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We evaluated biochemical changes in skeletal muscle of women with breast cancer initiating aromatase inhibitors (AI), including oxidation of ryanodine receptor RyR1 and loss of stabilizing protein calstabin1, and detailed measures of muscle function. Fifteen postmenopausal women with stage I–III breast cancer planning to initiate AI enrolled. Quadriceps muscle biopsy, dual-energy x-ray absorptiometry, isokinetic dynamometry, Short Physical Performance Battery, grip strength, 6-min walk, patient-reported outcomes, and serologic measures of bone turnover were assessed before and after 6 months of AI. Post-AI exposure, oxidation of RyR1 significantly increased (0.23 ± 0.37 vs. 0.88 ± 0.80, p < 0.001) and RyR1-bound calstabin1 significantly decreased (1.69 ± 1.53 vs. 0.74 ± 0.85, p < 0.001), consistent with dysfunctional calcium channels in skeletal muscle. Grip strength significantly decreased at 6 months. No significant differences were seen in isokinetic dynamometry measures of muscle contractility, fatigue resistance, or muscle recovery post-AI exposure. However, there was significant correlation between oxidation of RyR1 with muscle power (r = 0.60, p = 0.02) and muscle fatigue (r = 0.57, p = 0.03). Estrogen deprivation therapy for breast cancer resulted in maladaptive changes in skeletal muscle, consistent with the biochemical signature of dysfunctional RyR1 calcium channels. Future studies will evaluate longer trajectories of muscle function change and include other high bone turnover states, such as bone metastases. [ABSTRACT FROM AUTHOR]

The United States Food and Drug Administration (FDA) implemented "the Program" in 2012 to promote greater transparency and increased communication between the FDA and applicants of New Molecular Entity (NME) New Drug Applications (NDA) and original Biologics License Applications (BLA). We examined 128 publicly available NME NDA and original BLA approval packages reviewed and approved under the Program with the goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor. This research found that the timing of communications between FDA and the Sponsor through the Mid-Cycle Communication (MCC) was consistent with the 21st-century Desk Reference Guide (DRG); 90% of internal FDA Mid-Cycle Meetings, MCCs with the applicant, and corresponding issuance of MCC minutes were within the target date. The content and format of the MCC were also consistent with the DRG and across disciplines. Almost all MCCs reviewed included a discussion on significant review issues, including major safety concerns. FDA's preliminary opinion on the necessity of a Risk Evaluation and Mitigation Strategy (REMS), which was predictive of REMS requirement at approval. The FDA's MCC comment on advisory committee meeting plans was highly predictive; if the MCC indicated an AC was planned, an AC meeting was held 91% of the time. With respect to the MCC, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the review of a NME NDA or original BLA. [ABSTRACT FROM AUTHOR]

Little is known about the influence of social and environmental contexts on Latino hypertension-related disparities. This study examined the influence of social determinants of cardiovascular health on medically treated hypertension, contrasting established vs. new Latino destination states. Logistic regression models were fitted to analyze 2017 Behavioral Risk Factors Surveillance Survey data from 8,999 Latinos. Overall, 70.4% indicated having treated hypertension. History of diabetes (OR = 2.60) and access to healthcare (OR = 2.38) were associated with treated hypertension, regardless of destination state. In established destinations, Latinos who graduated high school (OR = 1.19) or attended college (OR = 1.32) had higher odds of treated hypertension; whereas those who completed college were less likely to have treated hypertension (OR = 0.80). In contrast, in both new and non-destination states, the odds of treated hypertension were consistently lower across levels of educational attainment. Results highlight the need for cardiovascular-risk reduction interventions to incorporate the social and environmental context in the development process. [ABSTRACT FROM AUTHOR]

The United States Food and Drug Administration (FDA) implemented the PDUFA V New Molecular Entity (NME) Program (the Program) in 2012 to promote greater transparency and increased communication between the FDA review team and applicants of NME New Drug Applications (NDA) and original Biologics License Applications (BLA). We reviewed 128 publicly available NME NDA and original BLA approval packages, submitted after October 2012 and approved by July 2018. Our research had a goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor for approved drugs reviewed under the Program. This research found that communications issued within the first 74 days were consistent with the 21st Century Desk Reference Guide (DRG) targets; forecasted dates of other projected interactions included in the Filing Communication (FC) letter were often within 4 weeks of target. The content and format of the FC letter became more consistent with time, often including templated text. Approximately half the FC letters contained at least 1 filing review issue; however, not all appeared to be substantive. The FDA's preliminary comment on advisory committee meeting plans were predictive; 95% correlated with the need (or lack thereof) for an advisory committee meeting. Approximately 62% of FC letters contained actionable labeling comments, with nearly all related to editorial changes. With respect to the FC letter, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the filing and review of a NME NDA or original BLA. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials have evaluated the efficacy of low-dose CT (LDCT) lung cancer screening on lung cancer (LC) outcomes. Objective: Meta-analyze LDCT lung cancer screening trials. Methods: We identified studies by searching PubMed, Google Scholar, the Cochrane Registry, ClinicalTrials.gov, and reference lists from retrieved publications. We abstracted data on study design features, stage I LC diagnoses, LC and overall mortality, false positive results, harm from invasive diagnostic procedures, overdiagnosis, and significant incidental findings. We assessed study quality using the Cochrane risk-of-bias tool. We used random-effects models to calculate relative risks and assessed effect modulators with subgroup analyses and meta-regression. Results: We identified 9 studies that enrolled 96,559 subjects. The risk of bias across studies was judged to be low. Overall, LDCT screening significantly increased the detection of stage I LC, RR = 2.93 (95% CI, 2.16–3.98), I2 = 19%, and reduced LC mortality, RR = 0.84 (95% CI, 0.75–0.93), I2 = 0%. The number needed to screen to prevent an LC death was 265. Women had a lower risk of LC death (RR = 0.69, 95% CI, 0.40–1.21) than men (RR = 0.86, 95% CI, 0.66–1.13), p value for interaction = 0.11. LDCT screening did not reduce overall mortality, RR = 0.96 (95% CI, 0.91–1.01), I2 = 0%. The pooled false positive rate was 8% (95% CI, 4–18); subjects with false positive results had < 1 in 1000 risk of major complications following invasive diagnostic procedures. The most valid estimates for overdiagnosis and significant incidental findings were 8.9% and 7.5%, respectively. Discussion: LDCT screening significantly reduced LC mortality, though not overall mortality, with women appearing to benefit more than men. The estimated risks for false positive results, screening complications, overdiagnosis, and incidental findings were low. Long-term survival data were available only for North American and European studies limiting generalizability. [ABSTRACT FROM AUTHOR]

