Carbetocin reduces the need for additional uterotonics in elective caesarean delivery: a systematic review,meta-analysis and trial sequential analysis of randomised controlled trials

BackgroundCarbetocin has been found to be superior to oxytocin in terms of need for additional uterotonics and prevention of postpartum haemorrhage at caesarean delivery. However, this is based on combined data from labouring and non-labouring parturients and it remains unclear how effective carbetocin is in the purely elective setting. The aim of this review was to compare carbetocin to oxytocin in elective caesarean delivery.MethodsMedline, Embase, CINAHL, Web of Science, and the Cochrane databases were searched for randomised controlled trials in any language. The primary outcome was need for additional uterotonics. Secondary outcomes were mean blood loss, need for blood transfusion and incidence of postpartum haemorrhage >1000 mL.ResultsNine studies with a total of 1962 patients were included. Trial sequential analysis confirmed that the information size (n=1692) had surpassed that required (n=1166) in order to demonstrate a statistically significant reduction in the use of additional uterotonics. Need for additional uterotonics was reduced by 53% with carbetocin compared to oxytocin (OR 0.47, 95% CI 0.34 to 0.64; P <0.001, I²=63.5). The number needed-to-treat was 11. The risk of bias, data heterogeneity and inconsistency in reporting bleeding outcomes made it difficult to reach definite conclusions about prevention of PPH.ConclusionsCarbetocin is associated with a reduced need for additional uterotonics when compared with oxytocin at elective caesarean delivery. Standardisation of bleeding-related outcomes in studies is necessary to facilitate synthesis of data in future analyses.     

Pharmacodynamics of combined estrogen–progestin oral contraceptives: 4. Effects on uterine and cervical epithelia

ABSTRACT

Introduction: Steroid hormones are responsible for specific changes in the endometrium during the menstrual cycle, when they are sequentially secreted and, because of this, in the early days sequential combined oral contraceptive regimens were utilized. The same basic concept has been utilized with multi-phasic regimens, in order to produce endometrial pictures mimicking the normal cycle.

Areas covered: The Endometrial effects of progestins and estrogens; combined monophasic high- (50 μg), medium- (30 μg), low- (20 μg), ultralow- (15 μg) estrogen content; sequential regimens; multiphasic combinations; treatment schedules.

Cervical effects of combined high-dose and sequential combinations, including evidence for an increase in malignant lesions.

Expert opinion: Overall, combined oral contraceptives (COCs) inhibit normal proliferative changes and the endometrium becomes thin, narrow, with widely spaced glands and pre-decidual changes in the stroma. During the first few cycles the progestin induces a coexistence of proliferative and secretory features; with time, the picture changes because the progestin induces a down-regulation of estrogen receptors, resulting in tortuous glands similar to those in the secretory phase, but characterized by a quiescent, atrophic glandular epithelium.

In the cervical epithelium, under the influence of high-dose COCs, endocervical glands became hypersecretory and in some instances, distinctive type of atypical polypoid endocervical hyperplasia is found.     

Sequential Therapy Based on Evolvement of Patterns: A New Model for Treatment of Alzheimer’s Disease

In order to solve the problem of long-term (>9 months) efficacy in the treatment of Alzheimer''s disease (AD) by conventional therapy (CT), a staged and multiply-targeted sequential therapy based on the evolvement of patterns (STEP) was developed. Its main innovations include: (1) the time order of evolution of patterns defined by Chinese medicine (CM) in AD was found, that is, "the orderly pattern evolution starting from Shen (Kidney) deficiency, progressing to phlegm, stasis and fire, and worsening to severe toxin as well as functional collapse"; (2) the cascade hypothesis of Shen deficiency in AD and its sequential therapy based on Shen-reinforcing was proposed, that is, "reinforcing Shen in the early stage and throughout the whole process, resolving phlegm, activating blood and purging fire in the middle stage, detoxifying and replenishing vitality to stop the collapse in the advanced stage", and through meta-analysis, clinical drug use was optimized, thus the leap from "inferential selection" to "evidence-based selection" was realized; (3) the STEP regimen combined with CT maintained cognitive and behavioral stability in AD patients for at least 12 months, with cognitive enhancement and behavioral synergy after 9 months, and cognitive benefit was superior to CT at 9, 12, 15, 18, 21, and 24 months, respectively. The 2-year cognitive improvement rate was increased by 25.64% (P=0.020) and the cognitive deterioration rate was decreased by 48.71% (P=0.000). Among them, the cognitive and functional benefits of Shen-reinforcing therapy for very early AD (350 cases) for 1 year were better than the placebo (P<0.001), and the dementia conversion rate was reduced by 8.85% (P=0.002). The behavioral symptomatic relief of patients with vascular dementia received fire-purging therapy (540 cases) was superior to those received CT (P=0.016). These data suggested that the STEP regimen has synergistic effects on CTs at least in terms of cognitive benefit, and the earlier the use, the greater the benefit will have. Therefore, the STEP regimen should be considered as one of the clinical options, particularly for the dearth of effective pharmaceutical or immunological interventions that are currently available for AD.     

