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Background and Objectives: Despite the increasing number of sexual and gender minority (SGM) patients in the United States and designation by the National Institutes of Health as a population with health disparities, available tools are lacking to train medical students on appropriate care for this population. Therefore, we developed and implemented a novel, self-directed, 2-week online elective for undergraduate medical students. The objective of our study was to evaluate the effectiveness of this course in increasing medical students' competency and confidence in caring for SGM patients., Methods: We developed the curriculum using Kern's six-step model for curriculum development. We created anonymous pre- and postcourse surveys using the standardized Lesbian, Gay, Bisexual, Transgender Development of Clinical Skills Survey (LGBT-DOCSS) questionnaire to assess cultural competence, as well as a 5-point Likert-scored survey to assess self-perceived confidence in the care of SGM patients. We tested the statistical significance in pre- and postsurvey scores via paired sample t tests in R (R Project for Statistical Computing)., Results: We found statistically significant increases in the LGBT-DOCSS categories of clinical preparedness (P<.001), basic knowledge (P<.001), overall competency (P<.001), and self-perceived confidence in caring for SGM patients (P<.001, N=33)., Conclusions: The course represents an effective solution for increasing medical students' self-perceived competence and confidence in caring for SGM patients. The flexibility and ease of the online format may be appealing to both students and institutions, and ultimately can serve to increase access to crucial content that is largely absent from current undergraduate medical education. Future evaluation efforts will be required to determine whether the course impacts long-term behavioral changes and outcomes.

Introduction: Adolescent varicocele is a common urologic condition with a spectrum of outcomes, leading to variations in management. Testicular hypotrophy is a common indication for surgery Routine monitoring may be an appropriate form of management for many adolescents with testicular hypotrophy, as studies have shown that a large proportion of these patients may experience catch-up growth of the ipsilateral testis. Furthermore, there are few longitudinal studies which have correlated patient specific factors to catch-up growth. We aimed to determine the frequency of testicular catch up-growth in adolescents with varicocele while also examining if patient specific factors such as BMI, BMI percentile, or height correlated with testicular catch-up growth., Methods: A retrospective chart review found adolescent patients who presented to our institution with varicocele from 1997 to 2019. Patients between the ages of 9 and 20 years with left-sided varicocele, a clinically significant testicular size discrepancy, and at least two scrotal ultrasounds at least one year apart were included in analysis. Testicular size discrepancy of greater than 15% on scrotal ultrasound was considered clinically significant. Testicular size was estimated in volume (mL) via the Lambert formula. Statistical relationships between testicular volume differential and height, body mass index (BMI), and age were described with Spearman correlation coefficients (ρ)., Results: 40 patients had a testicular volume differential of greater than 15% at some point during their clinical course and were managed non-operatively with observation and serial testicular ultrasounds. On follow-up ultrasound, 32/40 (80%) had a testicular volume differential of less than 15%, with a mean age of catch up growth at 15 years (SD 1.6, range 11-18 years). There were no significant correlations between baseline testicular volume differential and baseline BMI (ρ = 0.00, 95% CI [-0.32, 0.32]), baseline BMI percentile (ρ = 0.03, 95% CI [-0.30, 0.34]), or change in height over time (ρ = 0.05, 95% CI [-0.36, 0.44])., Discussion: The majority of adolescents with varicocele and testicular hypotrophy exhibited catch-up growth with observation, suggesting that surveillance is an appropriate form of management in many adolescents. These findings are consistent with previous studies and further indicate the importance of observation for the adolescent varicocele. Further research is warranted to determine patient specific factors that correlate with testicular volume differential and catch up growth in the adolescent varicocele., (Copyright © 2023 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: An increasing number of gender diverse individuals are presenting for gender affirming care. An option for genital gender affirming surgery (gGAS) in transmasculine individuals is metoidioplasty, creating a small neophallus from enlarged clitoral tissue following prolonged testosterone exposure. The goal of this study is to understand factors which contribute to greater exposed neophallus length following metoidioplasty., Methods: We performed a retrospective chart review on patients presenting to a single academic institution who underwent a metoidioplasty. All operations were performed using the Belgrade technique with or without urethral lengthening depending on patient preference., Results: Twenty-seven patients underwent metoidioplasty from 2017-2022. Sixteen had recorded stretched clitoral length (pre-operatively) and exposed neophallus length (post-operatively). The median length of time on testosterone therapy was 4.6 years. The median stretched clitoral length was 5.8 cm, and exposed neophallus length was 6 cm. There was a strong correlation between pre-operative length and post-operative length (ρ=0.9; P<0.0001). There were no correlations between pre-operative length or exposed neophallus length and BMI (ρ=-0.02, P=0.93; ρ=0.05, P=0.83, respectively). Time on testosterone does not correlate with stretched clitoral length nor exposed neophallus length (ρ=-0.28, P=0.15; ρ=-0.35, P=0.18, respectively)., Conclusions: Patients considering metoidioplasty often wonder how large their neophallus will be. We found that patients can expect exposed neophallus length to be about 0.6 cm longer than their pre-operative stretched clitoral length. No evidence of association of time on testosterone nor BMI with exposed neophallus length was found. This information is crucial for gender diverse patients to make informed decisions about gGAS., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-155/coif). SDN reports board membership with payment at the Journal of Urology. The other authors have no conflicts of interest to declare., (2023 Translational Andrology and Urology. All rights reserved.)

Introduction: Surgical repair of pectus excavatum and carinatum in children has historically been associated with severe postoperative pain and prolonged hospitalization. Enhanced Recovery After Surgery (ERAS) is a multidisciplinary, multimodal approach designed to fast-track surgical care. However, obstacles to implementation have led to very few within pediatric surgery. The aim of this study is to outline the process of development and implementation of an ERAS protocol for pectus surgical repair using fundamental principles of implementation science., Methods: A multidisciplinary team of providers worked collaboratively to develop an ERAS protocol for surgical repair of pectus excavatum and carinatum and methods for identifying eligible patients. The surgical champion collaborated with all end users to review and revise the ERAS protocol, assessing all foreseeable barriers and facilitators prior to implementation., Results: Our entire pediatric surgery team, nurses at every stage (clinic/preoperative/recovery/floor), physical therapy, and information technology contributed to the creation and implementation of an ERAS protocol with seven phases of care. The finalized version was implemented by end users focusing on four main areas: pain control, ambulation, diet, and education. Barriers and facilitators were continually addressed with an iterative process to improve the success of implementation., Conclusions: This is one of the first studies in children which details the step-by-step process of developing and implementing an ERAS protocol for pectus excavatum and carinatum. The process of development and implementation of an ERAS protocol as outlined in this manuscript can serve as a model for future ERAS protocols in pediatric surgery., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To understand experiences of patients with genitourinary cancer who experienced delayed cancer care due to the COVID-19 pandemic., Methods: We conducted a mixed methods study with an explanatory sequential design. Qualitative findings are reported here. Patients with muscle invasive bladder, advanced prostate or kidney cancer were eligible. Participants were selected for interviews if they self-reported low (0-3/10) or high (6-10/10) levels of distress on a previous survey. Participants were interviewed about their experiences. Interviews were transcribed, coded and categorised using thematic data analysis methodology., Results: Eighteen patients were interviewed. Seven had prostate cancer, six bladder cancer and five kidney cancer. Six themes were derived from the interviews: (1) arriving at cancer diagnosis was hard enough, (2) response to treatment delay, (3) labelling cancer surgery as elective, (4) fear of COVID-19 infection, (5) quality of patient-provider relationship and communication and (6) what could have been done differently., Conclusion: These findings offer insight into the concerns of patients with genitourinary cancers who experienced treatment delays due to COVID-19. This information can be applied to support patients with cancers more broadly, should treatment delays occur in the future., (© 2022 John Wiley & Sons Ltd.)

