Impact of an interatrial shunt device on survival and heart failure hospitalization in patients with preserved ejection fraction

Aims: Impaired left ventricular diastolic function leading to elevated left atrial pressures, particularly during exertion, is a key driver of symptoms and outcomes in heart failure with preserved ejection fraction (HFpEF). Insertion of an interatrial shunt device (IASD) to reduce left atrial pressure in HFpEF has been shown to be associated with short‐term haemodynamic and symptomatic benefit. We aimed to investigate the potential effects of IASD placement on HFpEF survival and heart failure hospitalization (HFH). Methods and results: Heart failure with preserved ejection fraction patients participating in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure study (Corvia Medical) of an IASD were followed for a median duration of 739 days. The theoretical impact of IASD implantation on HFpEF mortality was investigated by comparing the observed survival of the study cohort with the survival predicted from baseline data using the Meta‐analysis Global Group in Chronic Heart Failure heart failure risk survival score. Baseline and post‐IASD implant parameters associated with HFH were also investigated. Based upon the individual baseline demographic and cardiovascular profile of the study cohort, the Meta‐analysis Global Group in Chronic Heart Failure score‐predicted mortality was 10.2/100 pt years. The observed mortality rate of the IASD‐treated cohort was 3.4/100 pt years, representing a 33% lower rate (P = 0.02). By Kaplan–Meier analysis, the observed survival in IASD patients was greater than predicted (P = 0.014). Baseline parameters were not predictive of future HFH events; however, poorer exercise tolerance and a higher workload‐corrected exercise pulmonary capillary wedge pressure at the 6 months post‐IASD study were associated with HFH. Conclusions: The current study suggests IASD implantation may be associated with a reduction in mortality in HFpEF. Large‐scale ongoing randomized studies are required to confirm the potential benefit of this therapy

Clinical population pharmacokinetics and toxicodynamics of linezolid

Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxico-dynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/ liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs o

Incidence of WHO stage 3 and 4 conditions following initiation of Anti-Retroviral Therapy in resource limited settings

To determine the incidence of WHO clinical stage 3 and 4 conditions during early anti-retroviral therapy (ART) in resource limited settings (RLS)

Prospective randomized comparison of open versus laparoscopic management of splenic artery aneurysms: a 10-year study

Abstract BACKGROUND: The literature does not support the choice between open and laparoscopic management of splenic artery aneurysms (SAA). METHODS: We designed a prospective, randomized comparison between open and laparoscopic surgery for SAA. Primary end points were types of surgical procedures performed and clinical outcomes. Analysis was developed on an intention-to-treat basis. RESULTS: Fourteen patients were allocated to laparotomy (group A) and 15 to laparoscopy (group B). Groups displayed similar patient- and aneurysm-related characteristics. The conversion rate to open surgery was 13.3 %. The type of surgical procedure performed on the splenic artery was similar in the two groups: aneurysmectomy with splenic artery ligature or direct anastomosis was performed in 51 % and 21 % of patients in group A and in 60 % and 20 % in group B, respectively. The splenectomy rate was similar (14 % vs. 20 %). Postoperative splenic infarction was observed in one case in each group. Laparoscopy was associated with shorter procedures (p = 0.0003) and lower morbidity (25 % vs. 64 %, p = 0.045). Major morbidity requiring interventional procedures and blood transfusion was observed only in group A. Laparoscopy was associated with quicker resumption of oral diet (p < 0.001), earlier drain removal (p = 0.046), and shorter hospital stay (p < 0.01). During a mean follow-up of 50 months, two patients in group A required hospital readmission. In group B, two patients developed a late thrombosis of arterial anastomoses. CONCLUSIONS: Our study demonstrates that laparoscopy permits multiple technical options, does not increase the splenectomy rate, and reduces postoperative complications. It confirms the supposed clinical benefits of laparoscopy when ablative procedures are required but laparoscopic anastomoses show poor long-term results

A novel method for predicting the response variability of friction-damped gas turbine blades

