Measuring functional limitations after venous thromboembolism: Optimization of the Post-VTE Functional Status (PVFS) Scale.

INTRODUCTION: We recently proposed a scale for assessment of patient-relevant functional limitations following an episode of venous thromboembolism (VTE). Further development of this post-VTE functional status (PVFS) scale is still needed. METHODS: Guided by the input of VTE experts and patients, we refined the PVFS scale and its accompanying manual, and attempted to acquire broad consensus on its use. RESULTS: A Delphi analysis was performed involving 53 international VTE experts with diverse scientific and clinical backgrounds. In this process, the number of scale grades of the originally proposed PVFS scale was reduced and descriptions of the grades were improved. After these changes, a consensus was reached on the number/definitions of the grades, and method/timing of the scale assessment. The relevance and potential impact of the scale was confirmed in three focus groups totaling 18 VTE patients, who suggested additional changes to the manual, but not to the scale itself. Using the improved manual, the κ-statistics between PVFS scale self-reporting and its assessment via the structured interview was 0.75 (95%CI 0.58-1.0), and 1.0 (95%CI 0.83-1.0) between independent raters of the recorded interview of 16 focus groups members. CONCLUSION: We improved the PVFS scale and demonstrated broad consensus on its relevance, optimal grades, and methods of assessing among international VTE experts and patients. The interobserver agreement of scale grade assignment was shown to be good-to-excellent. The PVFS scale may become an important outcome measure of functional impairment for quality of patient care and in future VTE trials.

Determining the minimal clinically important difference for the PEmbQoL questionnaire, a measure of pulmonary embolism-specific quality of life.

Essentials The minimal clinically important difference (MCID) for PEmbQoL has not yet been determined. We estimated the MCID for PEmbQoL and its subscales via anchor- and distribution-based approaches. Our results indicate that MCID for PEmbQoL appears to be 15 points. Our work enables interpretation of changes or differences in PEmbQoL. SUMMARY: Background Pulmonary embolism (PE) reduces quality of life (QOL). The PEmbQoL questionnaire, a PE-related QOL measure, was recently developed and validated and has been used to quantify disease-specific QOL in clinical studies of patients with PE. However, to date, interpretation of PEmbQoL scores has been limited by a lack of information on the minimal clinically important difference (MCID) of this measure. Objective To determine the MCID for PEmbQoL and its subscales using anchor-based and distribution-based approaches. Methods We analyzed data from the ELOPE Study, a prospective, multicenter cohort study of long-term outcomes after a first episode of acute PE. At baseline and 1, 3, 6 and 12 months after PE, we measured generic QOL (SF-36), PE-specific QOL (PEmbQoL) and dyspnea severity (UCSD Shortness of Breath Questionnaire). We used time-varying repeated-measures mixed-effect models to estimate anchor-based MCID and effect sizes to estimate distribution-based MCID. Results Eighty-two patients participated in this sub-study. Their mean age was 49.4 years, 60% were male and 84% had PE diagnosed in an outpatient setting. Using both anchor- and distribution-based approaches, the MCID for PEmbQoL appears to be 15 points. Based on this MCID, 42%, 59%, 66% and 75% of patients experienced at least one MCID unit of improvement in PEmbQoL from baseline to 1, 3, 6 and 12 months, respectively. Conclusion Our results provide new information on the MCID of PEmbQoL, a PE-specific QOL questionnaire that can be used by researchers and clinicians to measure and interpret changes in PE-specific QOL over time, or as an outcome in clinical trials.

Development of a clinical prediction model for the postthrombotic syndrome in a prospective cohort of patients with proximal deep vein thrombosis.

