Faculty Bibliography

CONTEXT: Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of progression while on AS are debated. OBJECTIVE: To review primary data on markers, genetic factors, and risk stratification for patient selection and predictors of progression during AS. EVIDENCE ACQUISITION: Electronic searches were conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 2014 for original articles on biomarkers and risk stratification for AS. EVIDENCE SYNTHESIS: Patient factors associated with AS outcomes in some studies include age, race, and family history. Multiple studies provide consistent evidence that a lower percentage of free prostate-specific antigen (PSA), a higher Prostate Health Index (PHI), a higher PSA density (PSAD), and greater biopsy core involvement at baseline predict a greater risk of progression. During follow-up, serial measurements of PHI and PSAD, as well as repeat biopsy results, predict later biopsy progression. While some studies have suggested a univariate relationship between urinary prostate cancer antigen 3 (PCA3) and transmembrane protease, serine 2-v-ets avian erythroblastosis virus E26 oncogene homolog gene fusion (TMPRSS2:ERG) with adverse biopsy features, these markers have not been consistently shown to independently predict AS outcomes. No conclusive data support the use of genetic tests in AS. Limitations of these studies include heterogeneous definitions of progression and limited follow-up. CONCLUSIONS: There is a growing body of literature on patient characteristics, biopsy features, and biomarkers with potential utility in AS. More data are needed on practical applications such as combining these tests into multivariable clinical algorithms and long-term outcomes to further improve AS in the future. PATIENT SUMMARY: Several PSA-based tests (free PSA, PHI, PSAD) and the extent of cancer on biopsy can help to stratify the risk of progression during active surveillance. Investigation of several other markers is under way.

CONTEXT: Epidemiological studies and animal models demonstrate that endocrine-disrupting chemicals (EDCs) contribute to cognitive deficits and neurodevelopmental disabilities. OBJECTIVE: The objective was to estimate neurodevelopmental disability and associated costs that can be reasonably attributed to EDC exposure in the European Union. DESIGN: An expert panel applied a weight-of-evidence characterization adapted from the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and approximate burden of disease. Cost estimation as of 2010 utilized lifetime economic productivity estimates, lifetime cost estimates for autism spectrum disorder, and annual costs for attention-deficit hyperactivity disorder. Setting, Patients and Participants, and Intervention: Cost estimation was carried out from a societal perspective, ie, including direct costs (eg, treatment costs) and indirect costs such as productivity loss. RESULTS: The panel identified a 70-100% probability that polybrominated diphenyl ether and organophosphate exposures contribute to IQ loss in the European population. Polybrominated diphenyl ether exposures were associated with 873 000 (sensitivity analysis, 148 000 to 2.02 million) lost IQ points and 3290 (sensitivity analysis, 3290 to 8080) cases of intellectual disability, at costs of euro9.59 billion (sensitivity analysis, euro1.58 billion to euro22.4 billion). Organophosphate exposures were associated with 13.0 million (sensitivity analysis, 4.24 million to 17.1 million) lost IQ points and 59 300 (sensitivity analysis, 16 500 to 84 400) cases of intellectual disability, at costs of euro146 billion (sensitivity analysis, euro46.8 billion to euro194 billion). Autism spectrum disorder causation by multiple EDCs was assigned a 20-39% probability, with 316 (sensitivity analysis, 126-631) attributable cases at a cost of euro199 million (sensitivity analysis, euro79.7 million to euro399 million). Attention-deficit hyperactivity disorder causation by multiple EDCs was assigned a 20-69% probability, with 19 300 to 31 200 attributable cases at a cost of euro1.21 billion to euro2.86 billion. CONCLUSIONS: EDC exposures in Europe contribute substantially to neurobehavioral deficits and disease, with a high probability of >euro150 billion costs/year. These results emphasize the advantages of controlling EDC exposure.

CONTEXT: Rapidly increasing evidence has documented that endocrine-disrupting chemicals (EDCs) contribute substantially to disease and disability. OBJECTIVE: The objective was to quantify a range of health and economic costs that can be reasonably attributed to EDC exposures in the European Union (EU). DESIGN: A Steering Committee of scientists adapted the Intergovernmental Panel on Climate Change weight-of-evidence characterization for probability of causation based upon levels of available epidemiological and toxicological evidence for one or more chemicals contributing to disease by an endocrine disruptor mechanism. To evaluate the epidemiological evidence, the Steering Committee adapted the World Health Organization Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria, whereas the Steering Committee adapted definitions recently promulgated by the Danish Environmental Protection Agency for evaluating laboratory and animal evidence of endocrine disruption. Expert panels used the Delphi method to make decisions on the strength of the data. RESULTS: Expert panels achieved consensus at least for probable (>20%) EDC causation for IQ loss and associated intellectual disability, autism, attention-deficit hyperactivity disorder, childhood obesity, adult obesity, adult diabetes, cryptorchidism, male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median cost of euro157 billion (or $209 billion, corresponding to 1.23% of EU gross domestic product) annually across 1000 simulations. Notably, using the lowest end of the probability range for each relationship in the Monte Carlo simulations produced a median range of euro109 billion that differed modestly from base case probability inputs. CONCLUSIONS: EDC exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those EDCs with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs.

