Association Between Common Urologic Medications and Onset of Alzheimer's Disease and Related Dementias in Men With Prostate Cancer Managed by Different Primary Treatment Modalities.

OBJECTIVE: To understand the relationship between common urologic medications phosphodiesterase-5 inhibitors (PDE5i) and anticholinergics (AC) and risk of dementia onset in men who underwent different primary treatments for prostate cancer. MATERIALS AND METHODS: Patients (>50years) with prostate cancer (1998-2022) without Alzheimer's disease or related dementias were selected from Cancer of the Prostatic Strategic Urologic Research Endeavor Registry. Minimum medication use was 3months. Fine-Gray regression was performed to determine the association between medication exposure and dementia onset ≥12months after primary treatment in men matched on age, race, comorbid conditions, smoking, and type of clinical site, with competing risk of death. RESULTS: Among 5937 men (53% PDE5i; 14% AC), PDE5i users were younger (63 vs 70, P < .01) with less CAD, CVA, DM (all P < .01); AC users were older (68 vs 66, P < .01) with higher incidence of comorbidities (P < .01). Median months of use was 24.3 (IQR 12.1, 48.7) for PDE5i and 12.2 (IQR 6.1, 24.3) for AC users. Cumulative incidence of Alzheimer's disease or related dementias was 6.5% at 15years. PDE5i (P = .07) and AC (P = .06) were not associated with dementia regardless of primary treatment modality. CONCLUSION: In this retrospective cohort study, PDE5i and AC use do not appear independently associated with risk of dementia. Notably, our cohort was generally healthy and younger which may limit our ability to detect significance. We recommend prospective investigation into association between PDE5i and dementia and advise continued judicious stewardship of AC in older patient populations.

Thermostable variants constructed via the structure-guided consensus method also show increased stability in salts solutions and homogeneous aqueous-organic media.

Enzyme instability is a major factor preventing widespread adoption of enzymes for catalysis. Stability at high temperatures and in the presence of high salt concentrations and organic solvents would allow enzymes to be employed for transformations of compounds not readily soluble in low temperature or in purely aqueous systems. Furthermore, many redox enzymes require costly cofactors for function and consequently a robust cofactor regeneration system. In this work, we demonstrate how thermostable variants developed via an amino acid sequence-based consensus method also showed improved stability in solutions with high concentrations of kosmotropic and chaotropic salts and water-miscible organic solvents. This is invaluable to protein engineers since deactivation in salt solutions and organic solvents is not well understood, rendering a priori design of enzyme stability in these media difficult. Variants of glucose 1-dehydrogenase (GDH) were studied in solutions of different salts along the Hofmeister series and in the presence of varying amounts of miscible organic solvent. Only the most stable variants showed little deactivation dependence on salt-type and salt concentration. Kinetic stability, expressed by the deactivation rate constant k(d,obs), did not always correlate with thermodynamic stability of variants, as measured by melting temperature T(m). However, a strong correlation (R(2) > 0.95) between temperature stability and organic solvent stability was found when plotting T(50)(60) versus C(50)(60) values. All GDH variants retained stability in homogeneous aqueous-organic solvents with >80% v/v of organic solvent.

Cation and strong co-solute effects on protein kinetic stability.

Degradation of proteins is important for the operating life of biocatalysts and the shelf life of protein pharmaceuticals. We have previously found that the deactivating effects of salts on proteins can be correlated to an indicator of ion hydration, the B-viscosity coefficient of the anion in solution. Here, we test the influence of cations on protein kinetic stability by observing deactivation of mRFP (monomeric red fluorescent protein) in ammonium, caesium and chloride salt solutions, and we find that mRFP deactivation does not depend on cation hydration. We also measure mRFP deactivation in solutions containing denaturants (guanidinium chloride or urea) or stabilizing co-solutes (glycerol or sucrose) frequently encountered in many protein formulations to test whether hydration of these co-solutes can be used to indicate their relative effects on protein kinetic stability. We find that mRFP deactivation in solutions containing kosmotropic salts or stabilizers reaches a limiting rate and that hydration of denaturants is not an indicator of their denaturing strength.

Total and specific complementary and alternative medicine use in a large cohort of men with prostate cancer.

