Efficacy and cost of home-initiated auto-nCPAP versus conventional nCPAP

STUDY OBJECTIVES: To compare in a multicenter prospective study the efficacy and cost of conventional nasal continuous positive airway pressure (nCPAP) initiated at the sleep laboratory versus auto-nCPAP initiated at home. DESIGN: Patients with severe obstructive sleep apnea syndrome (OSAS) were randomized to treatment with either the REM+ auto device in constant mode at the effective pressure determined by titration at the sleep laboratory (n=17) or the REM+ auto device in automatic mode initiated at the patients home by a nurse (n=18). After 2 months, the efficacy and cost of nCPAP therapy and the time from diagnosis to nCPAP were evaluated. All values are reported as means +/- SD. PATIENTS: Thirty-five subjects with newly diagnosed OSAS (8 women and 27 men, mean age: 54.3 +/- 10.6 years, apnea-hypopnea index (AHI) 58.1 +/- 14.0 h(-1)). INTERVENTIONS: N/A MEASUREMENTS AND RESULTS: Both treatments were used properly and induced similar decreases in the AHI (7.6 +/- 6.9 vs. 10.4 +/ -12.5 h(-1) for auto-nCPAP and conventional nCPAP, respectively; NS) and Epworth Sleepiness score (from 15.5 +/- 4.7 to 7.5 +/- 3.4 vs. 14.7 +/- 3.9 to 7.6 +/- 3.4 for auto-nCPAP and conventional nCPAP, respectively; NS). With auto-nCPAP initiated at home, the time from diagnosis to final adjustment of nCPAP was shorter (16.3 +/- 5.0 vs. 47.2 +/- 46.5 days with conventional nCPAP, P < 0.02) and the cost was lower (1,263 +/- 352 vs. 1720+/-455 E, respectively; P < 0.05). CONCLUSIONS: Treatment of OSAS with auto-nCPAP initiated at home is effective and reliable and reduces the time from diagnosis to therapy and the cost of treatment.     

Approaches for modeling within subject variability in pharmacometric count data analysis: dynamic inter-occasion variability and stochastic differential equations

Parameter variation in pharmacometric analysis studies can be characterized as within subject parameter variability (WSV) in pharmacometric models. WSV has previously been successfully modeled using inter-occasion variability (IOV), but also stochastic differential equations (SDEs). In this study, two approaches, dynamic inter-occasion variability (dIOV) and adapted stochastic differential equations, were proposed to investigate WSV in pharmacometric count data analysis. These approaches were applied to published count models for seizure counts and Likert pain scores. Both approaches improved the model fits significantly. In addition, stochastic simulation and estimation were used to explore further the capability of the two approaches to diagnose and improve models where existing WSV is not recognized. The results of simulations confirmed the gain in introducing WSV as dIOV and SDEs when parameters vary randomly over time. Further, the approaches were also informative as diagnostics of model misspecification, when parameters changed systematically over time but this was not recognized in the structural model. The proposed approaches in this study offer strategies to characterize WSV and are not restricted to count data.     

Population pharmacodynamics in patients receiving tinzaparin for the prevention and treatment of deep vein thrombosis.

OBJECTIVES: We conducted population anticoagulant pharmacodynamic analysis for patients administered the low-molecular weight heparin tinzaparin. METHODS: Data from 425 patients (2,631 observations) who participated in 2 Phase III clinical studies were utilized in an analysis based on a pharmacodynamic structural model of anti-Xa activity using non-linear mixed effects modeling techniques. Anti-Xa activity from patients participating in a multicenter, randomized, double-blind clinical trial comparing intravenous once daily subcutaneous tinzaparin (175 IU/kg) with heparin for the treatment of deep vein thrombosis (DVT) was first examined using a 2-compartment model with first-order absorption and endogenous anti-Xa activity. Covariates included renal function, body weight, age, gender, race, obesity, concomitant administration of warfarin, and diabetes. RESULTS: The population estimates and 90% confidence intervals (CI) for oral clearance (CL) and apparent volume of distribution of the plasma compartment (Vc) were 0.0176 l/h/kg (CI = 0.012-0.023) and 0.098 l/kg (CI = 0.088 - 0.109), respectively. The elimination half-life was 3.9 h (CI = 2.5-5.2). These estimates are similar to findings in healthy volunteers. The inter-patient variability in clearance was related to plasma creatinine and percent above ideal body weight. Clearance decreased by 22% for patients with severe renal function impairment (creatinine clearance < 30 ml/min), and by about 25% in obese patients (BMI > 30 kg/m2). CONCLUSIONS: Changes of these magnitudes were not clinically important in pooled clinical trial safety and efficacy analyses. Body weight was not a significant covariate in the model supporting the observations in earlier well-defined trials, where tinzaparin was dosed on a weight basis (lU/kg). Clearance was not influenced by age, race or gender. The same model was applied to data obtained from a prospective, randomized, double-blind clinical trial comparing tinzaparin (4,500 IU) to enoxaparin (40 mg) once daily in patients undergoing total hip replacement. Model parameters were similar to those previously obtained supporting the extension of these results across dose and indication. Population analysis in patients with disease and heterogeneity indicated similar pharmacodynamics as in volunteers, supporting weight-based dosing and identified the dependence of clearance on obesity and severe renal function, although the magnitude of these effects are probably not clinically significant.     