Essentials We developed a prediction model for postthrombotic syndrome (PTS) after deep vein thrombosis (DVT). High risk predictors were iliac vein DVT, BMI>35 and moderate-severe Villalta category. Patients with a score ≥4 had an odds ratio of 5.9 (95% CI 2.1-16.6) for PTS. SOX-PTS score may select DVT patients for close monitoring or aggressive strategies to treat DVT. SUMMARY: Background Postthrombotic syndrome (PTS) is a chronic complication that develops in 20-50% of patients after deep vein thrombosis (DVT). Although individual risk factors for PTS have been characterized, the ability to predict which DVT patients are likely to develop PTS remains limited. Objective To develop a clinical prediction score for PTS in patients with DVT. Methods The derivation cohort consisted of participants in the SOX Trial, a randomized double-blind placebo-controlled trial of elastic compression stockings versus placebo stockings worn for 2 years after DVT to prevent PTS in patients with a first proximal DVT, enrolled in 24 community and tertiary-care hospitals from 2004 to 2010. Multivariable logistic regression analysis of baseline characteristics was performed. The outcome was the occurrence of PTS, diagnosed starting from 6 months or later according to Ginsberg's criteria. Results Seven hundred and sixty-two patients were included in the analysis. The median follow-up was 728 days. The model includes three independent predictors, and has a range of possible scores from 0 to 5. High-risk predictors were: index DVT in the iliac vein; body mass index of ≥ 35 kg m-2 ; and moderate-severe Villalta severity category at DVT diagnosis. As compared with patients with a score of 0, those with a score of ≥ 4 had an odds ratio of 5.9 (95% confidence interval 2.1-16.6) for developing PTS. Conclusions To our knowledge, this is the first clinical prediction score for PTS. We identified three independent predictors that, when combined, predicted PTS risk after a first proximal DVT. The SOX-PTS score requires external validation before it can be considered for clinical use.

Long-term outcomes of cancer-related isolated distal deep vein thrombosis: the OPTIMEV study.

Essentials Clinical significance of cancer-related isolated distal deep vein thrombosis (iDDVT) is unknown. We studied patients with iDDVT, with and without cancer, and proximal DVT with cancer. Cancer-related iDDVT patients have a much poorer prognosis than iDDVT patients without cancer. Cancer-related iDDVT patients have a similar prognosis to cancer-related proximal DVT patients. SUMMARY: Background Isolated distal deep vein thrombosis (iDDVT) (infra-popliteal DVT without pulmonary embolism [PE]) is a frequent event and, in the absence of cancer, is usually considered to be a minor form of venous thromboembolism (VTE). However, the clinical significance of cancer-related iDDVT is unknown. Methods Using data from the observational, prospective multicenter OPTIMEV cohort, we compared, at 3 years, the incidences of death, VTE recurrence and major bleeding in patients with cancer-related iDDVT with those in cancer patients with isolated proximal DVT (matched 1:1 on age and sex) and patients with iDDVT without cancer (matched 1:2 on age and sex). Results As compared with patients with cancer-related isolated proximal DVT (n = 92), those with cancer-related iDDVT (n = 92) had a similar risk of death (40.8% per patient-year (PY) vs. 38.3% per PY; aHR = 1.0, 95% CI[0.7-1.4]) and of major bleeding (3.8% per PY vs. 3.6% per PY, aCHR = 0.9 [0.3-3.2]) and a higher risk of VTE recurrence (5.4% per PY vs. 11.5% per PY; aCHR = 1.8 [0.7-4.5]). As compared with patients with iDDVT without cancer (n = 184), those with cancer-related iDDVT had a nine times higher risk of death (3.5% per PY vs. 38.3% per PY; aHR = 9.3 [5.5-15.9]), a higher risk of major bleeding (1.8% per PY vs. 3.6% per PY; aCHR = 2.0 [0.6-6.1]) and a higher risk of VTE recurrence (5.0% per PY vs. 11.5% per PY; aCHR = 2.0 [1.0-3.7]). The results remained similar in the subgroup of patients without history of VTE. Conclusion Patients with cancer-related iDDVT seem to have a prognosis that is similar to that of patients with cancer-related isolated proximal DVT and a dramatically poorer prognosis than patients with iDDVT without cancer. This underlines the high clinical significance of cancer-related iDDVT and the need for additional studies.

Long-term risk of venous thromboembolism recurrence after isolated superficial vein thrombosis.

Essentials Long-term risk of recurrence of isolated superficial vein thrombosis (SVT) is under-studied. We analyzed data from a cohort of first SVT and proximal deep vein thrombosis (DVT) without cancer. The risk of recurrence as DVT or pulmonary embolism is twice lower in SVT patients. However, overall risk of recurrence is similar between SVT and proximal DVT patients. Click to hear Dr Decousus' perspective on superficial vein thrombosis SUMMARY: Background Isolated superficial vein thrombosis (iSVT) (without concomitant deep vein thrombosis [DVT] or pulmonary embolism [PE]) is a frequent event, but available data on long-term outcomes are scarce and retrospective. Therefore, we aimed to determine prospectively the risk and type of venous thromboembolism (VTE) recurrence after iSVT and compare them with those of proximal DVT. Methods Using data from the prospective, multicenter, observational, OPTIMEV study, we assessed, at 3 years and after anticoagulants were stopped, the incidence and the type of VTE recurrence (iSVT/DVT/PE) of patients with a first objectively confirmed iSVT without cancer (n = 285), and compared these with those of patients with a first proximal DVT without cancer (n = 262). Results As compared with proximal DVT patients, iSVT patients had a similar overall incidence of VTE recurrence (5.4% per patient-year [PY] versus 6.5% per PY, adjusted hazard ratio [aHR] 0.9, 95% confidence interval [CI] 0.5-1.6), but iSVT recurred six times more often as iSVT (2.7% versus 0.6%, aHR 5.9, 95% CI 1.3-27.1) and 2.5 times less often as deep-VTE events (2.5% versus 5.9%, aHR 0.4, 95% CI 0.2-0.9). Varicose vein status did not influence the risk or the type of VTE recurrence. Saphenian junction involvement by iSVT was not associated with a higher risk of recurrence (5.2% per PY versus 5.4% per PY), but was associated with recurrence exclusively as deep-VTE events. Conclusion In patients with a first iSVT without cancer, after stopping anticoagulants, the incidence of deep-VTE recurrence is half that of DVT patients, but the overall risk of recurrence is similar. Ssaphenian junction involvement seems to influence the risk of deep-VTE recurrence, whereas varicose vein status has no impact or a low impact on VTE recurrence.

The postthrombotic syndrome: current evidence and future challenges.

Postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT) that develops in 20-50% of patients. PTS manifests as a spectrum of symptoms and signs of chronic venous insufficiency that can impose significant morbidity and have a negative impact on quality of life. Chronic venous hypertension caused by a combination of residual venous obstruction and valvular reflux is believed to play a major role in the pathophysiology of PTS. The Villalta scale is the most widely applied clinical scale used to diagnose and define PTS. Proximal DVT and recurrent ipsilateral DVT are the two principal established risk factors for PTS, and efforts in recent years have been focused on identifying a combination of clinical and biomarker predictors that will define high-risk patients and possibly new therapeutic targets. The best way to prevent PTS is to prevent the occurrence of DVT, and to provide optimal anticoagulation for the acute phase of DVT once it occurs. Recent years have brought progress in our understanding of the role of endovascular techniques in the prevention and treatment of PTS and the subgroups of patients that may benefit from these modalities. Pharmacomechanical catheter-directed thrombolysis is the most promising interventional modality for prevention of PTS. This review summarizes the current state of evidence on PTS of the lower limbs, and highlights areas where uncertainty still exists that require further research.

Predictive value of markers of inflammation in the postthrombotic syndrome: a systematic review: inflammatory biomarkers and PTS.

BACKGROUND: The postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT). Inflammation may contribute to its pathophysiology. OBJECTIVES: We conducted a systematic review of studies that analyzed the association between biomarkers of inflammation and PTS in DVT patients. METHODS: The electronic databases PubMed, EMBASE, Medline, Scopus and Web of Science were searched for studies published until March 2015 that measured blood inflammation biomarker levels in adult DVT patients and reported their association with PTS development. Two reviewers independently performed full text assessment and data extraction. RESULTS: Ten studies were included. Nine reported on the association between C-reactive protein and PTS; Interleukin (IL)-6 was measured in six studies; IL-8 in four studies; Intracellular adhesion molecule (ICAM)-1 in three studies; IL-10 and vascular cell adhesion molecule-1 in two studies; and monocyte chemotactic protein-1, matrix metalloprotease-9, P-Selectin, tumor necrosis factor α and erythrocyte sedimentation rate were measured in one study. Studies differed in terms of populations included, exclusion criteria, methods used for biomarker measurement and statistical measures of association between biomarkers and PTS. We were able to metaanalyze results only for IL-6 and found no significant association. Descriptively, ICAM-1 was significantly associated with PTS in two out of three studies that measured it. Other biomarkers did not demonstrate a significant association with PTS. CONCLUSIONS: Our systematic review found conflicting results regarding the role of inflammatory biomarkers as predictors of PTS. ICAM -1 appears to be a promising marker for further investigation.