INTRODUCTION: Increasing evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to male reproductive diseases and disorders. PURPOSE: To estimate the incidence/prevalence of selected male reproductive disorders/diseases and associated economic costs that can be reasonably attributed to specific EDC exposures in the European Union (EU). METHODS: An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer-reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. The cost-of-illness estimation utilized multiple peer-reviewed sources. RESULTS: The expert panel identified low epidemiological and strong toxicological evidence for male infertility attributable to phthalate exposure, with a 40-69% probability of causing 618 000 additional assisted reproductive technology procedures, costing euro4.71 billion annually. Low epidemiological and strong toxicological evidence was also identified for cryptorchidism due to prenatal polybrominated diphenyl ether exposure, resulting in a 40-69% probability that 4615 cases result, at a cost of euro130 million (sensitivity analysis, euro117-130 million). A much more modest (0-19%) probability of causation in testicular cancer by polybrominated diphenyl ethers was identified due to very low epidemiological and weak toxicological evidence, with 6830 potential cases annually and costs of euro848 million annually (sensitivity analysis, euro313-848 million). The panel assigned 40-69% probability of lower T concentrations in 55- to 64-year-old men due to phthalate exposure, with 24 800 associated deaths annually and lost economic productivity of euro7.96 billion. CONCLUSIONS: EDCs may contribute substantially to male reproductive disorders and diseases, with nearly euro15 billion annual associated costs in the EU. These estimates represent only a few EDCs for which there were sufficient epidemiological studies and those with the highest probability of causation. These public health costs should be considered as the EU contemplates regulatory action on EDCs.

CONTEXT: Obesity and diabetes are epidemic in the European Union (EU). Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a contributor, independent of diet and physical activity. OBJECTIVE: The objective was to estimate obesity, diabetes, and associated costs that can be reasonably attributed to EDC exposures in the EU. DESIGN: An expert panel evaluated evidence for probability of causation using weight-of-evidence characterization adapted from that applied by the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and burden of disease. Cost estimation as of 2010 utilized published cost estimates for childhood obesity, adult obesity, and adult diabetes. Setting, Patients and Participants, and Intervention: Cost estimation was performed from the societal perspective. RESULTS: The panel identified a 40% to 69% probability of dichlorodiphenyldichloroethylene causing 1555 cases of overweight at age 10 (sensitivity analysis: 1555-5463) in 2010 with associated costs of euro24.6 million (sensitivity analysis: euro24.6-86.4 million). A 20% to 39% probability was identified for dichlorodiphenyldichloroethylene causing 28 200 cases of adult diabetes (sensitivity analysis: 28 200-56 400) with associated costs of euro835 million (sensitivity analysis: euro835 million-16.6 billion). The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and euro15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with euro607 million in associated costs. Prenatal bisphenol A exposure was identified to have a 20% to 69% probability of causing 42 400 cases of childhood obesity, with associated lifetime costs of euro1.54 billion. CONCLUSIONS: EDC exposures in the EU contribute substantially to obesity and diabetes, with a moderate probability of >euro18 billion costs per year. This is a conservative estimate; the results emphasize the need to control EDC exposures.

BACKGROUND: Integrating mobile phone technologies in addiction treatment is of increasing importance and may optimize patient engagement with their care and enhance the delivery of existing treatment strategies. Few studies have evaluated mobile phone and text message (TM) use patterns in persons enrolled in addiction treatment, and none have assessed the use in safety net, office-based buprenorphine practices. METHODS: A 28-item, quantitative and qualitative semistructured survey was administered to opiate-dependent adults in an urban, publicly funded, office-based buprenorphine program. Survey domains included demographic characteristics, mobile phone and TM use patterns, and preferences pertaining to their recovery. RESULTS: Surveyors approached 73 of the 155 eligible subjects (47%); 71 respondents completed the survey. Nearly all participants reported mobile phone ownership (93%) and TM use (93%), and most reported "very much" or "somewhat" comfort sending TM (79%). Text message contact with 12-step group sponsors, friends, family members, and counselors was also described (32%). Nearly all preferred having their providers' mobile phone number (94%), and alerting the clinic via TM in the event of a potential relapse to receive both supportive TM and a phone call from their buprenorphine provider was also well received (62%). CONCLUSIONS: Mobile phone and TM use patterns and preferences among this sample of office-based buprenorphine participants highlight the potential of adopting patient-centered mobile phone-based interventions in this treatment setting.

