Explaining survival differences between two consecutive studies with allogeneic stem cell transplantation in patients with chronic myeloid leukemia

Purpose

In the two consecutive German studies III and IIIA on chronic myeloid leukemia, between 1995 and 2004, 781 patients were randomized to receive either allogeneic hematopoietic stem cell transplantation with a related donor or continued drug treatment. Despite comparable transplantation protocols and most centers participating in both studies, the post-transplant survival probabilities for patients transplanted in first chronic phase were significantly higher in study IIIA (144 patients) than in study III (113 patients). Prior to the decision on a combined analysis of both studies, reasons for this discrepancy had to be investigated.

Methods

The Cox proportional hazard cure model was used to identify prognostic factors for post-transplant survival.

Results

Donor–recipient matching for human leukocyte antigen, patient age, time between diagnosis and transplantation, and calendar time showed a significant influence on survival and/or the incidence of cure. Added as a further factor, affiliation to study IIIA had no significant impact any longer.

Conclusions

Discrepancies in influential prognostic factors explained the different post-transplant survival probabilities between the studies. The significance of calendar time suggests a lack of consistency of transplantation practice over time. Accordingly, the prerequisite for a common assessment of overall survival in the two randomized transplantation arms was not met. Moreover, our analyses provide an independent validation of established prognostic factors and their cutoffs. The statistical approach in investigating and modeling potential prognostic factors for survival sets an example for the examination of studies with unexpected outcome differences in concurrent treatment arms.     

Implementing Phytosterols Into Medical Practice as a Cholesterol-Lowering Strategy: Overview of Efficacy,Effectiveness, and Safety

More than 200 clinical trial reports and several meta-analyses have demonstrated that phytosterols (PSs), natural components of plants, induce clinically relevant reductions in blood low-density lipoprotein cholesterol levels. Here we review data regarding the biochemical effects and potential cardiovascular benefit of PSs as part of the dietary management of dyslipidemia. In addition to discussing the efficacy, effectiveness, and safety of PSs as hypocholesterolemic agents, this review provides an overview of PSs as an adjunctive therapy to cholesterol-lowering pharmaceuticals. Given this lack of evidence regarding the benefits of PSs for reducing cardiovascular end points, this review also discusses the present knowledge that exists about the ability for therapeutic dosages of PSs to confer protection from cardiovascular-related mortality and morbidity. Finally, this review summarizes the factors that affect PS efficacy and the Canadian regulations that govern the use of PSs as cholesterol-lowering agents in foods and supplements.     

Do patient and ward-related characteristics influence the use of coercive measures? Results from the EUNOMIA international study

Purpose

This study aims to identify whether selected patient and ward-related factors are associated with the use of coercive measures. Data were collected as part of the EUNOMIA international collaborative study on the use of coercive measures in ten European countries.

Methods

Involuntarily admitted patients (N = 2,027) were divided into two groups. The first group (N = 770) included patients that had been subject to at least one of these coercive measures during hospitalization: restraint, and/or seclusion, and/or forced medication; the other group (N = 1,257) included patients who had not received any coercive measure during hospitalization. To identify predictors of use of coercive measures, both patients’ sociodemographic and clinical characteristics and centre-related characteristics were tested in a multivariate logistic regression model, controlled for countries’ effect.

Results

The frequency of the use of coercive measures varied significantly across countries, being higher in Poland, Italy and Greece. Patients who received coercive measures were more frequently male and with a diagnosis of psychotic disorder (F20–F29). According to the regression model, patients with higher levels of psychotic and hostility symptoms, and of perceived coercion had a higher risk to be coerced at admission. Controlling for countries’ effect, the risk of being coerced was higher in Poland. Patients’ sociodemographic characteristics and ward-related factors were not identifying as possible predictors because they did not enter the model.

Conclusions

The use of coercive measures varied significantly in the participating countries. Clinical factors, such as high levels of psychotic symptoms and high levels of perceived coercion at admission were associated with the use of coercive measures, when controlling for countries’ effect. These factors should be taken into consideration by programs aimed at reducing the use of coercive measures in psychiatric wards.     

Adherence to osteoporosis guideline: survey among Czech general practitioners

Rationale and objectives

General practitioners (GPs) play an important role in management of patients at risk of osteoporosis (OP). The objectives were to assess (1) knowledge about OP and use of OP clinical guideline in comparison with other information sources and (2) association between the use of individual information sources and knowledge and self-reported quality of care among GPs.

Methods

Survey among random sample of Czech GPs was performed to find out their attitudes and role in OP management. The return rate of the postal questionnaire was 38% (525 respondents). Quality of care was assessed using three indicators: suspicion on OP, referral to the specialist and initial check-up.

Results

Respondents (median age 52 years, 59% women) had a very good knowledge of several risk factors, while others, namely low body mass index, history of hip fracture in mother and smoking were perceived as risk factors by only 40%, 45% and 55% of respondents, respectively. 10% of GPs stated the correct answer regarding daily calcium intake recommended for postmenopausal women. The OP guideline was considered accessible by 83% of respondents and used repeatedly by 54%. Use of the guideline correlated positively with knowledge score (P < 0.001), while use of each individual other source of information did not. Use of the guideline correlated with all three indicators of quality of care. Use of each other information source correlated only with a maximum of two indicators.

Conclusion

We identified areas of insufficient knowledge that should be targeted in educational activities for GPs. It is recommended to further motivate GPs to use their clinical guidelines regularly.     

Gremlin 1 depletion in vivo causes severe enteropathy and bone marrow failure

The intestinal epithelium is perpetually renewed from a stem cell niche in the base of crypts to maintain a healthy bowel mucosa. Exit from this niche and maturation of epithelial cells requires tightly controlled gradients in BMP signalling, progressing from low BMP signalling at the crypt base to high signalling at the luminal surface. The BMP antagonist gremlin 1 (Grem1) is highly expressed by subepithelial myofibroblasts adjacent to the intestinal crypts but its role in regulating the stem cell niche and epithelial renewal in vivo has not been explored. To explore the effects of Grem1 loss in adulthood following normal growth and development, we bred mice (ROSA26CreER-Grem1 ^flx/flx) in which Grem1 could be deleted by tamoxifen administration. While Grem1 remained intact, these mice were healthy, grew normally, and reproduced successfully. Following Grem1 depletion, the mice became unwell and were euthanised (at 7–13 days). Post-mortem examination revealed extensive mucosal abnormalities throughout the small and large intestines with failure of epithelial cell replication and maturation, villous atrophy, and features of malabsorption. Bone marrow hypoplasia was also observed with associated early haematopoietic failure. These results demonstrate an essential homeostatic role for gremlin 1 in maintaining normal bowel epithelial function in adulthood, suggesting that abnormalities in gremlin 1 expression can contribute to enteropathies. We also identified a previously unsuspected requirement for gremlin 1 in normal haematopoiesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Rapid Detection and Identification of Mucormycetes in Bronchoalveolar Lavage Samples from Immunocompromised Patients with Pulmonary Infiltrates by Use of High-Resolution Melt Analysis

Rapid differential diagnostics of pulmonary infiltrates suspected of invasive fungal disease in an immunocompromised host and early initiation of effective antifungal therapy are crucial for patient outcomes. There are no serological tests available to detect mucormycetes; therefore, PCR-based methods are highly suitable. We validated our previously published PCR followed by high-resolution melt analysis (PCR/HRMA) to detect Rhizopus spp., Rhizomucor pusillus, Lichtheimia corymbifera, and Mucor spp. in bronchoalveolar lavage (BAL) samples from immunocompromised patients who were at risk of invasive fungal disease. All PCR/HRMA-positive samples were retested using novel real-time quantitative PCR (RQ PCR) assays specific to the species identified. In total, between January 2009 and December 2012 we analyzed 99 BAL samples from 86 patients with pulmonary abnormalities using PCR/HRMA. Ninety (91%) BAL samples were negative, and 9 (9%) samples were positive. The sensitivity and specificity of PCR/HRMA were 100% and 93%, respectively. By combining the positive results of PCR/HRMA with positive RQ PCR results, the specificity was raised to 98%. PCR/HRMA, due to its high negative predictive value (99%), represents a fast and reliable tool for routine BAL sample screening for the differential diagnosis of pulmonary infiltrates in immunocompromised patients for the four most clinically important mucormycetes.     

Cardiac involvement in hypertension

Despite improved patient detection and pharmacologic therapy, the effect of treatment of hypertension on mortality from coronary artery-related events remains unresolved. Left ventricular (LV) hypertrophy, a known consequence of hypertension, is associated with an excess mortality independent of other known cardiovascular risk factors. Recently, LV hypertrophy accompanying hypertension has been associated with ominous ventricular arrhythmias. However, it does not necessarily follow that regression of LV hypertrophy will reduce this increased mortality. Diastolic dysfunction, manifested by reduced ventricular distensibility of the hypertrophying left ventricle, appears to be an early characteristic of the hypertensive heart since echocardiographic techniques have demonstrated diastolic filling abnormalities in untreated essential hypertensives even before significant LV hypertrophy appears. Not all antihypertensive agents diminish LV mass and improve diastolic dysfunction. Certain sympatholytic agents, calcium antagonists, β-adrenergic blockers, and the angiotensin-converting enzyme inhibitors appear to diminish LV hypertrophy. However, future studies are needed to determine if these agents that appear to reverse findings of LV hypertrophy and improve diastolic dysfunction will also reduce risk of coronary artery disease and related events.