Survivin, ß-catenin, and ki-67 immunohistochemical expression in canine perivascular wall tumors: Preliminary assessment of prognostic significance.

High survivin expression has been correlated with poor outcomes in several canine tumors but not in soft tissue tumors (STTs). Survivin is a target gene of the Wnt/ß-catenin pathway, which is involved in human STT oncogenesis. Immunohistochemistry for survivin, ß-catenin, and Ki-67 was performed on 41 canine perivascular wall tumors (cPWTs), and statistical associations of protein expression and histopathologic and clinical variables with clinical outcomes were investigated. Immunohistochemically, there was nuclear positivity (0.9%-12.2% of tumor cells) for survivin in 41/41 (100%), cytoplasmic positivity (0 to > 75% of tumor cells) for survivin in 31/41 (76%), nuclear positivity (2.9%-67.2% of tumor cells) for ß-catenin in 24/41 (59%), and cytoplasmic positivity (0% to > 75% of tumor cells) for ß-catenin in 23/41 (56%) of cPWTs. All tumors expressed nuclear Ki-67 (2.2%-23.5%). In univariate analysis and multivariate analysis (UA and MA, respectively), every 1% increase of nuclear survivin was associated with an increase of the instantaneous death risk by a factor of 1.15 [hazard ratio (HR) = 1.15; P = .007]. Higher nuclear survivin was associated with grade II/III neoplasms (P = .043). Expression of cytoplasmic survivin, nuclear and cytoplasmic ß-catenin, and nuclear Ki-67 were not significantly associated with prognosis in UA nor MA. Tumor size was a significant prognostic factor for local recurrence in UA [subdistribution HR (SDHR) = 1.19; P = .02] and for reduced overall survival time in MA. According to UA and MA, a unitary increase of mitotic count was associated with an increase of the instantaneous death risk by a factor of 1.05 (HR = 1.05; P = .014). Nuclear survivin, mitotic count, and tumor size seem to be potential prognostic factors for cPWTs. In addition, survivin and ß-catenin may represent promising therapeutic targets for cPWTs.

Reference intervals for thyroid biomarkers to enhance the assessment of thyroid status in childhood and adolescence.

OBJECTIVES: The determination of assay-dependent upper and lower reference limits (URL, LRL) of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) during childhood and adolescence, is challenging. METHODS: Thyroid hormones were measured via the Abbott Alinity system in 502 euthyroid children partitioned in the following age groups: ≤2, 2.1-10, and 10.1-18 years. The 97.5th and 2.5th percentiles (URL and LRL) were derived according to CLSI EP28- A3c guidelines. Quantile regression models were used to assess: (a) 90% confidence intervals of the URL and LRL, (b) the effect of age on URL and LRL within each age class and on overall age range, (c) the difference between the URLs and LRLs estimated for each age partition with an estimate of the confidence interval divided by the reference interval being derived (CI/RI). RESULTS: The CI/RI for the LRLs are smaller as compared to the URLs, except for FT4 for the 2.1-10 years age group. Considering the CI/RI and the overlap between CIs across the three age groups, one single LRL might be considered for TSH, FT3 and FT4 between 0 and 18 years. However, for the URL, there was a noticeable decrease in the URL over the 3 age groups for all three biomarkers, with there being no overlap in CIs for the URL between the ≤2 vs. the 10.1-19 years age groups. CONCLUSIONS: A common LRL for TSH, FT4 and FT3 for patients aged ≤18 years may be utilized when these biomarkers are measured with the Alinity system. For the URLs the use of age-specific URLs for these biomarkers is recommended.

Disease activity and disease-related factors are drivers of patient global assessment in rheumatoid arthritis: a real-life cross-sectional study.