OBJECTIVES: To assess specific complementary and alternative medicine (CAM) use in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a large, community-based national registry of men with prostate cancer. METHODS: We examined more than 50 types of CAM use in a large, national, community-based registry of men with prostate cancer (CaPSURE). Participants completed biannual surveys within 2 years of diagnosis and treatment. We analyzed associations of CAM use with sociodemographic and clinical features, using chi-square tests and multivariate logistic regression. RESULTS: One third of 2582 respondents reported using CAM. Common practices included vitamin and mineral supplements (26%), herbs (16%), antioxidants (13%), and CAM for prostate health (12%; eg, saw palmetto, selenium, vitamin E, lycopene). In multivariate analyses, users were more likely to have other comorbid conditions, worse cancer grade at diagnosis, higher incomes, more education, and to live in the West. CONCLUSIONS: Complementary and alternative medicine use was associated with sociodemographic and clinical characteristics in this large sample of men with prostate cancer. These results should be considered by health care professionals counseling men with prostate cancer regarding diet and secondary prevention.

Patient satisfaction with oral versus nonoral therapeutic approaches in onychomycosis.

The follow-up results of a 9-month observational study of 150 onychomycosis patients treated with a variety of mechanical, topical, and oral therapies by podiatric physicians and dermatologists are presented. Changes from baseline in toenail condition and patient satisfaction were assessed at 4- and 9-month follow-up. At 9 months, patients who had received oral therapy reported significantly fewer onychomycosis-related problems in social situations, including embarrassment or self-consciousness about the appearance of nails, avoidance of contact by others, being perceived as unclean or untidy, and the desire to keep their nails concealed. Patient-reported satisfaction with the treatment program was significantly higher for those receiving oral therapy than for those receiving nonoral therapy.

Androgen deprivation therapy for patients with clinically localized (stages T1 to T3) prostate cancer and for patients with biochemical recurrence after radical prostatectomy.

Recently published studies suggest a benefit for androgen deprivation therapy (ADT) delivered early in the course of prostate cancer. However, the use of ADT specifically in patients with clinically localized disease or biochemical-disease recurrence after local therapy is not well defined. Potential candidates for primary ADT include patients who are poor candidates for definitive local therapy because of advanced age or comorbid conditions, as well as patients with significant local disease who refuse standard therapy. Treatment strategies designed to minimize the side effects of prolonged therapy, such as intermittent ADT or antiandrogen monotherapy, show promise as alternatives to continuous ADT in some patients. The role of ADT in patients with clinically localized and recurrent prostate cancer, whether it is delivered in a continuous or intermittent fashion, must be determined in randomized, prospective trials.

Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females.

CONTEXT: Low-grade squamous intraepithelial lesions (LSILs) have been described as a benign cytological consequence of active human papillomavirus (HPV) replication. Several studies have reported that certain behavioral and biological risks exist for LSIL, suggesting that HPV alone is not sufficient for the development of LSIL. However, because most of these studies have been cross-sectional, it is not known whether behavioral and biological risks are simply risks for HPV infection itself. OBJECTIVE: To prospectively examine risks of incident HPV infection in HPV-negative females and of incident LSIL development in females with HPV infection. DESIGN: Prospective cohort study conducted between 1990-2000, with a median follow-up of 50 months. SETTING AND PARTICIPANTS: Females aged 13 to 21 years who attended 2 family planning clinics in the San Francisco bay area; 496 had prevalent HPV infection and 105 were HPV-negative. MAIN OUTCOME MEASURE: Incident development of HPV infection and LSIL, analyzed by various demographic, behavioral, and clinical risk factors. RESULTS: Fifty-four incident HPV infections occurred in the 105 females who were HPV-negative at study entry (median duration of follow-up for those who remained HPV-negative was 26 months). Multivariable analysis showed that risks of HPV included sexual behavior (relative hazard [RH], 10.10; 95% confidence interval [CI], 3.24-31.50 per new partner per month), history of herpes simplex virus (RH, 3.54; 95% CI, 1.37-9.10), and history of vulvar warts (RH, 2.73; 95% CI, 1.27-5.87). Current use of oral contraceptives had a significantly protective effect (RH, 0.49; 95% CI, 0.28-0.86). Among the 496 individuals who were HPV-positive at baseline or in follow-up, there were 109 incident cases of LSIL during the follow-up interval, with a median follow-up time of 60 months for those who never developed LSIL. Human papillomavirus infection was the most significant risk factor for development of LSIL. The multivariable model showed the following risks for LSIL: HPV infection for less than 1 year (RH, 7.40; 95% CI, 4.74-11.57); HPV infection for 1 to 2 years (RH, 10.27; 95% CI, 5.64-18.69); HPV infection for 2 to 3 years (RH, 6.11; 95% CI, 1.86-20.06); and daily cigarette smoking (RH, 1.67; 95% CI, 1.12-2.48). CONCLUSION: Our results indicate distinct risks for HPV and LSIL. In addition, most women with HPV infection in our study did not develop LSIL within a median follow-up period of 60 months. These findings underscore the hypothesis that certain biological risks thought to be associated with LSIL are, in fact, risks for acquisition of HPV. Cigarette smoking was a risk specific to LSIL, supporting the role of tobacco in neoplastic development.