Severe hypothyroidism after contrast enema in premature infants

Premature newborns are particularly vulnerable to iatrogenic hypothyroidism due to iodine exposure, usually through skin absorption of iodine-containing disinfectants or intravenous administration of iodinated contrast agents. We report here a case of severe iatrogenic hypothyroidism with goiter and cholestasis, discovered six weeks after a contrast enema using sodium ioxitalamate, an iodinated contrast agent. Prematurity, intrauterine growth retardation, and enteral feeding intolerance could explain why this complication occurred after contrast enema. Our observations suggest that indications of contrast enema in neonates need to be carefully considered, and when necessary, thyroid function should be monitored, especially in very premature infants.     

Whole‐brain structural connectivity in dyskinetic cerebral palsy and its association with motor and cognitive function

Dyskinetic cerebral palsy (CP) has long been associated with basal ganglia and thalamus lesions. Recent evidence further points at white matter (WM) damage. This study aims to identify altered WM pathways in dyskinetic CP from a standardized, connectome‐based approach, and to assess structure‐function relationship in WM pathways for clinical outcomes. Individual connectome maps of 25 subjects with dyskinetic CP and 24 healthy controls were obtained combining a structural parcellation scheme with whole‐brain deterministic tractography. Graph theoretical metrics and the network‐based statistic were applied to compare groups and to correlate WM state with motor and cognitive performance. Results showed a widespread reduction of WM volume in CP subjects compared to controls and a more localized decrease in degree (number of links per node) and fractional anisotropy (FA), comprising parieto‐occipital regions and the hippocampus. However, supramarginal gyrus showed a significantly higher degree. At the network level, CP subjects showed a bilateral pathway with reduced FA, comprising sensorimotor, intraparietal and fronto‐parietal connections. Gross and fine motor functions correlated with FA in a pathway comprising the sensorimotor system, but gross motor also correlated with prefrontal, temporal and occipital connections. Intelligence correlated with FA in a network with fronto‐striatal and parieto‐frontal connections, and visuoperception was related to right occipital connections. These findings demonstrate a disruption in structural brain connectivity in dyskinetic CP, revealing general involvement of posterior brain regions with relative preservation of prefrontal areas. We identified pathways in which WM integrity is related to clinical features, including but not limited to the sensorimotor system. Hum Brain Mapp 38:4594–4612, 2017. © 2017 Wiley Periodicals, Inc.     

Function of human alveolar macrophages after a 3-day course of azithromycin in healthy volunteers

Azithromycin (AZM) is a new macrolide antibiotic with a high intracellular/extracellular concentration ratio. Immunomodulatory and antiinflammatory properties have been reported with other macrolides, especially erythromycin. The aim of the present study was to evaluate the effect of AZM on the production of proinflammatory mediators by alveolar macrophages (AM) up to 4 weeks after a 3-day course of AZM (500 mg, once a day). Nineteen non-smoking healthy male subjects were investigated with bronchoscopy and bronchoalveolar lavage. Group 1 received no treatment. Groups 2, 3, and 4 were bronchoscoped 1, 7 and 30 days, respectively, after AZM administration. AZM concentrations were simultaneously measured in plasma and in AM extracts. In serum, AZM levels were higher in group 2 (32.8 +/- 14.2 micrograms/l), at the lower limit of detection in group 3 (2.8 +/- 1.7 micrograms/l), and no longer detectable in group 4. In AM extracts, the highest concentrations were measured in group 2 (51.6 +/- 28.3 ng/microliter) and in group 3 (31.8 +/- 17.2 ng/microliter), and were detected up to 30 days after treatment in group 4 (2.9 +/- 2.3 ng/microliter). There was no significant differences between groups for blood or BAL proinflammatory cytokines levels (TNF-alpha, IL-1 beta, IL-6), and for superoxide generation by AM. We conclude that a 3-day course of AZM 500 mg/day in healthy subjects does not alter the proinflammatory cytokine profile in blood and in AM despite the prolonged tissue impregnation by this drug.     

男性与女性性高潮潜伏期的对照研究

目的 通过有稳定性生活的女性来调查她们的性高潮潜伏期与其配偶的射精潜伏期之间的关系，以便进一步了解男性早泄的发病率，以及与女性的关系。方法 采用自制的调查问卷对两组不同女性的样本进行调查。结果 平均男性射精潜伏期是12～13min，女性最快达到性高潮的平均时间是8～9min，女性理想的射精潜伏期是13～18min。重度早泄6％～10％，轻到中度20％～40％。结论 早泄是唯一一种诊断标准要参照女性性生活满意度的性功能障碍，除个别严重的病例外，造成早泄的一个不可忽略的重要原因是错配，在研究和治疗早泄的同时也应该重视女性性高潮潜伏期延迟这个相对应的性功能障碍。     

Lack of effect of experimental hypovolemia on imipenem muscle distribution in rats assessed by microdialysis

The aim of this study was to investigate the influence of hypovolemia on the distribution of imipenem in muscle extracellular fluid determined by microdialysis in awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Imipenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced by removing 40% of the initial blood volume over 30 min. Imipenem was infused intravenously at a dose of 70 mg . kg(-1) over 30 min, and microdialysis samples were collected for 120 min from hypovolemic (n = 8) and control (n = 8) rats. The decay of the free concentrations in blood and muscle with time were monoexponential, and the concentration profiles in muscle and blood were virtually superimposed in both groups. Accordingly, the ratios of the area under the concentration-time curve (AUC) for tissue (muscle) to the AUC for blood were always virtually equal to 1. Hypovolemia induced a 23% decrease in the clearance (P < 0.05) of imipenem, with no statistically significant alteration of its volume of distribution. This study showed that imipenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. In particular, free imipenem concentrations in blood and muscle were always virtually identical.     

Arterial blood gases during exercise: Validity of transcutaneous measurements

OBJECTIVE: To investigate the validity of transcutaneous measurements of blood gas tensions for the assessment of partial arterial pressure of oxygen (PaO(2)) and carbon dioxide (PaCO(2)) during treadmill exercise. DESIGN: Experimental, self-controlled against a reference standard. SETTING: Lung function laboratory. PATIENTS: Eighty-one patients with various lung diseases. INTERVENTIONS: At rest and at symptom-limited peak exercise, puncture of the radial artery with concurrent transcutaneous measures of blood gases. MAIN OUTCOME MEASURES: Arterial blood samples were analyzed with a radiometer to measure PaO(2) and PaCO(2). A microgas apparatus was used to measure gas tensions transcutaneously. Values obtained transcutaneously (TcPO(2), TcPCO(2)) were compared with those obtained by blood sample. TcPO(2) was adjusted as close as possible to the PaO(2) obtained in the same conditions, with the correction factor of the apparatus. Values obtained transcutaneously were compared with those obtained by blood sample to establish the sensitivity and specificity of the noninvasive method. RESULTS: Mean differences +/- standard deviation between transcutaneous and arterial tension at peak exercise were 0.4 +/- 7.0mmHg and 2.1 +/- 3.3mmHg for PaO(2) and PaCO(2), respectively. The transcutaneous device enabled us to predict a decrease in PaO(2) (>or=2mmHg) from rest to exercise with a sensitivity of 92.1% and a specificity of 90% and an increase in PaCO(2) with a sensitivity of 88% and a specificity of 58.9%. CONCLUSIONS: Although transcutaneous measurement are sufficiently sensitive and specific to detect patients whose PaO(2) decreases during exercise, its precision is not sufficient for gas exchange calculations.