Comparative assessment of radiation therapy-induced vasculitis using [18F]FDG-PET/CT in patients with non-small cell lung cancer treated with proton versus photon radiotherapy.

PURPOSE: To assess radiation therapy (RT)-induced vasculitis in patients with non-small cell lung cancer (NSCLC) by examining changes in the uptake of 18F-fluoro-D-deoxyglucose ([18F]FDG) by positron emission tomography/computed tomography (PET/CT) images of the ascending aorta (AA), descending aorta (DA), and aortic arch (AoA) before and after proton and photon RT. METHOD: Thirty-five consecutive locally advanced NSCLC patients were definitively treated with proton (n = 27) or photon (n = 8) RT and concurrent chemotherapy. The patients were prospectively enrolled to undergo [18F]FDG-PET/CT imaging before and 3 months after RT. An adaptive contrast-oriented thresholding algorithm was applied to generate mean standardized uptake values (SUVmean) for regions of interest (ROIs) 3 mm outside and 3 mm inside the outer perimeter of the AA, DA, and AoA. These ROIs were employed to exclusively select the aortic wall and remove the influence of blood pool activity. SUVmeans before and after RT were compared using two-tailed paired t-tests. RESULTS: RT treatments were associated with increased SUVmeans in the AA, DA, and AoA-1.9%, 0.3%, and 1.3% for proton and 15.8%, 9.5%, and 15.5% for photon, respectively. There was a statistically significant difference in the ∆SUVmean (post-RT SUVmean - pre-RT SUVmean) in patients treated with photon RT when compared to ∆SUVmean in patients treated with proton RT in the AA (p = 0.043) and AoA (p = 0.015). There was an average increase in SUVmean that was related to dose for photon patients (across structures), but that was not seen for proton patients, although the increase was not statistically significant. CONCLUSION: Our results suggest that patients treated with photon RT for NSCLC may exhibit significantly more RT-induced inflammation (measured as ∆SUVmean) in the AA and AoA when compared to patients who received proton RT. Knowledge gained from further analyses in larger cohorts could aid in treatment planning and help prevent the significant morbidity and mortality associated with RT-induced vascular complications. TRIAL REGISTRATION: NCT02135679.

Sidestream Dark Field (SDF) imaging of oral microcirculation in the assessment of systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is a systemic disease characterised by abnormalities in small blood vessels, skin and organ fibrosis. It is assessed using generalised skin thickening scores, autoantibodies and nailfold capillaroscopy. Sidestream Dark Field imaging (SDF) is a non-invasive imaging tool that assesses microcirculation. This study aims to investigate the potential of using SDF as a diagnostic tool in SSc. METHOD: Oral microcirculation of 20 patients with SSc was compared to 20 age and gender matched controls using SDF imaging. Sublingual, buccal and incisor regions of the mouth were examined. All volunteers were female averaging 48.0 (24-64) years old. Vasculature was assessed by calculating the De Backer score and Functional Capillary Density (FCD) on an imaging software. RESULTS: At all regions of the mouth, SSc patients had a significantly lower De Backer score compared to controls (SSc 3.484 ±â€¯0.1361/mm vs Control 5.184 ±â€¯0.1896/mm, unpaired t-test p < 0.0001). The SSc patients showed significantly lower FCDs compared to controls at all areas as well (SSc 19.65 ±â€¯0.9445% vs Control 29.45 ±â€¯1.681%, unpaired t-test, p < 0.0001). The incisor regions had significantly higher De Backer and FCD scores than buccal and sublingual regions in both control and SSc patients (one way anova, p < 0.05). De Backer/FCD scores showed significant correlation against Rodnan Skin Scores in patients with SSc (Pearson correlation, p < 0.05). CONCLUSIONS: SSc patients showed decreased oral vasculature compared to controls. SDF imaging has shown the ability to be a useful diagnostic tool in the assessment of SSc.

Computerised analysis of intrapartum fetal heart rate patterns and adverse outcomes in the INFANT trial.

OBJECTIVE: To assess if a computerised decision support system reliably identified abnormal fetal heart rate (FHR) patterns in fetuses with adverse neonatal outcomes in the INFANT trial, and whether its use reduced substandard care. DESIGN: Prospective cohort study within a randomised controlled trial. SETTING: Twenty-four maternity units in the UK and Ireland. POPULATION OR SAMPLE: A total of 46 614 labours between January 6 2010 and August 31 2013 in the INFANT trial. METHODS: Panel review of intrapartum and neonatal care in infants with adverse outcome, and an assessment of the effectiveness of computerised interpretation of fetal heart rate in reducing substandard care. Descriptive analysis of other factors associated with adverse outcome. MAIN OUTCOME MEASURES: Incidence and detection rate of abnormal fetal heart rate patterns, other characteristics associated with perinatal adverse outcome, and frequency of substandard care. RESULTS: Computer interpretation of FHR patterns was deemed to be completely valid in only 24 of 71 (33.8%) cases of adverse outcome. On a scale of 0-10 (completely invalid to completely valid), 28 cases (39.4%) had a score of 6 or less, mainly due to lack of recognition of decelerations (15 cases), or reduced variability (seven cases), or failure to recognise tachysystole (five cases). There were multiple associated factors that modified the clinical assessment of FHR patterns. There was substandard care in 45/71 cases (63%). CONCLUSION: A significant proportion of abnormal fetal heart rate patterns were not detected accurately by computer analysis, and its use did not reduce the incidence of substandard care. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme (project number 06.38.01). TWEETABLE ABSTRACT: Improved recognition of abnormal fetal heart rate patterns is insufficient to reduce the incidence of substandard care.

Factors influencing health-related quality of life in patients with Type 1 diabetes.

AIMS: Generic, preference-based measures of health-related quality of life (HRQoL) are a common input to the economic evaluation of new health technologies. As such, it is important to explore what characteristics of patients with Type 1 diabetes might impact scores on such measures. METHODS: This study utilizes baseline data from a cluster-randomized trial that recruited patients with Type 1 diabetes at six centers across Ireland. Health-related quality of life was assessed using the three-level EuroQol EQ-5D (EQ-5D) measure. Patients' responses to individual dimensions of the EQ-5D were explored. To see which patient factors influenced EQ-5D scores, multivariate regression analysis was conducted with EQ-5D scores as the outcome variable. RESULTS: Data was available for 437 Type 1 diabetes patients. The median age of these patients was 40 (IQR: 31-49) years and 53.8% were female. Overall, patients reported a high HRQoL based on EQ-5D scores (0.87 (SD: 0.19). Fifty-four percent of patients reported a perfect HRQoL. For those that reported problems, the most common dimension was the anxiety/depression dimension of the EQ-5D (29.6%). In the multivariate regression analysis, self-reported mental illness (- 0.22 (95% CI: -0.34, - 0.10)) and being unemployed (- 0.07 (95% CI: -0.13, - 0.02)) were negatively associated with EQ-5D scores (p < 0.05). The influence of self-reported mental illness was persistent in sensitivity analyses. CONCLUSIONS: The study results indicate that patients with Type 1 diabetes report a high HRQoL based on responses to the EQ-5D. However, there are a substantial number of Type 1 diabetes patients that report problems in the anxiety/depression dimension, which may provide avenues to improve patients' HRQoL. TRIAL REGISTRATION: Current Controlled Trials ISRCTN79759174 .

Biases introduced by filtering electronic health records for patients with "complete data".

OBJECTIVE: One promise of nationwide adoption of electronic health records (EHRs) is the availability of data for large-scale clinical research studies. However, because the same patient could be treated at multiple health care institutions, data from only a single site might not contain the complete medical history for that patient, meaning that critical events could be missing. In this study, we evaluate how simple heuristic checks for data "completeness" affect the number of patients in the resulting cohort and introduce potential biases. MATERIALS AND METHODS: We began with a set of 16 filters that check for the presence of demographics, laboratory tests, and other types of data, and then systematically applied all 216 possible combinations of these filters to the EHR data for 12 million patients at 7 health care systems and a separate payor claims database of 7 million members. RESULTS: EHR data showed considerable variability in data completeness across sites and high correlation between data types. For example, the fraction of patients with diagnoses increased from 35.0% in all patients to 90.9% in those with at least 1 medication. An unrelated claims dataset independently showed that most filters select members who are older and more likely female and can eliminate large portions of the population whose data are actually complete. DISCUSSION AND CONCLUSION: As investigators design studies, they need to balance their confidence in the completeness of the data with the effects of placing requirements on the data on the resulting patient cohort.

Gender Differences in Receipt of National Institutes of Health R01 Grants Among Junior Faculty at an Academic Medical Center: The Role of Connectivity, Rank, and Research Productivity.

OBJECTIVE: To determine whether there were gender differences in likelihood of receiving a first National Institutes of Health (NIH) R01 award among 5445 instructors and assistant professors at Harvard Medical School (HMS). MATERIALS AND METHODS: Data on R01 award principal investigators were obtained from NIH ExPORTER and linked with faculty data. Using Cox proportional hazard regression, we examined the association of gender with receipt of first R01 award between 2008 and 2015 accounting for demographics, research productivity metrics, and professional characteristics. RESULTS: Compared to males, females had fewer publications, lower h-index, smaller coauthor networks and were less likely to be assistant professors (p < 0.0001). Four hundred and thirteen of 5445 faculty (7.6%) received their first R01 award during the study period. There was no gender difference in receipt of R01 awards in age-adjusted (hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.70-1.08) or multivariable-adjusted models (HR: 1.07, 95% CI: 0.86-1.34). Compared to white males, there was a nonsignificant 10%, 18%, and 30% lower rate of R01 receipt among white, Asian or Pacific Islander, and underrepresented minority females, respectively. These differences were eliminated in the multivariable-adjusted model. Network reach, age, HMS start year, h-index, academic rank, previous K award, terminal degree, and HMS training were all significant predictors of receiving an R01 award. CONCLUSIONS: A relatively small proportion of HMS junior faculty obtained their first NIH R01 award during the study period. There was no significant gender difference in likelihood of award. However, we are unable to distinguish faculty that never applied from those who applied and were not successful.

The Z0011 Trial: Is this the end of axillary ultrasound in the pre-operative assessment of breast cancer patients?

OBJECTIVES: The Z0011 trial questioned the role of axillary ultrasound (AxUS) in preoperative staging of breast cancer in patients with ≤2 positive sentinel lymph nodes (SLN). The purpose of this study was to correlate the number of abnormal nodes on AxUS with final nodal burden and determine the utility of AxUS with sampling (AxUS + S) in preoperative staging. METHODS: Six hundred and seventy-nine patients underwent pre-operative AxUS. Suspicious nodes were sampled. Negative axillae proceeded to SLN biopsy. The number of abnormal nodes identified on ultrasound and final histology as well as sensitivity and specificity for AxUS + S were calculated. Subgroup analysis was performed on Z0011 eligible patients. RESULTS: Two hundred and ninety-six patients had positive axillary nodes on final histology with 169 detected by AxUS + S (sensitivity 86.2%, specificity 100%, PPV 100 %, NPV 71.9%). Patients with nodal metastases identified by AxUS had a mean burden of 7.3 nodes on histology (1 node on AxUS = 5.2 nodes on histology, 2 nodes on AxUS = 7.5 nodes, >2 nodes = 10.1 nodes). Patients diagnosed on SLNB had a mean burden of 2.2 nodes. CONCLUSION: A single nodal metastasis detected on AxUS + S correlated with a mean of 5.2 nodes on final histology highlighting that AxUS remains essential in guiding appropriate management of the axilla in breast cancer. KEY POINTS: • Axillary ultrasound +/- sampling is an essential technique in preoperative axillary staging. • Axillary ultrasound findings correlate with final histological axillary node disease burden. • Axillary ultrasound can help triage patients who require axillary lymph node dissection. • The role of axillary ultrasound in breast cancer staging continues to evolve.

Structured care of diabetes in general practice: a qualitative study of the barriers and facilitators.

This qualitative study explored general practitioner's and practice nurse's perceptions of barriers and facilitators to the proposed transfer of diabetes care to general practice. Qualitative data were collected through five focus groups. Participants included GPs (n = 55) and practice nurses (n = 11) representing urban (44%), rural (29%) and mixed (27%) practices, in the Irish Mid-West region. Barriers and facilitators were mentioned 631 times (100%). Barriers were mentioned 461 times (73%), facilitators 170 times (27%). The most frequently identified barriers were lack of financial incentive (119/631; 19%), lack of access to secondary resources (93/631; 15%), lack of staff and increased workload (59/631; 9%) and time constraints (52/631; 8%). Identified facilitators were access to secondary care (49/631;7.8%), the holistic nature of general practice and continuity of care (48/631;7.6%). Although many are enthusiastic, there remains significant reluctance among GPs and practice nurses to take responsibility for diabetes care without addressing these barriers.

Prevention and treatment of venous thromboembolism--International Consensus Statement.

The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE).

Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy.

BACKGROUND: The Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Study 403) demonstrated that zoster vaccine was efficacious through 4 years after vaccination. The Short-Term Persistence Substudy (STPS) was initiated after the SPS to further assess the persistence of vaccine efficacy. METHODS: The STPS re-enrolled 7320 vaccine and 6950 placebo recipients from the 38 546-subject SPS population. Methods of surveillance, case determination, and follow-up were analogous to those in the SPS. Vaccine efficacy for herpes zoster (HZ) burden of illness, incidence of postherpetic neuralgia (PHN), and incidence of HZ were assessed for the STPS population, for the combined SPS and STPS populations, and for each year through year 7 after vaccination. RESULTS: In the STPS as compared to the SPS, vaccine efficacy for HZ burden of illness decreased from 61.1% to 50.1%, vaccine efficacy for the incidence of PHN decreased from 66.5% to 60.1%, and vaccine efficacy for the incidence of HZ decreased from 51.3% to 39.6%, although the differences were not statistically significant. Analysis of vaccine efficacy in each year after vaccination for all 3 outcomes showed a decrease in vaccine efficacy after year 1, with a further decline thereafter. Vaccine efficacy was statistically significant for the incidence of HZ and the HZ burden of illness through year 5. CONCLUSIONS: Vaccine efficacy for each study outcome was lower in the STPS than in the SPS. There is evidence of the persistence of vaccine efficacy through year 5 after vaccination but, vaccine efficacy is uncertain beyond that point.

A systematic review of dynamometry and its role in hand trauma assessment.

The dynamometer was developed by American neurologists and came into general use in the late 19th century. It is still used in various ways as a diagnostic and prognostic tool in clinical settings. In this systematic review we assessed in detail the different uses of dynamometry, its reliability, different dynamometers used and the influence of rater experience by bringing together and evaluating all published literature in this field. It was found that dynamometry is applied in a wide range of medical conditions. Furthermore, the great majority of studies reported acceptable to high reliability of dynamometry. Jamar mechanical dynamometer was used most often in the studies reviewed. There were mixed results concerning the effect of rater experience. The factors influencing the results of dynamometry were identified as age, gender, body weight, grip strength, BMI, non/dominant hand, assessing upper/lower limbs, rater and patient's strength and the distance from the joint where the dynamometer is placed. This review provides an understanding of the relevance and significance of dynamometry which should serve as a starting point to guide its use in hand trauma assessment. On the basis of our findings, we suggest that hand dynamometry has a great potential, and could be used more often in clinical practice.

Behavioral and pharmacological assessment of a potential new mouse model for mania.

Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the Clock or DAT genes, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least 2weeks and response to treatments was evaluated. Olanzapine (1mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2-0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.

A phase 2, randomized, double-blind safety and pharmacokinetic assessment of respiratory syncytial virus (RSV) prophylaxis with motavizumab and palivizumab administered in the same season.

BACKGROUND: Respiratory syncytial virus (RSV) is an important pathogen causing annual epidemics of bronchiolitis and pneumonia among infants worldwide. High-risk infants currently receive RSV prophylaxis with palivizumab, a humanized RSV monoclonal antibody (MAb). In preclinical in vitro and in vivo (cotton-rat model) studies, motavizumab, a new RSV MAb, was shown to have greater anti-RSV activity than palivizumab. Motavizumab is currently under review for licensing approval. Since both MAbs may be available concurrently, this study evaluated their safety and tolerability when administered sequentially during the same RSV season. METHODS: Between April 2006 and May 2006, 260 high-risk infants were randomly assigned 1:1:1 to receive monthly intramuscular injections: 2 doses of motavizumab followed by 3 doses of palivizumab (M/P); 2 doses of palivizumab followed by 3 doses of motavizumab (P/M); or 5 doses of motavizumab (control). Adverse events (AEs, serious AEs [SAEs]), development of antidrug antibody (ADA), and serum drug trough concentrations were assessed. RESULTS: Most children received all 5 doses (246/260 [94.6%]) and completed the study (241/260 [92.7%]). While overall AE rates were similar (mostly level 1 or 2 in severity), SAEs and level 3 AEs occurred more frequently in the M/P group (SAEs: 22.9% M/P, 8.4% P/M, 11.8% motavizumab only; level 3 AEs: 15.7% M/P, 6.0% P/M, 6.5% motavizumab only). This trend in AE rates occurred before and after switching from motavizumab to palivizumab, suggesting a cause other than the combined regimen. Frequencies of AEs judged by the investigator to be related to study drug were similar among groups. Two deaths occurred on study (both in the M/P group, before palivizumab administration); neither was considered by the site investigator to be related to study drug. Mean serum drug trough concentrations were comparable among groups; ADA detection was infrequent (5.1% or less of any group). CONCLUSIONS: The conclusions drawn from this study are limited by the small sample size per group. However, within this small study, overall AE rates, serum drug trough concentrations, and development of ADA associated with administering motavizumab and palivizumab sequentially to high-risk children appear comparable to administering motavizumab alone during the same RSV season. TRIAL REGISTRATION: clinicaltrials.gov NCT00316264.