Cost of treatment for onychomycosis. Data from a 9-month observational study.

OBJECTIVES: To estimate component and total costs of treatment and to examine differences in cost and cost effectiveness between oral antifungal medication and local therapy for patients with toenail onychomycosis. DESIGN: Prospective, observational study of patients with onychomycosis who visited dermatologists and podiatrists in the US. Physicians provided data on clinical management, disease severity, nail improvement and resource utilisation. Patients completed questionnaires on resource utilisation and symptoms at base-line, 4 and 9 months. To estimate costs, reported utilisation was multiplied by unit costs expressed in 1997 US dollars ($US) and derived in 2 ways: first, using Medicare fees; and second, using standard physician fees. RESULTS: After adjustment for key demographic and clinical variables, participants receiving oral medication had higher total costs based on standard fees ($US794 vs $US575) and medication costs ($US564 vs $US109), lower procedure costs ($US0 vs $US122) and physician visit costs ($US200 vs $US330), and greater clinical effectiveness as measured by global improvement rating (86 vs 35%) and Toenail Symptom Index (94 vs 49%). For participants receiving oral medication, 90% of total costs were incurred during the first 4 months of follow-up, whereas for those receiving local therapy, costs were more evenly distributed throughout the study period. Incremental cost-effectiveness analysis showed $US304 to $US491 per additional case improved with oral medication over a 9-month timeframe. Extrapolation of these results using 2 time-points (months 4 and 9) suggested that cost equivalence would be reached 17 to 21 months following the initiation of treatment. CONCLUSIONS: During 9 months of follow-up in patients with toenail onychomycosis, the use of oral antifungal medication resulted in superior patient outcomes, but at higher total cost compared with local therapy.

Under staging and under grading in a contemporary series of patients undergoing radical prostatectomy: results from the Cancer of the Prostate Strategic Urologic Research Endeavor database.

PURPOSE: We determined the prevalence of under staging and under grading in contemporary patients undergoing radical prostatectomy in academic and community based urology practices, and defined important predictors of under staging in this population. MATERIALS AND METHODS: We compared clinical T stage and biopsy Gleason score with pathological T stage and prostatectomy Gleason score in 1,313 patients enrolled in the Cancer of the Prostate Strategic Urologic Research Endeavor database, a longitudinal registry of patients with prostate cancer, who underwent radical prostatectomy, including 53% since 1995. Under grading was determined for the primary and secondary Gleason patterns and defined as a biopsy Gleason pattern of 1 to 3 that became pathological Gleason pattern 4 or 5. Under staging was defined as a clinically organ confined tumor that was extraprostatic stages pT3 to 4 or N+ at radical prostatectomy. Univariate and multivariate analysis was performed to determine important risk factors for under staging and significant risk factors were used to identify the likelihood of under staging in clinically relevant patient subgroups. The importance of the percent of positive biopsies in regard to the likelihood of under staging was determined by assigning patients to previously described risk groups based on serum prostate specific antigen (PSA) at diagnosis and biopsy Gleason score. RESULTS: Under grading of primary and secondary Gleason patterns occurred in 13% and 29% of patients, respectively, while under staging occurred in 24%. Univariate and multivariate analysis revealed that PSA at diagnosis, biopsy Gleason score and the percent of positive biopsies were significant predictors of under staging. The percent of positive biopsies appeared to be most important for predicting the likelihood of extraprostatic disease extension in intermediate or high risk disease based on serum PSA at diagnosis and biopsy Gleason grade. CONCLUSIONS: The prevalence of under grading and under staging in contemporary patients undergoing radical prostatectomy may be lower than previously reported. PSA at diagnosis, biopsy Gleason score and the percent of positive biopsies are important predictors of under staging. The percent of positive biopsies should be incorporated into risk assessment models of newly diagnosed prostate cancer.

Does the completeness of prostate sampling predict outcome for patients undergoing radical prostatectomy?: data from the CAPSURE database.

OBJECTIVES: To determine whether more complete sampling of the radical prostatectomy (RP) specimen better predicts outcome after surgery. METHODS: We reviewed pathology reports from 1383 patients enrolled in CaPSURE (a longitudinal registry of patients with prostate cancer) who underwent RP. Specimens were considered step-sectioned only if the entire specimen was submitted for analysis and if sections were taken at 0.5-cm intervals or less. Otherwise, specimens were considered non-step-sectioned. Pathologic stage, Gleason score, surgical margin status, and outcome were compared between groups. Prostate-specific antigen (PSA) recurrence was defined as a PSA level of 0.2 ng/mL or greater on two consecutive occasions after RP. Secondary cancer treatment consisted of radiation or androgen deprivation after RP. Adjuvant treatments occurred within 6 months of RP, and nonadjuvant treatments occurred more than 6 months after RP. Kaplan-Meier event rates of PSA recurrence and secondary treatment were calculated for patients in the step-sectioned and non-step-sectioned groups. RESULTS: No significant differences were found between patients in the step-sectioned and non-step-sectioned groups with respect to pathologic tumor stage, prostatectomy Gleason score, or margin status. Patients in whom step-sectioning was performed had a lower serum PSA at diagnosis than patients in the non-step-sectioned group. When examining all patients, no differences were observed in the use of secondary treatments or PSA recurrence based on the method of pathologic analysis. However, patients with negative margins in whom step-sectioning was performed exhibited significantly lower secondary nonadjuvant treatment use and appeared to have a lower risk of PSA recurrence than similar patients in the non-step-sectioned group. CONCLUSIONS: These data suggest that more complete pathologic analysis of the surgical specimen may better predict outcome for some patients undergoing RP. Additional research is warranted to determine whether such differences justify the additional resources necessary to recommend routine step-sectioning.

Patterns of treatment of patients with prostate cancer initially managed with surveillance: results from The CaPSURE database. Cancer of the Prostate Strategic Urological Research Endeavor.

PURPOSE: We determined the demographic and clinical profile of men who elect surveillance as the initial management of prostate cancer as well as the incidence and predictors of secondary treatment of these patients. MATERIALS AND METHODS: The Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE) is a national disease registry of patients with various stages and treatments of prostate cancer. Using this database of 4,458 men we identified 329 (8.2%) who elected surveillance as the initial management of prostate cancer. Patients choosing watchful waiting were compared to other CaPSURE participants using the chi-square test. The likelihood of treatment initiation in the watchful waiting group was calculated using the Kaplan-Meier method. After adjusting for patient age, race, prostate specific antigen (PSA) at diagnosis, clinical T stage and total Gleason score the Cox proportional hazards regression model was used to determine significant predictors of treatment initiation. RESULTS: Compared with others in the database, patients on watchful waiting were more likely to be 75 years old or older (51% versus 16%, p <0.001), white (93% versus 85%, p <0.001), and have lower serum PSA (p <0.001), organ confined disease (97% versus 88%, p <0.001) and a total Gleason score of 7 or less (97% versus 88%, p <0.001). In the watchful waiting group there was a 52% likelihood of treatment initiation within 5 years of the diagnosis. Significant predictors of secondary treatment were age younger than 65 years and elevated serum PSA at diagnosis. Neither race, extraprostatic stage cT3 disease nor higher total Gleason score was a significant predictor of treatment. CONCLUSIONS: Men who elect initial watchful waiting for prostate cancer tend to be older, have lower serum PSA and more favorable disease characteristics than those who seek treatment. PSA at diagnosis is the dominant factor for predicting secondary treatment.

