Side effects of analgesia may significantly reduce quality of life in symptomatic multiple myeloma: a cross-sectional prevalence study

Background Pain is a common symptom in patients with multiple myeloma (MM). Many patients are dependent on analgesics and in particular opioids, but there is limited information on the impact of these drugs and their side effects on health-related quality of life (HRQoL). Method In a cross-sectional study, semi-structured interviews were performed in 21 patients attending the hospital with symptomatic MM on pain medications. HRQoL was measured using items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. Results Patients were able to recall a median of two (range 0–4) analgesics. They spontaneously identified a median of two (range 1–5) side effects attributable to their analgesic medications. Patients’ assessment of HRQoL based on the EORTC QLQ-C30 questions 29/30 was mean 48.3 (95 % CI; 38.7–57.9) out of 100. Patients’ assessment of their HRQoL in the hypothetical situation, in which they would not experience any side effects from analgesics, was significantly higher: 62.6 (53.5–71.7) (t test, p=0.001). Conclusion This study provides, for the first time, evidence that side effects of analgesics are common in symptomatic MM and may result in a statistically and clinically significant reduction of self-reported HRQoL

Insulin Resistance Is Not Conserved in Myotubes Established from Women with PCOS

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among premenopausal women, who often develop insulin resistance. We tested the hypothesis that insulin resistance in skeletal muscle of patients with polycystic ovary syndrome (PCOS) is an intrinsic defect, by investigating the metabolic characteristics and gene expression of in vitro differentiated myotubes established from well characterized PCOS subjects.Using radiotracer techniques, RT-PCR and enzyme kinetic analysis we examined myotubes established from PCOS subjects with or without pioglitazone treatment, versus healthy control subjects who had been extensively metabolically characterized in vivo. Results. Myotubes established from PCOS and matched control subjects comprehensively expressed all insulin-sensitive biomarkers; glucose uptake and oxidation, glycogen synthesis and lipid uptake. There were no significant differences between groups either at baseline or during acute insulin stimulation, although in vivo skeletal muscle was insulin resistant. In particular, we found no evidence for defects in insulin-stimulated glycogen synthase activity between groups. Myotubes established from PCOS patients with or without pioglitazone treatment also showed no significant differences between groups, neither at baseline nor during acute insulin stimulation, although in vivo pioglitazone treatment significantly improved insulin sensitivity. Consistently, the myotube cultures failed to show differences in mRNA levels of genes previously demonstrated to differ in PCOS patients with or without pioglitazone treatment (PLEK, SLC22A16, and TTBK).These results suggest that the mechanisms governing insulin resistance in skeletal muscle of PCOS patients in vivo are not primary, but rather adaptive.ClinicalTrials.gov NCT00145340

Higher free testosterone in the third trimester was associated with lower abdominal circumference at birth in boys:Odense child cohort

Objective: To investigate associations between maternal testosterone status and offspring birth anthropometrics. Design: Population-based prospective cohort study. Setting: University Hospital. Population: 1486 mother–child dyads from Odense Child Cohort. Methods: Maternal blood samples were collected at gestational weeks 27–30 and free testosterone (FT) levels were calculated using the Vermeulen equation from total testosterone (TT) analysed by mass spectrometry and sex hormone binding globulin. Associations between FT or TT levels and birth anthropometrics were analysed with multiple linear regression models according to offspring sex with adjustment for maternal age, parity, smoking and educational level. Analyses were repeated with polycystic ovary syndrome as exposure for offspring birth anthropometrics. Main outcome measures: Offspring birth weight (BW), birth length, abdominal and head circumferences. Results: Maternal mean (SD) age was 30.2 (4.5) years and pre-pregnancy body mass index was 23.5 (5.3) kg/m2. In boys (n = 787), higher FT was associated with lower birth weight (adjusted doubling constant = −65.53, P = 0.010), shorter birth length (adjusted doubling constant = −0.43, P &lt; 0.001), and lower abdominal circumference (adjusted doubling constant = −0.39, P &lt; 0.001); Higher TT was associated with lower abdominal circumference (adjusted doubling constant = −0.25, P = 0.028). In girls, no associations were found between maternal FT or TT and offspring anthropometrics. Conclusions: Higher maternal free testosterone exposure was linked to reduced birth weight, length and abdominal circumference in boys, whereas girls were not susceptible to maternal testosterone exposure.</p

Long-term impact of four different strategies for delivering an on-line curriculum about herbs and other dietary supplements