Despite that the Patient Global Assessment (PGA) is widely used for measuring Rheumatoid Arthritis (RA) disease activity to define the remission state of the disease, the primary contributors influencing patients' ratings are still debated. This study aims to determine which clinical, sociodemographic and lifestyle-related contextual factors might be key drivers of PGA in RA. This single-center cross-sectional study recruited 393 consecutive adult RA patients. Median age 60 years, females 306 (77.9%). Data related to disease activity were assessed by using Simplified Disease Activity Index (SDAI), severity by Health Assessment Questionnaire (HAQ), and impact by RA Impact of Disease (RAID). Sociodemographic/lifestyle features were collected. Disease remission was calculated using Boolean-based criteria 1.0 and 2.0. Quantile regression models were used for univariate and multivariate analysis. The remission rate progressively increased from 15% by using SDAI with a Boolean 1.0-based definition to 43.5% using a Boolean 2.0-based remission. Among factors related to disease activity, the use of low-dose corticosteroids, the RAID items pain and sleep difficulties were predictive for worse PGA scores (p = 0.01). Among factors related to disease severity HAQ score and RAID total were independent factors associated with higher median PGA (p = 0.02 and p < 0.001). RAID's physical well-being was related to PGA scores (p = 0.01). An increasing trend in PGA was observed in longstanding diseases (> 15 years). Our results confirmed that there is no unambiguous interpretation of the PGA score. It is a measure related to some disease activity parameters, but it is also influenced by contextual factors related to disease severity and impact. These data highlighted that PGA should have a broad interpretation, thus supporting the proposal of a dual targets (biological and impact) approach to obtain a more accurate estimate of disease activity.

Diagnosis of SARS-CoV-2 in children: accuracy of nasopharyngeal swab compared to nasopharyngeal aspirate.

The tests currently used for the identification of SARS-CoV-2 include specimens taken from the upper and lower respiratory tract. Although recommendations from the World Health Organization prioritise the usage of a nasopharyngeal swab (NS), nasopharyngeal aspirates (NPA) are thought to be superior in identifying SARS-CoV-2 in children. To our knowledge, however, no paediatric study has been published on the subject. The aim of this study is to evaluate the diagnostic performances of NS referred to NPA for SARS-CoV-2 in children. We calculated the sensitivity and specificity of the NS referred to the NPA of the whole sample and considered both age and collection period as covariates in different analyses. We collected 300 paired samples. The NS had a specificity of 97.7% and a sensitivity of 58.1%. We found similar results for the group of subjects ≥ 6 years old, while for subjects < 6 years old, the sensitivity was 66.7% and the specificity 97.8%. Considering period as a covariate, the sensitivity and specificity for patients hospitalised in March (31 patients, 52 records) were 70.0% and 97.6%, while for patients involved in the follow-up (16 patients, 57 records), they were 57.2% and 89.7%. The NS has a low sensitivity in detecting SARS-CoV-2 in children when referred to the NPA, whereas its specificity is high. Our results suggest that in children under 6 years of age, NSs should be preferred whenever possible. Though statistically not significant, the sensitivity of the NS rises when performed before the NPA.

Acute pulmonary embolism in patients presenting pulmonary deterioration after hospitalisation for non-critical COVID-19.

BACKGROUND: Emerging evidence suggests an association between COVID-19 and acute pulmonary embolism (APE). AIMS: To assess the prevalence of APE in patients hospitalised for non-critical COVID-19 who presented clinical deterioration, and to investigate the association of clinical and biochemical variables with a confirmed diagnosis of APE in these subjects. METHODS: All consecutive patients admitted to the internal medicine department of a general hospital with a diagnosis of non-critical COVID-19, who performed a computer tomography pulmonary angiography (CTPA) for respiratory deterioration in April 2020, were included in this retrospective cohort study. RESULTS: Study populations: 41 subjects, median (interquartile range) age: 71.7 (63-76) years, CPTA confirmed APE = 8 (19.51%, 95% confidence interval (CI): 8.82-34.87%). Among patients with and without APE, no significant differences were found with regards symptoms, comorbidities, treatment, Wells score and outcomes. The optimal cut-off value of d-dimer for predicting APE was 2454 ng/mL, sensitivity (95% CI): 63 (24-91), specificity: 73 (54-87), positive predictive value: 36 (13-65), negative predictive value: 89 (71-98) and AUC: 0.62 (0.38-0.85). The standard and age-adjusted d-dimer cut-offs, and the Wells score ≥2 did not associate with confirmed APE, albeit a cut-off value of d-dimer = 2454 ng/mL showed an relative risk: 3.21; 95% CI: 0.92-13.97; P = 0.073. Heparin at anticoagulant doses was used in 70.73% of patients before performing CTPA. CONCLUSION: Among patients presenting pulmonary deterioration after hospitalisation for non-critical COVID-19, the prevalence of APE is high. Traditional diagnostic tools to identify high APE pre-test probability patients do not seem to be clinically useful. These results support the use of a high index of suspicion for performing CTPA to exclude or confirm APE as the most appropriate diagnostic approach in this clinical setting.

Kaplan-Meier Curves, Cox Model, and P-Values Are Not Enough for the Prognostic Evaluation of Tumor Markers: Statistical Suggestions for a More Comprehensive Approach.

The assessment of prognostic markers is key to the improvement of therapeutic strategies for cancer patients. Some promising markers may fail to be applied in clinical practice, or some useless markers may be applied, because of misleading results ensuing from inadequate planning of the study and/or from an oversimplified statistical analysis. This commentary illustrates and discusses the main issues involved in planning an effective clinical study and the subsequent statistical analysis for the prognostic evaluation of a cancer marker. Another aim is to extend the most applied statistical models (ie, those using Kaplan-Meier and Cox) to enable the choice of the best-suited methods for study endpoints. Specifically, for tumor-centered endpoints like tumor recurrence, the issue of competing risks is highlighted. For markers measured on a continuous numerical scale, a loss of relevant prognostic information may occur by setting arbitrary cutoffs; thus, the methods to analyze the original scale are explained. Furthermore, because the P-value is not a sufficient criterion to assess the usefulness of a marker in clinical practice, measures for evaluating the ability of the marker to discriminate between "good" and "bad" prognoses are illustrated. Several tumor markers are considered both in human and veterinary medicine. Given the similarity between markers for human breast cancer and canine mammary cancer, an application of the statistical methods discussed within the article to a public dataset from human breast cancer patients is shown.

The burden of air pollution and temperature on Raynaud's phenomenon secondary to systemic sclerosis.

OBJECTIVES: to evaluate the effect of air pollution (ozone - O3 and particulate matter <=10 µm and <=2.5 µm - PM10 and PM2.5) on the severity of Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). DESIGN: cross-sectional, observational, and single centre study. SETTING AND PARTICIPANTS: all consecutive SSc patients residing in Lombardy (Northern Italy) were enrolled. PM10, PM2.5, and O3 concentrations were calculated for each patient at municipality resolution in the week before the evaluation. Similar considerations were made for meteorological variables (temperature and humidity). MAIN OUTCOME MEASURES: patients were asked to assess RP severity during the week before the evaluation according to a visual analogue scale (VAS). Ordinal logistic regression models were fitted to evaluate the short-term effect of temperature and air pollution with respect to RP. A univariate linear regression model was created to consider the association between temperature and pollutants. RESULTS: in this study, 87 SSc patients were enrolled. Temperature was confirmed to strongly influence RP severity. PM10 and PM.5 were found to significantly worsen RP severity for the first four days before the evaluation, including the day of the visit, and as mean up to six days before the evaluation. O3 seemed to exert a protective effect on RP severity that was significant for the first four days before the evaluation, including the day of the visit, and as mean up to seven days before the evaluation. CONCLUSIONS: since the overwhelming effect of temperature on RP, final conclusions about the exact contribution of pollutants on RP severity cannot be drawn because of the strong inter-correlation between air pollution and temperature.

Evidence of macro- and micro-angiopathy in scleroderma: An integrated approach combining 22-MHz power Doppler ultrasonography and video-capillaroscopy.

OBJECTIVE: We aimed to study in SSc patients macrovascular involvement by using power Doppler ultrasound (PDUS) and microvascular one by PDUS and nailfold video-capillaroscopy (NVC) and to examine the association between history of digital ulcers (HDU) and imaging (PDUS and NVC) parameters. METHODS: NVC and PDUS were systematically performed in 106 consecutive SSc patients at the 3rd and 4th finger of the dominant hand after exclusion of ulnar artery occlusion (UAO). 22 MHz PDUS measurements included nailbed and fingertip qualitatively graded, and resistivity index (RI) of ulnar and radial proper digital arteries. Capillary number/mm was calculated by NVC on the same digits examined by PDUS. RESULTS: Vascularization at fingertip and nailbed showed a good correlation between them and to capillary number. RI, representative of macrovascular involvement, did not correlate to microvascular involvement as assessed by PDUS and NVC. RI and capillary number at NVC showed significant correlation to HDU while fingertip and nailbed vascularization as assessed by PDUS did not. As such, PDUS and NVC provide different and potentially complementary information on SSc-related peripheral macro- and micro-vascular involvement. CONCLUSION: Macro- and micro-vascular involvement in SSc patients are different processes and are not present at the same time in every patient. Thus, both these aspects should be carefully evaluated in SSc patients.