Background: We aimed to develop a clinically practical, multi-domain tool for measuring and monitoring self-reported and caregiver-reported symptoms of older patients. Most existing tools are disease specific, single-domain, or too lengthy for clinical practice. SymTrak was developed to be brief, clinically actionable, sensitive to change, broadly applicable to multiple chronic conditions, culturally sensitive, and easily understood. Methods: SymTrak was developed from multidisciplinary expert panels, existing data, extant instruments, and focus groups. Results: Items tapped psychological, functional, cognitive, pain, sleep, fatigue, and other physical symptoms. Focus groups preferred 3 to 5 item response options, but were neutral regarding frequency versus severity format. Four frequency options (never, sometimes, often, always) were chosen for all items to balance clinical brevity with sensitivity to change. Physician and nurse practitioner focus groups highly valued instrument performance: administrable within 5 minutes; easily retrievable visual graphics from medical records; viewable at item, domain and total-score levels. SymTrak was perceived as more useful for tracking than screening. Clinicians preferred a single brief physical symptom domain instead of multi-item pain, sleep, and fatigue domains. Patient and caregiver focus groups valued item wording: simple language; and applicability regardless of roles. They provided numerous helpful item revisions during "think aloud" interviewing, held subsequent to focus group sessions. They also rated SymTrak highly useful on an 8-item usability scale and were enthusiastic about its use as a communication aid with providers. Version 1.0 (25 items) was finalized and is currently being psychometrically tested. Conclusions: Focus groups of clinicians, patients, and caregivers were helpful in developing Version 1.0 of SymTrak and evaluated it to be useful for tracking symptoms in primary care

Background: Despite evidence of CV benefit of modest BP control in older patients, it is unclear when overly-aggressive treatment results in risk of fall injury that exceeds the CV benefits. Methods: Design: Longitudinal observation Sample: 5518 participants in the biennial Health and Retirement Study, age >65, with self-reported hypertension and taking BP medications, and who had BP measured by an enhanced HRS exam in 2008 or 2010 (randomly-assigned, mutually-exclusive cohorts). Measures: 2-year self-reported fall injury requiring medical care or acute CV event (stroke, infarction, heart failure), as a multinomial outcome: CV or fall injury, CV only, fall only, neither event. Increasing SBP control was tested in categories: (1) untreated or (2) inadequately- treated SBP >160 mmHg; (3) adequate treatment 121-159 mmHg, (3) overly-aggressive treatment to <120 mmHg. Analysis: Multinomial logistic regression to calculate net changes in risk across categories of BP control, controlling for age and sex. Results: Fall injury (12%) increased with age and was more prevalent than CV event (5%). Net harm of overly-controlling BP to <120 mmHg (compared to adequate control) was significant after age 73 (fig). Conclusions: Aggressiveness of BP care should be individualized by patient to steer clear of net harm, especially for older adults at advanced ages. (Figure Presented)

We conducted a review of articles published in 2013 to identify high-quality research in medical education that was relevant to general medicine education practice. Our review team consisted of six general internists with expertise in medical education of varying ranks, as well as a professional medical librarian. We manually searched 15 journals in pairs, and performed an online search using the PubMed search engine for all original research articles in medical education published in 2013. From the total 4,181 citations identified, we selected 65 articles considered most relevant to general medicine educational practice. Each team member then independently reviewed and rated the quality of each selected article using the modified Medical Education Research Study Quality Instrument. We then reviewed the quality and relevance of each selected study and grouped them into categories of propensity for inclusion. Nineteen studies were felt to be of adequate quality and were of moderate to high propensity for inclusion. Team members then independently voted for studies they felt to be of the highest relevance and quality within the 19 selected studies. The ten articles with the greatest number of votes were included in the review. We categorized the studies into five general themes: Improving Clinical Skills in UME, Inpatient Clinical Teaching Methods, Advancements in Continuity Clinic, Handoffs/Transitions in Care, and Trainee Assessment. Most studies in our review of the 2013 literature in general medical education were limited to single institutions and non-randomized study designs; we identified significant limitations of each study. Selected articles may inform future research and practice of medical educators.

INTRODUCTION & OBJECTIVES: Many elderly men do not receive curative treatment for high risk, non-metastatic prostate cancer (HRnMPCa) despite high mortality with conservative management. We aimed to assess how age and comorbidity affect treatment of men with HRnMPCa. MATERIAL & METHODS: The proportion of men with HRnMPCa treated curatively in Sweden in 2001 to 2012 was assessed in this nationwide, population-based study. 19,190 men with HRnMPCa below age 80 at date of diagnosis were identified in the National Prostate Cancer Register (NPCR) and 95,948 age-matched control men were without prostate cancer retrieved from the Register of the Total Population. 10-year survival in control men, stratified by age and Charlson Comorbidity Index (CCI) was used as a measure of the life expectancy of the men with prostate cancer. RESULTS: The proportion receiving curative treatment co-varied with life expectancy in men below age 70, but not in men in their seventies with CCI 0-1. For example, only 10% of men aged 75-80 years with CCI 0 received curative treatment despite a 52% 10-year survival probability, whereas half of men younger than 70 years with similar life expectancy received curative treatment. The use of curative treatment for HRnMPCa increased during the study period in all counties, but a threefold difference between counties for men aged 70-80 years with CCI 0-1 remained in 2009-2012. CONCLUSIONS: Otherwise healthy men in their seventies with HRnMPCa were less likely to receive treatment than younger men with a similar life expectancy. The disparities in use of curative treatment highlight the need for improved assessment of life expectancy