Large Scale Association Analysis Identifies Three Susceptibility Loci for Coronary Artery Disease

Genome wide association studies (GWAS) and their replications that have associated DNA variants with myocardial infarction (MI) and/or coronary artery disease (CAD) are predominantly based on populations of European or Eastern Asian descent. Replication of the most significantly associated polymorphisms in multiple populations with distinctive genetic backgrounds and lifestyles is crucial to the understanding of the pathophysiology of a multifactorial disease like CAD. We have used our Lebanese cohort to perform a replication study of nine previously identified CAD/MI susceptibility loci (LTA, CDKN2A-CDKN2B, CELSR2-PSRC1-SORT1, CXCL12, MTHFD1L, WDR12, PCSK9, SH2B3, and SLC22A3), and 88 genes in related phenotypes. The study was conducted on 2,002 patients with detailed demographic, clinical characteristics, and cardiac catheterization results. One marker, rs6922269, in MTHFD1L was significantly protective against MI (OR = 0.68, p = 0.0035), while the variant rs4977574 in CDKN2A-CDKN2B was significantly associated with MI (OR = 1.33, p = 0.0086). Associations were detected after adjustment for family history of CAD, gender, hypertension, hyperlipidemia, diabetes, and smoking. The parallel study of 88 previously published genes in related phenotypes encompassed 20,225 markers, three quarters of which with imputed genotypes The study was based on our genome-wide genotype data set, with imputation across the whole genome to HapMap II release 22 using HapMap CEU population as a reference. Analysis was conducted on both the genotyped and imputed variants in the 88 regions covering selected genes. This approach replicated HNRNPA3P1-CXCL12 association with CAD and identified new significant associations of CDKAL1, ST6GAL1, and PTPRD with CAD. Our study provides evidence for the importance of the multifactorial aspect of CAD/MI and describes genes predisposing to their etiology

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Positive correlations between physical activity level and composite indices of femoral neck strength in a group of young overweight and obese men

International audienceObjectiveThe aim of this study was to examine the associations between physical activity level and composite indices of femoral neck strength in a group of young overweight and obese Lebanese men.MethodsEighty overweight and obese (body mass index (BMI) > 25 kg/m2) young men whose ages range between 18 and 35 years participated in this study. Weight and height were measured, and BMI was calculated. Body composition and femoral neck (FN) bone mineral density were measured by dual-energy X-ray absorptiometry (DXA). Compressive strength index (CSI), bending strength index (BSI) and impact strength index (ISI) were calculated. Physical activity level was evaluated by the global physical activity questionnaire (GPAQ). Maximum oxygen consumption (VO2 max, in L/min) was measured using a valid device.ResultsWeight, BMI, fat mass and fat mass percentage were negatively correlated to CSI, BSI and ISI. Physical activity level (h/week) was positively correlated to CSI, BSI and ISI while VO2 max (mL/min/kg) was positively correlated to CSI and ISI. The positive associations between physical activity and composite indices of femoral neck strength (CSI, BSI and ISI) remained significant after adjustment for body weight.ConclusionOur study conducted on overweight and obese men shows that physical activity level is a positive determinant of composite indices of femoral neck strength. In overweight men, increasing physical activity level may help to prevent osteoporotic fractures later in lifeObjectifLe but de cette étude était d’examiner les relations entre le niveau d’activité physique et les indices de résistance osseuse du col fémoral chez un groupe de jeunes hommes en surpoids et obèses.MéthodesQuatre-vingts jeunes hommes libanais âgés de 18 à 35 ans en surpoids et obèses (indice de masse corporelle (IMC) > 25 kg/m2) ont participé à cette étude. Le poids et la taille ont été mesurés et l’IMC a été calculé. La composition corporelle et la DMO du col fémoral ont été mesurés par absorptiométrie biphotonique à rayons-X (DXA). L’indice de force en compression (CSI), l’indice de force en flexion (BSI) et l’indice de force aux contraintes (ISI) ont été calculés. Le niveau d’activité physique a été évalué par un questionnaire validé (GPAQ). La consommation maximale d’oxygène (VO2 max, en L/min) a été mesurée par un appareil valide.RésultatsLe poids, l’IMC, la masse grasse et le pourcentage de la masse grasse étaient négativement corrélés aux indices de résistance osseuse du col fémoral. Le niveau d’activité physique (h/semaine) était positivement corrélé au CSI, au BSI et à l’ISI alors que la VO2 max (mL/min/kg) était positivement corrélée au CSI et à l’ISI. Les corrélations positives entre le niveau d’activité physique et les indices de résistance osseuse du col fémoral (CSI, BSI et ISI) ont persisté après ajustement pour le poids.ConclusionNotre étude menée sur des jeunes hommes en surpoids et obèses montre que le niveau d’activité physique est un déterminant positif des indices de résistance osseuse du col fémoral. Chez les hommes en surpoids et obèses, l’augmentation du niveau d’activité physique peut aider à prévenir les fractures ostéoporotiques plus tard dans la vie

Influence of Physical Activity Level on Composite Indices of Femoral Neck Strength in a Group of Young Overweight Men.

International audienceThe aim of the present study was to explore the influence of physical activity level on composite indices of femoral neck strength (compression strength index [CSI], bending strength index, and impact strength index) in a group of young overweight men. To do so, we compared composite indices of femoral neck strength in active overweight men and insufficiently active overweight men. They were divided into 2 groups based on their physical activity level: 70 active overweight men (engaging in more than 150 minutes of physical activity per week; 8.7 ± 4.8 h/wk) and 26 insufficiently active overweight men (engaging in less than 150 minutes of physical activity per week; 1.2 ± 0.7 h/wk). Height (m) and weight (kg) were measured, and body mass index (kg/m) was calculated. Bone mineral density was measured by dual-energy X-ray absorptiometry at whole body, lumbar spine, total hip, and femoral neck. Body weight, lean mass, fat mass, and body mass index were not significantly different between the 2 groups. CSI, bending strength index, and impact strength index were significantly higher in active overweight men compared to insufficiently active overweight men. After adjustment for age, physical activity (h/wk) and lean mass, only CSI remained higher in active overweight men compared to insufficiently active overweight men. This study suggests that, in young overweight men, being active (engaging in more than 150 minutes of physical activity per week) is associated with greater composite indices of femoral neck strength. To our knowledge, this is the first study that finds a significant difference regarding composite indices of femoral neck strength between 2 groups of young overweight men with different levels of physical activity

The effect of antiresorptive drugs on implant therapy : Systematic review and meta-analysis

Objectives: A considerable portion of the adult population has received and/or is receiving treatment with antiresorptive drugs (ARDs). It is thus relevant to assess possible side effects of ARD intake in connection to various aspects of implant ther‐ apy. The aim of this study was to answer the focused question “In patients with sys‐ temic intake of ARDs, what is the outcome and complication rate of implant therapy including associated bone grafting procedures comparing to patients without sys‐ temic intake of ARDs?” Materials and Methods: Original studies fulfilled predefined inclusion criteria (e.g., case series, cohort studies, case–control studies, and controlled and/or randomized controlled clinical trials; retro‐ or prospective design; and ≥10 patients with systemic intake of ARDs). Various patient‐, medication‐, and intervention‐related parameters [i.e., implant loss, grafting procedure complication/failure, peri‐implant marginal bone levels/loss, medication‐related osteonecrosis of the jaws (MRONJ), and peri‐ implantitis] were extracted, and meta‐analyses and quality assessment were performed. Results: Twenty‐four studies with bisphosphonate (BP) intake (mainly low dose for osteoporosis treatment) and seven studies on hormone replacement therapy (HRT), including ≥10 patients, and controls not taking the medication were identified. Furthermore, seven studies on MRONJ associated with implants were included. Meta‐analyses based on four studies reporting on patient level and eight studies re‐ porting on implant level showed no significant differences in terms of implant loss between patients on BPs (mainly low dose for osteoporosis treatment) and controls. Furthermore, low‐dose BP intake did not compromise peri‐implant marginal bone levels. Based on two studies, no negative effect of HRT was observed on the implant level, while HRT appeared to exert a marginally significant negative effect regarding implant survival on the patient level and regarding peri‐implant marginal bone levels. Based on six studies reporting single‐patient data, MRONJ in patients on BP for os‐ teoporosis appeared in 70% of the cases >36 months after start of drug intake, while in patients with cancer, MRONJ appeared in 64% of the cases ≤36 months after first BP intake. Conclusion: Low‐dose oral BP intake for osteoporosis treatment, in general, does not compromise implant therapy, that is, patients on ARDs do not lose more implants nor get more implant‐related complications/failures comparing to implant patients with‐ out BP intake. There is almost no information available on the possible effect on im‐ plant therapy of high‐dose BPs or other widely used ARDs (e.g., denosumab), or on the success or safety of bone grafting procedures. Patients with high‐dose ARD in‐ take for management of malignancies, patients on oral BP over a longer period of time, and patients with comorbidities should be considered as high‐risk patients for MRONJ