Are we drawing the right conclusions from randomised placebo-controlled trials? A post-hoc analysis of data from a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Assumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms equally, and that treatment effects are additional to the placebo effect. However, these assumptions have recently been challenged, and different mechanisms may potentially be operating in the placebo and treatment arms. The objective of the current study was to explore the nature of placebo versus pharmacological effects by comparing predictors of the placebo response with predictors of the treatment response in a randomised, placebo-controlled trial of a phytotherapeutic combination for the treatment of menopausal symptoms. A substantial placebo response was observed but no significant difference in efficacy between the two arms.</p> <p>Methods</p> <p>A <it>post hoc </it>analysis was conducted on data from 93 participants who completed this previously published study. Variables at baseline were investigated as potential predictors of the response on any of the endpoints of flushing, overall menopausal symptoms and depression. Focused tests were conducted using hierarchical linear regression analyses. Based on these findings, analyses were conducted for both groups separately. These findings are discussed in relation to existing literature on placebo effects.</p> <p>Results</p> <p>Distinct differences in predictors were observed between the placebo and active groups. A significant difference was found for study entry anxiety, and Greene Climacteric Scale (GCS) scores, on all three endpoints. Attitude to menopause was found to differ significantly between the two groups for GCS scores. Examination of the individual arms found anxiety at study entry to predict placebo response on all three outcome measures individually. In contrast, <it>low </it>anxiety was significantly associated with improvement in the active treatment group. None of the variables found to predict the placebo response was relevant to the treatment arm.</p> <p>Conclusion</p> <p>This study was a <it>post hoc </it>analysis of predictors of the placebo versus treatment response. Whilst this study does not explore neurobiological mechanisms, these observations are consistent with the hypotheses that 'drug' effects and placebo effects are not necessarily additive, and that mutually exclusive mechanisms may be operating in the two arms. The need for more research in the area of mechanisms and mediators of placebo versus active responses is supported.</p> <p>Trial Registration</p> <p>International Clinical Trials Registry ISRCTN98972974.</p

Identification of the UDP-glucose-4-epimerase required for galactofuranose biosynthesis and galactose metabolism in A. niger

Microbial Biotechnolog

Major flaws in conflict prevention policies towards Africa : the conceptual deficits of international actors’ approaches and how to overcome them

Current thinking on African conflicts suffers from misinterpretations oversimplification, lack of focus, lack of conceptual clarity, state-centrism and lack of vision). The paper analyses a variety of the dominant explanations of major international actors and donors, showing how these frequently do not distinguish with sufficient clarity between the ‘root causes’ of a conflict, its aggravating factors and its triggers. Specifically, a correct assessment of conflict prolonging (or sustaining) factors is of vital importance in Africa’s lingering confrontations. Broader approaches (e.g. “structural stability”) offer a better analytical framework than familiar one-dimensional explanations. Moreover, for explaining and dealing with violent conflicts a shift of attention from the nation-state towards the local and sub-regional level is needed.Aktuelle Analysen afrikanischer Gewaltkonflikte sind häufig voller Fehlinterpretationen (Mangel an Differenzierung, Genauigkeit und konzeptioneller Klarheit, Staatszentriertheit, fehlende mittelfristige Zielvorstellungen). Breitere Ansätze (z. B. das Modell der Strukturellen Stabilität) könnten die Grundlage für bessere Analyseraster und Politiken sein als eindimensionale Erklärungen. häufig differenzieren Erklärungsansätze nicht mit ausreichender Klarheit zwischen Ursachen, verschärfenden und auslösenden Faktoren. Insbesondere die richtige Einordnung konfliktverlängernder Faktoren ist in den jahrzehntelangen gewaltsamen Auseinandersetzungen in Afrika von zentraler Bedeutung. Das Diskussionspapier stellt die große Variationsbreite dominanter Erklärungsmuster der wichtigsten internationalen Geber und Akteure gegenüber und fordert einen Perspektivenwechsel zum Einbezug der lokalen und der subregionalen Ebene für die Erklärung und Bearbeitung gewaltsamer Konflikte

Unbearability of suffering at the end of life: the development of a new measuring device, the SOS-V

AbstractBackgroundUnbearable suffering is an important issue in end-of-life decisions. However, there has been no systematic, prospective, patient-oriented research which has focused on unbearable suffering, nor is there a suitable measurement instrument. This article describes the methodological development of a quantitative instrument to measure the nature and intensity of unbearable suffering, practical aspects of its use in end-stage cancer patients in general practice, and studies content validity and psychometric properties.MethodsRecognizing the conceptual difference between unbearability of suffering and extent or intensity of suffering, we developed an instrument. The compilation of aspects considered to be of importance was based on a literature search. Psychometric properties were determined on results of the first interviews with 64 end-stage cancer patients that participated in a longitudinal study in the Netherlands.ResultsThe instrument measures five domains: medical signs and symptoms, loss of function, personal aspects, aspects of environment, and nature and prognosis of the disease. Sixty nine aspects were investigated, and an overall score was asked. In 64 end-stage cancer patients the instrument was used in total 153 times with an average interview time varying from 20-40 minutes. Cronbachs alpha's of the subscales were in majority above 0.7. The sum scores of (sub)scales were correlated strongly to overall measures on suffering.ConclusionThe SOS-V is an instrument for measuring the unbearability of suffering in end-stage cancer patients with good content validity and psychometric properties, which is feasible to be used in practice. This structured instrument makes it possible to identify and study unbearable suffering in a quantitative and patient-oriented way