Predicting the response of gas turbine blades with underplatform friction dampers is challenging due to the combination of frictional nonlinearity and system uncertainty: a traditional Monte Carlo approach to predicting response distributions requires a large number of nonlinear simulations which is computationally expensive. This paper presents a new approach based on the principle of Maximum Entropy that provides an estimate of the response distribution that is approximately two orders of magnitude faster than Monte Carlo Harmonic Balance Method simulations. The premise is to include the concept of `computational uncertainty': incorporating lack of knowledge of the solution as part of the uncertainty, on the basis that there are diminishing returns in computing precise solutions to an uncertain system. To achieve this, the method uses a describing function approximation of the friction-damped part of the system; chooses an ignorance prior probability density function for the complex value of the describing function based on Coulombs friction law; updates the distribution using an estimate of the mean solution, the admissible domain of solutions, and the principle of Maximum Entropy; then carries out a linear Monte Carlo simulation to estimate the response distribution. The approach is validated by comparison with HBM simulations and experimental tests, using an idealised academic system consisting of a periodic array of beams (with controllable uncertainty) coupled by single-point friction dampers. Comparisons with two- and eight-blade systems show generally good agreement. Predicting the response statistics of the maximum blade amplitude reveals specific well-understood circumstances when the method is less effective. Predictions of the overall blade response statistics agree with Monte Carlo HBM extremely well across a wide range of excitation amplitudes and uncertainty levels. Critically, experimental comparisons reveal the care that is needed in accurately characterising uncertainty in order to obtain agreement of response percentiles. The new method allowed fast iteration of uncertainty parameters and correlations to achieve good agreement, which would not have been possible using traditional methods.Mitsubishi Heavy Industrie

Predicting response bounds for friction-damped gas turbine blades with uncertain friction coupling

Friction dampers are often used to reduce high amplitude vibration within gas turbines: they are a robust solution that are able to withstand extreme operating environments. Although the turbine blades are manufactured to tight tolerances, there can be significant variability in the overall response of the assembly. Uncertainties associated with the frictional contact properties are a major factor contributing to this variability. This paper applies a recently developed method for predicting response bounds to friction-damped gas turbines when the characteristics of the friction dampers are unknown, including uncertainty regarding the underlying functional form of the friction law. The approach taken is to represent the frictional contact using a describing function, and formulate an optimisation problem to seek upper and lower bounds on a chosen response metric, such as displacement amplitude. Constraints are chosen that describe known properties of the frictional nonlinearity, without needing to specify a particular constitutive law. The method was validated by comparison with numerical and experimental results from an idealised test system. The experimental test rig consisted of an array of eight beams coupled by pin-contact friction dampers. A modal description of this test rig formed the basis of a numerical model, which uses the Harmonic Balance Method (HBM) for nonlinear simulations. A set of Monte Carlo tests was carried out numerically and experimentally for both a two-beam sub-assembly as well as for the full eight-beam assembly. Comparisons with numerical results showed excellent agreement providing confident verification of the implementation, and comparisons with experimental results revealed that the bounds became less conservative as the system complexity increased. Overall the results are promising: upper and lower response bounds for an array of friction-damped systems can be computed at similar cost to a single HBM simulation, giving reliable bounds that are valid for both parametric and model uncertainties associated with the friction couplings.Mitsubishi Heavy Industrie

Phenotypic attributes of postpartum ovulation and other fertility measures in Friesian-Jersey crossbred cows

ABSTRACT Reproductive performance is an important factor contributing to on-farm efficiency and profitability. The purpose of this study was to define and quantify a set of fertility phenotypes for 352 Friesian-Jersey crossbred heifers, and determine key factors contributing to these indicators. Heats were observed and recorded prior to herd start of mating, and CIDRs were used to treat non-cycling heifers (51) once mating started. Progesterone samples were collected twice weekly, and luteal activity was identified where concentrations were &gt;0.9 ng/ml for blood and &gt;3.0 ng/ml for milk samples. Commencement of luteal activity was defined by either one elevated sample (CLA1) or two consecutive elevated samples (CLA2). For untreated heifers, the average intervals to CLA1 and CLA2 were 29.6 days (sd=14.3) and 34.1 days (sd=16.9) respectively. Other phenotypes were evaluated for conception and intervals to first heat, first service and successful service. Significant relationships were established between body condition score (BCS) at calving and the intervals to CLA. For every unit decline in BCS at calving there was an increase of 7.4 days to CLA1 and 8.8 days to CLA2. The evaluated fertility phenotypes, and their key contributing factors will be used in another study to identify related quantitative trait loci (QTL)

Persistence on therapy and propensity matched outcome comparison of two subcutaneous interferon beta 1a dosages for multiple sclerosis

To compare treatment persistence between two dosages of interferon &beta;-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon &beta;-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon &beta;-1a in either dosage (22 &micro;g or 44 &micro;g) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as &ldquo;lack of efficacy&rdquo; (3.3% vs. 1.7%), &ldquo;scheduled stop&rdquo; (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 &micro;g vs. 44 &micro;g dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. Treatment discontinuations were more common in interferon &beta;-1a 22 &micro;g SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from &ldquo;real-world&rdquo; database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry