Evaluating the Impact of Oleocanthal and Oleacein on Skin Aging: Results of a Randomized Clinical Study.

The prevalence of skin aging and the request for effective treatments have driven dermatological research towards natural solutions. This study investigates the anti-aging efficacy of two bioactive natural polyphenols, Oleocanthal and Oleacein, in a skincare formulation. A single-blind, randomized clinical trial involved 70 participants, using a comprehensive exclusion criterion to ensure participant safety and study integrity. Participants applied the Oleocanthal and Oleacein 1% serum formulation twice daily for 30 days. The efficacy was objectively assessed using the VISIA® Skin Analysis System at baseline, after 15 days, and after 30 days. Results indicated significant wrinkle reduction in most groups. For women aged 45-79 years, the mean change was -33.91% (95% CI: -46.75% to -21.07%). For men aged 20-44 years, it was -51.93% (95% CI: -76.54% to -27.33%), and for men aged 45-79 years, it was -46.56% (95% CI: -58.32% to -34.81%). For women aged 20-44 years, the change was -25.68% (95% CI: -63.91% to 12.54%), not statistically significant. These findings highlight the potential of EVOO-derived polyphenols in anti-aging skincare, particularly for older adults. This research paves the way for further exploration into natural compounds in dermatology, particularly for aging skin management.

Asthma and incident coronary heart disease: an observational and Mendelian randomisation study.

BACKGROUND: Observational studies suggest asthma is a risk factor for coronary heart disease (CHD) and sex modifies the risk, but they may suffer from methodological limitations. To overcome these, we applied a "triangulation approach", where different methodologies, with different potential biases, were leveraged to enhance confidence in findings. METHODS: First, we conducted an observational study using UK medical records to match asthma patients 1:1, by age, sex and general practitioner (GP) practice, to the general population. We measured the association between asthma and incident CHD (myocardial infarction: hospitalisation/death) by applying minimal sufficient adjustment: model 1, smoking, body mass index, oral corticosteroids, atopy and deprivation; model 2, additionally adjusting for healthcare behaviour (GP consultation frequency). Second, we conducted a Mendelian randomisation (MR) study using data from the UK Biobank, Trans-National Asthma Genetic Consortium (TAGC) and Coronary Artery Disease Genome-wide Replication and Meta-analysis consortium (CARDIoGRAM). Using 64 asthma single nucleotide polymorphisms, the effect of asthma on CHD was estimated with inverse variance-weighted meta-analysis and methods that adjust for pleiotropy. RESULTS: In our observational study (n=1 522 910), we found asthma was associated with 6% increased risk of CHD (model 1: HR 1.06, 95% CI 1.01-1.13); after accounting for healthcare behaviour, we found no association (model 2: HR 0.99, 95% CI 0.94-1.05). Asthma severity did not modify the association, but sex did (females: HR 1.11, 95% CI 1.01-1.21; males: HR 0.91, 95% CI 0.84-0.98). Our MR study (n=589 875) found no association between asthma and CHD (OR 1.01, 95% CI 0.98-1.04) and no modification by sex. CONCLUSIONS: Our findings suggest that asthma is not a risk factor for CHD. Previous studies may have suffered from detection bias or residual confounding.

The causal relationship between gastro-oesophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two-sample Mendelian randomisation study.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GORD causes IPF or because IPF causes GORD, or because of confounding by factors, such as smoking, associated with both GORD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GORD and IPF are causally related. METHODS: A bidirectional two-sample MR was performed to estimate the causal effect of GORD on IPF risk and of IPF on GORD risk, using genetic data from the largest GORD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available. RESULTS: GORD increased the risk of IPF, with an OR of 1.6 (95% CI 1.04-2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GORD, with an OR of 0.999 (95% CI 0.997-1.000; p=0.245). CONCLUSIONS: We found that GORD increases the risk of IPF, but found no evidence that IPF increases the risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated.

A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease.