Our analysis shows that some clinicians are recognizing fracture, disease severity, and back pain as osteoporosis risk and appropriately managing osteoporosis. The Veterans Health Administration cares for more than 200,000 men living with prostate cancer.[1] Many Veterans receive androgen deprivation therapy (ADT) for their PCa and while ADT can improve PCa clinical outcomes, it can also reduce bone density. [Extracted from the article]

Objectives: Post-imaging mathematical prediction models (MPMs) provide guidance for the management of solid pulmonary nodules by providing a lung cancer risk score from demographic and radiologists-indicated imaging characteristics. We hypothesized calibrating the MPM risk score threshold to a local study cohort would result in improved performance over the original recommended MPM thresholds. We compared the pre- and post-calibration performance of four MPM models and determined if improvement in MPM prediction occurs as nodules are imaged longitudinally. Materials and methods: A common cohort of 317 individuals with computed tomography-detected, solid nodules (80 malignant, 237 benign) were used to evaluate the MPM performance. We created a web-based application for this study that allows others to easily calibrate thresholds and analyze the performance of MPMs on their local cohort. Thirty patients with repeated imaging were tested for improved performance longitudinally. Results: Using calibrated thresholds, Mayo Clinic and Brock University (BU) MPMs performed the best (AUC = 0.63, 0.61) compared to the Veteran's Affairs (0.51) and Peking University (0.55). Only BU had consensus with the original MPM threshold; the other calibrated thresholds improved MPM accuracy. No significant improvements in accuracy were found longitudinally between time points. Conclusions: Calibration to a common cohort can select the best-performing MPM for your institution. Without calibration, BU has the most stable performance in solid nodules ≥ 8 mm but has only moderate potential to refine subjects into appropriate workup. Application of MPM is recommended only at initial evaluation as no increase in accuracy was achieved over time. Key Points: • Post-imaging lung cancer risk mathematical predication models (MPMs) perform poorly on local populations without calibration. • An application is provided to facilitate calibration to new study cohorts: the Mayo Clinic model, the U.S. Department of Veteran's Affairs model, the Brock University model, and the Peking University model. • No significant improvement in risk prediction occurred in nodules with repeated imaging sessions, indicating the potential value of risk prediction application is limited to the initial evaluation. [ABSTRACT FROM AUTHOR]

Given the relatively small impact of prostate cancer screening on cancer mortality, experts are now suggesting that chemoprevention with 5-alpha-reductase inhibitors (5-ARI) may be a more effective strategy for cancer control. Two large placebo-controlled randomized trials found that men receiving 5-ARI were about 25% less likely than controls to be detected with cancer. However, most cancers were detected on routine biopsies required by study protocols. The benefit from receiving 5-ARI was minimal among men who underwent biopsy for clinical indications. Additionally, men receiving 5-ARI were more likely than controls to be diagnosed with high-grade cancers, though post-hoc analyses adjusting for biases accounted for the excess risk in one of the studies. A recent guideline recommended that men considering prostate cancer screening also consider chemoprevention. The rationale is that reducing cancer incidence, given the known risks for overdiagnosis and subsequent overtreatment, is sufficient justification for chemoprevention. However, a large randomized controlled trial found that screening was associated with a 70% increase in prostate cancer diagnosis--which chemoprevention would then reduce by 25%. This does not seem an acceptable trade-off especially because the potential increased risk for high-grade cancers could lead to higher cancer mortality. [ABSTRACT FROM AUTHOR]

Background: The occurrence and timing of prostate biopsy following an elevated prostate-specific antigen (PSA) test varied considerably in randomized screening trials.Objective: Examine practice patterns in routine clinical care in response to an elevated PSA test (≥4 ng/μl) and determine whether time to biopsy was associated with cancer stage at diagnosis.Design: Retrospective cohort study.Participants: All veterans (n=13,591) in the Pacific Northwest VA Network with a PSA ≥4 ng/μl between 1998 and 2006 and no previous elevated PSA tests or prostate biopsy.Main Measures: We assessed follow-up care including additional PSA testing, urology consults, and biopsies. We compared stage at diagnosis for men who were biopsied within 24 months vs. those men biopsied and diagnosed>24 months after the elevated PSA test.Key Results: Two-thirds of patients received follow-up evaluation within 24 months of the elevated PSA test: 32.8% of men underwent a biopsy, 15.5% attended a urology visit but were not biopsied, and 18.8% had a subsequent normal PSA test. Younger age, higher PSA levels, more prior PSA tests, no co-payment requirements, existing urologic conditions, low body mass index, and low comorbidity scores were associated with more complete follow-up. Among men who underwent radical prostatectomy, a delayed diagnosis was not significantly associated with having a pathologically advanced-stage cancer (T3/T4), although we found an increased likelihood of presenting with stage T2C relative to stage T2A or T2B cancer.Conclusions: Follow-up after an elevated PSA test is highly variable with more than a third of men receiving care that could be considered incomplete. A delayed diagnosis was not associated with poorer prognosis. [ABSTRACT FROM AUTHOR]