Comorbidity burden conditions the prognostic performance of D-dimer in elderly patients with acute pulmonary embolism.

INTRODUCTION: The prognostic accuracy of D-dimer for risk assessment in acute Pulmonary Embolism (APE) patients may be hampered by comorbidities. We investigated the impact of comorbidity burden (CB) by using the Charlson Comorbidity Index (CCI), on the prognostic ability of D-dimer to predict 30 and 90-day mortality in hemodynamically stable elderly patients with APE. METHODS: All patients aged >65 years with normotensive APE, consecutively evaluated in the Emergency Department since 2010 through 2014 were included in this retrospective cohort study. Area under the curve (AUC) and ½ Net Reclassification Improvement (NRI) were calculated. RESULTS: Study population: 162 patients, median age: 79.2 years. The optimal cut-off value of CCI score for predicting mortality was ≤1 (Low CB) and >1 (High CB), AUC = 0.786. Higher levels of D-dimer were associated with an increased risk death at 30 (HR = 1.039, 95%CI:1.000-1.080, p = 0.049) and 90 days (HR = 1.039, 95%CI:1.009-1.070, p = 0.012). When added to simplified Pulmonary Embolism Severity Index (sPESI) score, D-dimer increased significantly the AUC for predicting 30-day mortality in Low CB (AUC = 0.778, 95%CI:0.620-0.937, ½NRI = 0.535, p = 0.015), but not in High CB patients (AUC = 0.634, 95%CI:0.460-0.807, ½ NRI = 0.248, p = 0.294). Similarly, for 90-day mortality D-dimer increased significantly the AUC in Low CB (AUC = 0.786, 95%CI:0.643-0.929, ½NRI = 0.424, p-value = 0.025), but not in High CB patients (AUC = 0.659, 95%CI:0.541-0.778, ½NRI = 0.354, p-value = 0.165). CONCLUSION: In elderly patients with normotensive APE, comorbidities condition the prognostic performance of D-dimer, which was found to be a better predictor of death in subjects with low CB. These results support multimarker strategies for risk assessment in this population.

Modeling the covariates effects on the hazard function by piecewise exponential artificial neural networks: an application to a controlled clinical trial on renal carcinoma.

BACKGROUND: In exploring the time course of a disease to support or generate biological hypotheses, the shape of the hazard function provides relevant information. For long follow-ups the shape of hazard function may be complex, with the presence of multiple peaks. In this paper we present the use of a neural network extension of the piecewise exponential model to study the shape of the hazard function in time in dependence of covariates. The technique is applied to a dataset of 247 renal cell carcinoma patients from a randomized clinical trial. RESULTS: An interaction effect of treatment with number of metastatic lymph nodes but not with pathologic T-stage is highlighted. CONCLUSIONS: Piecewise Exponential Artificial Neural Networks demonstrate a clinically useful and flexible tool in assessing interaction or time-dependent effects of the prognostic factors on the hazard function.

Acute and chronic effects of two different intravenous iloprost regimens in systemic sclerosis: a pragmatic non-randomized trial.

OBJECTIVES: I.v. iloprost (ILO) may be used in the treatment of refractory RP and digital ulcers. We aim to evaluate the acute and chronic effects of two different ILO regimens by power Doppler US (PDUS) and nailfold videocapillaroscopy. METHODS: In this 3-month single-centre pragmatic non-randomized trial, 96 SSc patients were included and stratified according to ILO treatment as: no ILO (group A), ILO once monthly (group B) and ILO for five consecutive days (group C). Resistivity index (RI), finger pulp blood flow and periungual vascularization by PDUS, and sum of capillaries apex width in 1 mm by nailfold videocapillaroscopy were evaluated. Results were adjusted for the average outdoor temperature at the place of residence. RESULTS: An acute ILO effect was observed for only finger pulp blood flow in groups B and C (P < 0.001 and P < 0.005, respectively). An acute effect was observed for RI and periungual vascularization only in group B. A progressive increase was observed for other parameters without statistical difference. ILO effects were not observed any longer before the following infusion. Some parameters (finger pulp blood flow in group B and RI in group C) showed a statistically higher increase the lower the outdoor temperature was. CONCLUSION: ILO had an acute effect as assessed by PDUS, especially in group B. By contrast, an ILO chronic effect was not detectable before the following infusion in both treatment groups. More studies are needed to define how often ILO should be administered.

