Eliminating ambiguous treatment effects using estimands

Most reported treatment effects in medical research studies are ambiguously defined, which can lead to misinterpretation of study results. This is because most studies do not attempt to describe what the treatment effect represents, and instead require readers to deduce this based on the reported statistical methods. However, this approach is fraught, as many methods provide counterintuitive results. For example, some methods include data from all patients, yet the resulting treatment effect applies only to a subset of patients, whereas other methods will exclude certain patients while results will apply to everyone. Additionally, some analyses provide estimates pertaining to hypothetical settings where patients never die or discontinue treatment. Herein we introduce estimands as a solution to the aforementioned problem. An estimand is a clear description of what the treatment effect represents, thus saving readers the necessity of trying to infer this from study methods and potentially getting it wrong. We provide examples of how estimands can remove ambiguity from reported treatment effects and describe their current use in practice. The crux of our argument is that readers should not have to infer what investigators are estimating; they should be told explicitly

On integrability of Hirota-Kimura type discretizations

We give an overview of the integrability of the Hirota-Kimura discretization method applied to algebraically completely integrable (a.c.i.) systems with quadratic vector fields. Along with the description of the basic mechanism of integrability (Hirota-Kimura bases), we provide the reader with a fairly complete list of the currently available results for concrete a.c.i. systems.Comment: 47 pages, some minor change

Management of a pregnant woman with fibromuscular dysplasia

No abstract available

Blood pressure changes after renal denervation at 10 European expert centers

We did a subject-level meta-analysis of the changes (Δ) in blood pressure (BP) observed 3 and 6 months after renal denervation (RDN) at 10 European centers. Recruited patients (n=109; 46.8% women; mean age 58.2 years) had essential hypertension confirmed by ambulatory BP. From baseline to 6 months, treatment score declined slightly from 4.7 to 4.4 drugs per day. Systolic/diastolic BP fell by 17.6/7.1 mm Hg for office BP, and by 5.9/3.5, 6.2/3.4, and 4.4/2.5 mm Hg for 24-h, daytime and nighttime BP (P0.03 for all). In 47 patients with 3- and 6-month ambulatory measurements, systolic BP did not change between these two time points (P0.08). Normalization was a systolic BP of <140 mm Hg on office measurement or <130 mm Hg on 24-h monitoring and improvement was a fall of 10 mm Hg, irrespective of measurement technique. For office BP, at 6 months, normalization, improvement or no decrease occurred in 22.9, 59.6 and 22.9% of patients, respectively; for 24-h BP, these proportions were 14.7, 31.2 and 34.9%, respectively. Higher baseline BP predicted greater BP fall at follow-up; higher baseline serum creatinine was associated with lower probability of improvement of 24-h BP (odds ratio for 20-μmol l(-1) increase, 0.60; P=0.05) and higher probability of experiencing no BP decrease (OR, 1.66; P=0.01). In conclusion, BP responses to RDN include regression-to-the-mean and remain to be consolidated in randomized trials based on ambulatory BP monitoring. For now, RDN should remain the last resort in patients in whom all other ways to control BP failed, and it must be cautiously used in patients with renal impairment

The efficacy of indwelling pleural catheter placement versus placement plus talc sclerosant in patients with malignant pleural effusions managed exclusively as outpatients (IPC-PLUS): study protocol for a randomised controlled trial

BACKGROUND: Malignant pleural effusions (MPEs) remain a common problem, with 40,000 new cases in the United Kingdom each year and up to 250,000 in the United States. Traditional management of MPE usually involves an inpatient stay with placement of a chest drain, followed by the instillation of a pleural sclerosing agent such as talc, which aims to minimise further fluid build-up. Despite a good success rate in studies, this approach can be expensive, time-consuming and inconvenient for patients. More recently, an alternative method has become available in the form of indwelling pleural catheters (IPCs), which can be inserted and managed in an outpatient setting. It is currently unknown whether combining talc pleurodesis with IPCs will provide improved pleural symphysis rates over those of IPCs alone. METHODS/DESIGN: IPC-PLUS is a patient-blind, multicentre randomised controlled trial (RCT) comparing the combination of talc with an IPC to the use of an IPC alone for inducing pleurodesis in MPEs. The primary outcome is successful pleurodesis at five weeks post-randomisation. This study will recruit 154 patients, with an interim analysis for efficacy after 100 patients, and aims to help to define the future gold standard for outpatient management of patients with symptomatic MPEs. DISCUSSION: IPC-PLUS is the first RCT to examine the practicality and utility of talc administered via an IPC. The study remains in active recruitment and has the potential to significantly alter how patients requiring pleurodesis for MPE are approached in the future. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN73255764) on 23 August 2012

The influence of liver dysfunction on cyclosporine pharmacokinetics -A comparison between 70 per cent hepatectomy and complete bile duct ligation in dogs-

The influence of experimentally induced hepatic dysfunction on the pharmacokinetics of Cyclosporine A (CsA) was determined in dogs. The pharmacokinetics of oral (PO) and intravenous (IV) CsA were studied before and after 70 per cent hepatectomy or complete bile duct ligation (CBDL). Changes in liver function were monitored by serial measurements of serum bilirubin, and by the maximum removal rate (Rmax) and plasma disappearance rate (ICG-K) of indocyanine green (ICG). Concentrations of CsA in whole blood were measured by HPLC. Seventy per cent hepatectomy caused significant liver dysfunction: the ICG-Rmax decreased by 47.7±7.1 per cent (mean±SD) and the ICG-K decreased by 61.3±9.7 per cent during the first week after hepatectomy. At the same time, the systemic clearance (CLs) of IV-CsA decreased by 43.9±8.2 per cent, the area under the concentration curve (AUC) of IV-CsA increased by 35.4±20.8 per cent and the bioavailability of CsA decreased by 26.4±14.8 per cent. CBDL also induced significant liver dysfunction: the ICG-Rmax decreased by 39.1±12.8 per cent and the ICG-K decreased by 65.6±3.6 per cent in the second week after the operation. During the same period, the AUC of PO-CsA decreased by 69.9±10.7 per cent and the bioavailability of CsA also decreased markedly by 73.9±15.6 per cent. These data indicate that hepatic impairment significantly influences the pharmacokinetics of CsA, not only by the changes in intestinal absorption, but also by those in hepatic, metabolism. Dose adjustment is therefore necessary in the presence of hepatic dysfunction in order to maintain an adequate blood concentration of CsA without causing side effects. © 1989 The Japan Surgical Society

On the construction of high-order force gradient algorithms for integration of motion in classical and quantum systems

A consequent approach is proposed to construct symplectic force-gradient algorithms of arbitrarily high orders in the time step for precise integration of motion in classical and quantum mechanics simulations. Within this approach the basic algorithms are first derived up to the eighth order by direct decompositions of exponential propagators and further collected using an advanced composition scheme to obtain the algorithms of higher orders. Contrary to the scheme by Chin and Kidwell [Phys. Rev. E 62, 8746 (2000)], where high-order algorithms are introduced by standard iterations of a force-gradient integrator of order four, the present method allows to reduce the total number of expensive force and its gradient evaluations to a minimum. At the same time, the precision of the integration increases significantly, especially with increasing the order of the generated schemes. The algorithms are tested in molecular dynamics and celestial mechanics simulations. It is shown, in particular, that the efficiency of the new fourth-order-based algorithms is better approximately in factors 5 to 1000 for orders 4 to 12, respectively. The results corresponding to sixth- and eighth-order-based composition schemes are also presented up to the sixteenth order. For orders 14 and 16, such highly precise schemes, at considerably smaller computational costs, allow to reduce unphysical deviations in the total energy up in 100 000 times with respect to those of the standard fourth-order-based iteration approach.Comment: 23 pages, 2 figures; submitted to Phys. Rev.

A Novel Approach for Ellipsoidal Outer-Approximation of the Intersection Region of Ellipses in the Plane

In this paper, a novel technique for tight outer-approximation of the intersection region of a finite number of ellipses in 2-dimensional (2D) space is proposed. First, the vertices of a tight polygon that contains the convex intersection of the ellipses are found in an efficient manner. To do so, the intersection points of the ellipses that fall on the boundary of the intersection region are determined, and a set of points is generated on the elliptic arcs connecting every two neighbouring intersection points. By finding the tangent lines to the ellipses at the extended set of points, a set of half-planes is obtained, whose intersection forms a polygon. To find the polygon more efficiently, the points are given an order and the intersection of the half-planes corresponding to every two neighbouring points is calculated. If the polygon is convex and bounded, these calculated points together with the initially obtained intersection points will form its vertices. If the polygon is non-convex or unbounded, we can detect this situation and then generate additional discrete points only on the elliptical arc segment causing the issue, and restart the algorithm to obtain a bounded and convex polygon. Finally, the smallest area ellipse that contains the vertices of the polygon is obtained by solving a convex optimization problem. Through numerical experiments, it is illustrated that the proposed technique returns a tighter outer-approximation of the intersection of multiple ellipses, compared to conventional techniques, with only slightly higher computational cost