Pendred syndrome is an autosomal recessive disorder characterized by hearing loss and goiter and is caused by bi-allelic mutations (homozygous or compound heterozygous) of the PDS ( SLC26A4) gene. The incidence of Pendred syndrome is 7.5-10/100,000 in the general population, and it carries a 1 % risk of developing thyroid carcinoma. Herein, we report a case of a patient with Pendred syndrome who developed a follicular variant of papillary thyroid carcinoma (FVPTC)-that is approximately at an odd of 1/1,000,000. Targeted next-generation sequencing with ThyroSeq v2 was performed on the tumor, and only a TP53 mutation ( TP53 p.R175H) was identified. The mutation was limited to the tumor nodule of FVPTC as shown by immunohistochemistry. This report represents the first extensive molecular study of a Pendred syndrome-associated thyroid carcinoma. The evidences support that thyroid carcinomas arising from dyshormonogenetic goiter require additional genetic alteration in addition to the purported thyroid-stimulating hormone (TSH) overstimulation. It is intrigue to note that the mutant p53 is involved in the development of a low-grade malignant thyroid tumor as FVPTC in this patient. [ABSTRACT FROM AUTHOR]

BACKGROUND: Guidelines recommend against treating localized prostate cancer (PCa) in men with a greater than 10-year life expectancy. However, physicians have difficulty accurately estimating life expectancy. OBJECTIVE: We used data from a population-based observational study to develop a nomogram to estimate long-term other-cause mortality based on self-reported health status (SRHS), race/ethnicity, and age at diagnosis. DESIGN: This was an observational study. SUBJECTS: Men diagnosed with localized PCa from October 1994 through October 1995 participated in the study. MAIN MEASURES: Initial measures obtained 6 months after diagnosis included sociodemographic and tumor characteristics, treatment, and a single item on the SRHS, with response options ranging from excellent to poor. We used Surveillance, Epidemiology, and End-Results program data to determine date and cause of death through December 2010. We estimated other-cause mortality with proportional hazards survival analyses, accounting for competing risks. KEY RESULTS: We evaluated 2,695 men, of whom 74 % underwent aggressive therapy (surgery or radiotherapy). At the initial survey, 18 % reported excellent (E), 36 % very good (VG), 31 % good (G), and 15 % fair/poor (F/P) health. Healthier men were younger, and more likely to be white, better educated, and to undergo surgery. At follow-up, 44 % of the cohort had died; 78 % of deaths were from causes other than PCa. SRHS predicted other-cause mortality; for men reporting E, VG, G, F/P health, the cumulative incidences of other-cause mortality were 20 %, 29 %, 40 %, and 53 %, respectively, p < 0.001. Compared to a reference of excellent SRHS, multivariable hazard ratios (95 % CI) for other-cause mortality for men reporting VG, G, and F/P health were 1.22 (0.97-1.54), 1.73 (1.38-2.17), and 2.71 (2.11-3.48), respectively. CONCLUSIONS: Responses to a one-item SRHS measure were strongly associated with other-cause mortality 15 years after PCa diagnosis. Men reporting fair/poor health had substantial risks for other-cause mortality, suggesting limited benefit for undergoing aggressive treatment. SRHS can be considered in supporting informed decision-making about PCa treatment. [ABSTRACT FROM AUTHOR]

The incidence of colorectal cancer (CRC) among Hispanics in the state of New Mexico has increased in the past decade while that among whites has declined significantly. Using the 2006 New Mexico Behavioral Risk Factor Surveillance System (BRFSS) survey, we compared CRC screening among Hispanics and whites by gender to examine the influence of demographic, socioeconomic, preventive health, and clinical measures on the utilization of CRC screening. Although we found no ethnic differences in the prevalence of current breast, cervical and cancer screening, Hispanics were less likely to be current with CRC screening than whites. These differences were observed across a range of socioeconomic and other explanatory measures and in both genders. Hispanics also had a higher prevalence of CRC-related risk factors than whites, including inactivity, obesity, and diabetes, and ranked lower for most socioeconomic measures. Adjusting for healthcare coverage, education, and income in logistic regression models eliminated the Hispanic-white differences in CRC screening among men, and substantially reduced but did not eliminate screening differences among women. Innovative methods are needed to reach Hispanics to raise awareness of and participation in CRC screening. Because many CRC risk factors are potentially modifiable, appropriate cultural and linguistic interventions tailored to specific Hispanic subgroups and aimed at promoting CRC screening and reducing CRC risk factors may decrease ethnic disparities in CRC incidence. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although guidelines recommend against prostate-specific antigen (PSA) screening in elderly men with limited life expectancy, screening is common. OBJECTIVE: We sought to identify medical center characteristics associated with screening in this population. DESIGN/PARTICIPANTS: We conducted a prospective study of 622,262 screen-eligible men aged 70+ seen at 104 VA medical centers in 2003. MAIN MEASURES: Primary outcome was the percentage of men at each center who received PSA screening in 2003, based on VA data and Medicare claims. Men were stratified into life expectancy groups ranging from favorable (age 70-79 with Charlson score = 0) to limited (age 85+ with Charlson score ≥1 or age 70+ with Charlson score ≥4). Medical center characteristics were obtained from the 1999-2000 VA Survey of Primary Care Practices and publicly available VA data sources. KEY RESULTS: Among 123,223 (20%) men with limited life expectancy, 45% received PSA screening in 2003. Across 104 VAs, the PSA screening rate among men with limited life expectancy ranged from 25-79% (median 43%). Higher screening was associated with the following center characteristics: no academic affiliation (50% vs. 43%, adjusted RR = 1.14, 95% CI 1.04-1.25), a ratio of midlevel providers to physicians ≥3:4 (55% vs. 45%, adjusted RR = 1.20, 95% CI 1.09-1.32) and location in the South (49% vs. 39% in the West, adjusted RR = 1.25, 95% CI 1.12-1.40). Use of incentives and high scores on performance measures were not independently associated with screening. Within centers, the percentages of men screened with limited and favorable life expectancies were highly correlated ( r = 0.90). CONCLUSIONS: Substantial practice variation exists for PSA screening in older men with limited life expectancy across VAs. The high center-specific correlation of screening among men with limited and favorable life expectancies indicates that PSA screening is poorly targeted according to life expectancy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate whether statin use was associated with recurrent adenomatous polyps. Methods: We conducted a retrospective cohort study. We used electronic health records to evaluate veterans who underwent polypectomy between January 1, 1999 and December 31, 2001 and surveillance colonoscopy by December 2006. We obtained data on pathology, demographics, body mass index, comorbidity, habits, family history, and medications. We used multivariate proportional hazards regression models to analyze data. Results: We evaluated 197 eligible patients from among 821 who underwent colonoscopy during this period; their mean (SD) age was 63.1 (8.8) years, 192 (98%) were men, and 80 (41%) non-Hispanic white. Surveillance colonoscopy was performed after a mean (SD) 1207 (452) days and 108 (55%) patients had recurrent adenomas. During follow-up, 88 (47%) of patients received statins, but use was not protective against recurrent adenomas (hazard ratio = 1.36, 95% CI 0.35-8.27). Only number of polyps at initial colonoscopy predicted recurrent adenomas (1.98, 95% CI 1.27-3.08). Conclusions: The use of statins was not protective against the recurrence of adenomatous polyps. [ABSTRACT FROM AUTHOR]

Sex differences in muscle fatigue-resistance have been observed in a variety of muscles and under several conditions. This study compared the time to task failure (TTF) of a sustained isometric elbow extensor (intensity 15% of maximal strength) contraction in young men (n = 12) and women (n = 11), and examined if their neurophysiologic adjustments to fatigue differed. Motor-evoked potential amplitude (MEP), silent period duration, interference electromyogram (EMG) amplitude, maximal muscle action potential (M (max)), heart rate, and mean arterial pressure were measured at baseline, during the task, and during a 2-min ischemia period. Men and women did not differ in TTF (478.2 +/- 31.9 vs. 500.4 +/- 41.3 s; P = 0.67). We also performed an exploratory post hoc cluster analysis, and classified subjects as low (n = 15) or high endurance (n = 8) based on TTF (415.3 +/- 16.0 vs. 626.7 +/- 25.8 s, respectively). The high-endurance group exhibited a lower MEP and EMG at baseline (MEP 16.3 +/- 4.1 vs. 37.2 +/- 3.0% M (max), P < 0.01; EMG 0.98 +/- 0.18 vs. 1.85 +/- 0.26% M (max), P = 0.03). These findings suggest no sex differences in elbow extensor fatigability, in contrast to observations from other muscle groups. The cluster analyses results indicated that high- and low-endurance groups displayed neurophysiologic differences at baseline (before performing the fatigue task), but that they did not differ in fatigue-induced changes in their neurophysiologic adjustments to the task. [ABSTRACT FROM AUTHOR]

We performed two experiments to describe the magnitude of delayed-onset muscle soreness (DOMS) associated with blood flow restriction (BFR) exercise and to determine the contribution of the concentric (CON) versus eccentric (ECC) actions of BFR exercise on DOMS. In experiment 1, nine subjects performed three sets of unilateral knee extension BFR exercise at 35% of maximal voluntary contraction (MVC) to failure with a thigh cuff inflated 30% above brachial systolic pressure. Subjects repeated the protocol with the contralateral limb without flow restriction. Resting soreness (0-10 scale) and algometry (pain-pressure threshold; PPT) were assessed before and 24, 48 and 96 h post-exercise. Additionally, MVC and vastus lateralis cross-sectional area (CSA) were measured as indices of exercise-induced muscle damage. At 24-h post-exercise, BFR exercise resulted in more soreness than exercise without BFR (2.8 +/- 0.3 vs 1.7 +/- 0.5) and greater reductions in PPT (15.2 +/- 1.7 vs. 20 +/- 2.3 N) and MVC (14.1 +/- 2.5% decrease vs. 1.5 +/- 4.5% decrease) (p

Colorectal cancer can be prevented via screening by the detection and removal of colorectal adenomas. Few data exist on screening capacity by rural/urban areas. Therefore, the aims of this work were to evaluate current colorectal cancer endoscopy screening capacity and to estimate potential volume for rural and urban regions in Arizona. Gastroenterologists and colorectal surgeons practicing in Arizona completed a survey ( n = 105) that assessed current colonoscopy and sigmoidoscopy screening and estimated future capacity. Resources needed to increase capacity were identified, and differences between rural and urban regions were examined. Responders were more likely to practice in an urban region (89.5%). Physicians reported performing 8,717 endoscopic procedures weekly (8,312 in urban and 405 in rural regions) and the vast majority were colonoscopies (91% in urban and 97% in rural regions). Urban physicians estimated being able to increase their capacity by 35.7% (95% confidence interval 34.7–35.7) whereas rural physicians estimated an increase of 53.1% (95% confidence interval 48.1–58.0). The most commonly cited resource needed to increase capacity was a greater number of physicians in urban regions (52.1%); while the top response in rural areas was appropriate compensation (54.6%). Lastly, 27.3% of rural physicians noted they did not need additional resources to increase their capacity. In conclusion, Arizona has the ability to expand colorectal cancer screening endoscopic capacity; this potential increase was more pronounced in rural as compared to urban regions. [ABSTRACT FROM AUTHOR]

The value of self-monitoring blood glucose (SMBG) in type 2 diabetes is controversial. To determine SMBG testing rates are positively associated with glycemic control in veterans on oral hypoglycemic agents (OHA). Observational database study. Southwestern Healthcare Network veterans taking OHA in 2002 and followed through the end of 2004. OHA and glucose test strip (GTS) prescriptions were derived from pharmacy files. Subjects were categorized into five groups according to their end-of-study treatment status: group 1 (no medication changes), group 2 (increased doses of initial OHA), group 3 (started new OHA), group 4 (both OHA interventions), and group 5 (initiated insulin). We then used multiple linear regression analyses to examine the relationship between the SMBG testing rate and hemoglobin A1c (HbA1c) within each group. We evaluated 5,862 patients with a mean follow-up duration of 798 ± 94 days. Overall, 44.2% received GTS. Ultimately, 47% of subjects ended up in group 1, 21% in group 2, 9% in group 3, 8% in group 4, and 16% in group 5. A univariate analysis showed no association between the SMBG testing rate and HbA1c. However, after stratifying by group and adjusting for initial OHA dose, we found that more frequent testing was associated with a significantly lower HbA1c in groups 1, 4, and 5. The effect ranged from −0.22% to -0.94% for every ten GTS/week. Higher SMBG testing rates were associated with lower HbA1c, but only when stratifying the analyses to control for treatment intensification. [ABSTRACT FROM AUTHOR]

BACKGROUND: The use of androgen deprivation therapy (ADT) for prostate cancer has increased substantially in recent years. exposing more men to potential treatment complications, including osteoporosis and fractures. OBJECTIVE: To determine whether men treated with ADT for prostate cancer received osteoporosis screening, prevention, or treatment. DESIGN: Cross-sectional observational study using a retrospective review of electronic medical records. SUBJECTS: One hundred seventy-four patients with prostate cancer on ADT or status-post orchiectomy enrolled in primary care at the New Mexico Veterans Affairs Health Care System as of July 2005. MEASUREMENTS: Patient demographics, tumor characteristics (Gleason score, stage, last PSA value, documented bone metastases), history of hip or vertebral fracture, osteoporosis risk factors (number of ADT shots, diabetes, smoking, heavy alcohol use or prescriptions for corticosteroids, thyroid hormone or dilantin). We defined recommended management as performing DXA scans or prescribing bisphosphonates, calcitonin, calcium or vitamin D. RESULTS: Just 60 of 174 (34%) patients received recommended osteoporosis management based on DXA scans (13%) or treatment with oral or IV bisphosphonates (21%), calcitonin (1%), calcium (16%) or vitamin D (10%). On multivariate analysis, bone metastases, higher last PSA, and younger age at diagnosis were associated with recommended management, whereas Hispanic race/ethnicity was inversely associated. CONCLUSIONS: Most men treated with ADT for prostate cancer did not receive osteoporosis screening, prevention or treatment. Evidence for advanced cancer though not risk factors for osteoporosis or fracture—was associated with receiving osteoporosis management. Further research is needed to identify optimal strategies for screening, prevention, and treatment in this population. [ABSTRACT FROM AUTHOR]

Background: Screening elderly men for prostate cancer is not recommended because definitive treatments are unlikely to extend life expectancy.Objective: Describe clinical outcomes after a negative prostate biopsy in a population-based cohort of men ages 65 and older.Design: Retrospective cohort study.Participants: 9,410 Medicare-eligible men who underwent a prostate biopsy in Los Angeles or New Mexico in 1992.Measurements: We used Medicare and SEER databases to identify a cohort with an initial negative biopsy (n = 7,119) and to ascertain survival, subsequent PSA testing, prostate biopsies, and prostate cancer detection and treatment through 1997.Results: The overall 5-year survival was 79.4% (95% CI 78.4-80.3), but only 74.6% (72.4-76.7) for men ages 75-79 at the time of the initial negative biopsy and 55.0% (51.9-57.9) for men ages 80+. During a median 4.5 years follow-up, a cumulative 75.0% (73.9-76.1) of the cohort underwent PSA testing. Among men ages 75-79 and 80+, the cumulative proportions that underwent PSA testing were 75.4% (73.0-77.8) and 74.3% (71.1-77.5), respectively. Additionally, 29.1% (26.7-31.6) of men ages 75-79 and 20.1% (17.6-23.1) of men ages 80+ underwent repeat prostate biopsy, and 10.9% (9.4-12.7) and 8.3% (6.6-10.4), respectively, were diagnosed with cancer. Among men ages 75+ with localized cancers, approximately 34% received definitive treatment.Conclusions: High proportions of men ages 75+ underwent PSA testing and repeat prostate biopsies after an initial negative prostate biopsy. Given the known harms and uncertain benefits for finding and treating localized cancer in elderly men, most continued PSA testing after a negative biopsy is potentially inappropriate. [ABSTRACT FROM AUTHOR]

Molecular genetic analyses in Schizosaccharomyces pombe rely on selectable markers that are used in cloning vectors or to mark targeted gene deletions and other integrated constructs. In this study, we used genetic mapping data and genomic sequence information to predict the identity of the S. pombe lys2 + gene, which is homologous to Saccharomyces cerevisiae LYS4 +. We confirmed this prediction, showing that the cloned SPAC343.16 gene can complement a lys2-97 mutant allele, and constructed the lys2 +-based cloning vector pRH3. In addition, we deleted the S. pombe his7 + gene with a lys2 +-marked polymerase chain reaction (PCR) product and the S. pombe lys2 + gene with a his7 +-marked PCR product. Strains carrying these deletions of lys2 + or his7 + serve as relatively efficient hosts for the deletion of the ade6 + gene by lys2 +- or his7 +-marked PCR products when compared with hosts carrying lys2 or his7 point mutations. Therefore, these studies provide plasmids and strains allowing the use of lys2 + as a selectable marker, along with improved strains for the use of his7 + to mark gene deletions. [ABSTRACT FROM AUTHOR]

