Interacting Multiple Try Algorithms with Different Proposal Distributions

We propose a new class of interacting Markov chain Monte Carlo (MCMC) algorithms designed for increasing the efficiency of a modified multiple-try Metropolis (MTM) algorithm. The extension with respect to the existing MCMC literature is twofold. The sampler proposed extends the basic MTM algorithm by allowing different proposal distributions in the multiple-try generation step. We exploit the structure of the MTM algorithm with different proposal distributions to naturally introduce an interacting MTM mechanism (IMTM) that expands the class of population Monte Carlo methods. We show the validity of the algorithm and discuss the choice of the selection weights and of the different proposals. We provide numerical studies which show that the new algorithm can perform better than the basic MTM algorithm and that the interaction mechanism allows the IMTM to efficiently explore the state space

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Efficacy of a novel perfluorocarbon-based intrapulmonary drug delivery system

Introduction: We sought to determine the efficacy of a novel intrapulmonary perfluorocarbon (PFC) based antibiotic delivery system in a rat model of pneumococcal pneumonia. Methods: Wistar rats (400-500 g) were inoculated with 8x10' type 3 pneumococcus via direct intratracheal (IT) injection. Twenty-four h after inoculation, rats received no treatment (control, n=15), 10 mg IM ampicillin (AMP, n =10), 10 ml lavage with an AMP containing (1 mg/ml) microparticulate dispersion in PFC (AMPPFC; Alliance Pharmaceutical Corp.; n=ll). Animals were monitored daily for survival for 10 days. AMP concentrations, were determined in serum and lung homogenates using a bioassay. The log-rank test with Bonferroni's correction was used to determine differences in mortality among groups. The null hypothesis was rejected for a critical p&lt;0.017. Results: Mortality was significantly higher in controls than AMPPFC (100% vs 18%, p &lt; 0.017). There was a trend favoring treatment with AMPPFC compared to AMP (18% vs 70% mortality, p&lt;0.019). The table shows serum and lung antibiotic concentrations (n=2) Time (h) AMP (jig/ml) AMPPFC Qig/ml) Serum Lung Serum Lung 1 15 2 15 500 2 1 1 2 120 3 0 0 1 60 4 0 0 2 50 8 0 0 0 15 24 0 0 0 10 48 0 0 0 3 72 0 0 0 2 Conclusions: PFC-based IT antibiotic microparticulate formüations may be more effect than systemic antibiotic therapy alone in the treatment of severe pneumonia

Liquid ventilation with perflubron in the treatment of rats with pneumococcal pneumonia.

OBJECTIVE: To determine the efficacy of liquid ventilation using a medical-grade perfluorocarbon (perflubron) combined with parenteral or intratracheal antibiotics in a rat model of pneumonia. DESIGN: Prospective, laboratory investigation. SETTING: Experimental laboratory in a university medical center. SUBJECTS: Wistar rats (n = 112). INTERVENTIONS: One day after intratracheal inoculation with Streptococcus pneumoniae, rats received one of five experimental treatments or no treatment (control): modified liquid ventilation (MLV), intramuscular ampicillin, MLV plus intramuscular ampicillin, MLV with intratracheal ampicillin, or MLV plus ampicillin PulmoSpheres. MEASUREMENTS AND MAIN RESULTS: Animals receiving MLV plus intramuscular ampicillin, MLV with intratracheal ampicillin, or MLV plus ampicillin PulmoSpheres had significantly improved 10-day survival rates (85%, 72%, and 72%, respectively) compared with all other groups (0% to 25%). CONCLUSIONS: MLV in combination with either intramuscular, intratracheal, or PulmoSpheres ampicillin improved survival as compared with MLV alone or the same dose of antibiotics delivered intramuscularly

Partial liquid ventilation with perfluorocarbon in the treatment of rats with lethal pneumococcal pneumonia.

BACKGROUND: Partial liquid ventilation with perfluorocarbon is a new therapeutic strategy to treat various lung disorders. The current study was undertaken to determine the efficacy of partial liquid ventilation with a perfluorocarbon (FC-77) in the treatment of pneumococcal pneumonia in rats. METHODS: Male Wistar rats (weight, 275-300 g; n, 75) were infected via direct intratracheal inoculation with ca 10(9) colony-forming units of viable Streptococcus pneumoniae, serotype 3, and 24 h after infection were placed into one of five groups, each containing 15 rats. The groups were (1) no treatment, (2) one intramuscular injection of penicillin G benzathine (200,000 U), (3) partial liquid ventilation with FC-77, (4) partial liquid ventilation with FC-77 and a single intramuscular dose of penicillin G benzathine (200,000 U), and (5) gas ventilation. Animals were observed every 24 h for survival. RESULTS: All untreated or gas-ventilated animals or animals that received only partial liquid ventilation were dead by 7 days. Those receiving only partial liquid ventilation survived longer than untreated controls, but ultimately all succumbed by day 7. Survival was 40% for penicillin-treated rats compared with controls (P &lt; 0.05) and 80% for animals treated with both partial liquid ventilation and penicillin versus antibiotic alone (P &lt; 0.05). CONCLUSIONS: These observations suggest that partial liquid ventilation with perfluorocarbon in combination with antibiotic administration may be an effective therapeutic modality in pneumococcal pneumonia