Comorbidity assessment as predictor of short and long-term mortality in elderly patients with hemodynamically stable acute pulmonary embolism.

Elderly patients presenting with acute pulmonary embolism (PE) frequently have significant underlying comorbidities which may condition the prognosis. The current study aimed to determine the ability of Charlson comorbidity index (CCI) score to predict short and long-term mortality in elderly patients with hemodynamically stable acute PE. All hemodynamically stable patients aged >65 years with acute PE, evaluated in the Emergency Department since 2010 through 2014, were included in this retrospective cohort study. CCI, simplified pulmonary embolism severity index (sPESI) scores and vital status were recorded. Were included 162 patients with confirmed PE, out of 657 suspected cases (24.7%). Median age: 79.2 years, 74.1% presented an sPESI > 1 and 61.1% a CCI > 1. The overall 30, 90-day and 2-year mortality was 11.7% (95%CI 6.6-16.6), 19.8% (95%CI 13.4-25.7) and 31.8% (95%CI 24.1-38.8). For 30-day mortality sPESI showed an AUC 0.642 (95%CI 0.511-0.772) and adding CCI as covariate did not increase its prognostic performance. For 90-day mortality, in an adjusted model including sPESI and CCI, CCI showed a HR 1.282 (95%CI 1.151-1.429, p-value < 0.001), and sPESI a HR = NS(p-value = 0.267). For 2-year mortality, in an adjusted model including sPESI and CCI, CCI showed a HR 1.295 (95%CI 1.180-1.421, p-value < 0.001) and sPESI a HR = NS(p-value = 0.353). In elderly patients with hemodynamically stable PE, the CCI score was found to be an independent predictor of mortality. CCI shows a significantly better ability to predict 90-day and 2-year mortality than sPESI. The assessment of comorbidity burden by using the CCI score may be proposed as an useful tool to predict mortality in these patients.

An international SUrvey on non-iNvaSive tecHniques to assess the mIcrocirculation in patients with RayNaud's phEnomenon (SUNSHINE survey).

To canvas opinion concerning the role of non-invasive techniques in the assessment of patients with Raynaud's phenomenon (Rp) in clinical and research settings: four nailfold capillaroscopy methods [videocapillaroscopy (NVC), dermoscopy, stereomicroscopy, digital USB microscopy], four laser Doppler methods (laser Doppler flowmetry, imaging, anemometry/velocimetry, laser speckle contrast analysis), thermographic imaging, and upper limb arterial Doppler ultrasound. Emails with a link to the survey were sent to physicians from the European Scleroderma Trials and Research group (EUSTAR), the EULAR Study Group on Microcirculation in Rheumatic Diseases (SG_MC/RD) and members of the pediatric rheumatology Email board. The main descriptive analysis related to physicians looking after adult patients, with some analysis also of opinions from paediatric rheumatologists. 106 'adult physicians' responded (a response rate of 25.8%), of whom 68.9% were European, and 81.1% practising for more than 10 years. Nineteen paediatricians responded. The most widely available technique was NVC (72.7%). Nailfold capillaroscopy was most frequently performed by the physician him/herself, using different types of equipment relating to availability. Most rheumatologists reported high levels of appropriateness for NVC in both clinical and research settings for global assessment and differential diagnosis of Rp. Other techniques were less used. Of all the different techniques, nailfold capillaroscopy was the one most used in both clinical and research settings by adult physicians, the majority of whom use NVC in their everyday practice. The low proportion of clinicians using other techniques suggests that these are currently mainly research tools, available only in specialist centres.

Prognostic value of D-dimer in elderly patients with Pulmonary Embolism.

