American Brachytherapy Society Task Group Report: Use of androgen deprivation therapy with prostate brachytherapy-A systematic literature review.

PURPOSE: Prostate brachytherapy (PB) has well-documented excellent long-term outcomes in all risk groups. There are significant uncertainties regarding the role of androgen deprivation therapy (ADT) with brachytherapy. The purpose of this report was to review systemically the published literature and summarize present knowledge regarding the impact of ADT on biochemical progression-free survival (bPFS), cause-specific survival (CSS), and overall survival (OS). METHODS AND MATERIALS: A literature search was conducted in Medline and Embase covering the years 1996-2016. Selected were articles with >100 patients, minimum followup 3 years, defined risk stratification, and directly examining the role and impact of ADT on bPFS, CSS, and OS. The studies were grouped to reflect disease risk stratification. We also reviewed the impact of ADT on OS, cardiovascular morbidity, mortality, and on-going brachytherapy randomized controlled trials (RCTs). RESULTS: Fifty-two selected studies (43,303 patients) were included in this review; 7 high-dose rate and 45 low-dose rate; 25 studies were multi-institutional and 27 single institution (retrospective review or prospective data collection) and 2 were RCTs. The studies were heterogeneous in patient population, risk categories, risk factors, followup time, and treatment administered, including ADT administration and duration (median, 3-12 months);71% of the studies reported a lack of benefit, whereas 28% showed improvement in bPFS with addition of ADT to PB. The lack of benefit was seen in low-risk and favorable intermediate-risk (IR) disease and most high-dose rate studies. A bPFS benefit of up to 15% was seen with ADT use in patients with suboptimal dosimetry, those with multiple adverse risk factors (unfavorable IR [uIR]), and most high-risk (HR) studies. Four studies reported very small benefit to CSS (2%). None of the studies showed OS advantage; however, three studies reported an absolute 5-20% OS detriment with ADT. Literature suggests that OS detriment is more likely in older patients or those with pre-existing cardiovascular disease. Four RCTs with an adequate number of patients and well-defined risk stratification are in progress. One RCT will answer the question regarding the role of ADT with PB in favorable IR patients and the other three RCTs will focus on optimal duration of ADT in the uIR and favorable HR population. CONCLUSIONS: Patients treated with brachytherapy have excellent long-term disease outcomes. Existing evidence shows no benefit of adding ADT to PB in low-risk and favorable IR patients. UIR and HR patients and those with suboptimal dosimetry may have up to 15% improvement in bPFS with addition of 3-12 months of ADT, with uncertain impact on CSS and a potential detriment on OS. To minimize morbidity, one should exercise caution in prescribing ADT together with PB, in particular to older men and those with existing cardiovascular disease. Due to the retrospective nature of this evidence, significant selection, and treatment bias, no definitive conclusions are possible. RCT is urgently needed to define the potential role and optimal duration of ADT in uIR and favorable HR disease.

Gene-environment interplay between parent-child relationship problems and externalizing disorders in adolescence and young adulthood.

BACKGROUND: Previous studies have shown that genetic risk for externalizing (EXT) disorders is greater in the context of adverse family environments during adolescence, but it is unclear whether these effects are long lasting. The current study evaluated developmental changes in gene-environment interplay in the concurrent and prospective associations between parent-child relationship problems and EXT at ages 18 and 25 years. METHOD: The sample included 1382 twin pairs (48% male) from the Minnesota Twin Family Study, participating in assessments at ages 18 years (mean = 17.8, s.d. = 0.69 years) and 25 years (mean = 25.0, s.d. = 0.90 years). Perceptions of parent-child relationship problems were assessed using questionnaires. Structured interviews were used to assess symptoms of adult antisocial behavior and nicotine, alcohol and illicit drug dependence. RESULTS: We detected a gene-environment interaction at age 18 years, such that the genetic influence on EXT was greater in the context of more parent-child relationship problems. This moderation effect was not present at age 25 years, nor did parent-relationship problems at age 18 years moderate genetic influence on EXT at age 25 years. Rather, common genetic influences accounted for this longitudinal association. CONCLUSIONS: Gene-environment interaction evident in the relationship between adolescent parent-child relationship problems and EXT is both proximal and developmentally limited. Common genetic influence, rather than a gene-environment interaction, accounts for the long-term association between parent-child relationship problems at age 18 years and EXT at age 25 years. These results are consistent with a relatively pervasive importance of gene-environmental correlation in the transition from late adolescence to young adulthood.

General and substance-specific predictors of young adult nicotine dependence, alcohol use disorder, and problem behavior: replication in two samples.

BACKGROUND: This paper presents two replications of a heuristic model for measuring environment in studies of gene-environment interplay in the etiology of young adult problem behaviors. METHODS: Data were drawn from two longitudinal, U.S. studies of the etiology of substance use and related behaviors: the Raising Healthy Children study (RHC; N=1040, 47% female) and the Minnesota Twin Family Study (MTFS; N=1512, 50% female). RHC included a Pacific Northwest, school-based, community sample. MTFS included twins identified from state birth records in Minnesota. Both studies included commensurate measures of general family environment and family substance-specific environments in adolescence (RHC ages 10-18; MTFS age 18), as well as young adult nicotine dependence, alcohol and illicit drug use disorders, HIV sexual risk behavior, and antisocial behavior (RHC ages 24, 25; MTFS age 25). RESULTS: Results from the two samples were highly consistent and largely supported the heuristic model proposed by Bailey et al. (2011). Adolescent general family environment, family smoking environment, and family drinking environment predicted shared variance in problem behaviors in young adulthood. Family smoking environment predicted unique variance in young adult nicotine dependence. Family drinking environment did not appear to predict unique variance in young adult alcohol use disorder. CONCLUSIONS: Organizing environmental predictors and outcomes into general and substance-specific measures provides a useful way forward in modeling complex environments and phenotypes. Results suggest that programs aimed at preventing young adult problem behaviors should target general family environment and family smoking and drinking environments in adolescence.

Medication adherence in a comparative effectiveness trial for bipolar disorder.

OBJECTIVE: Psychopharmacology remains the foundation of treatment for bipolar disorder, but medication adherence in this population is low (range 20-64%). We examined medication adherence in a multisite, comparative effectiveness study of lithium. METHOD: The Lithium Moderate Dose Use Study (LiTMUS) was a 6-month, six-site, randomized effectiveness trial of adjunctive moderate dose lithium therapy compared with optimized treatment in adult out-patients with bipolar I or II disorder (N=283). Medication adherence was measured at each study visit with the Tablet Routine Questionnaire. RESULTS: We found that 4.50% of participants reported missing at least 30% of their medications in the past week at baseline and non-adherence remained low throughout the trial (<7%). Poor medication adherence was associated with more manic symptoms and side-effects as well as lower lithium serum levels at mid- and post-treatment, but not with poor quality of life, overall severity of illness, or depressive symptoms. CONCLUSION: Participants in LiTMUS were highly adherent with taking their medications. The lack of association with possible predictors of adherence, such as depression and quality of life, could be explained by the limited variance or other factors as well as by not using an objective measure of adherence.

A review of the evidence on the effectiveness of children's vision screening.

Screening programmes enable health conditions to be identified so that effective interventions can be offered. The aim of this review was to determine: (1) the effectiveness of children's vision screening programmes; (2) at what age children should attend vision screening; and (3) what form vision screening programmes should take to be most effective. A literature review on the effectiveness of vision screening programmes in children aged 0-16 years was undertaken. Eligible studies/reviews were identified through clinical databases, hand searches and consultation with expert reviewers. The methodological quality of papers was rated using National Health and Medical Research Council (NHMRC) guidelines. Screening of children 18 months to 5 years, and subsequent early treatment, led to improved visual outcomes. The benefit was primarily through treatment of amblyopia, with improved visual acuity of the amblyopic eye. However, the overall quality of the evidence was low. The implication of improved visual acuity (e.g. any potential impact on quality of life) was not considered. Without consideration of 'quality of life' values, such as loss of vision in one eye or possibility of future bilateral vision loss, the cost-effectiveness of screening is questionable. Screening and treating children with uncorrected refractive error can improve educational outcomes. Evidence suggested that screening occur in the preschool years. Orthoptists were favoured as screening personnel; however, nurses could achieve high sensitivity and specificity with appropriate training. Further research is required to assess the effectiveness of neonatal screening. Most studies suggested that children's vision screening was beneficial, although programme components varied widely (e.g. tests used, screening personnel and age at testing). Research is required to clearly define any improvements to quality of life and any related economic benefits resulting from childhood vision screening. The evidence could be used to guide optimization of existing programmes.

Vitamin E supplement use and the incidence of cardiovascular disease and all-cause mortality in the Framingham Heart Study: Does the underlying health status play a role?

BACKGROUND: Observational studies generally showed beneficial associations between supplemental vitamin E intake and cardiovascular disease (CVD) risk whereas intervention trials reported adverse effects of vitamin E supplements. We hypothesize that these discordant findings result from differing underlying health status of study participants in observational and intervention studies. OBJECTIVE: Determine if the relation between supplemental vitamin E intake and CVD and all-cause mortality (ACM) depends on pre-existing CVD. DESIGN: Proportional hazards regression to relate supplemental vitamin E intake to the 10-year incidence of CVD and ACM in 4270 Framingham Study participants stratified by baseline CVD status. RESULTS: Eleven percent of participants used vitamin E supplements at baseline. In participants with pre-existing CVD, there were 28 (44%) and 20 (32%) incident cases of CVD and ACM in the vitamin E supplement users versus 249 (47%) and 202 (38%) in the non-users, respectively (CVD HR, 0.90; 95% CL, 0.60-1.32; ACM HR, 0.74; 95% CL, 0.46-1.17). In participants without pre-existing CVD, there were 51 (13%) and 47 (12%) cases of CVD and ACM in the vitamin E supplement group versus 428 (13%) and 342 (10%) in the non-vitamin E supplement group, respectively (CVD HR, 1.00; 95% CL, 0.75-1.34; ACM HR 1.20; 95% CL, 0.89-1.64). CONCLUSION: CVD status has no apparent influence on the association of supplemental vitamin E intake and risk for CVD and ACM in this large, community-based study. Further research is needed to clarify the basis for the discrepant results between intervention and observational studies of supplemental vitamin E intake.

Population-based study of biochemical and survival outcomes after permanent 125I brachytherapy for low- and intermediate-risk prostate cancer.

OBJECTIVES: To analyze the biochemical and survival outcomes after permanent low-dose-rate prostate brachytherapy in a large, consecutive, population-based cohort of patients. METHODS: A total of 1006 consecutive implants were performed from July 20, 1998 to October 23, 2003 for men with low-risk and "low-tier" intermediate-risk prostate cancer. The prescribed minimal peripheral dose was 144 Gy, using 0.33 mCi (125)I sources and a preplan technique with a strong posterior-peripheral dose bias. Most patients (65%) had received 6 months of androgen deprivation therapy. Supplemental external beam radiotherapy was not used. The prognostic features, dose metrics, and follow-up data were prospectively collected. Kaplan-Meier and Cox regression analyses were used to assess the factors associated with freedom from biochemical recurrence and survival. RESULTS: The median patient age at treatment was 66 years. The median follow-up was 54 months for biochemical outcomes and 66 months for survival. The actuarial freedom from biochemical recurrence rate was 95.6% +/- 1.6% at 5 years and 94.0% +/- 2.2% at 7 years. On multivariate analysis, the pretreatment prostate-specific antigen level (P = .03) and androgen deprivation therapy use (P = .04) were predictive of the freedom from biochemical recurrence. The actuarial rates of distant metastasis and disease-specific death at 5 years were both <1%. The overall survival rate at 5 years was 95.2% +/- 1.4% and was 93.4% +/- 1.8% at 7 years. On multivariate analysis, only age was predictive of overall survival (P = .011). CONCLUSIONS: When consistently planned and delivered, low-dose-rate brachytherapy, without supplemental external beam radiotherapy or intraoperative planning, can produce cancer-specific outcomes for men with low- and "low-tier" intermediate-risk prostate cancer at least equal to that produced by dose-escalated external beam radiotherapy or surgical prostatectomy.

Rural environments reduce the genetic influence on adolescent substance use and rule-breaking behavior.

BACKGROUND: There is increasing evidence that certain environmental factors can modify genetic effects. This is an important area of investigation as such work will help to guide the development of new intervention programs. In this paper, we address whether rural environments moderate the genetic influence on adolescent substance use and rule-breaking behavior (i.e. externalizing psychopathology). METHOD: Over 1200 Minnesotan 17-year-old twins were classified as either urban or rural. Externalizing behavior was operationalized as the use and abuse of alcohol and drugs along with symptoms of conduct, oppositional defiant, and antisocial personality disorders. Biometric factor modeling estimated whether the relative contribution of genetic and shared environmental factors varied from urban to rural settings. RESULTS: Residency effects reached statistical significance in the male sample only. In urban environments, externalizing behavior was substantially influenced by genetic factors, but in rural environments, shared environmental factors became more influential. This was apparent at both the individual-variable and factor levels. CONCLUSIONS: These findings suggest a gene-environment interaction in the development of male adolescents' problem behaviors, including substance use. The results fit within an expanding literature demonstrating both the contextual nature of the heritability statistic and how certain environments may constrain the expression of genetic tendencies.

Preferences for sexual information resources in patients treated for early-stage prostate cancer with either radical prostatectomy or brachytherapy.

OBJECTIVE: To identify the preferences for sexual information resources of patients before and after definitive treatment for early-stage prostate cancer with either radical prostatectomy (RP) or brachytherapy. PATIENTS AND METHODS: Two hundred patients (mean age 64 years) treated with either RP or brachytherapy were recruited from radiation oncology (100) and urology (100) outpatient clinics. Patients completed a survey questionnaire to identify the types of information used, preferred sources of information, knowledge of treatments for erectile dysfunction (ED), effect of sexual function on the treatment decision, and the International Index of Erectile Function (IIEF) to assess their current level of sexual function. RESULTS: Urologists were identified as the main source of sexual information. Written information, Internet access and videos were identified as preferred sources of information before and after treatment. The effects of treatment on sexual function had no apparent significant influence on the men's definitive treatment choice. Compared with patients in the brachytherapy group, patients in the RP group reported having significantly higher levels of sexual desire (P < 0.001) after treatment, but otherwise the erectile domains of the groups were remarkably similar. Two-thirds of patients wanted more information on the effects of treatment on sexual function, and on available treatments for ED. CONCLUSIONS: These results support the need for physicians to offer patients access to information on the effect of treatment for early-stage prostate cancer on erectile function before and after treatment.

Adequacy of pain assessment and pain relief and correlation of patient satisfaction in 68 ED fast-track patients.

INTRODUCTION: The new standards of the joint commission on accreditation of healthcare organizations specify the patient's right to appropriate assessment and management of pain. With this impetus, we looked at our own practice to see how well we assess and manage patients with pain. METHODS: Patients who presented with minor nonemergent pain were interviewed on arrival, and then again before discharge, with use of a structured questionnaire. A total of 68 completed pain surveys were analyzed. RESULTS: With use of a visual analog scale, patients rated their pain on arrival and at discharge; they also rated pain they were willing to accept when it was time for discharge. Sixty percent of the patients went home with more pain than they were willing to accept. Fifty-one percent of the patients were offered something for pain, and only half of them said the pain relief was adequate. The median time from arrival to administration of pain medication was 104 minutes. Surprisingly, the median patient satisfaction rating for overall care was "very good." DISCUSSION: This survey revealed that acute pain conditions are underevaluated and undertreated in one fast-track setting, suggesting that ED staff need more education about the management of acute pain. It also showed that relying on patient satisfaction surveys as surrogate markers for how well we manage pain is erroneous.

Use of amphipathic polymers to deliver a membrane protein to lipid bilayers.

Data are presented which suggest that a class of amphiphilic polymers known as 'amphipols' may serve as a vehicle for delivering complex integral membrane proteins into membranes. The integral membrane protein diacylglycerol kinase (DAGK) was maintained in soluble form by either of two different amphipols. Small aliquots of these solutions were added to pre-formed lipid vesicles and the appearance of DAGK catalytic activity was monitored as an indicator of the progress of productive protein insertion into the bilayers. For one of the two amphipols tested, DAGK was observed to productively transfer from its amphipol complex into vesicles with moderate efficiency. Results were not completely clear for the other amphipol.

Timing of postoperative adjustment in adjustable suture strabismus surgery.

PURPOSE: The use of adjustable sutures in strabismus surgery has increased the rate of surgical success. Little data are available on the optimum timing for postoperative adjustment after strabismus surgery. We wanted to compare 2 common practices of adjustable suture technique after strabismus surgery. METHODS: Two comparable groups of 40 patients each, who had strabismus surgery with adjustable suture technique, were prospectively studied. Group A had early adjustment the same day of the surgery about 6 hours after the operation, and group B had late adjustment the next day about 24 hours after the operation. Subjective scoring tables were used to evaluate the pain felt by the patient before, during, and after the adjustment and any difficulties of the adjustment process. Requirements of postoperative pain medications and final alignment 6 weeks after surgery were also compared. RESULTS: Despite adequate statistical power, no significant differences were found between the groups regarding pain before, during, and after adjustment, difficulties performing the adjustment, and final alignment after 6 weeks (P > .05). Both adjustment schedules were equally associated with mild to moderate pain before, during, and after the adjustment. In the first 24 hours after surgery, no overall difference in the use of pain medications was found. Nausea and vomiting in the first 24 postoperative hours were more common in the early adjustment group (P = .02). CONCLUSION: The surgeon can feel free to choose the timing for postoperative adjustment. However, when performing an early adjustment, the surgeon should be especially prepared to control nausea and vomiting.

