The incidence of all-cause, cardiovascular and respiratory disease admission among 20,252 users of lisinopril vs. perindopril: a cohort study

Background: Major international guidelines do not offer explicit recommendations on any specific angiotensin-converting enzyme inhibitor (ACEI) agent over another within the same drug group. This study compared the effectiveness of lisinopril vs. perindopril in reducing the incidence of hospital admission due to all-cause, cardiovascular disease and respiratory disease. Methods: Adult patients who received new prescriptions of lisinopril or perindopril from 2001 to 2005 in all public hospitals and clinics in Hong Kong were included, and followed up for ≥2 years. The incidence of admissions due to all-cause, cardiovascular disease and respiratory disease were evaluated, respectively, by using Cox proportional hazard regression models. The regression models were constructed with propensity score matching to minimize indication biases. Results: A total of 20,252 eligible patients with an average age of 64.5 years (standard deviation 15.0) were included. The admission rate at 24 months within the date of index prescription due to any cause, cardiovascular disease and respiratory disease among lisinopril vs. perindopril users was 24.8% vs. 24.8%, 13.7% vs. 14.0% and 6.9% vs. 6.3%, respectively. Lisinopril users were significantly more likely to be admitted due to respiratory diseases (adjusted hazard ratios [AHR] = 1.25, 95% CI 1.08 to 1.43, p = 0.002 at 12 months; AHR = 1.17, 95% CI 1.04 to 1.31, p = 0.009 at 24 months) and all causes (AHR = 1.12, 95% CI 1.05 to 1.19, p < 0.001 at 24 months) than perindopril users. Conclusions: These findings support intra-class differences in the effectiveness of ACEIs, which could be considered by clinical guidelines when the preferred first-line antihypertensive drugs are recommended

Impact of infection control interventions on rates of Staphylococcus aureus bacteraemia in National Health Service acute hospitals, East Midlands, UK, using interrupted time-series analysis

Background: Reducing healthcare-associated infection (HCAI) is a UK national priority. Multiple national and regional interventions aimed at reduction have been implemented in National Health Service acute hospitals, but assessment of their effectiveness is methodologically challenging. Aim: To assess the effectiveness of national and regional interventions undertaken between 2004 and 2008 on rates of meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-sensitive Staphylococcus aureus (MSSA) bacteraemia within acute hospitals in the East Midlands, using interrupted time-series analysis. Methods: We used segmented regression to compare rates of MRSA and MSSA bacteraemia in the pre-intervention, implementation, and post-intervention phases for combined intervention packages in eight acute hospitals. Findings: Most of the change in MSSA and MRSA rates occurred during the implementation phase. During this phase, there were significant downward trends in MRSA rates for seven of eight acute hospital groups; in four, this was a steeper quarter-on-quarter decline compared with the pre-intervention phase, and, in one, an upward trend in the pre-intervention phase was reversed. Regarding MSSA, there was a significant positive effect in four hospital groups: one upward trend during the pre-intervention phase was reversed, two upward trends plateaued, and in one hospital group an indeterminate trend decreased significantly. However, there were significant increasing trends in quarterly MSSA rates in four hospital groups during the implementation or post-intervention periods. Conclusion The impact of interventions varied by hospital group but the overall results suggest that national and regional campaigns had a beneficial impact on MRSA and MSSA bacteraemia within the East Midlands

Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR

The role of lipids in inflammasome activation remains underappreciated. The phospholipid, platelet-activating factor (PAF), exerts multiple physiological functions by binding to a G protein-coupled seven-transmembrane receptor (PAFR). PAF is associated with a number of inflammatory disorders, yet the molecular mechanism underlying its proinflammatory function remains to be fully elucidated. We show that multiple PAF isoforms and PAF-like lipids can activate the inflammasome, resulting in IL-1β and IL-18 maturation. This is dependent on NLRP3, ASC, caspase-1, and NEK7, but not on NLRC4, NLRP1, NLRP6, AIM2, caspase-11, or GSDMD. Inflammasome activation by PAF also requires potassium efflux and calcium influx but not lysosomal cathepsin or mitochondrial reactive oxygen species. PAF exacerbates peritonitis partly through inflammasome activation, but PAFR is dispensable for PAF-induced inflammasome activation in vivo or in vitro. These findings reveal that PAF represents a damage-associated signal that activates the canonical inflammasome independently of PAFR and provides an explanation for the ineffectiveness of PAFR antagonist in blocking PAF-mediated inflammation in the clinic

Variation in Target Attainment of Beta-Lactam Antibiotic Dosing Between International Pediatric Formularies.

As antimicrobial susceptibility of common bacterial pathogens decreases, ensuring optimal dosing may preserve the use of older antibiotics in order to limit the spread of resistance to newer agents. Beta-lactams represent the most widely prescribed antibiotic class, yet most were licensed prior to legislation changes mandating their study in children. As a result, significant heterogeneity persists in the pediatric doses used globally, along with quality of evidence used to inform dosing. This review summarizes dosing recommendations from the major pediatric reference sources and tries to answer the questions: Does beta-lactam dose heterogeneity matter? Does it impact pharmacodynamic target attainment? For three important severe clinical infections-pneumonia, sepsis, and meningitis-pharmacokinetic models were identified for common for beta-lactam antibiotics. Real-world demographics were derived from three multicenter point prevalence surveys. Simulation results were compared with minimum inhibitory concentration distributions to inform appropriateness of recommended doses in targeted and empiric treatment. While cephalosporin dosing regimens are largely adequate for target attainment, they also pose the most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin, and meropenem doses as potentially requiring review/optimization in order to preserve the use of these agents in future

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Real Roots of Random Polynomials and Zero Crossing Properties of Diffusion Equation

We study various statistical properties of real roots of three different classes of random polynomials which recently attracted a vivid interest in the context of probability theory and quantum chaos. We first focus on gap probabilities on the real axis, i.e. the probability that these polynomials have no real root in a given interval. For generalized Kac polynomials, indexed by an integer d, of large degree n, one finds that the probability of no real root in the interval [0,1] decays as a power law n^{-\theta(d)} where \theta(d) > 0 is the persistence exponent of the diffusion equation with random initial conditions in spatial dimension d. For n \gg 1 even, the probability that they have no real root on the full real axis decays like n^{-2(\theta(2)+\theta(d))}. For Weyl polynomials and Binomial polynomials, this probability decays respectively like \exp{(-2\theta_{\infty}} \sqrt{n}) and \exp{(-\pi \theta_{\infty} \sqrt{n})} where \theta_{\infty} is such that \theta(d) = 2^{-3/2} \theta_{\infty} \sqrt{d} in large dimension d. We also show that the probability that such polynomials have exactly k roots on a given interval [a,b] has a scaling form given by \exp{(-N_{ab} \tilde \phi(k/N_{ab}))} where N_{ab} is the mean number of real roots in [a,b] and \tilde \phi(x) a universal scaling function. We develop a simple Mean Field (MF) theory reproducing qualitatively these scaling behaviors, and improve systematically this MF approach using the method of persistence with partial survival, which in some cases yields exact results. Finally, we show that the probability density function of the largest absolute value of the real roots has a universal algebraic tail with exponent {-2}. These analytical results are confirmed by detailed numerical computations.Comment: 32 pages, 16 figure

Robust diffraction-limited near-infrared-to-near-ultraviolet wide-field imaging from stratospheric balloon-borne platforms — super-pressure balloon-borne imaging telescope performance

At a fraction of the total cost of an equivalent orbital mission, scientific balloon-borne platforms, operating above 99.7% of the Earth’s atmosphere, offer attractive, competitive, and effective observational capabilities—namely, space-like seeing, transmission, and backgrounds—which are well suited for modern astronomy and cosmology. The Super-pressure Balloon-borne Imaging Telescope (SUPERBIT) is a diffraction-limited, wide-field, 0.5 m telescope capable of exploiting these observing conditions in order to provide exquisite imaging throughout the near-infrared to near-ultraviolet. It utilizes a robust active stabilization system that has consistently demonstrated a 48 mas 1σ sky-fixed pointing stability over multiple 1 h observations at float. This is achieved by actively tracking compound pendulations via a three-axis gimballed platform, which provides sky-fixed telescope stability at < 500 mas and corrects for field rotation, while employing high-bandwidth tip/tilt optics to remove residual disturbances across the science imaging focal plane. SUPERBIT’s performance during the 2019 commissioning flight benefited from a customized high-fidelity science-capable telescope designed with an exceptional thermo- and opto-mechanical stability as well as a tightly constrained static and dynamic coupling between high-rate sensors and telescope optics. At the currently demonstrated level of flight performance, SUPERBIT capabilities now surpass the science requirements for a wide variety of experiments in cosmology, astrophysics, and stellar dynamics

Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study

BACKGROUND: Assessment of the effect of influenza on populations, including risk of infection, illness if infected, illness severity, and consultation rates, is essential to inform future control and prevention. We aimed to compare the community burden and severity of seasonal and pandemic influenza across different age groups and study years and gain insight into the extent to which traditional surveillance underestimates this burden. METHODS: Using preseason and postseason serology, weekly illness reporting, and RT-PCR identification of influenza from nasal swabs, we tracked the course of seasonal and pandemic influenza over five successive cohorts (England 2006-11; 5448 person-seasons' follow-up). We compared burden and severity of seasonal and pandemic strains. We weighted analyses to the age and regional structure of England to give nationally representative estimates. We compared symptom profiles over the first week of illness for different strains of PCR-confirmed influenza and non-influenza viruses using ordinal logistic regression with symptom severity grade as the outcome variable. FINDINGS: Based on four-fold titre rises in strain-specific serology, on average influenza infected 18% (95% CI 16-22) of unvaccinated people each winter. Of those infected there were 69 respiratory illnesses per 100 person-influenza-seasons compared with 44 per 100 in those not infected with influenza. The age-adjusted attributable rate of illness if infected was 23 illnesses per 100 person-seasons (13-34), suggesting most influenza infections are asymptomatic. 25% (18-35) of all people with serologically confirmed infections had PCR-confirmed disease. 17% (10-26) of people with PCR-confirmed influenza had medically attended illness. These figures did not differ significantly when comparing pandemic with seasonal influenza. Of PCR-confirmed cases, people infected with the 2009 pandemic strain had markedly less severe symptoms than those infected with seasonal H3N2. INTERPRETATION: Seasonal influenza and the 2009 pandemic strain were characterised by similar high rates of mainly asymptomatic infection with most symptomatic cases self-managing without medical consultation. In the community the 2009 pandemic strain caused milder symptoms than seasonal H3N2