Evaluation of FRAX® score use in Maltese osteoporosis management guidelines

Objectives: Recent years have brought a shift towards evidence-based fracture risk engines. Fracture Risk Assessment Tool (FRAX®) is one such diagnostic tool used to evaluate the ten-year probability of osteoporotic fracture risk. The aim of this study was to evaluate the Maltese FRAX® score-based osteoporosis management guidelines and identify the suitability of using such a risk factor engine-based protocol. Study design: Data from 702 patients presenting for bone mineral density (BMD) estimation in 2010- 2011 were collected. In this period, local guidelines were devised but not yet put into practice so all referred patients underwent BMD estimation. These patients were below 65 years of age and above the minimum age for FRAX® use: 40 years. Data included Age, Weight, Height, BMI and the presence of any risk factor components of the FRAX® score tool. BMD was assessed using Norland/Hologic densitometers. FRAX® scores (excluding BMD) for each patient were calculated using the online tool www.shef.ac.uk/FRAX as accessed in 2014. The resulting major osteoporotic fracture risk was compared to age-specific assessment thresholds as set by Kanis et al. (2013). Thus the appropriateness (or otherwise) of densitometry measurements as dictated by local guidelines was determined. Main outcome measures: The main outcome measures in this study were the femoral neck and vertebral body BMD. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of using the FRAX®-based guidelines in under 65 year olds were calculated. Results: Local guidelines for managing <65 year olds were found to have a PPV of 11.26% and a NPV of 94.38 % Conclusion: FRAX®-guided local guidelines are well suited at excluding non-osteoporotic patients (False omission rate of 5.62 %). Positive likelihood ratio for the protocol was found to be 1.27. This means that 1 in every 8.8 patients that would have been referred for BMD estimation were actually osteoporotic.peer-reviewe

Ovarian granulosa cell tumor : a clinicopathological series

Introduction: Granulosa cell tumours (GCT) are uncommon neoplasms, accounting for 2-5% of all ovarian carcinomas. The pathogenesis of these tumours is characterised by differentiation towards the follicular granulosa cell. However, the exact cell of origin is disputed, with the granulosa cell, thecal cell or fibroblast having been proposed as putative progenitors. A granulosa stem-cell has been described, which has also been suggested as a cell of origin. Approximately 65% of patients are postmenopausal at the time of diagnosis and, in these patients, the morphology of the tumour conforms to the so-called adult-type GCT. A minority of tumours, however, present at a younger age, and these tumours typically exhibit juvenile-type GCT morphology. However, this is by no means a pathological dogma and both tumour forms have been described at any age. This case series includes all cases of ovarian GCT diagnosed at Mater Dei Hospital, Malta, between 2008 and 2016. GCT cases were identified through the hospital histopathological records after the appropriate data protection clearance. This case series aims to showcase the variable natural history and presenting features of juvenile-type and adult-type GCTs, while emphasising the need for indefinite long-term follow up protocols.peer-reviewe

Translating HbA1c measurements into estimated average glucose values in pregnant women with diabetes

Aims/hypothesis This study aimed to examine the relationship between average glucose levels, assessed by continuous glucose monitoring (CGM), and HbA1c levels in pregnant women with diabetes to determine whether calculations of standard estimated average glucose (eAG) levels from HbA1c measurements are applicable to pregnant women with diabetes. Methods CGM data from 117 pregnant women (89 women with type 1 diabetes; 28 women with type 2 diabetes) were analysed. Average glucose levels were calculated from 5–7 day CGM profiles (mean 1275 glucose values per profile) and paired with a corresponding (±1 week) HbA1c measure. In total, 688 average glucose–HbA1c pairs were obtained across pregnancy (mean six pairs per participant). Average glucose level was used as the dependent variable in a regression model. Covariates were gestational week, study centre and HbA1c. Results There was a strong association between HbA1c and average glucose values in pregnancy (coefficient 0.67 [95% CI 0.57, 0.78]), i.e. a 1% (11 mmol/mol) difference in HbA1c corresponded to a 0.67 mmol/l difference in average glucose. The random effects model that included gestational week as a curvilinear (quadratic) covariate fitted best, allowing calculation of a pregnancy-specific eAG (PeAG). This showed that an HbA1c of 8.0% (64 mmol/mol) gave a PeAG of 7.4–7.7 mmol/l (depending on gestational week), compared with a standard eAG of 10.2 mmol/l. The PeAG associated with maintaining an HbA1c level of 6.0% (42 mmol/mol) during pregnancy was between 6.4 and 6.7 mmol/l, depending on gestational week. Conclusions/interpretation The HbA1c–average glucose relationship is altered by pregnancy. Routinely generated standard eAG values do not account for this difference between pregnant and non-pregnant individuals and, thus, should not be used during pregnancy. Instead, the PeAG values deduced in the current study are recommended for antenatal clinical care

Mechanisms for reducing low back pain: a mediation analysis of a multifaceted intervention in workers in elderly care

Purpose A multifaceted workplace intervention consisting of participatory ergonomics, physical training, and cognitive–behavioural training (CBT) has shown effectiveness for reducing low back pain (LBP). However, the mechanisms of action underlying these intervention components are not well understood. Methods This was a mediation analysis of a cluster-randomised controlled trial of a multifaceted intervention in 420 workers in elderly care. Mediation analysis was carried out via structural equation modelling. Potential mediators investigated were: fear-avoidance beliefs, perceived muscle strength, use of assistive devices at work and perceived physical exertion at work. LBP outcomes assessed were: days with LBP, LBP intensity and days with bothersome LBP. Results There were no significant indirect effects of the intervention on LBP outcomes. There were significant effects of the intervention on both fear-avoidance measures [β = − 0.63, 95% CI (1.23, 0.03); β = − 1.03, 95% CI (− 1.70, − 0.34)] and the use of assistive devices [β = − 0.55, 95% CI (− 1.04, − 0.05)], but not on perceived muscle strength [β = − 0.18, 95% CI (− 0.50, 0.13)] or physical exertion [β = − 0.05, 95% CI (− 0.40, 0.31)]. The only potential mediator with a significant effect on LBP outcomes was physical exertion, which had a significant effect on LBP intensity [β = 0.14, 95% CI (0.04, 0.23)]. Conclusions A multifaceted intervention consisting of participatory ergonomics, physical training, and CBT was able to decrease fear-avoidance beliefs and increase use of assistive devices in the workplace. However, these changes did not explain the effect of any of the intervention components on days with LBP, LBP intensity and days with bothersome LBP

Long-term weight loss trajectories following participation in a randomised controlled trial of a weight management programme for men delivered through professional football clubs:a longitudinal cohort study and economic evaluation

Background: Obesity is a major public health concern requiring innovative interventions that support people to lose weight and keep it off long term. However, weight loss maintenance remains a challenge and is under-researched, particularly in men. The Football Fans in Training (FFIT) programme engages men in weight management through their interest in football, and encourages them to incorporate small, incremental physical activity and dietary changes into daily life to support long term weight loss maintenance. In 2011/12, a randomised controlled trial (RCT) of FFIT demonstrated effectiveness and cost-effectiveness at 12 months. The current study aimed to investigate long-term maintenance of weight loss, behavioural outcomes and lifetime cost-effectiveness following FFIT. Methods: A longitudinal cohort study comprised 3.5-year follow-up of the 747 FFIT RCT participants. Men aged 35-65 years, BMI≥28 kg/m2 at RCT baseline who consented to long-term follow-up (n=665) were invited to participate: those in the FFIT Follow-Up Intervention group (FFIT-FU-I) undertook FFIT in 2011 during the RCT; the FFIT Follow-Up Comparison group (FFIT-FU-C) undertook FFIT in 2012 under routine (non-research) conditions. The primary outcome was objectively-measured weight loss (from baseline) at 3.5 years. Secondary outcomes included changes in self-reported physical activity and diet at 3.5 years. Cost-effectiveness was estimated at 3.5 years and over participants’ lifetime. Results: Of 665 men invited, 488 (73%; 65% of the 747 RCT participants) attended 3.5-year measurements. The FFIT-FU-I group sustained a mean weight loss of 2.90 kg (95% CI 1.78, 4.02; p<0.001) 3.5 years after starting FFIT; 32.2% (75/233) weighed ≥5% less than baseline. The FFIT-FU-C group had lost 2.71 kg (1.65, 3.77; p<0.001) at the 3.5-year measurements (2.5 years after starting FFIT); 31.8% (81/255) weighed ≥5% less than baseline. There were significant sustained improvements in self-reported physical activity and diet in both groups. The estimated incremental cost-effectiveness of FFIT was £10,700-£15,300 per QALY gained at 3.5 years, and £1,790-£2,200 over participants’ lifetime. Conclusions: Participation in FFIT under research and routine conditions leads to long-term weight loss and improvements in physical activity and diet. Investment in FFIT is likely to be cost-effective as part of obesity management strategies in countries where football is popular

Development and validation of an improved algorithm for overlaying flexible molecules

A program for overlaying multiple flexible molecules has been developed. Candidate overlays are generated by a novel fingerprint algorithm, scored on three objective functions (union volume, hydrogen-bond match, and hydrophobic match), and ranked by constrained Pareto ranking. A diverse subset of the best ranked solutions is chosen using an overlay-dissimilarity metric. If necessary, the solutions can be optimised. A multi-objective genetic algorithm can be used to find additional overlays with a given mapping of chemical features but different ligand conformations. The fingerprint algorithm may also be used to produce constrained overlays, in which user-specified chemical groups are forced to be superimposed. The program has been tested on several sets of ligands, for each of which the true overlay is known from protein–ligand crystal structures. Both objective and subjective success criteria indicate that good results are obtained on the majority of these sets

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action

Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

UNLABELLED: Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275

Narcissism and the strategic pursuit of short-term mating : universal links across 11 world regions of the International Sexuality Description Project-2.

Previous studies have documented links between sub-clinical narcissism and the active pursuit of short-term mating strategies (e.g., unrestricted sociosexuality, marital infidelity, mate poaching). Nearly all of these investigations have relied solely on samples from Western cultures. In the current study, responses from a cross-cultural survey of 30,470 people across 53 nations spanning 11 world regions (North America, Central/South America, Northern Europe, Western Europe, Eastern Europe, Southern Europe, Middle East, Africa, Oceania, Southeast Asia, and East Asia) were used to evaluate whether narcissism (as measured by the Narcissistic Personality Inventory; NPI) was universally associated with short-term mating. Results revealed narcissism scores (including two broad factors and seven traditional facets as measured by the NPI) were functionally equivalent across cultures, reliably associating with key sexual outcomes (e.g., more active pursuit of short-term mating, intimate partner violence, and sexual aggression) and sex-related personality traits (e.g., higher extraversion and openness to experience). Whereas some features of personality (e.g., subjective well-being) were universally associated with socially adaptive facets of Narcissism (e.g., self-sufficiency), most indicators of short-term mating (e.g., unrestricted sociosexuality and marital infidelity) were universally associated with the socially maladaptive facets of narcissism (e.g., exploitativeness). Discussion addresses limitations of these cross-culturally universal findings and presents suggestions for future research into revealing the precise psychological features of narcissism that facilitate the strategic pursuit of short-term mating