Noninvasive Prenatal Test Results Indicative of Maternal Malignancies:A Nationwide Genetic and Clinical Follow-Up Study

PURPOSE: Noninvasive prenatal testing (NIPT) for fetal aneuploidy screening using cell-free DNA derived from maternal plasma can incidentally raise suspicion for cancer. Diagnostic routing after malignancy suspicious-NIPT faces many challenges. Here, we detail malignancy suspicious-NIPT cases, and describe the clinical characteristics, chromosomal aberrations, and diagnostic routing of the patients with a confirmed malignancy. Clinical lessons can be learned from our experience. METHODS: Patients with NIPT results indicative of a malignancy referred for tumor screening between April 2017 and April 2020 were retrospectively included from a Dutch nationwide NIPT implementation study, TRIDENT-2. NIPT profiles from patients with confirmed malignancies were reviewed, and the pattern of chromosomal aberrations related to tumor type was analyzed. We evaluated the diagnostic contribution of clinical and genetic examinations. RESULTS: Malignancy suspicious-NIPT results were reported in 0.03% after genome-wide NIPT, and malignancies confirmed in 16 patients (16/48, 33.3%). Multiple chromosomal aberrations were seen in 23 of 48 patients with genome-wide NIPT, and a malignancy was confirmed in 16 patients (16/23, 69.6%). After targeted NIPT, 0.005% malignancy suspicious-NIPT results were reported, in 2/3 patients a malignancy was confirmed. Different tumor types and stages were diagnosed, predominantly hematologic malignancies (12/18). NIPT data showed recurrent gains and losses in primary mediastinal B-cell lymphomas and classic Hodgkin lymphomas. Magnetic resonance imaging and computed tomography were most informative in diagnosing the malignancy. CONCLUSION: In 231,896 pregnant women, a low percentage (0.02%) of NIPT results were assessed as indicative of a maternal malignancy. However, when multiple chromosomal aberrations were found, the risk of a confirmed malignancy was considerably high. Referral for extensive oncologic examination is recommended, and may be guided by tumor-specific hallmarks in the NIPT profile

Lectin Switching During Dengue Virus Infection

Dengue virus receptors are relatively poorly characterized, but there has been recent interest in 2 C-type lectin molecules, dendritic cell–specific intercellular adhesion molecule 3 (ICAM-3)–grabbing nonintegrin (DC-SIGN) and its close homologue liver/lymph node–specific ICAM-3–grabbing integrin (L-SIGN), which can both bind dengue and promote infection. In this report we have studied the interaction of dengue viruses produced in insect cells, tumor cell lines, and primary human dendritic cells (DCs) with DC-SIGN and L-SIGN. Virus produced in primary DCs is unable to interact with DC-SIGN but remains infectious for L-SIGN–expressing cells. Skin-resident DCs may thus be a site of initial infection by insect-produced virus, but DCs will likely not participate in large-scale virus replication during dengue infection. These results reveal that differential glycosylation of dengue virus envelope protein is highly dependent on cell state and suggest that studies of virus tropism using virus prepared in insect cells or tumor cell lines should be interpreted with caution

Identification of superior reference genes for data normalisation of expression studies via quantitative PCR in hybrid roses (Rosa hybrida)

<p>Abstract</p> <p>Background</p> <p>Gene expression studies are a prerequisite for understanding the biological function of genes. Because of its high sensitivity and easy use, quantitative PCR (qPCR) has become the gold standard for gene expression quantification. To normalise qPCR measurements between samples, the most prominent technique is the use of stably expressed endogenous control genes, the so called reference genes. However, recent studies show there is no universal reference gene for all biological questions. Roses are important ornamental plants for which there has been no evaluation of useful reference genes for gene expression studies.</p> <p>Results</p> <p>We used three different algorithms (BestKeeper, geNorm and NormFinder) to validate the expression stability of nine candidate reference genes in different rose tissues from three different genotypes of <it>Rosa hybrida </it>and in leaves treated with various stress factors. The candidate genes comprised the classical "housekeeping genes" (<it>Actin, EF-1α, GAPDH</it>, <it>Tubulin </it>and <it>Ubiquitin</it>), and genes showing stable expression in studies in <it>Arabidopsis </it>(<it>PP2A, SAND, TIP </it>and <it>UBC</it>). The programs identified no single gene that showed stable expression under all of the conditions tested, and the individual rankings of the genes differed between the algorithms. Nevertheless the new candidate genes, specifically, <it>PP2A </it>and <it>UBC</it>, were ranked higher as compared to the other traditional reference genes. In general, <it>Tubulin </it>showed the most variable expression and should be avoided as a reference gene.</p> <p>Conclusions</p> <p>Reference genes evaluated as suitable in experiments with <it>Arabidopsis thaliana </it>were stably expressed in roses under various experimental conditions. In most cases, these genes outperformed conventional reference genes, such as <it>EF1-α </it>and <it>Tubulin</it>. We identified <it>PP2A</it>, <it>SAND </it>and <it>UBC </it>as suitable reference genes, which in different combinations may be used for normalisation in expression analyses via qPCR for different rose tissues and stress treatments. However, the vast genetic variation found within the genus <it>Rosa</it>, including differences in ploidy levels, might also influence expression stability of reference genes, so that future research should also consider different genotypes and ploidy levels.</p

BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD

Purpose The aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group. Methods A retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto-immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching. Results Thirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0-9.0) in the BRCA group as a whole, 6.5 (IQR 4.0-8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5-9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0-11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50). Conclusions Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserv