Summary Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of ...skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00321620 , and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1 months (15·0–19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71–0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 13%) than in the zoledronic acid group (55 6%; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 2% vs 12 1%; p=0·09). Interpretation Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Funding Amgen.
Summary Background For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued ...indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. Methods TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4–16 years and had abnormal TCD flow velocities (≥200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov , number NCT01425307. Findings Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140–146) in children who received standard transfusions and 138 cm/s (135–142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10–8·98). Non-inferiority (p=8·82 × 10−16 ) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five 8% patients with hydroxycarbamide and three events in one 2% patient for transfusions). Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. Funding National Heart, Lung, and Blood Institute, National Institutes of Health.
Background African American men with chronic kidney disease (CKD) progress to end-stage renal disease more rapidly than African American women or whites. Uncontrolled hypertension worsens CKD, and ...disparities in hypertension control may contribute to disparities in CKD progression. Study Design Cross-sectional. Setting & Participants 10,827 individuals with CKD and self-reported hypertension screened in the Kidney Early Evaluation Program. Predictors African American race, sex. Outcomes Hypertension control (blood pressure <130 mm Hg systolic and/or <80 mm Hg diastolic). Measurements Self-report, physical examination (blood pressure), laboratory data (serum creatinine, microalbuminuria by urine dipstick). We calculated estimated glomerular filtration rates by using the 4-variable isotope dilution mass spectrometry Modification of Diet in Renal Disease Study equation. We classified CKD as early (stages 1 to 2) or late (stages 3 to 5) based on estimated glomerular filtration rate and microalbuminuria. Results In individuals with early CKD, African American women (odds ratio OR, 1.47; 95% confidence interval CI, 1.14 to 1.88), white men (OR, 1.85; 95% CI, 1.39 to 2.46), and white women (OR, 1.69; 95% CI, 1.28 to 2.22) had greater odds of hypertension control (blood pressure <130/80 mm Hg) than African American men. In individuals with late CKD, white men (OR, 1.66; 95% CI, 1.10 to 2.52) and white women (OR, 1.67; 95% CI, 1.13 to 2.46) had greater odds of hypertension control than African American men. No differences were seen between African American men and women with late CKD. Limitations No information for medication regimens. Conclusions African American men with CKD have poorly controlled hypertension compared with African American women and whites, particularly in the early stages of disease. Efforts to aggressively treat hypertension in this population may help narrow the race and sex disparities in progression to end-stage renal disease.
...the sensitivity for identification of foods causing EE ranged from 77% to 97%, depending on the food. ...the combination of SPT and APT in designing a diet plan has a high success rate for food ...elimination or food reintroduction in EE with the exception of milk.
Objective
Survival differences in oral cancer between black and white patients have been reported, but the contributing factors, especially the role of stage, are incompletely understood. ...Furthermore, the outcomes for Hispanic and Asian patients have been scarcely examined.
Study Design
Retrospective, population-based national study.
Setting
Surveillance, Epidemiology, and End Results 18 Custom database (January 1, 2010, to December 31, 2014).
Subjects and Methods
In total, 7630 patients with primary squamous cell carcinoma in the oral cavity were classified as non-Hispanic white (white), non-Hispanic black (black), Hispanic, or Asian. Cox regression was used to obtain unadjusted and adjusted hazard ratios (HRs) of 5-year mortality for race/ethnicity with sequential adjustments for stage and other covariates. Logistic regression was used to examine the relationship between race/ethnicity and stage with adjusted odds ratios (aORs).
Results
The cohort consisted of 75.0% whites, 7.6% blacks, 9.1% Hispanics, and 8.3% Asians. Compared to whites, the unadjusted HR for all-cause mortality for blacks was 1.68 (P < .001), which attenuated to 1.15 (P = .039) after adjusting for stage and became insignificant after including insurance. The unadjusted HRs for all-cause mortality were not significant for Hispanics and Asians vs whites. Compared to whites, blacks and Hispanics were more likely to present at later stages (aORs of 2.63 and 1.42, P < .001, respectively).
Conclusion
The greater mortality for blacks vs whites was largely attributable to the higher prevalence of later stages at presentation and being uninsured among blacks. There was no statistically significant difference in mortality for Hispanics vs whites or Asians vs whites.
Objectives The UK Small Aneurysm Trial (UKSAT) and the American Aneurysm Detection and Management (ADAM) trial both concluded that early elective open surgery does not confer any late survival ...advantage in patients with small abdominal aortic aneurysm (AAA) with diameter 4.0 to 5.5 cm. However, two trials of endovascular aneurysm repair in small AAA have started based upon speculation that a sub-group of particularly fit patients, with low operative mortality, may benefit from early intervention. Here we investigate whether the fittest patients from the UKSAT might have benefited from early intervention. Methods A total of 1090 patients randomized into the UKSAT between 1991 and 1995 were followed for an average of 12 years for mortality. Baseline data were used to calculate the Customized Probability Index (CPI), a validated prognostic risk score for operative mortality after elective open aneurysm repair that assigns risk points for history of cardiac, pulmonary, and renal disease and subtracts risk points for use of statins and beta-blockers. Cox regression was used to assess any differences in all-cause or aneurysm-related mortality between policies of early surgery or surveillance across the fitness spectrum. Tests for interaction used CPI scores as a continuous variable but patients also were stratified into tertile groups for descriptive purposes. Hazard ratios were adjusted for age, gender, and aneurysm diameter. Results A total of 714 deaths (95 aneurysm-related) occurred in 8485 person-years (number of patients multiplied by average years of conditional follow-up). The mean (standard deviation SD) CPI score was 8.1 (9.9) with similar scores between randomized groups. The tertile groups had mean (SD) scores of −1.8 (3.7) for the 389 fittest patients, 8.8 (3.3) for the 438 moderately fit, 21.4 (6.6) for the 261 least fit with missing scores in 2 patients. The tests for interaction were non-significant for both all-cause ( P = .176) and aneurysm-related mortality (.178). However, for the least fit patients a survival advantage was seen in the early surgery group; adjusted hazard ratios 0.73 (95% confidence interval CI 0.56-0.96) and 0.46 (95% CI 0.22-0.98) for all-cause and aneurysm-related mortality respectively. Conclusion Early elective surgery did not confer any survival benefit in the fittest patients. On the contrary, the possibility of a survival benefit from early intervention in patients of poor fitness merits further investigation through meta-analysis or validation in other prospective studies.
In 1997, the National Heart, Lung, and Blood Institute of the National Institutes of Health established a Registry to better characterize the demographic, clinical, physiologic and radiographic ...features of patients with lymphangioleiomyomatosis (LAM). Herein we report data collected at enrollment from patients who had either undergone transplant prior to enrollment, underwent transplant during the 5-year study, or were evaluated/wait-listed for lung transplant during the 5-year study.
The LAM Registry enrolled patients from six clinical centers between August 1998 and October 2001. On entry, patients filled-out questionnaires covering their medical history, symptoms, treatment and quality of life (SF-36 and St. George's Respiratory Questionnaire). Enrollees underwent blood laboratory work and testing for arterial blood gases and pulmonary function. Follow-up was done at 6-month and/or yearly intervals. Diagnoses were confirmed by biopsy or typical clinical presentation plus computerized tomography (CT) findings confirmed by independent expert radiologists. A total of 243 women were enrolled. Of these, 13 (5.3%) had been transplanted at time of entry (Group A), 21 (8.6%) were transplanted during the study (Group B), and 48 (19.8%) were either wait-listed for transplant or underwent evaluation after enrollment during the study period (Group C). The remaining 161 (66.3%) registrants were neither considered for nor listed for transplant during the Registry period (Group D).
One-third of patients in a large sample of LAM patients had either been transplanted or were being considered for transplant. At enrollment, patients who had already been transplanted and those not in need of transplant (Groups A and D) had better pulmonary function and quality-of-life scores compared with patients who subsequently underwent lung transplant during the Registry period (Group B).