Impact of positive surgical margins on prostate cancer recurrence and the use of secondary cancer treatment: data from the CaPSURE database.

PURPOSE: We determined the impact of positive surgical margins on prostate specific antigen (PSA) recurrence and secondary treatment in patients who underwent radical prostatectomy as definitive local treatment for prostate cancer. MATERIALS AND METHODS: We reviewed the pathology reports of 1,383 patients in the CaPSURE database, a longitudinal disease registry of men with prostate cancer, who underwent radical prostatectomy as definitive local treatment. Pathological stage, Gleason score, and the number and location of any positive surgical margins were determined in each patient. PSA recurrence was defined as PSA 0.2 ng./ml. or greater on 2 consecutive occasions after radical prostatectomy. Secondary cancer treatment consisted of radiation or androgen deprivation after radical prostatectomy. Adjuvant and nonadjuvant secondary treatment was given within and more than 6 months after radical prostatectomy, respectively. Kaplan-Meier event rates of PSA recurrence and secondary treatment were calculated for patients with positive and negative surgical margins. We performed multivariate Cox proportional hazards analysis to adjust for clinical differences in groups. RESULTS: Patients with positive surgical margins were significantly more likely to undergo secondary adjuvant or nonadjuvant cancer treatment and have PSA recurrence than those with negative margins. After adjusting for patient age, ethnicity, PSA at diagnosis, pathological stage and Gleason score, surgical margin status was an important independent predictor of PSA recurrence and secondary treatment (p = 0.06 and 0.0011, respectively). The number of positive margins and positive margin location had little impact on the outcomes measured. CONCLUSIONS: These data indicate that surgical margin status is an independent predictor of PSA recurrence and secondary cancer treatment in patients who underwent radical prostatectomy as definitive local therapy for prostate cancer.

The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women.

OBJECTIVES: The objectives of this study were to describe the early natural history of human papillomavirus (HPV) infection by examining a cohort of young women positive for an HPV test and to define within this cohort (1) the probability of HPV regression, (2) the risk of having a squamous intraepithelial lesion, and (3) factors that were associated with HPV regression. STUDY DESIGN: The study was a cohort analytic design. An inception cohort of 618 women positive for HPV participated. HPV testing, cytologic evaluation, and colposcopic evaluation were performed at 4-month intervals. HPV testing was characterized for two groups: low risk (five types rarely associated with cancers) and high risk (nine types most commonly associated with cancers). RESULTS: Estimates provided by Kaplan-Meier curves showed that approximately 70% of women were found to have HPV regression by 24 months. Women with low-risk HPV type infections were more likely to show HPV regression than were women with high-risk HPV type infections (log rank test p = 0.002). The relative risk for the development of high-grade squamous intraepithelial lesion (HSIL) was 14.1 (95% confidence interval: 2.3, 84.5) for women with at least three positive tests for high-risk HPV preceding the development of the HSIL compared with that for women with negative tests for high-risk HPV. However, 88% of women with persistent positive HPV tests have not had HSIL to date. No factors associated with high-risk HPV type regression were identified except for a negative association with an incident history of vulvar condyloma (relative risk = 0.5 [95% confidence interval: 0.3 to 0.8]). CONCLUSION: Most young women with a positive HPV test will become negative within a 24-month period. Persistent positive tests with oncogenic HPV types represented a significant risk for the development of HSIL. However, we found that most young women with persistent positive HPV tests did not have cytologically perceptible HSIL over a 2-year period. Factors thought to be associated with the development of HSIL were found not to be important in HPV regression.

Female adolescents at high, moderate, and low risk of exposure to HIV: differences in knowledge, beliefs, and behavior.