The safety and efficacy of early-initiation exercise training after acute venous thromboembolism: a randomized clinical trial.

BACKGROUND: Exercise training after myocardial infarction is the standard of care within a cardiac rehabilitation setting. However, there is scant evidence regarding the safety and efficacy of early exercise training following a venous thromboembolism (VTE). METHODS: Eligible consenting participants were randomly allocated, on an individual basis, to either a 3-month exercise and behavioral weight loss intervention group or a control group. The primary clinical outcomes were change in health behavior (body weight and physical activity) and objectively measured fitness (Vo2peak ). RESULTS: From 2013 to 2014, 239 patients presented to a community-based specialty clinic after an acute VTE; 43 (18%) of these met the eligibility criteria for inclusion in the study. Of these, 19 (44%) consented to participate (nine in the intervention group; 10 in the control group). There were no adverse events in either group over a 3-month period. The mean difference in body weight between the intervention and control groups was - 4.6 kg (95% confidence interval [CI] - 11.4 to 2.2) in favor of the intervention. The mean difference in duration of physical activity from baseline to 3 months between the intervention and control groups was 133 min (95% CI 7-248) in favor of the intervention. There was a significant change in fitness over a 3-month period for the intervention group (baseline Vo2peak , 26.1 ± 5.4 mL O2 kg(-1)  min(-1) ; postintervention Vo2peak , 29.8 ± 5.4 mL O2 kg(-1)  min(-1) ). CONCLUSION: Early initiation of exercise training resulted in improvements in physical activity and fitness, and did not result in adverse events while individuals were receiving therapeutic anticoagulation. These are the first data on initiation of an exercise training and behavioral weight loss program in the early post-VTE setting.

Small-for-gestational-age birth and maternal plasma antioxidant levels in mid-gestation: a nested case-control study.

OBJECTIVE: To assess whether maternal plasma antioxidant levels in mid-pregnancy are associated with small-for-gestational-age (SGA) birth. DESIGN: Case-control study nested within a population-based cohort study. SETTING: Four hospitals in Montreal, Canada. POPULATION: Pregnant women recruited before 24 weeks of gestation, whose pregnancies were not complicated by pre-eclampsia or preterm delivery. METHODS: Blood samples were obtained at 24-26 weeks and assayed for nutritionally derived antioxidant levels in SGA cases (n = 324) and randomly selected controls with birthweights between the 25th and 75th centiles (n = 672). We performed logistic regression analyses using the standardised z-score of each antioxidant as the main independent variable, after summing highly correlated antioxidants or combining via principle component analysis. We adjusted for risk factors for SGA that were associated with antioxidant levels. MAIN OUTCOME MEASURES: SGA, birthweight <10th centile for gestational age and sex. RESULTS: Retinol was positively associated with risk of SGA (adjusted odds ratio [OR] 1.41; 95% confidence interval [95% CI] 1.22-1.63, per SD increase). Carotenoids (log of the sum of ß-carotene, lutein/zeaxanthin, α- and ß-cryptoxanthin) were negatively associated with SGA (adjusted OR 0.64; 95% CI 0.54-0.78, per SD increase). We found no significant associations between SGA and lycopene or any of the forms of vitamin E assessed, including α-tocopherol, corrected α-tocopherol (per nmol/l of low-density lipoprotein articles), or γ-tocopherol. CONCLUSIONS: Elevated retinol may be associated with an increased risk of SGA, whereas elevated carotenoid levels may reduce the risk. A better understanding of the nature of these associations is required, however, before recommending specific nutritional interventions in an attempt to prevent SGA birth.

Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). OBJECTIVE: In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. METHODS: We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. RESULTS: Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. CONCLUSIONS: In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

Graduated compression stockings to treat acute leg pain associated with proximal DVT. A randomised controlled trial.

Acute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentre randomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in 24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. Patients were randomised to receive active ECS (knee length, 30-40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.

The VEINES-QOL/Sym questionnaire is a reliable and valid disease-specific quality of life measure for deep vein thrombosis in elderly patients.