Hypothesis: We hypothesized that children with cochlear implants (CIs) who demonstrate cross-modal reorganization by vision also demonstrate cross-modal reorganization by somatosensation and that these processes are interrelated and impact speech perception., Background: Cross-modal reorganization, which occurs when a deprived sensory modality's cortical resources are recruited by other intact modalities, has been proposed as a source of variability underlying speech perception in deaf children with CIs. Visual and somatosensory cross-modal reorganization of auditory cortex have been documented separately in CI children, but reorganization in these modalities has not been documented within the same subjects. Our goal was to examine the relationship between cross-modal reorganization from both visual and somatosensory modalities within a single group of CI children., Methods: We analyzed high-density electroencephalogram responses to visual and somatosensory stimuli and current density reconstruction of brain activity sources. Speech perception in noise testing was performed. Current density reconstruction patterns were analyzed within the entire subject group and across groups of CI children exhibiting good versus poor speech perception., Results: Positive correlations between visual and somatosensory cross-modal reorganization suggested that neuroplasticity in different sensory systems may be interrelated. Furthermore, CI children with good speech perception did not show recruitment of frontal or auditory cortices during visual processing, unlike CI children with poor speech perception., Conclusion: Our results reflect changes in cortical resource allocation in pediatric CI users. Cross-modal recruitment of auditory and frontal cortices by vision, and cross-modal reorganization of auditory cortex by somatosensation, may underlie variability in speech and language outcomes in CI children., Competing Interests: The authors disclose no conflicts of interest, financial or otherwise., (Copyright © 2022, Otology & Neurotology, Inc.)