Cost benefit of intermittent pneumatic compression for venous thromboembolism prophylaxis in general surgery.

AIM: In moderate to high-risk general surgical patients, the cost effectiveness of mechanical prophylaxis for venous thromboembolism (VTE) is uncertain. Therefore, we determined the costs and savings of intermittent pneumatic compression (IPC) plus graduated compression stockings (GCS). METHODS: Postoperative VTE events in the absence of prophylaxis, efficacy of prophylaxis and costs of prophylaxis have been obtained from the English literature and Medicare 2004 reimbursement schedule. RESULTS: In 1000 moderate to high risk general surgical patients, in the absence of prophylaxis, the cost of investigating and treating 72 patients with clinical suspicion of DVT and 32 with PE is calculated to be $263,779. This corresponds to a cost of $263 per surgical patient. The cost of IPC combined with TED stockings in 1000 similar patients would be $66 760, and the cost of diagnosis and treatment of the reduced numbers (69% reduction) of clinical VTE is $ 83,574 making a total of $150 344. This means a saving of $133,435 ($263,779 - $150,344) per 1000 patients. This corresponds to a saving of $113 per surgical patient. Sensitivity analysis demonstrates that despite variation in costs or efficacy for IPC plus GCS, marked savings persist. CONCLUSIONS: Prophylaxis with IPC not only prevents VTE but also saves money.

Changing patterns of medication use in patients with rheumatoid arthritis in a Medicaid population.

OBJECTIVE: To examine changes in patterns of medication utilization in patients with RA. METHODS: Data from Tennessee Medicaid (TennCare) databases (1995-2004) were used to identify adults with both a diagnosis of RA and at least one DMARD prescription each year. Annual age-specific utilization of DMARDs, glucocorticoids, NSAIDs and narcotics was measured on the last day of each year to determine the point prevalence of use of these agents. RESULTS: Records from 23 342 patients with treated RA were analysed. Most patients were females (78%) and white (74%). The median age was 57 yrs (interquartile range: 48-65). The proportion of patients who had a current DMARD prescription on the index date increased from 62% in 1995 to 71% in 2004 (P < 0.001). MTX was the most commonly used DMARD. By the end of 2004, 22% of patients had a current prescription for a biologic, and etanercept represented 51% of all biologic therapies. During the study period, the overall utilization of glucocorticoids decreased from 46% to 38% (P < 0.001), whereas NSAID utilization increased from 33% to 38% (P < 0.001), and use of narcotics increased from 38% to 55% (P < 0.001). A secondary analysis that identified RA patients based on diagnosis codes alone, showed similar patterns, but lower DMARD utilization which increased from 33% to 52% overall and from 0% to 16% for biologics. CONCLUSIONS: The utilization of DMARDs increased in TennCare patients with RA, and by 2004, use of biologics was substantial. Although glucocorticoid utilization decreased, use of both NSAIDs and narcotics increased.

Assessment of cell viability in a three-dimensional enzymatically cross-linked collagen scaffold.

Microbial transglutaminase (mTGase) is an enzyme that introduces a covalent bond between peptide bound glutamine and lysine residues. Proteins cross-linked in this manner are often more resistant to proteolytic degradation and show increased tensile strength. This study evaluates the effects of mTGase mediated cross-linking of collagen on the cellular morphology, behaviour and viability of murine 3T3 fibroblasts following their seeding into collagen scaffolds. Additionally, cell mediated scaffold contraction, porosity and level of cross-linking of the scaffold has been analysed using image analysis software, scanning electron microscopy (SEM), colorimetric assays, and Fourier transform infrared spectroscopy (FTIR). We demonstrate that the biocompatibility and cellular morphology, when comparing cultures of fibroblasts integrated in mTGase cross-linked collagen scaffolds with the native collagen counterparts, remained unaffected. It has been also elicited that the structural characteristics of collagen have been preserved while introducing enzymatically resistant covalent bonds.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Lipid-lowering agents and the risk of hip fracture in a Medicaid population.