There is increasing evidence for inflammation as a determinant in the pathogenesis of Parkinson's disease, but its role in parkinsonian neurodegeneration remains elusive. It is not clear whether inflammatory cascades are causes or consequences of dopamine neuron death. In the present study, we aim to perform an in-depth statistical investigation of the causal relationship between inflammation and Parkinson's disease using a two-sample Mendelian randomization design. Genetic instruments were selected using summary-level data from the largest genome-wide association studies to date (sample size ranging from 13 955 to 204 402 individuals) conducted on a European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist and tumour necrosis factor α. Genetic association data on Parkinson's disease (56 306 cases and 1 417 791 controls) and age at onset of Parkinson's disease (28 568 cases) were obtained from the International Parkinson's Disease Genomics Consortium. On primary analysis, causal associations were estimated on sets of strong (P-value < 5 × 10-8; F-statistic > 10) and independent (linkage disequilibrium r2 < 0.001) genetic instruments using the inverse-variance weighted method. In sensitivity analysis, we estimated causal effects using robust Mendelian randomization methods and after removing pleiotropic genetic variants. Reverse causation was also explored. We repeated the analysis on different data sources for inflammatory biomarkers to check the consistency of the findings. In all the three data sources selected for interleukin-6, we found statistical evidence for an earlier age at onset of Parkinson's disease associated with increased interleukin-6 concentration [years difference per 1 log-unit increase = -2.364, 95% confidence interval (CI) = -4.789-0.060; years difference per 1 log-unit increase = -2.011, 95% CI = -3.706 to -0.317; years difference per 1 log-unit increase = -1.569, 95% CI = -2.891 to -0.247]. We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist and tumour necrosis factor α on both Parkinson's disease and its age at onset. Results after excluding possible pleiotropic genetic variants were consistent with findings from primary analyses. When investigating reverse causation, we did not find evidence for a causal effect of Parkinson's disease or age at onset on any biomarkers of inflammation. We found evidence for a causal association between the onset of Parkinson's disease and interleukin-6. The findings of this study suggest that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson's disease.

Patient's perception of intraoral scanning: a comparison between traditional and digital dental impression.

The purpose of this work was to assess the discomfort perceived by the patient during the intraoral scan procedure using the iTero Scanner. A sample of 33 patients was selected on the basis of parameters that identify a complete dentition. All treated patients underwent a traditional polyvinylsiloxane impression with double procedure and an intraoral scan in the same session. Subsequently they were given a questionnaire concerning the discomfort perceived by both procedures. Once the completed questionnaires were obtained, preliminary statistical tests were carried out to check if the distribution of scores assigned by patients to the two procedures differed significantly from a Gaussian distribution. Furthermore, the discomfort/preference indexes for the two procedures were compared using the Wilcoxon test for paired data. Finally, the Spearman correlation test was used. From the results of the preliminary normality tests, it was decided to use nonparametric type tests that gives the intraoral scan procedure more favorable scores relative to a minor discomfort. The use of intraoral scanning and more specifically of the iTero 2.9 scanner (despite a not small wand), represents an option largely preferred by patients in terms of reduction of discomfort and classic discomfort related to relief systems traditional imprint.

Hospital surge capacity in a tertiary emergency referral centre during the COVID-19 outbreak in Italy.

The first person-to-person transmission of the 2019 novel coronavirus in Italy on 21 February 2020 led to an infection chain that represents one of the largest known COVID-19 outbreaks outside Asia. In northern Italy in particular, we rapidly experienced a critical care crisis due to a shortage of intensive care beds, as we expected according to data reported in China. Based on our experience of managing this surge, we produced this review to support other healthcare services in preparedness and training of hospitals during the current coronavirus outbreak. We had a dedicated task force that identified a response plan, which included: (1) establishment of dedicated, cohorted intensive care units for COVID-19-positive patients; (2) design of appropriate procedures for pre-triage, diagnosis and isolation of suspected and confirmed cases; and (3) training of all staff to work in the dedicated intensive care unit, in personal protective equipment usage and patient management. Hospital multidisciplinary and departmental collaboration was needed to work on all principles of surge capacity, including: space definition; supplies provision; staff recruitment; and ad hoc training. Dedicated protocols were applied where full isolation of spaces, staff and patients was implemented. Opening the unit and the whole hospital emergency process required the multidisciplinary, multi-level involvement of healthcare providers and hospital managers all working towards a common goal: patient care and hospital safety. Hospitals should be prepared to face severe disruptions to their routine and it is very likely that protocols and procedures might require re-discussion and updating on a daily basis.

Modified bonded acrylic expander in patient with anterior crossbite and pseudo-class III.

The open-bite treatment can be considered one of the most difficult malocclusions to treat in children as well as in adult patients. Several papers show that the traditional maxillary expander device contribute to increase the vertical face dimension and bite opening due to posterior rotation of the mandible, buccal tipping of lateral segments and cuspal interferences. Other more specific studies compared the effects of traditional maxillary expander to those of bonded acrylic expander and evidenced that the acrylic expander can better control the vertical effects of the maxillary expansion by the resin bite plane on which the heavy occlusal forces are exerted. We decided to use an acrylic expander in order to prevent worsening of anterior openbite after a careful assessment of nasal airflow by the otorhinolaryngologist.

The New Trend of Pre-pectoral Breast Reconstruction: An Objective Evaluation of the Quality of Online Information for Patients Undergoing Breast Reconstruction.

The Web has increasingly become the major source of information about health care, and patients who need to undergo breast reconstruction often use the internet to acquire an initial knowledge on the subject. We would like to present our study that investigates the quality of published information on pre-pectoral breast reconstruction. We searched the term "Pre-pectoral breast reconstruction" on Google® and Yahoo®. Forty-two web sites were selected and underwent qualitative and quantitative assessment using the expanded EQIP tool. The analysis of document contents showed a critical lack of information about qualitative risks and side-effects descriptions, treatment of potential complications, alert signs for the patient and precautions that the patient may take. Health professionals should inform patients about the potential difficulties of identifying reliable informational web sites about pre-pectoral breast reconstruction. The quality of available information should be improved, especially the important topics included in the content data section of the modified EQIP tool.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Age at menarche and adult body mass index: a Mendelian randomization study.

BACKGROUND: Pubertal timing has psychological and physical sequelae. While observational studies have demonstrated an association between age at menarche and adult body mass index (BMI), confounding makes it difficult to infer causality. METHODS: The Mendelian randomization (MR) technique is not limited by traditional confounding and was used to investigate the presence of a causal effect of age at menarche on adult BMI. MR uses genetic variants as instruments under the assumption that they act on BMI only through age at menarche (no pleiotropy). Using a two-sample MR approach, heterogeneity between the MR estimates from individual instruments was used as a proxy for pleiotropy, with sensitivity analyses performed if detected. Genetic instruments and estimates of their association with age at menarche were obtained from a genome-wide association meta-analysis on 182,416 women. The genetic effects on adult BMI were estimated using data on 80,465 women from the UK Biobank. The presence of a causal effect of age at menarche on adult BMI was further investigated using data on 70,692 women from the GIANT Consortium. RESULTS: There was evidence of pleiotropy among instruments. Using the UK Biobank data, after removing instruments associated with childhood BMI that were likely exerting pleiotropy, fixed-effect meta-analysis across instruments demonstrated that a 1 year increase in age at menarche reduces adult BMI by 0.38 kg/m2 (95% CI 0.25-0.51 kg/m2). However, evidence of pleiotropy remained. MR-Egger regression did not suggest directional bias, and similar estimates to the fixed-effect meta-analysis were obtained in sensitivity analyses when using a random-effect model, multivariable MR, MR-Egger regression, a weighted median estimator and a weighted mode-based estimator. The direction and significance of the causal effect were replicated using GIANT Consortium data. CONCLUSION: MR provides evidence to support the hypothesis that earlier age at menarche causes higher adult BMI. Complex hormonal and psychological factors may be responsible.

Objective evaluation of ram and buck sperm motility by using a novel sperm tracker software.

