 of which involved VTE. In 8494 of these, VTE was the cause of the admission. Some 3961 patients (46.6%) were admitted for pulmonary embolism (PE); 45% were discharged from internal medicine, 41% from pneumology, and 14% from other departments. The average patient age was 65, the length of stay 13.8 days, and the global in-hospital mortality rate 13%. Some 4533 cases (53.4%) were admitted due to deep vein thrombosis (DVT): 38.5% to internal medicine, 21.30% to general surgery, 12.35% to angiology, and the remainder to other departments. The length of stay was 10.6 days with an in-hospital mortality rate of 2.20%. In 7721 cases, VTE was the secondary diagnosis (after excluding 2955 cases of superficial thrombophlebitis of the upper limbs); 74% was associated with a medical DRG. CONCLUSIONS: VTE is a frequent pathology in our hospitals. It shows a great variability in clinical practice although there are differences between patients treated by different specialists. VTE as secondary diagnosis was more frequent in medical inpatients.     

Quorum Sensing of Periodontal Pathogens

The term ‘quorum sensing’ describes intercellular bacterial communication which regulates bacterial gene expression according to population cell density. Bacteria produce and secrete small molecules, named autoinducers, into the intercellular space. The concentration of these molecules increases as a function of population cell density. Once the concentration of the stimulatory threshold is reached, alteration in gene expression occurs. Gram-positive and Gram-negative bacteria possess different types of quorum sensing systems. Canonical LuxI/R-type/acyl homoserine lactone mediated quorum sensing system is the best studied quorum sensing circuit and is described in Gram-negative bacteria which employ it for inter-species communication mostly. Gram-positive bacteria possess a peptide-mediated quorum sensing system. Bacteria can communicate within their own species (intra-species) but also between species (inter-species), for which they employ an autoinducer-2 quorum sensing system which is called the universal language of the bacteria. Periodontal pathogenic bacteria possess AI-2 quorum sensing systems. It is known that they use it for regulation of biofilm formation, iron uptake, stress response and virulence factor expression. A better understanding of bacterial communication mechanisms will allow the targeting of quorum sensing with quorum sensing inhibitors to prevent and control disease.Key Words: Quorum Sensing, Gram-Positive Bacteria, Gram-Negative Bacteria, Periodontitis     

Home diagnosis of obstructive sleep apnoea in coronary patients: validity of a simplified device automated analysis

Introduction

Our aim was to evaluate a type 3 portable simplified device as a screening tool for obstructive sleep apnoea (OSA) in coronary patients.

Materials and methods

In 50 patients selected independently from sleep complaints, we compared the number of respiratory events per hour of valid recording time counted automatically by the device and the number counted manually per hour of sleep on polysomnography performed at home during the same night.

Results

Five patients were excluded because of technical failures. Estimated OSA prevalences (95% confidence interval) for apnoea/hypopnoea index (AHI) cut-offs ≥5, ≥15, and ≥30 by polysomnography were 0.93 (0.81–0.98), 0.69 (0.53–0.81), and 0.27 (0.15–0.42), respectively. The device would have correctly diagnosed 75% of patients with severe OSA (AHI ≥30 by polysomnography) and would have classified the remaining 25% as having moderate OSA.

Discussion

This ambulatory device may prove valuable in reducing the costs of diagnosing and managing OSA in coronary patients.     

Effect of celiprolol treatment in hypertensive patients with sleep apnea.

The effects of a beta-blocker, celiprolol, on sleep and arterial blood pressure (BP) were evaluated during a single-blind study in seven hypertensive patients with sleep apnea. Diurnal ambulatory BP measurements with an automatic cuff-inflation device and polysomnography with simultaneous Finapres BP recording were performed separately on consecutive days at the end of two 21-day treatment periods involving placebo followed by celiprolol (200 mg/day). Age was 59 +/- 2.5 yr (m +/- sem) and body mass index 33.2 +/- 2.3 kg. m-2. Diurnal ambulatory BP was significantly lower with celiprolol than with placebo (systolic 139 +/- 4 vs 152 +/- 5 mmHg, diastolic 86 +/- 2 vs 96 +/- 2 mmHg). The apnea-hypopnea index was similar under celiprolol and placebo (48 +/- 7.4 vs 53 +/- 7.8, respectively), as were the total sleep time and percent of duration of the different sleep stages. Individual average BP values were significantly lower during REM sleep under celiprolol but remained similar under celiprolol and placebo in the other sleep stages. Variability of nocturnal BP (assessed by the SD of distribution of BP variations) was not affected by celiprolol. In conclusion, celiprolol which decreased daytime BP, did not affect sleep pattern or respiratory disturbances, or nocturnal BP variability related to apnea.     

Polarized entry of uropathogenic Afa/Dr diffusely adhering Escherichia coli strain IH11128 into human epithelial cells: evidence for alpha5beta1 integrin recognition and subsequent internalization through a pathway involving caveolae and dynamic unstable microtubules

Afa/Dr diffusely adhering Escherichia coli strain IH11128 bacteria basolaterally entered polarized epithelial cells by a CD55- and CD66e-independent mechanism through interaction with the alpha5beta1 integrin and a pathway involving caveolae and dynamic microtubules (MTs). IH11128 invasion within HeLa cells was dramatically decreased after the cells were treated with the cholesterol-extracting drug methyl-beta-cyclodextrin or the caveola-disrupting drug filipin. Disassembly of the dynamically unstable MT network by the compound 201-F resulted in a total abolition of IH11128 entry. In apically infected polarized fully differentiated Caco-2/TC7 cells, no IH11128 entry was observed. The entry of bacteria into apically IH11128-infected fully differentiated Caco-2/TC7 cells was greatly enhanced by treating cells with Ca2+-free medium supplemented with EGTA, a procedure that disrupts intercellular junctions and thus exposes the basolateral surface to bacteria. Basally infected fully differentiated polarized Caco-2/TC7 cells grown on inverted inserts mounted in chamber culture showed a highly significant level of intracellular IH11128 bacteria compared with cells subjected to the apical route of infection. No expression of CD55 and CD66e, the receptors for the Afa/Dr adhesins, was found at the basolateral domains of these cells. Consistent with the hypothesis that a cell-to-cell adhesion molecule acts as a receptor for polarized IH11128 entry, an antibody blockade using anti-alpha5beta1 integrin polyclonal antibody completely abolished bacterial entry. Experiments conducted with the laboratory strain E. coli K-12 EC901 carrying the recombinant plasmid pBJN406, which expresses Dr hemagglutinin, demonstrated that the dra operon is involved in polarized entry of IH11128 bacteria. Examined as a function of cell differentiation, the number of internalized bacteria decreased dramatically beyond cell confluency. Surviving intracellular IH11128 bacteria residing intracellularly had no effect on the functional differentiation of Caco-2/TC7 cells.     

An equivalence study of two low-molecular-weight heparins in the prevention and treatment of deep-vein thrombosis after total hip replacement

Low-molecular-weight heparins have been evaluated against unfractionated heparin and have been shown to have clinical benefits in the perioperative setting during orthopedic surgery. Two low-molecular-weight heparins, tinzaparin and enoxaparin, were assessed for equivalency in efficacy and safety in 499 patients undergoing elective hip replacement. The two anticoagulants were found to be effective and safe in this setting in the specified patient type. No statistical difference was observed in the incidence of bleeding. Clinical side effects tended to be greater in patients with a higher body mass index, which could serve as a possible indicator for the risk of deep vein thrombosis.