CONTEXT: Three recent nested case-control studies conducted in automated databases suggest that users of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have a risk of hip and other osteoporotic fractures half that of non-users of any lipid-lowering drug. However, this comparison may be biased by unmeasured factors associated with treated hyperlipidemias. OBJECTIVE: To compare the risk of hip fracture among users of statins and other lipid-lowering agents, which is less susceptible to bias than the comparisons performed in the previous studies. DESIGN AND SETTING: Retrospective cohort study conducted in the Tennessee Medicaid program between 1 January 1989 through 31 December 1998. SUBJECTS: New users of all lipid-lowering drugs and randomly selected non-user controls who at baseline were at least 50 years of age and did not have life threatening illness, nursing home residence, or diagnosed dementia or osteoporosis. There were 12506 persons with new use of statins, 4798 with new use of other lipid lowering drugs, and 17280 non-user controls. MAIN OUTCOME MEASURE: Fracture of the proximal femur (hip), excluding pathological fractures or those resulting from severe trauma. RESULTS: During 66690 person years of follow up, there were 186 hip fractures (2.8 per 1000). Relative to non-users, the adjusted incidence rate ratios (95% confidence interval) were 0.62 (0.45 to 0.85) for statin users and 0.44 (0.26 to 0.95) for other lipid-lowering drugs. When compared directly with the other drugs, the adjusted incidence rate ratio for statins was 1.42 (0.83-2.43). CONCLUSION: These data provide evidence that the previously observed protective effect of statins may be explained by unmeasured confounding factors.

[Treatment of severe intermittent claudication: ORACLE-PGE1 short term study. A randomised 40-week study. Evaluation of efficacy and costs]. / Trattamento della claudicatio intermittens severa: studio ORACLE-PGE1 short term. Registry e studio randomizzato a 40 settimane, valutazione di efficacia e costi.

BACKGROUND: The efficacy and cost of prostaglandin E1 (PGE1) in severe intermittent claudication was studied comparing a long-term protocol (LTP) with a short-term protocol (STP) in a randomised 40-week study. METHODS: Phase 1 was a 2-week run-in phase (no treatment) for both protocols. In LTP, phase 2 was the main treatment phase. Treatment was performed with 2-hour infusions (60 micro g PGE1, 5 days each week for 4 weeks. In phase 3 (4-week interval period), PGE1 was administered twice a week (same dosage). In phase 4 (40 weeks), no PGE1 were used. In STP, phase 2 treatment was performed in two days by a 2-hour infusion (60 micro g PGE1 twice a day in 2 days). The same cycle was repeated every 4 weeks. A treadmill test was performed at inclusion, at the beginning of each phase and at the end of weeks 12, 16, 20 32 and 40. A progressive training plan (walking) and reduction in risk factors plan was used in both groups. RESULTS: Out of the 1276 included patients 1165 completed the study (606 in LTP group; 559 in the STP). Drop-outs were 111. The two groups were comparable in distribution, risk factors and smoking. Intention-to-treat analysis indicated an increase in pain free walking distance (PFWD). The absolute and percent increase in pain-free walking distance (PFWD) was comparable in both LTP and STP groups with a significative increase in TWD at 4 weeks. At 20 and 40 weeks increase was up to 219% in the LTP and 460% in the STP group (p<0.02). Comparable results concerning PFWD were obtained in the two groups. Both treatments were well tolerated. No side effect was observed. Local effects were observed in 8.5% of the treated subjects in the LTP and 4% in the STP. The average cost of the LTP protocol was 8786 Euro. For STP the costs was 946 (10.8% of LTP). For both protocols the cost of the infusion was 24% of the total for the LTP and 35% in the STP. Therefore 75% of the cost is not drug-related. CONCLUSIONS: In conclusion between-group-analysis favours STP considering walking distance and costs. Results indicate good efficacy and tolerability of PGE1 treatment particularly STP.