PURPOSE: To prospectively evaluate the psychometric properties of the Venous Insufficiency Epidemiological and Economic Study (VEINES-QOL/Sym) questionnaire, an instrument to measure disease-specific quality of life and symptoms in elderly patients with deep vein thrombosis (DVT), and to validate a German version of the questionnaire. METHODS: In a prospective multicenter cohort study of patients aged ≥ 65 years with acute venous thromboembolism, we used standard psychometric tests and criteria to evaluate the reliability, validity, and responsiveness of the VEINES-QOL/Sym in patients with acute symptomatic DVT. We also performed an exploratory factor analysis. RESULTS: Overall, 352 French- and German-speaking patients were enrolled (response rate of 87 %). Both language versions of the VEINES-QOL/Sym showed good acceptability (missing data, floor and ceiling effects), reliability (internal consistency, item-total and inter-item correlations), validity (convergent, discriminant, known-groups differences), and responsiveness to clinical change over time in elderly patients with DVT. The exploratory factor analysis of the VEINES-QOL/Sym suggested three underlying dimensions: limitations in daily activities, DVT-related symptoms, and psychological impact. CONCLUSIONS: The VEINES-QOL/Sym questionnaire is a practical, reliable, valid, and responsive instrument to measure quality of life and symptoms in elderly patients with DVT and can be used with confidence in prospective studies to measure outcomes in such patients.

Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep vein thrombosis.

BACKGROUND: Isolated distal deep vein thrombosis (iDDVT) (i.e. without proximal DVT or pulmonary embolism) represents half of all cases of lower limb DVT. Its clinical significance and management are controversial. Data on long-term follow-up are scarce, especially concerning risk and predictors of venous thromboembolism (VTE) recurrence. METHODS: Using data from the OPTIMEV (OPTimisation de l'Interrogatoire dans l'évaluation du risque throMbo-Embolique Veineux) study, a prospective, observational, multicenter study, we compared, 3 years after an index VTE event and after discontinuation of anticoagulants, (i) the incidence and type of recurrence in patients without cancer with a first iDDVT vs. a first isolated proximal DVT (iPDVT) and (ii) predictors of recurrence after iDDVT. RESULTS: Compared with patients with iPDVT (n = 259), patients with an iDDVT (n = 490) had a lower annualized incidence of overall VTE recurrence (5.2% [95% confidence interval 3.6-7.6] vs. 2.7% [1.9-3.8], respectively; P = 0.02) but a similar incidence of pulmonary embolism recurrence (1.0% [0.5-2.3] vs. 0.9% [0.5-1.6], respectively; P = 0.83). An age of > 50 years, unprovoked character of index iDDVT, and involvement of more than one vein in one or both legs each independently tripled the risk of recurrence, with the latter then being ≥ 3% per patient-year. Neither muscular vein nor deep-calf vein location of iDDVT nor clot diameter with compression influenced the risk of recurrence. CONCLUSIONS: After stopping anticoagulants, patients with iDDVT have a significantly lower risk of overall VTE recurrence than did patients with iPDVT but a similar risk of serious recurrent VTE. Age > 50 years, unprovoked iDDVT, and number of thrombosed veins (more than one) influenced the risk of recurrence and may help to define patients at significant risk of recurrence.

Association between thrombophilia and the post-thrombotic syndrome: a systematic review and meta-analysis.

BACKGROUND: The postthrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT), occurring in 20-40% of patients. Identifying risk factors for PTS may be useful to provide patients with prognostic information and target prevention strategies. OBJECTIVE: To conduct a systematic review to assess whether, among patients with DVT, inherited and acquired thrombophilias are associated with a risk of PTS. METHODS: We searched the electronic databases PubMed, EMBASE, Scopus, and Web of Science for studies published from 1990 to 2013 that assessed any thrombophilia in adult DVT patients and its association with the development of PTS. We calculated odds ratios and 95% confidence intervals for PTS according to the presence of thrombophilia. Meta-analysis was performed using the random-effects model. RESULTS: Sixteen studies were included: 13 assessed factor V Leiden (FVL), 10 assessed prothrombin mutation, five assessed protein S and C deficiencies, three assessed antithrombin deficiency, four assessed elevated FVIII levels, and six assessed antiphospholipid antibodies. None of the meta-analyses identified any thrombophilia to be predictive of PTS. Both FVL and prothrombin mutation appeared protective among studies including patients with both first and recurrent DVT and studies in which more than 50% of patients had an unprovoked DVT. CONCLUSIONS: Our meta-analysis did not demonstrate a significant association between any of the thrombophilias assessed and the risk of PTS in DVT patients. Other biomarkers in the pathophysiological pathway may be more predictive of PTS.