Objective: We examined whether there were racial differences in initial treatment for clinically localized prostate cancer and investigated whether demographic, socioeconomic, clinical, or tumor characteristics could explain any racial differences.Design: Prospective cohort study.Setting: Population-based tumor registries in Connecticut, Los Angeles, and Atlanta.Participants: We evaluated 1144 African-American and non-Hispanic white men, aged 50 to 74 years, with clinically localized cancer diagnosed between October 1994 and October 1995.Measurements and Main Results: We obtained demographic, socioeconomic, and clinical data from patient surveys and medical record abstractions. We reported adjusted percentages for receiving treatment derived from multinomial logistic regression. We found an interaction between race and tumor aggressiveness. Among men with more aggressive cancers (PSA > or = 20 ng/mL or Gleason score > or = 8), African Americans were less likely to undergo radical prostatectomy than non-Hispanic whites (35.2% vs 52.0%), but more likely to receive conservative management (38.9% vs 16.3%, P=.003). Among the 71% of subjects with less aggressive cancers, African Americans and non-Hispanic whites were equally likely to receive either radical prostatectomy or radiation therapy (80.0% vs 84.5%, P=.2).Conclusions: African Americans with more aggressive cancers were less likely to undergo radical prostatectomy and more likely to be treated conservatively. These treatment differences may reflect African Americans' greater likelihood for presenting with pathologically advanced cancer for which surgery has limited effectiveness. Among men with less aggressive cancers-the majority of cases-there were no racial differences in undergoing radical prostatectomy or radiation therapy. [ABSTRACT FROM AUTHOR]

We examined whether there were racial differences in initial treatment for clinically localized prostate cancer and investigated whether demographic, socioeconomic, clinical, or tumor characteristics could explain any racial differences. Prospective cohort study. Population-based tumor registries in Connecticut, Los Angeles, and Atlanta. We evaluated 1144 African-American and non-Hispanic white men, aged 50 to 74 years, with clinically localized cancer diagnosed between October 1994 and October 1995. We obtained demographic, socioeconomic, and clinical data from patient surveys and medical record abstractions. We reported adjusted percentages for receiving treatment derived from multinomial logistic regression. We found an interaction between race and tumor aggressiveness. Among men with more aggressive cancers (PSA ≥ 20 ng/mL or Gleason score ≥ 8), African Americans were less likely to undergo radical prostatectomy than non-Hispanic whites (35.2% vs 52.0%), but more likely to receive conservative management (38.9% vs 16.3%, P= .003). Among the 71% of subjects with less aggressive cancers, African Americans and non-Hispanic whites were equally likely to receive either radical prostatectomy or radiation therapy (80.0% vs 84.5%, P= .2). African Americans with more aggressive cancers were less likely to undergo radical prostatectomy and more likely to be treated conservatively. These treatment differences may reflect African Americans’ greater likelihood for presenting with pathologically advanced cancer for which surgery has limited effectiveness. Among men with less aggressive cancers—the majority of cases—there were no racial differences in undergoing radical prostatectomy or radiation therapy. [ABSTRACT FROM AUTHOR]

Background: Prostate-specific antigen (PSA) levels between 4.0 to 10.0 ng/ml have poor specificity in prostate cancer screening, leading to unnecessary biopsies.Objective: To determine whether the free-to-total PSA ratio (F/T PSA) improved the diagnostic accuracy of these nonspecific PSA levels.Measurements and Main Results: MEDLINE searchedwas from 1986 to 1997. Additional studies were identified from article bibliographies and by searching urology journals. Two investigators independently identified English-language studies providing F/T PSA ratio test-operating characteristics data on > or = 10 cancer patients with PSA values between 2.0 and 10.0 ng/ml. Twenty-one of 90 retrieved studies met selection criteria. Two investigators independently extracted data on methodology and diagnostic performance. Investigator-selected cut points for the optimal F/T PSA ratio had a median likelihood ratio of 1.76 (interquartile range, 1.40 to 2.11) for a positive test and 0.27 (0.20 to 0.40) for a negative test. Assuming a 25% pretest probability of cancer, the posttest probabilities were 37% following a positive test and 8% following a negative test. The summary receiver operating characteristic curve showed that maintaining test sensitivity above 90% was associated with false positive rates of 60% to 90%. Methodologic problems limited the validity and generalizability of the literature.Conclusions: A negative test reduced the posttest probability of cancer to approximately 10%. However, patients may find that this probability is not low enough to avoid undergoing prostate biopsy. The optimal F/T PSA ratio cut point and precise estimates for test specificity still need to be determined. [ABSTRACT FROM AUTHOR]

Presents a population-base survey on prostate cancer testing rates in New Mexico. Use of random-digit dialing; Factors influencing prostate cancer testing; Determination of the link between patient factors and testing using multivariate logistic regression; Predictors for testing; Association between risks for prostate disease, health behaviors and testing.

Discusses the results of a mailed survey of primary care physicians in New Mexico to understand their cancer screening practices. Acceptance of age-appropriate cancer screening as integral part of primary care; Rate of self-reported screening for prostate and colorectal cancer; Screening rates influenced by introduction of evidence-based guidelines.

The worldwide growth of franchising has been phenomenal during the past decade. At the same time there has been increased media attention to questionable business practices in franchising. Similar to some trade associations and professions, franchising has sought self-regulation by developing codes of conduct or ethics. This study examines the codes of ethics covering franchising activities in 21 countries. The results reveal that there is considerable variation in the activities/issues covered by the codes. Specifically, the codes cover most stages of the franchising relationship, focus on a narrow set of stakeholders, are short on ethical guidance, and offer few enforcement provisions. The implications of these findings for international franchising and research are discussed. [ABSTRACT FROM AUTHOR]

Objectives: To characterize prostate-specific antigen (PSA) testing practices in a hospital-based primary care clinic, and to determine the outcomes of PSA testing, including urology referrals, biopsies, cancers detected, and cancer treatments.Design: Retrospective cohort study. Data were obtained from computerized Department of Veterans Affairs (VA) files and the statewide New Mexico Surveillance, Epidemiology, and End Results (SEER) tumor registry.Setting: Primary care clinics in a university-affiliated VA Medical Center.Patients: Subjects were 1,448 men without cancer undergoing PSA testing in 1993 with follow-up through 1994.Main Results: Twenty-one percent of clinic enrollees at least 40 years of age were tested with PSA, including 58 who were 75 years of age or older. By the end of 1994, 40.0% (95% confidence interval [CI] 37.2%, 42.8%) were retested; 25.6% (95% CI 21.7%, 29.5%) of initial retesting occurred within 6 months. Overall, 20.7% (95% CI 18.9%, 22.5%) of PSA tests in the cohort were for men aged 75 years or older and were repeated within 6 months. Among the 193 subjects with PSA values > or = 4.0 ng/mL, 86.0% (95% CI 81.1%, 90.9%) were followed-up in urology clinic, and 46.1% (95% CI 39.1%, 53.1%) underwent biopsy. Only 11 of 51 men aged 75 years or older who were referred to urologists for an elevated PSA underwent biopsy. Forty cancers were diagnosed-a detection rate of 2.8% (95% CI 2.0%, 3.6%). Of these, 28 were organ-confined, 7 had regional invasion, and 3 had distant metastases.Conclusions: Primary care providers frequently ordered PSA tests, but a substantial proportion of testing occurred outside recommended age ranges and screening intervals. Older patients with elevated PSA values often did not complete diagnostic workups. Better adherence to screening guidelines may limit the number of both PSA tests and urology referrals. [ABSTRACT FROM AUTHOR]

Inhibition of growth factor-stimulated DNA synthesis carried out in defined medium is often compared with inhibition of serum-stimulated DNA synthesis so as to assess the selectivity of growth-factor-receptor tyrosine kinase inhibitors such as tyrphostins. We investigated whether protein binding may influence the interpretation of these experiments. Protein binding of tyrphostins was determined by ultrafiltration, equilibrium dialysis or spectrophotometer, and was quantitated by high-performance liquid chromatography (HPLC). For growth factor-stimulated DNA synthesis, we used the non-small-cell lung cancer cell line L23/P stimulated by transforming growth factor alpha (TGF alpha). The epidermal growth factor (EGF)-receptor kinase was assayed by phosphorylation of a peptide substrate or by receptor autophosphorylation. Protein binding of a number of tyrphostins ranged from 64% to 98%. There was a positive correlation (r = 0.995) between the degree of protein binding and the hydrophobicity. Inhibition of the EGF-receptor tyrosine kinase activity by the highly protein-bound tyrphostin B56 [N-(4-phenylbutyl)-3,4-dihydroxybenzylidene cyanoacet-amide] was reduced by bovine serum albumin (BSA), but BSA had less of an effect on inhibition of the EGF-receptor kinase by the weakly protein-bound tyrphostin A47 (RG 50864: 3,4-dihydroxybenzylidene cyanothioacetamide). Tyrphostins B46 [N-(3-phenylpropyl)-3,4-dihydroxybenzylidene cyanoacetamide] and B56 (both highly protein-bound) inhibited DNA synthesis of L23/P cells with approximately 3-fold greater potency in 0.5% serum than in 10% serum, but the inhibition of DNA synthesis in 0.5% serum was reduced by the addition of BSA. Tyrphostins B46 and B56 inhibited DNA synthesis stimulated by TGF alpha in defined medium to a greater extent than DNA synthesis stimulated by serum. However, this apparent selectivity for inhibition of TGF alpha-stimulated DNA synthesis was lost when the protein concentration in the defined medium was made equivalent to that in the serum-containing medium. By contrast, BSA enhanced the selective inhibition of TGF alpha-stimulated DNA synthesis by tyrphostin A47. These results demonstrate that protein binding accounts for the apparent selectivity of some highly protein-bound tyrphostins for TGF alpha-stimulated DNA synthesis of L23/P cells. Therefore, protein binding should be taken into consideration in assessments of the selectivity of tyrphostins. [ABSTRACT FROM AUTHOR]

l-Carrageenan is a polysulphated carbohydrate that antagonises some heparin-binding growth factors. We assessed the effect of l-carrageenan on the proliferation of a panel of cell lines, some of which require heparin-binding growth factors for mitogenesis. The importance of growth factor antagonism for the anti-proliferative activity was also determined. Cell proliferation was determined by cell counts and a tetrazolium dye (MTT) assay, and DNA synthesis was determined by thymidine incorporation. The proliferation of the basic fibroblast growth factor (bFGF)-dependent endothelial cell line FBHE was inhibited by daily administration of l-carrageenan in a dose-dependent manner [concentration inhibiting cell growth by 50% (IC50 value), approx. 0.5 microgram/ml]. However, excess bFGF did not reverse the inhibitory effect. DNA synthesis was completely inhibited by concentrations of l-carrageenan that nonetheless allowed significant protein synthesis to occur. The proliferation of the androgen-dependent prostate-carcinoma cell line LNCaP was also inhibited by l-carrageenan (IC50 value, 5.5 micrograms/ml) and the cells were arrested at the G1/S boundary. l-Carrageenan inhibited DNA synthesis in MCF-7 cells stimulated by bFGF and transforming growth factor alpha (TGF alpha) but not in those stimulated by insulin-like growth factor 1 (IGF-1). Blocking IGF-1-mediated DNA synthesis with anti-IGF-1 receptor antibody alpha IR3 enhanced the inhibitory activity of l-carrageenan against MCF-7 cells grown in serum. A number of other transformed and non-transformed cell lines were either partially inhibited or not inhibited by l-carrageenan. l-Carrageenan had low anti-coagulant activity. l-Carrageenan is a selective anti-proliferative agent and warrants further investigation for anti-angiogenic therapy (in view of its activity against endothelial cells) and for the treatment of androgen-dependent prostate cancer. [ABSTRACT FROM AUTHOR]