Assessing depression with the MMPI and MMPI-2.

The usefulness of the MMPI (Hathaway & McKinley, 1951 ) and MMPI-2 (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) for diagnosing and assessing symptomatic depression has been the subject of considerable debate for a number of years. In this article, we review the relative contributions of the MMPI and MMPI-2 clinical and content scales in predicting depression. Positive predictive power, negative predictive power, and overall classification rate were computed for Scale 2 (D) of the MMPI and MMPI-2 and the Depression content scale (DEP) of the MMPI-2. Scale 2 (D) of both the MMPI and MMPI-2 appears to be moderately accurate in predicting depression. Although some studies suggest that the content scale DEP provides incremental validity over Scale 2 (D) of the MMPI-2, the results of this review indicate that the content scale DEP of the MMPI-2 does not exceed the diagnostic efficiency of Scale 2 in predicting depression.

CONQUEST 2.0: an emerging clinical performance measurement tool.

Variations in quality of healthcare have existed for many years, yet interest in measuring, understanding, and eliminating these variations has waxed and waned. The advent of managed care and its perceived focus on reducing costs has stimulated interest in variations in quality of care. In response to the need to better understand and measure quality, the Agency for Health Care Policy and Research (AHCPR) funded the development of a tool capable of categorizing clinical performance measures, a subset of quality measures, for comparing and evaluating them relative to a user's specific needs for measuring and improving quality. This research lead to the development of the COmputerized Needs-oriented QUality measurement Evaluation SysTem (CONQUEST)--a free software quality improvement tool that includes about 1,200 clinical performance measures. CONQUEST enables users to quickly identify measures of interest, compare them on the basis of factors of importance, and select measures that will help them measure and improve care.

Development of an ED teaching program aimed at reducing prehospital delays for patients with chest pain.

OBJECTIVE: Delays in providing thrombolytic agents to patients with chest pain occur mainly in the prehospital arena. To reduce prehospital delay in treating patients with chest pain, we created a discharge teaching video that emphasized calling 911 in the event of a possible heart attack and a written action plan to be posted near the telephone. We also gave patients their EKG readings to bring with them on their next visit to the emergency department. SETTING AND SAMPLE: All patients with chest pain admitted to the Chest Pain Observation Unit at Baystate Medical Center, Springfield, Mass, were eligible for this teaching effort. We tracked 127 nonconsecutive patients from January 1997 to May 1997. Of these patients, 108 were included in the study. RESULTS: We interviewed 102 patients (94%) 3 days after they were discharged from the Chest Pain Observation Unit. Within this group, 92% were able to describe what a heart attack might feel like, and 81.4% said they would call 911 or go to the hospital if they had symptoms of a heart attack. If they thought that their symptoms might be indigestion, 69% said they would take an antacid, then go to the hospital if they did not feel better. Fifty-one percent remembered what to do with their EKG readings, and 60.7% knew how to take their nitroglycerin correctly. CONCLUSION: We concluded that patients understood the message they were given and retained some of the material 3 days after discharge from the Chest Pain Observation Unit. The follow-up telephone calls revealed areas for improvement in the discharge teaching tools.

Chronic cerebral hypoperfusion elicits neuronal apoptosis and behavioral impairment.

Chronic reductions in cerebral blood flow associated with aging and progressive neurodegenerative disorders can precipitate cognitive failure. To assess whether chronic cerebrovascular insufficiency elicits neuronal apoptosis, apoptotic cell death in the hippocampus was quantitated in a rat model of permanent carotid occlusion. Bilateral carotid artery occlusion (2VO) was shown to induce apoptotic morphology and DNA strand breaks in hippocampal neurons 2 and 27 weeks after ligation. The rate of pyramidal cell apoptosis was higher at chronic (27 weeks) compared to sub-chronic (2 weeks) time points. 2VO-induced apoptosis resulted in a decrease in total pyramidal cell number at 27 weeks but not at earlier time points, indicating progressive neuronal loss. Working and reference memory errors in the radial arm maze were strongly correlated with the number of apoptotic neurons in CA1 but not CA3 pyramidal cell fields. These data provide the first indication that apoptotic loss of pyramidal neurons may play a role in memory impairment associated with clinical conditions of chronic cerebrovascular insufficiency.