BACKGROUND: Previous research has shown that internet education can lead to short-term improvements in clinicians' knowledge, confidence and communication practices. We wished to better understand the duration of these improvements and whether different curriculum delivery strategies differed in affecting these improvements. METHODS: As previously described, we conducted a randomized control trial comparing four different strategies for delivering an e-curriculum about herbs and other dietary supplements (HDS) to clinicians. The four strategies were delivering the curriculum by: a) email over 10 weeks; b) email within one week; c) web-site over 10 weeks; d) web-site within one week. Participants were surveyed at baseline, immediately after the course and 6–10 months after completing the course (long-term). Long-term outcomes focused on clinicians' knowledge, confidence and communication practices. RESULTS: Of the 780 clinicians who completed the course, 385 (49%) completed the long-term survey. Completers and non-completers of the long-term survey had similar demographics and professional characteristics at baseline. There were statistically significant improvements from baseline to long-term follow-up in knowledge, confidence and communication practices; these improvements did not differ by curriculum delivery strategy. Knowledge scores improved from 67.7 ± 10.3 at baseline to 78.8 ± 12.3 at long-term follow-up (P < 0.001). Confidence scores improved from 53.7 ± 17.8 at baseline to 66.9 ± 12.0 at long term follow-up (P < 0.001); communication scores improved from 2.6 ± 1.9 at baseline to 3.6 ± 2.1 (P < 0.001) at long-term follow-up. CONCLUSION: This e- curriculum led to significant and sustained improvements in clinicians' expertise about HDS regardless of the delivery strategy. Future studies should compare the impact of required vs. elective courses and self-reported vs. objective measures of behavior change

Third-trimester NT-proBNP for pre-eclampsia risk prediction: a comparison with sFlt-1/PlGF in a population-based cohort

BACKGROUND: The association between lower first-trimester N-terminal pro B-type natriuretic peptide (NT-proBNP) levels and increased pre-eclampsia risk remains poorly understood, contrasting with the elevated NT-proBNP levels observed at the time of pre-eclampsia diagnosis. OBJECTIVES: The aim of this study was to assess the utility of third-trimester NT-proBNP for assessing pre-eclampsia risk before onset. METHODS: NT-proBNP and the soluble Fms-like tyrosine kinase 1 to placental growth factor ratio (sFlt-1/PlGF) were measured in 1,476 pregnant individuals from the Odense Child Cohort at a median gestational age of 29 weeks (Q1-Q3: 28.4-29.4). Pre-eclampsia cases were categorized by timing: 11 individuals (0.7%) developed pre-eclampsia within 4 weeks, while 110 (7.5%) developed pre-eclampsia more than 4 weeks after sampling. RESULTS: Higher NT-proBNP levels were significantly associated with increased risk of pre-eclampsia within 4 weeks but reduced risk beyond 4 weeks. After adjusting for age, body mass index, nulliparity, systolic blood pressure, and the sFlt-1/PlGF ratio, the adjusted OR was 2.18 (95% CI: 0.88-5.42, P = 0.09) for onset within 4 weeks and 0.72 (95% CI: 0.55-0.93, P = 0.012) for onset beyond 4 weeks. However, combining NT-proBNP with the sFlt-1/PlGF ratio did not improve the predictive accuracy for short- or long-term pre-eclampsia risk compared to the sFlt-1/PlGF ratio alone. CONCLUSIONS: Unselected NT-proBNP screening in the early third trimester has limited clinical value for predicting short- or long-term pre-eclampsia risk when compared to angiogenic biomarkers

Differences and similarities between the EULAR/ASAS-EULAR and national recommendations for treatment of patients with psoriatic arthritis and axial spondyloarthritis across Europe

This is the first report comparing EULAR and national treatment recommendations for PsA patients across Europe, and the first this decade to compare ASAS-EULAR and national treatment recommendations in axSpA patients. An electronic survey was completed from October 2021–April 2022 by rheumatologists in 15 European countries. One and four countries followed all EULAR and ASAS-EULAR recommendations, respectively. Five countries had no national treatment recommendations for PsA and/or axSpA, but followed other regulations. In several countries, national treatment recommendations predated the most recent EULAR/ASAS-EULAR recommendations. Entry criteria for starting biologic/targeted synthetic disease-modifying anti-rheumatic drugs varied considerably. In several countries, for PsA patients with significant skin involvement, interleukin-17 inhibitors were not given preference. The positioning of Janus Kinase inhibitors differed and Phosphodiesterase-4 inhibitors were not in use/reimbursed in most countries. This study may motivate European countries to update their national treatment recommendations, to align them better with the latest international recommendations

Sex hormone-dependent host-microbiome interactions and cardiovascular risk (XCVD): design of a longitudinal multi-omics cohort study