This work offers researchers the first version of an open-source sperm tracker software (Sperm Motility Tracker, V1.0) containing a novel suit of algorithms to analyze sperm motility using ram and buck sperm as models. The computer-assisted semen analysis is used in several publications with increasing trend worldwide in the last years, showing the importance of objective methodologies to evaluate semen quality. However, commercial systems are costly and versatility is constrained. In the proposed method, segmentation is applied and the tracking stage is performed by using individual Kalman filters and a simplified occlusion handling method. The tracking performance in terms of precision (number of true tracks), the percentage of fragmented paths and percentage of correctly detected particles were manually validated by three experts and compared with the performance of a commercial motility analyzer (Microptic's SCA). The precision obtained with our sperm motility tracker was higher than the one obtained with a commercial software at the current acquisition frame rate of 25 fps (P < 0.0001), concomitantly with a similar percentage of fragmentized tracks (P = 0.0709) at sperm concentrations ranging 25-37 × 106 cells/mL. Moreover, our tracker was able to detect trajectories that were unseen by SCA. Kinetic values obtained by using both methods were contrasted. The higher values found were explained based on the better performance of our sperm tracker to report speed parameters for very fast motile sperm. To standardize results, acquisition conditions are suggested. This open-source sperm tracker software has a good plasticity allowing researchers to upgrade according requirements and to apply the tool for sperm from a variety of species.

The Effect of Iron Status on Risk of Coronary Artery Disease: A Mendelian Randomization Study-Brief Report.

OBJECTIVE: Iron status is a modifiable trait that has been implicated in cardiovascular disease. This study uses the Mendelian randomization technique to investigate whether there is any causal effect of iron status on risk of coronary artery disease (CAD). APPROACH AND RESULTS: A 2-sample Mendelian randomization approach is used to estimate the effect of iron status on CAD risk. Three loci (rs1800562 and rs1799945 in the HFE gene and rs855791 in TMPRSS6) that are each associated with serum iron, transferrin saturation, ferritin, and transferrin in a pattern suggestive of an association with systemic iron status are used as instruments. SNP (single-nucleotide polymorphism)-iron status association estimates are based on a genome-wide association study meta-analysis of 48 972 individuals. SNP-CAD estimates are derived by combining the results of a genome-wide association study meta-analysis of 60 801 CAD cases and 123 504 controls with those of a meta-analysis of 63 746 CAD cases and 130 681 controls obtained from Metabochip and genome-wide association studies. Combined Mendelian randomization estimates are obtained for each marker by pooling results across the 3 instruments. We find evidence of a protective effect of higher iron status on CAD risk (iron odds ratio, 0.94 per SD unit increase; 95% confidence interval, 0.88-1.00; P=0.039; transferrin saturation odds ratio, 0.95 per SD unit increase; 95% confidence interval, 0.91-0.99; P=0.027; log-transformed ferritin odds ratio, 0.85 per SD unit increase; 95% confidence interval, 0.73-0.98; P=0.024; and transferrin odds ratio, 1.08 per SD unit increase; 95% confidence interval, 1.01-1.16; P=0.034). CONCLUSIONS: This Mendelian randomization study supports the hypothesis that higher iron status reduces CAD risk. These findings may highlight a therapeutic target.

Age at Menarche and Time Spent in Education: A Mendelian Randomization Study.

Menarche signifies the primary event in female puberty and is associated with changes in self-identity. It is not clear whether earlier puberty causes girls to spend less time in education. Observational studies on this topic are likely to be affected by confounding environmental factors. The Mendelian randomization (MR) approach addresses these issues by using genetic variants (such as single nucleotide polymorphisms, SNPs) as proxies for the risk factor of interest. We use this technique to explore whether there is a causal effect of age at menarche on time spent in education. Instruments and SNP-age at menarche estimates are identified from a Genome Wide Association Study (GWAS) meta-analysis of 182,416 women of European descent. The effects of instruments on time spent in education are estimated using a GWAS meta-analysis of 118,443 women performed by the Social Science Genetic Association Consortium (SSGAC). In our main analysis, we demonstrate a small but statistically significant causal effect of age at menarche on time spent in education: a 1 year increase in age at menarche is associated with 0.14 years (53 days) increase in time spent in education (95% CI 0.10-0.21 years, p = 3.5 × 10-8). The causal effect is confirmed in sensitivity analyses. In identifying this positive causal effect of age at menarche on time spent in education, we offer further insight into the social effects of puberty in girls.