In a general population with acute Pulmonary Embolism (PE) elevated D-dimer concentrations associate with increased mortality. The aim of the study was to assess the ability of D-dimer to predict 30 and 90-days mortality in elderly patients with acute PE. Hemodynamically stable patients aged ≥65 years old with confirmed PE were included in this retrospective cohort study. A pulmonary computerized tomography angiography scan, D-dimer concentrations, simplified Pulmonary Embolism Severity Index (sPESI) variables and vital status were available for all patients. The study included 154 confirmed cases of PE (23.5 % of suspected), median age 79.1 years. D-dimer was higher in patients dead than in those alive at 30 (median 14,547 vs. 8340 ng/mL, p = 0.05) and 90 days (13,604 vs. 7973 ng/mL, p = 0.013). When adding D-dimer to sPESI, the discriminant capacity to predict mortality within 30 and 90 days was increased by 0.080 and 0.089, respectively. The contribution of D-dimer to the discriminating ability was NRI = 0.286 (95 % CI -0.198 to 0.770, p value: 0.247) at 30 days and NRI = 0.605 (95 % CI 0.223-0.988, p-value: 0.002) at 90 days.D-dimer concentration was associated with 30 and 90-days mortality and showed a higher discriminant capacity than sPESI alone to predict 90-days mortality. Adding D-dimer concentrations to sPESI score seems to improve its prognostic ability, supporting multivariable risk models as the best approach to estimate prognosis in elderly patients with PE.

Thromboprophylaxis with low-molecular-weight heparins: an assessment of the methodological quality of studies.

Low-molecular-weight heparin (LMWH) represents the standard of care for prophylaxis of venous thromboembolism (VTE). We conducted a review of the evidence supporting the use of the different LMWHs employed in VTE prophylaxis, in different clinical settings, and analyzed its progression over time. To evaluate the standards of methodological quality of studies, we elaborated a quality assessment tool. By electronic databases, PubMed, MEDLINE, and Scopus databases, 249 articles deemed eligible for the analysis were selected. Several LMWHs did not have publications in all clinical settings. Extended duration of prophylaxis was documented only for a few LMWH. The quality score yielded statistically significant differences between the medians of the four settings (p = 0.0021) with a higher score in major orthopedic surgery (median, 16; 95% confidence interval [CI], 15-16) when compared with general surgery (median, 14; 95% CI, 13-14; p < 0.001). Median score for studies published after the year 1990 was higher than for those published earlier (p < 0.001). We conclude that the quality of the studies supporting LMWH for VTE prophylaxis in the different clinical settings is not homogeneous and inferior for studies performed before the year 1990. Clinical interchangeability of LMWHs in clinical practice remains a critical issue, and the selection of a product should be based on evidence available for each agent, and for each clinical indication derived from clinical trials.

A comparison between nailfold capillaroscopy patterns in adulthood in juvenile and adult-onset systemic sclerosis: A EUSTAR exploratory study.

OBJECTIVE: Qualitative capillaroscopy patterns in juvenile- and adult-onset systemic sclerosis (SSc) were studied in adulthood using data from the EULAR Scleroderma Trials and Research (EUSTAR) database. METHODS: Data collected between June 2004 and April 2013 were examined with focus on capillaroscopy. In this retrospective exploratory study, series of patients with juvenile-onset SSc were matched with series of adult-onset SSc having the same gender and autoantibody profile. RESULTS: 30 of 123 patients with juvenile-onset and 2108 of 7133 with adult-onset SSc had data on capillaroscopy. Juvenile-onset SSc showed scleroderma pattern more frequently than adult-onset SSc (93.3% and 88%). The OR was 2.44 and 95% CI 0.57-10.41. An active scleroderma pattern was present in 58% of juvenile- and 61% of adult-onset SSc. The OR was 0.91 and 95% CI 0.28-2.93. The late scleroderma pattern was present in 61% of juvenile- and 55.5% of adult-onset SSc. The OR was 1.06 and 95% CI 0.34-3.56. CONCLUSION: This is the first exploratory study on the comparison of capillaroscopy between juvenile- and adult-onset SSc in adulthood. Juvenile-onset SSc had an increase prevalence of scleroderma pattern, but a similar distribution of the three patterns was suggested. Further studies are needed to define this issue.

A prospective multicentre study on the treatment of cardiovascular risk factors and claudication symptoms in patients with peripheral artery disease (the IDOMENEO study).

BACKGROUND: The objective of this prospective multicenter cohort study was to characterise the use of pharmacological and non-pharmacological treatment for cardiovascular disease (CVD) risk factors and intermittent claudication (IC) symptoms in clinical practice patients with peripheral artery disease (PAD), and to determine the care gap with international guidelines and evidence-based therapy. PATIENTS AND METHODS: From 2011 through 2013, participating centres enrolled consecutive patients with PAD of atherosclerotic, origin demonstrated by ultrasound, ankle brachial index (ABI) < 0.9 and symptoms of IC. A seven item grid was built for the assessment of care gap (percentage of patients eligible for a treatment who did not receive it). cerebrovascular disease or at least two CVD risk factors. Care gap was lower than 25 % for any method to stop smoking, lipid lowering agents, antiplatelet and/or anticoagulation therapy and any kind of exercise program; between 25% and 50% for ACE inhibitors/ angiotensin II antagonist therapy; between 50% and 75% for beta-blocker therapy; and higher than 75% for supervised exercise program and use of cilostazol. Patients with and without CADI cerebrovascular disease were differently treated with clopidogrel (27.3% and 4.8 %, p < 0.001), any antiplatelet/anticoagulant therapy (98.7% and 83.3 %, p <0.001) and beta-blockers (46.8% and 16.0%, p<0.001). RESULTS: All patients (232) presented at least one CVC risk factor, 90.2% at least two, and 91.5% had either established CAD or CONCLUSIONS: Many gaps with evidence-based recommendations are still present in the pattern of the use of pharmacological and non-pharmacological treatment for CVD risk factors and IC symptoms in clinical practice PAD patients.

Model-based estimation of measures of association for time-to-event outcomes.

BACKGROUND: Hazard ratios are ubiquitously used in time to event applications to quantify adjusted covariate effects. Although hazard ratios are invaluable for hypothesis testing, other adjusted measures of association, both relative and absolute, should be provided to fully appreciate studies results. The corrected group prognosis method is generally used to estimate the absolute risk reduction and the number needed to be treated for categorical covariates. METHODS: The goal of this paper is to present transformation models for time-to-event outcomes to obtain, directly from estimated coefficients, the measures of association widely used in biostatistics together with their confidence interval. Pseudo-values are used for a practical estimation of transformation models. RESULTS: Using the regression model estimated through pseudo-values with suitable link functions, relative risks, risk differences and the number needed to treat, are obtained together with their confidence intervals. One example based on literature data and one original application to the study of prognostic factors in primary retroperitoneal soft tissue sarcomas are presented. A simulation study is used to show some properties of the different estimation methods. CONCLUSIONS: Clinically useful measures of treatment or exposure effect are widely available in epidemiology. When time to event outcomes are present, the analysis is performed generally resorting to predicted values from Cox regression model. It is now possible to resort to more general regression models, adopting suitable link functions and pseudo values for estimation, to obtain alternative measures of effect directly from regression coefficients together with their confidence interval. This may be especially useful when, in presence of time dependent covariate effects, it is not straightforward to specify the correct, if any, time dependent functional form. The method can easily be implemented with standard software.

The definition of valvular and non-valvular atrial fibrillation: results of a physicians' survey.

AIMS: To assess different aspects of the definition of valvular/non-valvular atrial fibrillation (AF) used in clinical practice by physicians who usually treat this condition. METHODS AND RESULTS: We prospectively conducted a web-based survey including cardiologists and internists who attended continuing medical education courses on cardiovascular medicine. A questionnaire was drawn up, containing 17 questions clustered into five main topics: (A) known rheumatic aetiology; (B) site/type of valve involvement; (C) prosthetic heart valve; (D) haemodynamic relevance; (E) miscellaneous. The overall response rate was 22.4% (21.1% for cardiologists and 24% for internists). Coexistence of both medical history of rheumatic disease and clinical signs of valvular involvement were considered as essential prerequisites for the diagnosis of rheumatic AF by half of the respondents, and one-third assumed that lone aortic valve disease was sufficient for AF to be defined as valvular. A similar proportion of respondents considered that in the presence of mitral regurgitation, AF had to be defined as valvular. The majority of responding physicians considered the degree of valvular defect of lesser importance for the definition of valvular or non-valvular origin of AF. CONCLUSION: We found important heterogeneity and uncertainties in the answers given by physicians who usually treat patients with AF, as evidence of the lack of precise and unique definitions of the origin of AF (valvular/non-valvular). It is urgent to issue clear widely accepted definitions of the origin of AF, which should improve clinical practice and research.