Insights from examination of hearts from adults dying suddenly to the understanding of congenital cardiac malformations

Congenital heart disease is a rare but important finding in adults who experience sudden death. Examination of the congenitally malformed heart has historically been considered esoteric and best left to those with expertise. The Cardiac Risk in the Young cardiovascular pathology laboratory based at St George's University of London has now received over 6,000 cases. Of these, 21 congenitally malformed hearts were retained for research and educational purposes. Hearts were assessed using sequential segmental analysis, and causes of death were adjudicated based on thorough macroscopic examination and histology. Congenital malformations that were encountered included atrial septal defects, ventricular septal defects, tetralogy of Fallot, and transposition of the great arteries in both its regular and congenitally corrected variants. Findings also included hearts with mirror-imaged and isomeric atrial appendages. Direct causes of death included myocardial fibrosis, pulmonary hypertension, and hemorrhage. A small but notable proportion did not reveal a substrate for arrhythmia, raising the question of whether the terminal event was due to the congenital heart disease itself, or an underlying channelopathy. Here, we demonstrate the value of simple sequential segmental analysis in describing and categorizing the cases, with the concept of the “morphological method” serving to identify the distinguishing features of the cardiac components. Clin. Anat. 33:394–404, 2020. © 2019 Wiley Periodicals, Inc.     

Caution! Overestimation of treatment effects of corticosteroid therapy for community-acquired pneumonia in a meta-analysis of randomized controlled trials

It is well known that a meta-analysis of randomized controlled trials aims to increase the power and precision of the estimated intervention effects. However, when a meta-analysis includes a limited number of patients and a small number of events, overestimation of intervention effect estimates may occur and could cause spurious results. Although many biases can cause the overestimation, random error may be the most common cause. Trial sequential analysis (TSA) can explore the independent effect of random error on intervention effect estimates in meta-analyses and protect meta-analyses against overestimation due to random error.     

Development of autoimmune hepatitis in primary biliary cirrhosis.

AIM/BACKGROUND: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown aetiology. Up to 10% of patients with typical features of PBC will have additional features of autoimmune hepatitis (AIH). A subset, however, have no such features but go on to develop a 'sequential' AIH overlap syndrome. Objectives: Describe our experience with eight patients who developed AIH after the diagnosis of PBC was made. METHODS: We reviewed the charts of all PBC patients over a 9-year period (from 1996 to 2005). Only PBC patients with no features of AIH were included. RESULTS: There were 1476 patients with PBC. Of these, eight patients developed features of AIH overlap syndrome based on biochemical and histological parameters. Treatment included prednisone and azathioprine for 24 or more months. The majority of patients remained on ursodeoxycholic acid (UDCA) throughout treatment. Response to therapy was defined by improvement in enzymes, and was rapid for all patients. One patient was able to discontinue treatment with prednisone and azathioprine, while seven have continued on therapy to date. CONCLUSIONS: A 'sequential' overlap syndrome of AIH with PBC can occur. Treatment with prednisone and azathioprine may lead to a rapid improvement in aminotransferase levels.     

Simultaneous versus sequential optimal design for pharmacokinetic-pharmacodynamic models with FO and FOCE considerations

We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional nature of such models, differences in predicted responses are a consequence of different assumptions about how the models interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques have been explored in the literature where it was found that the sequential and FO approaches can produce biased results. It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature. We consider design for situations where all responses are continuous and extend this methodology to the case where a response may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such responses will offer little information about all parameters and hence a sequential optimization, in the form of product design optimality, may yield near optimal designs.     

左氧氟沙星序贯治疗下呼吸道感染的临床评价

目的评价左氧氟沙星序贯治疗下呼吸道感染(LRTIs)的有效性和安全性。方法采用开放试验,应用左氧氟沙星注射液0.3g治疗30例LRTIs患者,1～2次/d,静脉滴注,4～6d,序贯以0.2g,2次/d,口服,5～9d。结果痊愈率、有效率、细菌清除率分别为63.33%,86.67%,89.29%,不良反应轻微。结论左氧氟沙星序贯治疗下呼吸道感染疗效肯定,安全、经济、方便。     

A simulation study of three sequential methods for the comparison of two treatment groups when the response criterion is censored

Three recent sequential methods, group sequential analysis (GSA), the sequential probability ratio test (SPRT) and the triangular test (TT) are well suited to randomized clinical trials with a censored response criterion, as they do not require matched pairs of patients. We undertook a simulation study to investigate their statistical properties and to compare these three methods with the fixed-sample design. Our results suggest that the three methods have the expected statistical properties for size and power; they allow an important reduction of the average number of events before stopping, except with GSA when there is no treatment difference; the triangular test (closed design) appears the optimal design, as the variance of the number of events is smaller than with the sequential probability ratio test (open design) and analysis after every twenty new events does not alter the statistical properties of these sequential methods and enhances their usefulness.     

Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility

Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a study is appropriate, if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. An important aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional‐UMVUE and contrast it with other estimates, including naïve estimators, the well‐studied unconditional‐UMVUE and the mean and median Whitehead‐adjusted estimators. The conditional‐UMVUE appears to be a very good choice. Copyright © 2008 John Wiley & Sons, Ltd.