Background & Aims: Screening for pancreatic ductal adenocarcinoma (PDAC) in asymptomatic adults is not recommended, however, patients with new-onset diabetes (NoD) have an 8 times higher risk of PDAC than expected. A novel risk-tailored early detection strategy targeting high-risk NoD patients might improve PDAC prognosis. We sought to evaluate the cost effectiveness of this strategy., Methods: We compared PDAC early detection strategies targeting NoD individuals age 50 years and older at various minimal predicted PDAC risk thresholds vs standard of care in a Markov state-transition decision model under the health care sector perspective using a lifetime horizon., Results: At a willingness to pay (WTP) threshold of $150,000 per quality-adjusted life-year, the early detection strategy targeting patients with a minimum predicted 3-year PDAC risk of 1% was cost effective (incremental cost-effectiveness ratio, $116,911). At a WTP threshold of $100,000 per quality-adjusted life-year, the early detection strategy at the 2% risk threshold was cost effective (incremental cost-effectiveness ratio, $63,045). The proportion of PDACs detected at local stage, costs of treatment for metastatic PDAC, utilities of local and regional cancers, and sensitivity of screening were the most influential parameters. Probabilistic sensitivity analysis confirmed that at a WTP threshold of $150,000, early detection at the 1.0% risk threshold was favored (30.6%), followed by the 0.5% risk threshold (20.4%) vs standard of care (1.7%). At a WTP threshold of $100,000, early detection at the 1.0% risk threshold was favored (27.3%) followed by the 2.0% risk threshold (22.8%) vs standard of care (2.0%)., Conclusions: A risk-tailored PDAC early detection strategy targeting NoD patients with a minimum predicted 3-year PDAC risk of 1.0% to 2.0% may be cost effective., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: The use of objective measures in cochlear implant (CI) mapping, has greatly contributed to the refinement of the setting of audible and comfortable stimulation levels, which serve as the basis of the mapping process, especially in cases of infants and young children. In addition, objective measures can also confirm the integrity of the CI system. Current CI objective measures mainly reflect neural activity from the auditory nerve and brainstem site. An objective cortical CI measure that reflects directly central auditory activity is greatly needed, especially since it is closely related to CI outcomes in both children and adults. Recording the brain activity currently requires an external evoked potential (EP) system including scalp electrodes, rendering it impractical for widespread clinical use. This study aimed to assess the feasibility of recording cortical auditory evoked potentials (CAEPs) directly and solely through the cochlear implant in response to external acoustic stimulation in the non-implanted ear., Design: A total of nine CI users (four females and five males) participated, including seven post-lingual adults (23 to 72 years), and two pediatric cases, one teenager (15 years), and one child (8 years)-both pre-lingual. All participants had a residual hearing in the ear contralateral to the ear with CI. CAEPs were recorded in the implanted ear in response to acoustic stimulation of the non-implanted ear, consisting of a brief tonal stimulus at comfortable listening levels. Recordings used an intracranial montage consisting of an intracochlear apical electrode (active) and one of the two ( case and ring ) extra-cochlear implanted electrodes serving as reference electrodes. The CI CAEPs were compared with a single-channel conventional CAEP recording obtained simultaneously via scalp electrodes (Fz-mastoid) using a standard EP system and an external trigger from the CI system. Statistical comparisons were made between the CI and the scalp recorded CAEPs and for differences between the CI CAEP measures acquired using the ring and the case as the reference electrode., Results: CAEPs recorded directly and solely through the CI were equivalent to the standard scalp recorded CAEP responses. CAEP responses acquired using the case electrode as the reference were highly correlated in terms of morphology, latencies, and amplitudes of the CAEP components. The CI CAEP latencies of the two pediatric cases were consistent with their normal developed age group and delayed relative to adult CAEP latencies, as expected., Conclusions: This study demonstrated the feasibility of recording long latency CAEPs directly and solely through CI in adults with residual hearing, in response to acoustic stimulation of the non-implanted ear. The CI CAEPs closely resembled the CAEPs recorded simultaneously by an external EP system and via scalp electrodes. The ability to record directly from the implant, without the need of an external recording system, presents an innovative method with many clinical and research implications., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To understand perspectives of urology program directors (PDs) regarding the management and screening of resident mental health and burnout., Methods: After piloting and survey validation, an IRB-exempt 14 question survey was distributed to PDs of all 145 ACGME accredited urology residency programs. Statistical significance was determined using an alpha value of 0.05 and response plurality was determined by non-overlapping 95% confidence intervals., Results: A total of 72 PDs completed the survey (response rate = 49.6%). The majority of PDs (59.7%) do not use standardized screening for resident burnout or mental health. A statistically significant proportion of PDs agreed to implementing periodic mental health (75.0%, 95% CI [65.0%-75.0%]) and burnout (87.6%, 95% CI [79.9%-95.1%]) screening. Female PDs were more likely to agree to implementing mental health screening compared to male PDs (female=94.4% vs male=68.5%; P =.03). If mental health screening was implemented and a resident tested positive, PDs were most concerned about harm to a patient (72.2%, 95% CI [61.9-82.6]) and implications of a positive screen on future licensing and practice (55.6%, 95% CI [44.1-67.0])., Conclusion: Although the majority of urology PDs believe residents should be periodically screened for burnout and mental health, most do not currently screen their trainees. If mental health screening was implemented, PDs expressed concern about patient harm and challenges associated with future licensing. Our survey results suggest opportunities for improving management of resident burnout and mental health., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Studies have shown that healthcare-associated infections (HAIs) due to methicillin-resistant Staphylococcus aureus (MRSA) can lead to substantial healthcare costs in acute care settings. However, little is known regarding the consequences of these infections on patients in long-term care centers (LTCCs). The purpose of this study was to estimate the attributable cost of MRSA HAIs in LTCCs within the Department of Veterans Affairs (VA)., Methods: We performed a retrospective cohort study of patients admitted to VA LTCCs between 1 January 2009 and 30 September 2015. MRSA HAIs were defined as a positive clinical culture at least 48 hours after LTCC admission so as to exclude community-acquired infections. Positive cultures were further classified by site (sterile or nonsterile). We used multivariable generalized linear models and 2-part models to compare the LTCC and acute care costs between patients with and without an MRSA HAI., Results: In our primary analysis, there was no difference in LTCC costs between patients with and without a MRSA HAI. There was, however, a significant increase in the odds of being transferred to an acute care facility (odds ratio, 4.40 [95% confidence interval {CI}, 3.40-5.67]) and in acute care costs ($9711 [95% CI, $6961-$12 462])., Conclusions: Our findings of high cost and increased risk of transfer from LTCC to acute care are important because they highlight the substantial clinical and economic impact of MRSA infections in this population., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after percutaneous coronary intervention, but the clinical impact of implementing CYP2C19 genotyping in a real-world setting is unknown. The purpose of the study was to determine whether returning CYP2C19 genotype results along with genotype-guided pharmacotherapy recommendations using a rapid turnaround test would change antiplatelet prescribing following percutaneous coronary intervention.The primary outcome was the rate of prasugrel or ticagrelor prescribing in each arm. Secondary outcomes included agreement to the genotype-guided recommendations., Methods: At the time of percutaneous coronary intervention, participants were randomly assigned to prospective rapid point-of-care genotyping of CYP2C19 major alleles (*2, *3, *17) via salivary swab (genotyped group) or no genotyping (usual care) to guide antiplatelet drug selection. Interventional cardiologists at 2 cardiac catheterization laboratories within the same health system were provided genotype information along with genotype-guided pharmacotherapy recommendations., Results: A total of 504 participants were randomized, 249 to the genotyped and 255 to the usual care group. The participants were primarily men (73%); age, 63±10 years; and 50% had acute coronary syndromes. In the genotyped group, 28% were carriers of loss-of-function alleles (*2, *3). The use of prasugrel or ticagrelor was significantly higher in the genotyped group compared with the usual care group (30% versus 21%; odds ratio, 1.60 [95% CI, 1.07-2.42]; P =0.03). Within the genotyped group, 53% of loss-of-function allele carriers were started on prasugrel/ticagrelor, while 47% were started on clopidogrel., Conclusions: In a randomized controlled trial of clinical CYP2C19 genotyping implementation, pharmacogenetic test results significantly influenced antiplatelet drug prescribing; however, almost half of CYP2C19 loss-of-function carriers continued to receive clopidogrel. Interventional cardiologists consider both clinical and genetic factors when selecting antiplatelet therapy following percutaneous coronary intervention., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT02508116.

Objective: Auditory Neuropathy Spectrum Disorder (ANSD) affects approximately 5-15% of children with sensorineural hearing loss. ANSD is characterized by the presence of otoacoustic emissions (OAE) and an absent or abnormal auditory brainstem response (ABR). The purpose of this study was to investigate the prognostic value of slow-rate ABR in predicting the auditory cortical development and auditory speech perception outcomes in case studies of children with ANSD., Design: ABR waveform characteristics were collected at slow stimulation rates (5.1 clicks/second) and a fast stimulation rates (>11-31.1 clicks/second, rates typically used in a clinical setting) in 3 case reports of children with ANSD. P1 CAEP responses and measures of auditory speech perception using the Infant Toddler Meaningful Auditory Integration Scale (IT-MAIS) were also collected in these children. Retrospective analysis was performed to evaluate the prognostic value of slow- versus fast-rate ABR in predicting P1 CAEP responses and auditory speech perception outcomes in these children., Study Sample: Participants included case reports of 3 pediatric participants with a clinical diagnosis of ANSD., Results: Slow-rate ABR did not elicit significant improvements in waveform morphology compared to fast-rate ABR. P1 CAEP results were present in 2 out of 3 cases and were consistent with auditory speech perception outcomes., Conclusions: Even when ABR stimulation rates were slowed, ABR responses in these children with ANSD did not display any characteristic or replicable pattern, and ABR responses were not predictive of cortical auditory maturation or behavioral performance. In contrast, P1 CAEP responses provided valuable information regarding the maturational status of the auditory cortex and P1 CAEP responses were consistent with behavioral measures of auditory speech perception. Overall, results highlight the high prognostic value of P1 CAEP testing when used in conjunction with behavioral measures of auditory speech perception in children with ANSD., Competing Interests: Disclosure of Interest The authors report no conflicts of interest.

This review explores cross-modal cortical plasticity as a result of auditory deprivation in populations with hearing loss across the age spectrum, from development to adulthood. Cross-modal plasticity refers to the phenomenon when deprivation in one sensory modality (e.g. the auditory modality as in deafness or hearing loss) results in the recruitment of cortical resources of the deprived modality by intact sensory modalities (e.g. visual or somatosensory systems). We discuss recruitment of auditory cortical resources for visual and somatosensory processing in deafness and in lesser degrees of hearing loss. We describe developmental cross-modal re-organization in the context of congenital or pre-lingual deafness in childhood and in the context of adult-onset, age-related hearing loss, with a focus on how cross-modal plasticity relates to clinical outcomes. We provide both single-subject and group-level evidence of cross-modal re-organization by the visual and somatosensory systems in bilateral, congenital deafness, single-sided deafness, adults with early-stage, mild-moderate hearing loss, and individual adult and pediatric patients exhibit excellent and average speech perception with hearing aids and cochlear implants. We discuss a framework in which changes in cortical resource allocation secondary to hearing loss results in decreased intra-modal plasticity in auditory cortex, accompanied by increased cross-modal recruitment of auditory cortices by the other sensory systems, and simultaneous compensatory activation of frontal cortices. The frontal cortices, as we will discuss, play an important role in mediating cognitive compensation in hearing loss. Given the wide range of variability in behavioral performance following audiological intervention, changes in cortical plasticity may play a valuable role in the prediction of clinical outcomes following intervention. Further, the development of new technologies and rehabilitation strategies that incorporate brain-based biomarkers may help better serve hearing impaired populations across the lifespan., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Hypothesis: The purpose of this study was to examine changes in cortical development and neuroplasticity in a child with single-sided deafness (SSD) before and after cochlear implantation (CI)., Background: The extent to which sensory pathways reorganize in childhood SSD is not well understood and there is currently little evidence demonstrating the efficacy of CI in children with SSD., Methods: High-density 128-channel electroencephalography (EEG) was used to collect cortical auditory evoked potentials (CAEP), cortical visual evoked potentials (CVEP), and cortical somatosensory evoked potentials (CSSEP) in a child with SSD, pre-CI and at subsequent sessions until approximately 3 years post-CI in her right ear which occurred at age 9.86 years. Behavioral correlates of speech perception and sound localization were also measured., Results: Pre-CI, high-density EEG showed evidence of delayed auditory cortical response morphology, auditory cortical development strongly contralateral (to the normal hearing ear), evidence of increased cognitive load, and cross-modal reorganization by the visual and somatosensory modalities. The post-CI developmental trajectory provided clear evidence of age-appropriate development of auditory cortical responses, and decreased cross-modal reorganization, consistent with improved speech perception and sound localization., Conclusion: Post-CI, the child demonstrated age-appropriate auditory cortical development and improved speech perception and sound localization suggestive of significant benefits from cochlear implantation. Reversal of somatosensory recruitment was clearly apparent, and only a residual amount of visual cross-modal plasticity remained postimplantation. Overall, our results suggest that CI in pediatric SSD patients may benefit from a highly plastic cortex in childhood.

We review evidence for cross-modal cortical re-organization in clinical populations with hearing loss. Cross-modal plasticity refers to the ability for an intact sensory modality (e.g., vision or somatosensation) to recruit cortical brain regions from a deprived sensory modality (e.g., audition) to carry out sensory processing. We describe evidence for cross-modal changes in hearing loss across the age-spectrum and across different degrees of hearing impairment, including children with profound, bilateral deafness with cochlear implants, single-sided deafness before and after cochlear implantation, and adults with early-stage, mild-moderate, age-related hearing loss. Understanding cross-modal plasticity in the context of auditory deprivation, and the potential for reversal of these changes following intervention, may be vital in directing intervention and rehabilitation options for clinical populations with hearing loss.

We review evidence for a high degree of neuroplasticity of the central auditory pathways in early childhood, citing evidence of studies of the P1 and N1 cortical auditory evoked potentials in congenitally deaf children receiving cochlear implants at different ages during childhood, children with auditory neuropathy spectrum disorder and children with hearing loss and comorbid multiple disabilities. We discuss neuroplasticity, including cortico-cortical de-coupling and cross-modal re-organization that occurs in deafness. We provide evidence for the clinical utility of the P1 cortical auditory evoked potential (CAEP) as a non-invasive biomarker that can be used to objectively assess maturation of auditory cortex in clinical cases of cochlear implant patients and candidates. Finally, we present clinical case studies in which the P1 CAEP biomarker proved useful in clinical decision-making regarding intervention in cases of single-sided deafness, auditory neuropathy spectrum disorder, mild hearing loss and hypoplastic auditory nerve.

The global extent and distribution of forest trees is central to our understanding of the terrestrial biosphere. We provide the first spatially continuous map of forest tree density at a global scale. This map reveals that the global number of trees is approximately 3.04 trillion, an order of magnitude higher than the previous estimate. Of these trees, approximately 1.39 trillion exist in tropical and subtropical forests, with 0.74 trillion in boreal regions and 0.61 trillion in temperate regions. Biome-level trends in tree density demonstrate the importance of climate and topography in controlling local tree densities at finer scales, as well as the overwhelming effect of humans across most of the world. Based on our projected tree densities, we estimate that over 15 billion trees are cut down each year, and the global number of trees has fallen by approximately 46% since the start of human civilization.

Clinical trials evaluating medicines, medical devices, and procedures now commonly assess the economic value of these interventions. The growing number of prospective clinical/economic trials reflects both widespread interest in economic information for new technologies and the regulatory and reimbursement requirements of many countries that now consider evidence of economic value along with clinical efficacy. As decision makers increasingly demand evidence of economic value for health care interventions, conducting high-quality economic analyses alongside clinical studies is desirable because they broaden the scope of information available on a particular intervention, and can efficiently provide timely information with high internal and, when designed and analyzed properly, reasonable external validity. In 2005, ISPOR published the Good Research Practices for Cost-Effectiveness Analysis Alongside Clinical Trials: The ISPOR RCT-CEA Task Force report. ISPOR initiated an update of the report in 2014 to include the methodological developments over the last 9 years. This report provides updated recommendations reflecting advances in several areas related to trial design, selecting data elements, database design and management, analysis, and reporting of results. Task force members note that trials should be designed to evaluate effectiveness (rather than efficacy) when possible, should include clinical outcome measures, and should obtain health resource use and health state utilities directly from study subjects. Collection of economic data should be fully integrated into the study. An incremental analysis should be conducted with an intention-to-treat approach, complemented by relevant subgroup analyses. Uncertainty should be characterized. Articles should adhere to established standards for reporting results of cost-effectiveness analyses. Economic studies alongside trials are complementary to other evaluations (e.g., modeling studies) as information for decision makers who consider evidence of economic value along with clinical efficacy when making resource allocation decisions., (Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: The optimal BMI threshold above which gastric bypass surgery should be offered to obese patients is controversial. The objective of this study was to compare the impact of Roux-en-Y gastric bypass (RYGB) vs. diet and exercise (D&E) on life expectancy to find the BMI at which patients experience an improvement in their life expectancy by undergoing surgery., Methods: A Markov state transition model was designed to implement a decision tree that simulated the lives of obese patients. Life expectancies following RYGB and 2 years of D&E were estimated and compared. Ten thousand patients' lives were simulated in each weight-loss intervention group in the model. In addition to base case analysis (45 kg/m(2) BMI pre-intervention), sensitivity analysis of initial BMI at the start of the study was completed. Markov model parameters were extracted from the literature., Results: The impact of RYGB on survival relative to D&E depended on the patient's initial BMI. Compared to patients who underwent 2 years of "optimal" diet and exercise (7 % total body weight loss/year), RYGB improved long-term survival for patients above a BMI of 31.3 kg/m(2)., Conclusions: Roux-en-Y gastric bypass can improve long-term survival for patients with class I obesity. This study suggests that RYGB should not be reserved solely for patients with class II or III obesity.

Objective: First, we review the development and plasticity of the central auditory pathways in infants and children with hearing loss who are fitted with cochlear implants (CIs). Second, we describe case studies demonstrating the clinical utility of the P1 central auditory evoked potential (CAEP) for evaluating cortical auditory maturation in the rapidly increasing number of cochlear-implanted children who have multiple disabilities., Study Design: Children who receive CIs provide a platform to examine the trajectories of deprivation-induced and experience-dependent plasticity in the central auditory system. We review the evidence for, and time limits of sensitive periods for cortical auditory maturation framing an optimal period for cochlear implantation. Finally, we evaluate the use of the P1 biomarker as an objective assessment tool in the special case of children with multiple disabilities., Results: The P1 response was useful in assessing central auditory maturation in patients with CHARGE association, ANSD, and Pallister-Killian Syndrome concomitant with hearing loss., Conclusion: The presence of co-existing disabilities in addition to hearing loss poses unique challenges regarding both pre-intervention evaluation and post-intervention rehabilitation for children with multiple disabilities. When combined with a standard audiological test battery, the P1 CAEP biomarker has a useful role in objectively evaluating the maturation of central auditory pathways to determine the effectiveness of various intervention strategies in hearing-impaired children with multiple disabilities.

Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of α-synuclein due to genetic multiplication or point mutations leads to early onset disease. While α-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of α-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC α-synuclein transgenic mice, which overexpress α-synuclein under regulation of its own promoter, express α-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure α-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of α-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal α-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased α-synuclein and altered phagocytosis may provide a useful biomarker for human PD.

Background: Data on the cost-effectiveness of the behavioral treatment of obesity are not conclusive. The cost-effectiveness of treatment in primary care settings is particularly relevant., Methods: We conducted a within-trial cost-effectiveness analysis of a primary care-based obesity intervention. Study participants were randomized to: Usual Care (UC; quarterly visits with their primary care provider); Brief Lifestyle Counseling (BLC; quarterly provider visits plus monthly weight loss counseling visits) or Enhanced Brief Lifestyle Counseling (EBLC; all above interventions, plus choice of meal replacements or weight loss medication). A health-care payer perspective was used. Intervention costs were estimated from tracking data obtained prospectively. Quality-adjusted life years (QALYs) were estimated with the EuroQol-5D. We estimated cost per kilogram-year of weight loss and cost per QALY., Results: Weight losses after 2 years were 1.7, 2.9 and 4.6 kg for UC, BLC and EBLC, respectively (P=0.003 for comparison of EBLC vs UC). The incremental cost per kilogram-year lost was $292 for EBLC compared with UC (95% confidence interval (CI): $219-$437). The short-term incremental cost per QALY was $115,397, but the 95% CI were undefined. Comparison of short-term cost per kg with published estimates of longer-term cost per QALY suggested that the intervention could be cost-effective over the long term (≥ 10 years)., Conclusions: A primary care intervention that includes monthly counseling visits and a choice of meal replacements or weight loss medication could be a cost-effective treatment for obesity over the long term. However, additional studies are needed on the cost-effectiveness of behavioral treatment of obesity.

To estimate per-person and aggregate direct medical costs of overweight and obesity and to examine the effect of study design factors. PubMed (1968-2009), EconLit (1969-2009) and Business Source Premier (1995-2009) were searched for original studies. Results were standardized to compute the incremental cost per overweight person and per obese person, and to compute the national aggregate cost. A total of 33 US studies met review criteria. Among the four highest-quality studies, the 2008 per-person direct medical cost of overweight was $266 and of obesity was $1723. The aggregate national cost of overweight and obesity combined was $113.9 billion. Study design factors that affected cost estimates included use of national samples vs. more selected populations, age groups examined, inclusion of all medical costs vs. obesity-related costs only, and body mass index cut-offs for defining overweight and obesity. Depending on the source of total national healthcare expenditures used, the direct medical cost of overweight and obesity combined is approximately 5.0% to 10% of US healthcare spending. Future studies should include nationally representative samples, evaluate adults of all ages, report all medical costs and use standard body mass index cut-offs., (© 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.)

Heart failure (HF) afflicts nearly 6 million Americans and the prevalence continues to rise as the population ages. Hospital use for HF is high and about half of readmissions are believed to be preventable. Promoting self care through telehomecare is an emerging strategy for managing chronic illness. Hospitalized heart failure patients were randomly assigned at discharge to receive usual home care or telehomecare, nurse visits and daily use of monitoring devices such as blood pressure cuffs, scales, glucometers, and pulse oximetry to monitor their symptoms. Nurses at the home care agency monitored the results and interacted with patients as needed to teach self care and treat symptoms. Self care was measured at baseline, 60, 120, and 180 days using the Self Care Heart Failure Index. Despite improving the overall readmission rate, findings suggest telehomecare had no significant effect on self care over usual home care.

Objective: To examine the effect of a lifestyle intervention to produce weight loss and increased physical fitness on use and cost of medications to treat cardiovascular disease (CVD) risk factors in people with type 2 diabetes., Research Design and Methods: Look AHEAD is a multicenter randomized controlled trial of 5,145 overweight or obese individuals with type 2 diabetes, aged 45-76 years. An intensive lifestyle intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared with a diabetes support and education (DSE) condition. Medications prescribed to treat diabetes, hypertension, and hyperlipidemia were compared at baseline and 1 year. Medication costs were conservatively estimated using prices from a national online pharmacy., Results: Participants randomized to an ILI had significantly greater improvements in CVD risk parameters and reduced medication use and cost compared with those assigned to DSE. At 1 year, average number of medications prescribed to treat CVD risk factors was 3.1 +/- 1.8 for the ILI group and 3.6 +/- 1.8 for the DSE group (P < 0.0001), with estimated total monthly medication costs of $143 and $173, respectively (P < 0.0001). DSE participants meeting optimal care goals at 1 year were taking an average of 3.8 +/- 1.6 medications at an estimated cost of $194/month. ILI participants at optimal care required fewer medications (3.2 +/- 1.7) at lower cost ($154/month) (P < 0.001)., Conclusions: At 1 year, ILI significantly improved CVD risk factors, while at the same time reduced medication use and cost. Continued intervention and follow-up will determine whether these changes are maintained and reduce cardiovascular risk.

The TOwards a Revolution in COPD Health (TORCH) study was a 3-yr multicentre trial of 6,112 patients randomised to salmeterol (Salm), fluticasone propionate (FP), a Salm/FP combination (SFC) or placebo (P). Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed. For four regions, 3-yr all-cause hospitalisation, medication and outpatient care costs were calculated. The sample was restricted to the 21 countries (n = 4,237) in which European quality of life five-dimension (EQ-5D) data were collected in order to estimate the number of quality-adjusted life years (QALYs). Regression models were fitted to survival, study medication cost, other medication cost and EQ-5D data in order to estimate total cost, number of QALYs and cost per QALY, adjusted for missing data and region. SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars (USD) compared with P (95% confidence interval 21,400-123,500 USD). Estimates for Salm versus P (197,000 USD) and FP versus P (78,000 USD) were less favourable. The US estimates were greater than those from other regions; for SFC versus P, the cost per QALY was 77,100 (46,200-241,700) USD compared to 24,200 (15,200-56,100) USD in Western Europe. Compared with P, SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone, and is, therefore, preferred to these monotherapies on the grounds of cost-effectiveness.

This article provides an overview of the central issues regarding cost valuation and analysis for a decision maker's evaluation of costing performed within randomized controlled trials (RCTs). Costing involves specific choices for valuation and analysis that involve trade-offs. Understanding these choices and their implications is necessary for proper evaluation of how costs are valued and analyzed within an RCT and cannot be assessed through a checklist of adherence to general principles. Resource costing, the most common method of costing, involves measuring medical service use in study case report forms and translating this use into a cost by multiplying the number of units of each medical service by price weights for those services. A choice must be made as to how detailed the measurement of resources will be. Micro-costing improves the specificity of the cost estimate, but it is often impractical to precisely measure resources at this level and the price weights for these micro-units may not be available. Gross-costing may be more practical, and price weights are often easier to find and are more reliable, but important resource differences between treatment groups may be lost in the bundling of resources. Price weights can either be nationally determined or centre specific, but the appropriate price weight will depend on perspective, convenience, completeness and accuracy. Identifying the resource types and the appropriate price weights for these resources are the essential elements to an accurate valuation of costs. Once medical services are valued, the resulting individual patient cost estimates must be analysed. The difference in the mean cost between treatment groups is the important summary statistic for cost-effectiveness analysis from both the budgetary and the social perspectives. The statistical challenges with cost data typically stem from its skewed distribution and the resulting possibility that the sample mean may be inefficient and possibly inappropriate for statistical inference. Multivariable analysis of cost is useful, even if the data come from an RCT, but the same distributional problems that affect univariate tests of cost also affect use of cost as a dependent variable in a multivariable regression analysis. The generalized linear model (GLM) overcomes many of the problems of more common cost models, but caution must be used when applying this model because it is prone to mis-specification and precision losses in data with a heavy-tailed log error term. Attention to the appropriate cost valuation and analysis techniques reviewed here will help bring the same level of rigor and attention to the methodological issues in cost valuation as is currently applied to clinical evidence within RCTs.

Mytilus californianus foot protein three (Mcfp-3) was successfully expressed in the yeast, Kluyveromyces lactis. The first nine amino acids (YPYDVPDYA) from the human-influenza-virus hemagglutinin (HA) protein were fused to the amino terminus of Mcfp-3 (HA-Mcfp-3) to facilitate identification and purification. HA-Mcfp-3 was purified to a concentration of 1mg/L using HA affinity chromatography. The recovered polypeptide was resolved by SDS-PAGE and migrated primarily at 36 kDa, an increase of approximately 29 kDa over the calculated molecular weight of a HA-Mcfp-3 monomer. Significantly, release of Mcfp-3 by enterokinase treatment coincided with the formation of high molecular weight complexes. It is noteworthy that the complexes mimicked the previously reported insolubility of Mcfps found in vivo to denaturing and reducing conditions. These data demonstrate the successful expression of Mcfp-3 in K. lactis and show an intrinsic ability of Mcfp-3 to self-assemble into stable, higher molecular weight forms.

Objective: The study addressed whether a collaborative model for chronic care, described in part I (this issue), improves outcome for bipolar disorder., Methods: The intervention was designed to improve outcome by enhancing patient self-management skills with group psychoeducation; providing clinician decision support with simplified practice guidelines; and improving access to care, continuity of care, and information flow via nurse care coordinators. In an effectiveness design veterans with bipolar disorder at 11 Veterans Affairs hospitals were randomly assigned to three years of care in the intervention or continued usual care. Blinded clinical and functional measures were obtained every eight weeks. Intention-to-treat analysis (N=306) with mixed-effects models addressed the hypothesis that improvements would accrue over three years, consistent with social learning theory., Results: The intervention significantly reduced weeks in affective episode, primarily mania. Broad-based improvements were demonstrated in social role function, mental quality of life, and treatment satisfaction. Reductions in mean manic and depressive symptoms were not significant. The intervention was cost-neutral while achieving a net reduction of 6.2 weeks in affective episode., Conclusions: Collaborative chronic care models can improve some long-term clinical outcomes for bipolar disorder. Functional and quality-of-life benefits also were demonstrated, with most benefits accruing in years 2 and 3.

Outcome for bipolar disorder remains suboptimal despite the availability of efficacious treatments. To improve treatment effectiveness in clinical practice, a Veterans Affairs study team created a care model conceptually similar to the lithium clinics of the 1970s but augmented by principles of more recent collaborative care models for chronic medical illnesses. This intervention consists of improving patients' self-management skills through psychoeducation; supporting providers' decision making through simplified practice guidelines; and enhancing access to care, continuity of care, and information flow through the use of a nurse care coordinator. In this article, which is part I of a two-part report, the authors summarize the conceptual background and development of the intervention, describe the design of a three-year, 11-site randomized effectiveness trial, and report data describing its successful implementation. Trial design emphasized aspects of effectiveness to support generalizability of the findings and eventual dissemination of the intervention. Part II (see companion article, this issue) reports clinical, functional, and overall cost outcomes of the trial.

Objectives: A growing number of prospective clinical trials include economic end points. Recognizing the variation in methodology and reporting of these studies, the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) chartered the Task Force on Good Research Practices: Randomized Clinical Trials-Cost-Effectiveness Analysis. Its goal was to develop a guidance document for designing, conducting, and reporting cost-effectiveness analyses conducted as a part of clinical trials., Methods: Task force cochairs were selected by the ISPOR Board of Directors. Cochairs invited panel members to participate. Panel members included representatives from academia, the pharmaceutical industry, and health insurance plans. An outline and a draft report developed by the panel were presented at the 2004 International and European ISPOR meetings, respectively. The manuscript was then submitted to a reference group for review and comment., Results: The report addresses issues related to trial design, selecting data elements, database design and management, analysis, and reporting of results. Task force members agreed that trials should be designed to evaluate effectiveness (rather than efficacy), should include clinical outcome measures, and should obtain health resource use and health state utilities directly from study subjects. Collection of economic data should be fully integrated into the study. Analyses should be guided by an analysis plan and hypotheses. An incremental analysis should be conducted with an intention-to-treat approach. Uncertainty should be characterized. Manuscripts should adhere to established standards for reporting results of cost-effectiveness analyses., Conclusions: Trial-based cost-effectiveness studies have appeal because of their high internal validity and timeliness. Improving the quality and uniformity of these studies will increase their value to decision makers who consider evidence of economic value along with clinical efficacy when making resource allocation decisions.

Background: Classification of patients with unstable angina (UA) by Agency for Health Care Policy and Research (AHCPR) guidelines in the emergency department reliably stratifies risk of death or myocardial infarction (MI) for triage to outpatient evaluation (low-risk), hospitalization (high-risk), or additional testing (intermediate-risk). Cardiac troponin-I elevation may identify patients at higher risk, but the incremental value may vary with AHCPR clinical risk., Hypothesis: The objective of this study was to determine whether cardiac troponin-I had any additional value beyond triage based upon history, physical examination, and electrocardiogram, in the evaluation of patients with UA., Methods: In all, 212 consecutive patients with UA and normal serum creatine kinase (CK)-MB levels and elevated troponin-I were risk stratified by AHCPR guidelines to evaluate the incremental value of adding routine troponin-I measurements to our current model for risk stratification., Results: Primary events (death/nonfatal MI) occurred in 35% of high-risk, 15% of intermediate-risk, and 0% of low-risk patients (p < 0.001 by chi-square for trend). High troponin-I (> or =2.0 ng/dl) occurred in 48% of high-risk, 21% of intermediate-risk, and 19% of low-risk patients. The remaining patients in each risk group had indeterminate troponin-I levels (> or =0.4 < 2 ng/dl). Of those with high troponin-I, a primary event occurred in 36, 42, and 0% in the respective high-, intermediate-, and low-risk groups (p < 0.001). High troponin-I levels corresponded with a statistically significant increased rate of primary events only in patients at AHCPR intermediate risk: 42.4 vs. 7.3%, p < 0.001., Conclusion: The AHCPR guidelines risk stratify patients with UA. High troponin-I adds significant (p < 0.001) prognostic value in the patients at AHCPR intermediate risk and should be evaluated further in larger trials of such patients.

Objective: To determine whether newborn screening by tandem mass spectrometry (MS/MS) for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is cost-effective versus not screening and to define the contributions of disease, test, and population parameters on the decision., Methods: A decision-analytic Markov model was designed to perform cost-effectiveness and cost-utility analyses measuring the discounted, incremental cost per life-year saved and per quality-adjusted life-year saved of newborn screening for MCADD compared with not screening. A hypothetical cohort of neonates made transitions among a set of health states that reflected clinical status, morbidity, and cost. Outcomes were estimated for time horizons of 20 and 70 years. Probabilities and costs were derived from a retrospective chart review of a 32-patient cohort treated over the past 30 years at the Children's Hospital of Philadelphia, clinical experience with MCADD patient management, patient-family interviews, cost surveys, state sources, and published studies. In addition to older patients who came to medical attention by symptomatic presentation, our patient group included 6 individuals whose MCADD had been diagnosed by supplemental newborn screening. Estimates of the expected net changes in costs and life expectancy for MCADD screening were used to compute the incremental cost-effectiveness ratios. Sensitivity analyses were performed on key input variables, and 95% confidence intervals (CIs) were computed through second-order Monte Carlo simulations., Results: In our base-case analysis over the first 20 years of life, the cost of newborn screening for MCADD was approximately 11,000 dollars(2001 US dollars; 95% CI: <0-33,800 dollars) per life-year saved, or 5600 dollars (95% CI: <0-17,100 dollars) per quality-adjusted life-year saved compared with not screening. Over a 70-year horizon, the respective ratios were approximately 300 dollars (95% CI: <0-13,000 dollars) and 100 dollars (95% CI: <0-6900 dollars). The results were robust when tested over plausible ranges for diagnostic test sensitivity and specificity, MCADD prevalence, asymptomatic rate, and screening cost., Conclusions: Simulation modeling indicates that newborn screening for MCADD reduces morbidity and mortality at an incremental cost below the range for accepted health care interventions. At the 70-year horizon, the model predicts that almost all of the additional costs of screening would be offset by avoided sequelae.

Background: Low-density lipoprotein (LDL)-based guidelines are currently used to initiate and monitor cholesterol-lowering therapy., Methods: Using stratified analyses, data from the Framingham Heart Study and the Coronary Primary Prevention Trial were evaluated to determine whether (1) cholesterol levels (total cholesterol [TC] or LDL [low-density lipoprotein]) better discriminated risk for coronary heart disease (CHD) than cholesterol ratios (LDL/HDL [high-density lipoprotein] or TC/HDL); and (2) whether changes in ratios better predicted risk reduction than changes in levels., Results: Individuals with similar LDL/HDL ratios had similar risks for CHD regardless of whether they had high LDL levels or low LDL levels (23% vs 23% for the CPPT, 13.8% vs 14% for FHS men, and 8.6% vs 10.9% for FHS women). Among men with similar initial LDL/HDL ratios and similar changes in LDL/HDL ratios, risks for CHD did not differ (20.3% compared with 21.0%; p =0.96) between those with the largest and smallest reductions in LDL levels (21.3% compared with 6.5%). Among men with similar initial LDL levels and similar LDL reductions, a 20% reduction in risk for CHD was seen (19.5% compared with 24.5%; p =0.005) between those with the largest and smallest reductions in LDL/HDL ratios (23% compared with 4.6%). TC/HDL had predictive ability similar to LDL/HDL., Conclusions: Cholesterol levels do not provide incremental predictive value over cholesterol ratios in identifying people at risk for CHD. Changes in ratios are better predictors of successful CHD risk reduction than changes in levels. Future guidelines should consider incorporating ratios in initiating and monitoring successful lipid-lowering therapy.