A guide to GRADE guidelines for the readers of JTH.

More than 70 organizations worldwide have adopted the GRADE methodology for guideline development. The ninth iteration of the American Collage of Chest Physicians guidelines (AT9) adopted structural and policy changes that resulted in a greater adherence to GRADE guidance than previous iterations. The most important of these changes include minimizing the impact of financial and intellectual conflict of interest, increasing the rigor of evidence evaluation, acknowledging uncertainty in estimates of typical values and preferences, and awareness of the large variability in values and preferences. One of the consequences of the greater adherence to GRADE methodology is an increase in weak vs. strong recommendations in AT9. The result of the GRADE process highlights the desirability of higher-quality evidence both regarding the outcomes of alternative management strategies and regarding the distribution of values and preferences in patients considering those alternatives. It also encourages shared decision making in encounters between physicians and patients. Although some physicians might find the uncertainty underlying medical practice discouraging or unsettling, relative to denying or obscuring the uncertainty, acknowledging and addressing the uncertainty will lead to more credible, realistic, and useful recommendations.

Hyperphagia among patients with Bardet-Biedl syndrome.

BACKGROUND: The importance of hyperphagia as a cause for energy imbalance in humans with Bardet-Biedl syndrome (BBS) has not been established. We therefore compared hyperphagic symptoms in patients with BBS vs. controls. METHODS: We studied 13 patients with BBS and 23 non-syndromic controls with similar age, sex and body mass index (BMI) z-score. A 13-item hyperphagia questionnaire was completed by patients' parents/guardians. RESULTS: Total hyperphagia questionnaire score was higher in BBS than controls (27.6 ± 9.0 vs. 19.1 ± 7.9, P = 0.005). Behaviour and drive subscales were higher for BBS than controls (12.5 ± 4.1 vs. 7.8 ± 3.2, P = 0.001, and 11.2 ± 4.1 vs. 8.3 ± 3.8, P = 0.04, respectively); severity was not significantly different between groups (3.8 ± 1.5 vs. 3.0 ± 1.3, P = 0.072). After adjustment for demographic variables and BMI z-score, total and behaviour subscale scores remained significantly different between groups, suggesting food-seeking activity, rather than preoccupation with food may be the main hyperphagic feature among patients with BBS. CONCLUSION: Appetite dysregulation may contribute to obesity in BBS.

Risk of prostate cancer death in long-term users of warfarin: a population-based case-control study.

PURPOSE: Recent evidence suggests that warfarin use may be associated with a reduced risk of prostate cancer. We aimed to determine whether exposure to warfarin is also associated with a reduced risk of prostate cancer death. METHODS: A nested case-control study was conducted within a population-based cohort of 10,012 men aged ≥50 years with newly diagnosed prostate cancer between 1985 and 2002 and with no history of cancer since 1970 using the linked records of Saskatchewan Health and Saskatchewan Cancer Agency registry. We identified 2,309 cases who died of prostate cancer during follow-up. For each case, one control alive at the time of the case's death and matched for length of follow-up (±6 months) was randomly selected. Prescription counts were used to define warfarin exposure. Multivariate conditional logistic regression analysis was used to calculate the adjusted incidence rates of prostate cancer death in relation to warfarin use while adjusting for confounding by age, year of prostate cancer diagnosis, clinical stage and grade of cancer at diagnosis, Chronic Disease Score, and use of warfarin before diagnosis. RESULTS: Ever use of warfarin following a diagnosis of prostate cancer was associated with an adjusted rate ratio of 1.44 (95 % confidence interval (CI) 1.33-1.84) for prostate cancer death. The adjusted rate ratio with one-year use of warfarin was 1.77 (95 % CI 1.25-2.50) compared to never use. The unadjusted rate ratio with five-year use of warfarin was 0.64 (95 % CI 0.40-1.00) and remained unchanged in the adjusted analysis (0.65, 95 % CI 0.37-1.13), although no longer statistically significant. CONCLUSION: Our study does not provide conclusive evidence for a protective effect of long-term warfarin on prostate cancer-specific mortality. Moreover, short-term warfarin use may be associated with an increased risk of prostate cancer death.