Objective: To assess the risks and benefits of surgery for herniated lumbar discs (discectomy) and to evaluate the methodologic quality of the literature. Design: Literature synthesis. Study selection and data analysis: A structured MEDLINE search identified studies of standard, microsurgical, or percutaneous discectomy. Eligible studies had adult subjects, sample sizes of ≥30, clinical outcome data for ≥75% of patients, and follow-up of ≥1 year. Summary rates of successful outcomes, reoperations, and complications were obtained by a random-effects logistic regression model. Methodologic quality was assessed using established study design criteria. Results: Eighty-one studies met inclusion criteria. Most had substantial design flaws and/or omitted important clinical data. Randomized trials of standard discectomy showed better short-term sciatica relief following surgery; 65% to 85% of patients reported no sciatica one year after surgery, compared with only 36% of conservatively treated patients. No data from randomized trials were available for microdiscectomy or percutaneous discectomy, although most outcomes appeared comparable to those of standard discectomy. Approximately 10% of discectomy patients underwent further back surgery, and rates increased over time. The rate of serious complications, including death and permanent neurologic damage, was less than 1%. Conclusions: Most studies were poorly designed and reported. Standard discectomy appears to offer better short-term outcomes than does conservative treatment, but long-term outcomes are similar. Discectomies are relatively safe procedures, though reoperations are common and increase over time. Decisions for elective surgery must balance faster pain relief against the risks and costs of surgery. [ABSTRACT FROM AUTHOR]

The article presents a study on the immune toxicity in humans due to chronic or acute exposure in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at Quail Run Mobile Home Park in Missouri. The study involved in vivo assessment of cellular immune function and T lymphocyte subset analysis to detect TCDD exposure among participants. Results show T cell population and function disturbances in a small percentage of TCDD exposed residents.

The growth of international business (IB) and concerns about the relevance of IB research indicate the need for managerial input on the topic. A survey of 108 U.S. CEOs reveals that IB issues are an important part of their strategic agenda. Four types of IB issues are identified which reveal that American CEOs appear to be taking a proactive stance regarding the international arena. The CEOs were also found to hold diverse perceptions of IB issues. The implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Abstract. The relevance of paradigms focusing on rational and sociopolitical power in strategic decision-making is explored among three country clusters. The predictive validity of a model incorporating political and rational sources of power is established across the clusters. Moreover, country clusters appear to moderate the power relationships. [ABSTRACT FROM AUTHOR]

Presents econometric models that evaluate the return on investment of various risky portfolios. Nature of investment decision; Risk policy; Model for equity investment.

Modulators of protein kinase C (PKC) were used to investigate the role of this enzyme during Adriamycin-induced erythroid differentiation of K562 cells. Adriamycin (0.1 microM) induced erythroid differentiation in 60% +/- 10% of K562 cells. Phorbol myristate-12-acetate, an activator of protein kinase C, was strongly anti-proliferative to K562 cells (IC50, 8 nM) but did not induce erythroid differentiation. Staurosporine inhibited PKC from K562 cells (IC50, 8 nM) and blocked Adriamycin-induced erythroid differentiation, but only at concentrations marginally below those that inhibited proliferation (IC50, 81 nM), 1-(5-Isoquinolinylsulphonyl)-2-methylpiperazine (H-7) inhibited K562 PKC (IC50, 26 microM) but reduced Adriamycin-induced differentiation by less than 50% at concentrations of up to 600 microM. These data argue against a major role for PKC during Adriamycin-induced erythroid differentiation in K562 cells. [ABSTRACT FROM AUTHOR]

A total of 68 patients were treated in a phase I study of meta-azidopyrimethamine ethanesulphonate (MZPES)--a novel lipophilic dihydrofolate reductase (DHFR) antagonist. The dose was increased from 5.4 mg/m2 to 460 mg/m2 given as a 1-h infusion, with 460 mg/m2, 600 mg/m2 and 800 mg/m2 given as a 24-h infusion. The dose-limiting toxicity was nausea and vomiting, which was marked at doses above 360 mg/m2 by 1-h infusion and 600 mg/m2 by 24-h infusion. Above 250 mg/m2 patients also described subjective neurological symptoms, although no objective signs were apparent. Myelosuppression was not consistent at any dose level. No objective responses were seen. In view of the lack of anti-folate activity at toxic levels, no phase II trials are currently proposed; toxicological and in vitro studies will continue. [ABSTRACT FROM AUTHOR]

The article discusses the released of the user's guide for Medical Literature on developing skills in medical care and delivering evidence-base health care. It identifies the issues of unwarranted conclusions of noninferiority intention-to-treat analysis, per-protocol analysis and suboptimal standard treatment. It also notes on the key issue of setting the noninferiority threshold determining the differences in clinical effectiveness.

The article presents the authors' views on the article titled "Provider Recommendations for Colorectal Cancer Screening in Elderly Veterans," by Charles J. Kahi and colleagues published within this issue. According to the authors, Kahi and colleagues did not address whether physicians would emphasize on patient preferences or advocate informed decision-making. The authors opine that optimizing the targeting of cancer screening may require changes in the method of delivery of preventive care.

The author reflects on the creation and purpose of the section "Teaching Tips" of the "Journal of General Internal Medicine." It has been noted by the author that the creation of the section was a proposal from the Evidence Based Medicine Teaching Scripts Working Group. The purpose of the section is to write a series of articles with practical suggestions to clinical educators on how to teach specific topics in evidence based medicine.

The article discusses various reports published within the issue including one by Guerra and colleagues on screening discussions and another by Rimer and colleagues on shared decision making between physician and patient.

The article discusses various reports published within the issue including one that describes the tremendous potential of the biotechnology revolution to improve cancer screening through proteomics and another about the issues of Food and Drug Administration regulation and technology assessment.