Serum iron level and kidney function: a Mendelian randomization study.

Background: Iron depletion is a known consequence of chronic kidney disease (CKD), but there is contradicting epidemiological evidence on whether iron itself affects kidney function and whether its effect is protective or detrimental in the general population. While epidemiological studies tend to be affected by confounding and reverse causation, Mendelian randomization (MR) can provide unconfounded estimates of causal effects by using genes as instruments. Methods: We performed an MR study of the effect of serum iron levels on estimated glomerular filtration rate (eGFR), using genetic variants known to be associated with iron. MR estimates of the effect of iron on eGFR were derived based on the association of each variant with iron and eGFR from two large genome-wide meta-analyses on 48 978 and 74 354 individuals. We performed a similar MR analysis for ferritin, which measures iron stored in the body, using variants associated with ferritin. Results: A combined MR estimate across all variants showed a 1.3% increase in eGFR per standard deviation increase in iron (95% confidence interval 0.4­2.1%; P = 0.004). The results for ferritin were consistent with those for iron. Secondary MR analyses of the effects of iron and ferritin on CKD did not show significant associations but had very low statistical power. Conclusions: Our study suggests a protective effect of iron on kidney function in the general population. Further research is required to confirm this causal association, investigate it in study populations at higher risk of CKD and explore its underlying mechanism of action.

A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization.

Mendelian randomization (MR) uses genetic data to probe questions of causality in epidemiological research, by invoking the Instrumental Variable (IV) assumptions. In recent years, it has become commonplace to attempt MR analyses by synthesising summary data estimates of genetic association gleaned from large and independent study populations. This is referred to as two-sample summary data MR. Unfortunately, due to the sheer number of variants that can be easily included into summary data MR analyses, it is increasingly likely that some do not meet the IV assumptions due to pleiotropy. There is a pressing need to develop methods that can both detect and correct for pleiotropy, in order to preserve the validity of the MR approach in this context. In this paper, we aim to clarify how established methods of meta-regression and random effects modelling from mainstream meta-analysis are being adapted to perform this task. Specifically, we focus on two contrastin g approaches: the Inverse Variance Weighted (IVW) method which assumes in its simplest form that all genetic variants are valid IVs, and the method of MR-Egger regression that allows all variants to violate the IV assumptions, albeit in a specific way. We investigate the ability of two popular random effects models to provide robustness to pleiotropy under the IVW approach, and propose statistics to quantify the relative goodness-of-fit of the IVW approach over MR-Egger regression. © 2017 The Authors. Statistics in Medicine Published by JohnWiley & Sons Ltd.

In vivo monitoring of topical therapy for acne with reflectance confocal microscopy.

BACKGROUND: Acne vulgaris is a common disease of the pilosebaceous unit. The aim of the study was to evaluate compartment-specific treatment action through the microscopic non-invasive imaging of skin changes. METHODS: Mild-moderate acne patients, that were prescribed a topical anti-acne product, were followed by clinical and reflectance confocal microscopy (RCM) imaging every 14 days to 6 weeks. Mean and standard deviation of the scores were analyzed for each time point. RESULTS: After 2 weeks, the RCM count of papules/pustules and the RCM scores of exocytosis and dermal inflammation, decreased substantially. After 4 weeks, the RCM number of comedos was reduced. After 6 weeks, the number of regular follicles increased, while the infundibula with thickened bright border decreased significantly. CONCLUSION: The progressive reduction in the clinical scores was correlated with the improvement of the RCM parameters. RCM study of acne skin showed a different timing for inflammatory and hyperkeratotic components to achieve a significant reduction during topical therapy with the association of retinoid and antibacterial molecules. The microscopic changes observed showed the regularization of the skin and the improvement of acne related features. RCM may represent a useful tool for the objective assessment of treatment efficacy and individual response evaluation.

Acne: morphologic and vascular study of lesions and surrounding skin by means of optical coherence tomography.