INTRODUCTION: Cardiovascular diseases (CVDs) present differently in women and men, influenced by host-microbiome interactions. The roles of sex hormones in CVD outcomes and gut microbiome in modifying these effects are poorly understood. The XCVD study examines gut microbiome mediation of sex hormone effects on CVD risk markers by observing transgender participants undergoing gender-affirming hormone therapy (GAHT), with findings expected to extrapolate to cisgender populations. METHODS AND ANALYSES: This observational, longitudinal cohort study includes baseline, 1- and 2-year follow-ups with transgender participants beginning GAHT. It involves comprehensive phenotyping and microbiome genotyping, integrating computational analyses of high-dimensional data. Microbial diversity will be assessed using gut, skin, and oral samples via 16S rRNA and shotgun metagenomic sequencing of gut samples. Blood measurements will include sex hormones, CVD risk markers, cardiometabolic parameters, cytokines, and immune cell counts. Hair samples will be analysed for cortisol. Participants will complete online questionnaires on physical activity, mental health, stress, quality of life, fatigue, sleep, pain, and gender dysphoria, tracking medication use and diet to control for confounders. Statistical analyses will integrate phenomic, lifestyle, and multi-omic data to model health effects, testing gut microbiome mediation of CVD risk as the endocrine environment shifts between that typical for cisgender men to women and vice versa. ETHICS AND DISSEMINATION: The study adheres to Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the Charité Ethical Committee (EA1/339/21). Signed informed consent will be obtained. Results will be published in peer-reviewed journals and conferences and shared as accessible summaries for participants, community groups, and the public, with participants able to view their data securely after public and patient involvement review for accessibility. TRIAL REGISTRATION NUMBER: The XCVD study was registered on ClinicalTrials.gov (NCT05334888) as 'Sex-differential host-microbiome CVD risk - a longitudinal cohort approach (XCVD)" on 4 April 2022. Data set link can be found at https://classic. CLINICALTRIALS: gov/ct2/show/NCT05334888

Bone Loss in Diabetes: Use of Antidiabetic Thiazolidinediones and Secondary Osteoporosis

Clinical evidence indicates that bone status is affected in patients with type 2 diabetes mellitus (T2DM). Regardless of normal or even high bone mineral density, T2DM patients have increased risk of fractures. One class of antidiabetic drugs, thiazolidinediones (TZDs), causes bone loss and further increases facture risk, placing TZDs in the category of drugs causing secondary osteoporosis. Risk factors for development of TZD-induced secondary osteoporosis are gender (women), age (elderly), and duration of treatment. TZDs exert their antidiabetic effects by activating peroxisome proliferator-activated receptor-γ (PPAR-γ) nuclear receptor, which controls glucose and fatty acid metabolism. In bone, PPAR-γ controls differentiation of cells of mesenchymal and hematopoietic lineages. PPAR-γ activation with TZDs leads to unbalanced bone remodeling: bone resorption increases and bone formation decreases. Laboratory research evidence points toward a possible separation of unwanted effects of PPAR-γ on bone from its beneficial antidiabetic effects by using selective PPAR-γ modulators. This review also discusses potential pharmacologic means to protect bone from detrimental effects of clinically used TZDs (pioglitazone and rosiglitazone) by using combinational therapy with approved antiosteoporotic drugs, or by using lower doses of TZDs in combination with other antidiabetic therapy. We also suggest a possible orthopedic complication, not yet supported by clinical studies, of delayed fracture healing in T2DM patients on TZD therapy

Soluble CD36 Ectodomain Binds Negatively Charged Diacylglycerol Ligands and Acts as a Co-Receptor for TLR2

BACKGROUND:Cluster of differentiation 36 (CD36) is a transmembrane glycoprotein involved in many biological processes, such as platelet biology, angiogenesis and in the aetiopathology of atherosclerosis and cardiovascular diseases. Toll-like receptors (TLRs) are one of the most important receptors of the innate immune system. Their main function is the recognition of conserved structure of microorganisms. This recognition triggers signaling pathways that activate transcription of cytokines and co-stimulatory molecules which participate in the generation of an immune response against microbes. In particular, TLR2 has been shown to recognize a broad range of ligands. Recently, we showed that CD36 serves as a co-receptor for TLR2 and enhances recognition of specific diacylglycerides derived from bacteria. METHODOLOGY/ PRINCIPAL FINDINGS:Here, we investigate the mechanism by which CD36 contributes to ligand recognition and activation of TLR2 signaling pathway. We show that the ectodomain of murine CD36 (mCD36ED) directly interacts with negatively charged diacylglycerol ligands, which explains the specificity and selectivity of CD36 as a TLR2 co-receptor. We also show that mCD36ED amplifies the pro-inflammatory response to lipoteichoic acid in macrophages of wild-type mice and restores the pro-inflammatory response of macrophages from mice deficient in CD36 (oblivious), but not from mice deficient in cluster of differentiation 14 (CD14) (heedless). CONCLUSION/ SIGNIFICANCE: These data indicate that the CD36 ectodomain is the only relevant domain for activation of TLR2 signaling pathway and that CD36 and CD14 have a non-redundant role for loading ligands onto TLR2 in the plasma-membrane. The pro-inflammatory role of soluble CD36 can be relevant in the activation of the immune response against pathogens, as well as in the progression of chronic diseases. Therefore, an increased level of soluble forms of CD36, which has been reported to be increased in type II diabetic patients, could accelerate atherosclerosis by increasing the pro-inflammatory response to diacylglycerol ligands