In this large Registry of LAM patients, lung transplantation appears to be associated both with significantly improved lung function and quality of life compared with patients with advanced disease.
There has been no comparison of concordance rates for residents' and faculty members' interpretations of pulmonary embolism (PE) CT and ventilation/perfusion (V/Q) studies. If significantly different ...rates of agreement are demonstrable, this could influence which test is ordered during off hours. The purpose of this study was to evaluate how the performance of residents compared with that of faculty members in interpreting these two modalities.
Interobserver agreement between preliminary resident reports and final attending radiologist interpretations was calculated retrospectively for PE CT studies (n = 1,179) and V/Q scans (n = 331) interpreted by on-call residents from April 2007 to October 2008. Discordant cases were reviewed for clinical significance and outcomes at 3 months. Interobserver variability was also evaluated relative to residents' training levels and faculty members' years of experience.
Interobserver agreement between faculty members and residents was substantial, at 95% for PE CT (κ = 0.77) and 77.9% for V/Q scans (κ = 0.67). Although changes in interpretation were significantly more common with V/Q scans (22.1% vs 5%; χ(2) < .0001), the rates of clinically significant discrepancy did not differ significantly between the modalities (2.1% for V/Q vs 1.2% for PE CT; χ(2)P = .20). The overall discrepancy rate and the rate of clinically significant discrepancy did not correlate with residents' training levels or faculty members' years of experience.
Concordance rates for residents' interpretations of V/Q scans and PE CT studies were high, and discrepancies resulting in changes in patient management were rare for both modalities. Residents' preliminary interpretations of both modalities are reliable and safe for making initial patient management decisions.
This study aimed to identify possible correlates of putting condoms on after sex has begun and taking them off before sex has ended among male patients of an urban, public sexually transmitted ...disease clinic. Participants responded to a questionnaire and were largely African American men, 18 to 35 years old, who had used a condom during penile-vaginal intercourse at least three times in the past 3 months. In controlled analyses, men who were not highly motivated to use condoms correctly were nearly twice as likely to put a condom on after sex had begun. Men who reported erection loss during sex were about twice as likely to remove condoms before sex ended. Men reporting difficulties with the fit and feel of condoms were 2.5 times more likely to remove condoms early. Identified correlates may be amenable to clinic-based education and counseling augmented by offering a variety of condom brands and sizes to patients.
The current usual interstitial pneumonitis (UIP)/idiopathic pulmonary fibrosis CT scan classification system excludes probable UIP as a diagnostic category. We sought to determine the predictive ...effect of probable UIP on CT scan on histology and the effect of the promoter polymorphism in MUC5B (rs35705950) on histologic and CT scan UIP diagnosis. METHODS The cohort included 201 subjects with pulmonary fibrosis who had lung tissue samples obtained within 1 year of chest CT scan. UIP diagnosis on CT scan was categorized as inconsistent with, indeterminate, probable, or definite UIP by two to three pulmonary radiologists. Tissue slides were scored by two expert pulmonary pathologists. All subjects with available DNA (N = 200) were genotyped for rs35705950. RESULTS The proportion of CT scan diagnoses were as follows: inconsistent with (69 of 201, 34.3%), indeterminate (72 of 201, 35.8%), probable (34 of 201, 16.9%), and definite (26 of 201, 12.9%) UIP. Subjects with probable UIP on CT scan were more likely to have histologic probable/definite UIP than subjects with indeterminate UIP on CT scan (82.4% 28 of 34 vs 54.2% 39 of 72; P = .01). CT scan and microscopic honeycombing were not associated with each other ( P = .76). The minor (T) allele of the MUC5B polymorphism was associated with concordant CT scan and histologic UIP diagnosis ( P = .03). CONCLUSIONS Probable UIP on CT scan is associated with a higher rate of histologic UIP than indeterminate UIP on CT scan suggesting that they are distinct groups and should not be combined into a single CT scan category as currently recommended by guidelines. CT scan and microscopic honeycombing may be dissimilar entities. The T allele at rs35705950 predicts a UIP diagnosis by both chest CT scan and histology.
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