BACKGROUND: Acne vulgaris is a disease of the pilosebaceous unit, characterized by hyper-keratinization process, comedos formation and inflammatory reactions. OBJECTIVE: The definition of the morphology and the vascularization of acne lesions by means of dynamic optical coherence tomography (D-OCT), to non-invasively define the alterations occurring during the acne development and patient therapeutic management. METHODS: A set of standardized clinical pictures and D-OCT images were acquired from 114 acne lesions of 31 volunteers, presenting mild to moderate acne and evaluated by experts. Fifteen patients treated with oral antibiotics were followed during time at 0, 20, 40, and 60 days. RESULTS: Optical coherence tomography enabled to identify vascular and morphological aspects characterizing different types of acne lesions. Oral antibiotic treatment improved the morphologic features and decreased the digitally reconstructed vascular signal during time. CONCLUSION: The characterization of acne lesions and the identification of vascular pattern in acne lesions through D-OCT, corresponding to blood vessel dilation and inflammatory associated hyper-vascularization, may have important clinical consequences in the assessment of acne severity, therapeutic decisions and treatment efficacy monitoring.

Mendelian Randomization as an Approach to Assess Causality Using Observational Data.

Mendelian randomization refers to an analytic approach to assess the causality of an observed association between a modifiable exposure or risk factor and a clinically relevant outcome. It presents a valuable tool, especially when randomized controlled trials to examine causality are not feasible and observational studies provide biased associations because of confounding or reverse causality. These issues are addressed by using genetic variants as instrumental variables for the tested exposure: the alleles of this exposure-associated genetic variant are randomly allocated and not subject to reverse causation. This, together with the wide availability of published genetic associations to screen for suitable genetic instrumental variables make Mendelian randomization a time- and cost-efficient approach and contribute to its increasing popularity for assessing and screening for potentially causal associations. An observed association between the genetic instrumental variable and the outcome supports the hypothesis that the exposure in question is causally related to the outcome. This review provides an overview of the Mendelian randomization method, addresses assumptions and implications, and includes illustrative examples. We also discuss special issues in nephrology, such as inverse risk factor associations in advanced disease, and outline opportunities to design Mendelian randomization studies around kidney function and disease.

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Are strong opioids equally effective and safe in the treatment of chronic cancer pain? A multicenter randomized phase IV 'real life' trial on the variability of response to opioids.

BACKGROUND: Guidelines tend to consider morphine and morphine-like opioids comparable and interchangeable in the treatment of chronic cancer pain, but individual responses can vary. This study compared the analgesic efficacy, changes of therapy and safety profile over time of four strong opioids given for cancer pain. PATIENT AND METHODS: In this four-arm multicenter, randomized, comparative, of superiority, phase IV trial, oncological patients with moderate to severe pain requiring WHO step III opioids were randomly assigned to receive oral morphine or oxycodone or transdermal fentanyl or buprenorphine for 28 days. At each visit, pain intensity, modifications of therapy and adverse drug reactions (ADRs) were recorded. The primary efficacy end point was the proportion of nonresponders, meaning patients with worse or unchanged average pain intensity (API) between the first and last visit, measured on a 0-10 numerical rating scale. (NCT01809106). RESULTS: Forty-four centers participated in the trial and recruited 520 patients. Worst pain intensity and API decreased over 4 weeks with no significant differences between drugs. Nonresponders ranged from 11.5% (morphine) to 14.4% (buprenorphine). Appreciable changes were made in the treatment schedules over time. Each group required increases in the daily dose, from 32.7% (morphine) to 121.2% (transdermal fentanyl). Patients requiring adjuvant analgesics ranged from 68.9% (morphine) to 81.6% (oxycodone), switches varied from 22.1% (morphine) to 12% (oxycodone), discontinuation of treatment from 27% ( morphine) to 14.5% (fentanyl). ADRs were similar except for effects on the nervous system, which significantly prevailed with morphine. CONCLUSION: The main findings were the similarity in pain control, response rates and main adverse reactions among opioids. Changes in therapy schedules were notable over time. A considerable proportion of patients were nonresponders or poor responders. CLINICAL TRIAL REGISTRATION: NCT01809106 (https://clinicaltrials.gov/ct2/show/NCT01809106?term=cerp&rank=2).