PURPOSE: To examine differences in the beliefs and behaviors of female adolescents at varying degrees of probable risk for HIV transmission. METHODS: A clinically-based, ethnically diverse sample of 696 sexually active female adolescents was recruited from urban and suburban general adolescent, family planning, and public health clinics. Subjects were categorized into four risk status groups on the basis of their history of IV drug use, sexually transmitted disease (STD), and probable risk of contact with an infected individual (living in a high-risk geographic location, sexual promiscuity, sex with male homo/bisexuals). RESULTS: Females in the highest risk group showed high rates of substance use, anal intercourse, and intentions to have future risky sexual partners. A second high-risk group reported high rates of STDs, inconsistent condom use, and less AIDS knowledge. CONCLUSION: Different subsets of higher risk adolescents may require different intervention strategies.

Risks of human immunodeficiency virus infection among adolescents attending three diverse clinics.

This study was performed to identify specific high-risk behaviors, such as unprotected oral, anal, and vaginal intercourse and substance abuse, associated with human immunodeficiency virus infection among adolescents attending three diverse clinics located in a localized geographic area: a university-based clinic, a Planned Parenthood clinic, and an inner-city public health clinic (PHC). Six hundred seventy-one female and 207 male adolescents attending one of the three clinics completed a structured questionnaire. Similarities among patients at the clinic sites included high rates of anal intercourse (21%), unprotected vaginal sex (95%), oral sex (73%), and poor communication skills (42%). Some differences appeared as well, including higher rates of homosexual experiences, no birth control use, and having multiple partners among adolescents attending the PHC (p < 0.001). In contrast, adolescents attending either the university-based clinic or the Planned Parenthood Clinic had higher rates of substance abuse around sexual activity than those who attended the PHC (p < 0.001). We conclude that adolescents attending general medical clinics in the San Francisco Bay area engage in high-risk behaviors that place them at risk for transmission of human immunodeficiency virus even though many have had previous education about acquired immunodeficiency syndrome and sexually transmitted disease. Specific risk factors include unprotected receptive anal intercourse, unprotected vaginal intercourse with new and unknown partners, experience in homosexual behavior, high rates of oral sex, multiple partners, poor communication skills, and frequent use of illicit substances in conjunction with sex. The differences found among sites indicate the need for health care providers and prevention programs to provide emphasis on practices specific to the adolescents in their service area.

Comparison between colposcopic, cytologic, and histologic findings in women positive and negative for human papillomavirus DNA.

Little is known about the role of detection of human papillomavirus (HPV) DNA in exfoliated cells of the cervix in aiding the colposcopic diagnosis of cervical lesions. The purpose of our study was to compare the colposcopic findings of young women who were positive and negative for HPV DNA. Eighty-four women aged 13-22 years attending family planning clinics were examined colposcopically with the aide of acetic acid and Lugol's solution and without knowledge of HPV DNA status. Lesions identified were given scores based on the severity of observed colposcopic changes. Samples for cytology and HPV DNA testing, which included types 6, 11, 16, 18, 31, 33, and 35, were obtained at the time of the examination. Biopsies were performed on women with significant lesions identified on examination or with cytology suggestive of neoplasia. Students t-test and chi 2 analysis were performed to compare colposcopic variables and HPV DNA type. Of the 84 women examined, 17 were positive for HPV DNA; 9 had type 16/18. The average length of sexual activity was 2.7 years. Women with HPV 16/18 had a mean of 1.7 lesions visible at colposcopy compared to 0.7 lesions visible in those negative for HPV 16/18 (this included HPV DNA negative women and women positive for HPV types 6, 11, 31, 33, and 35) (p < 0.001). Women who were positive for HPV 16/18 also had higher lesional scores than the HPV 16/18-negative group (3.4 versus 1.0, respectively, p < 0.001). All four women who had dysplasia either on cytology or histology were positive for type 16/18.(ABSTRACT TRUNCATED AT 250 WORDS)

Childhood sexual learning and sex education in schools.

This article reviews the multiple sources of childhood sexual learning, including intrapersonal constructs and the role of external factors such as the family, peers, culture, and the media. A comprehensive definition of sexuality and sexual health is described. Data on the recent national survey of school-based sex education programs by the Alan Guttmacher Institute is reviewed. Building on this information, a justification for sexuality education within the context of comprehensive health education is addressed. Implications for nursing practice are discussed to include formalized linkages between the education and health professions within the domains of policy development, research, advocacy, program development, and clinical services.