Because of the potential for large variability among countries in the utilization and cost of health care resources, it is important to assess the appropriateness of combining economic data across the countries in a multinational clinical economic trial. We show how available tests for interaction can be applied to economic endpoints, including cost-effectiveness ratios and net health benefits. This analysis includes a characterization of possible interactions being quantitative or qualitative in nature. In the absence of interaction, a pooled estimate of the economic endpoint should be representative of the participating countries. We explore the analytic issues by further analysing data from the Scandinavian Simvastatin Survival Study (4S)., (Copyright 2003 John Wiley & Sons, Ltd.)

We performed an economic analysis of data from 180 women in a clinical trial of conventional-dose chemotherapy vs high-dose chemotherapy plus stem-cell transplantation for metastatic breast cancer responding to first-line chemotherapy. Data on resource use, including hospitalizations, medical procedures, medications, and diagnostic tests, were abstracted from subjects' clinical trial records. Resources were valued using the Medicare Fee Schedule for inpatient costs at one academic medical center and average wholesale prices for medications. Monthly costs were calculated and stratified by treatment group and clinical phase. Mean follow-up was 690 days in the transplantation group and 758 days in the conventional-dose chemotherapy group. Subjects in the transplantation group were hospitalized for more days (28.6 vs 17.8, P=0.0041) and incurred higher costs (US dollars 84055 vs US dollars 28169) than subjects receiving conventional-dose chemotherapy, with a mean difference of US dollars 55886 (95% CI, US dollars 47298-US dollars 63666). Sensitivity analyses resulted in cost differences between the treatment groups from US dollars 36528 to US dollars 75531. High-dose chemotherapy plus stem-cell transplantation resulted in substantial additional morbidity and costs at no improvement in survival. Neither the survival results nor the economic findings support the use of this procedure outside of the clinical trial setting.

Alcohol treatment services are increasingly combined with other health and social services to address the needs of multiple-problem clients. Hence, it has been of growing policy interest to find the most effective and the most cost-effective ways of linking these services. This symposium presents some recent studies in this area. The small but growing body of studies in this area has great potential to inform public policy debates.

Despite the availability of efficacious treatments for bipolar disorder, their effectiveness in general clinical practice is greatly attenuated, resulting in what has been called an 'efficacy-effectiveness gap'. In designing VA Cooperative Studies Program (CSP) Study #430 to address this gap, nine principles for conducting an effectiveness (in contrast to an efficacy) study were identified. These principles are presented and discussed, with specific aspects of CSP #430 serving as illustrations of how they can be implemented in an actual study. CSP #430 hypothesizes that an integrated, clinic-based treatment delivery system that emphasizes (1) algorithm-driven somatotherapy, (2) standardized patient education, and (3) easy access to a single primary mental health care provider to maximize continuity-of-care, will address the efficacy-effectiveness gap and improve disease, functional, and economic outcome. It is an 11-site, randomized controlled clinical trial of this multi-modal, clinic-based intervention versus usual VA care running from 1997 to 2003. The trial has enrolled 191 subjects in each arm, using minimal exclusion criteria to maximize the external validity of the study. Subjects are followed for 3 years. The intervention is highly specified in a series of operations manuals for each of the three components. Several continuous quality improvement (CQI) interventions, process measures, and statistical techniques deal with drift of care in both the intervention and usual care arms to ensure the internal validity of the study. CSP #430 is designed to have impact well beyond the VA, since it evaluates a basic health care operational principle: that augmenting ambulatory access for major mental illness will improve outcome and reduce overall treatment costs. If results are positive, this study will provide a reason to reconsider the prevailing trend toward limitation of ambulatory services that is characteristic of many managed care systems today.

In the last decade, major advances have been made in the statistical methods for quantifying uncertainty in stochastic cost-effectiveness studies. In this paper, we provide a guide to the literature in which we highlight the preferred methods for confidence interval estimation, new developments in the formulation of the cost-effectiveness problem, suggested ways for presenting results and the areas in which future research may develop. The overall approach taken is nontechnical, with an emphasis on graphical rather than algebraic presentation of methods.

Objective: To utilize health services research techniques in developing an episode of care using an administrative data set. This method is demonstrated for an episodic clinical condition, migraine., Data Sources: Medicaid administrative data set of 3,372 patients with a diagnosis of migraine (ICD-9-CM 346.0, 346.1) in the state of Pennsylvania between May 1990 and March 1992., Study Design: The duration of a migraine episode was measured by assessing the magnitude of resource utilization and the proportion of patients with charges in the period after the index migraine as compared to the period before the index migraine. A confidence interval (CI) was developed around each measure using bootstrap techniques., Data Collection Methods: All charge data were extracted daily for a 113-day observation period surrounding each index migraine in order to observe the duration of impact of a migraine diagnosis on resource utilization., Principal Findings: The lower limits of both the 95% and 99% CIs for the difference in charges are greater than 0 for three weeks. The lower limits of both CIs for the difference in the proportion of patients with charges are above 0 for six weeks., Conclusions: Our analysis demonstrates that a health services research framework can be used to define an episode of care for a chronic disease category such as migraine. This method can be used to evaluate episodes of care for clinical studies of limited or episodic conditions and to complement clinical expertise in developing time horizons for clinical trials.

In distinction to the classic conceptualization of mania and hypomania, a growing body of work indicates that these episodes are not typically characterized by euphoric mood and sense of increased well-being, but rather by significant dysphoric symptoms. However, few data exist concerning self-perceived quality of life in mania or hypomania. Such data are important both for better understanding of the illness, and are particularly important for developing appropriate cost-utility studies. Accordingly, we hypothesized that two measures of self-reported quality of life, the mental subscale of the Short Form-12 (SF-12) and the EuroQol, would show reduced quality of life in patients in manic/hypomanic or mixed episodes, compared to those who were euthymic. Eighty-six patients with bipolar disorder from four Department of Veterans Affairs (VA) medical centers were assessed in a cross-sectional design. Mood state was categorized by physician diagnosis and separately by patient self-report using the Internal State Scale (ISS). Self-reported quality of life was quantified using the SF-12 and EuroQol. Findings were identical regardless of how mood state was determined. The SF-12 mental subscale and EuroQol differed significantly across mood states. Patients with mania/hypomania were either less than (SF-12 mental subscale) or equal to (EuroQol) euthymic patients, while patients in a mixed episode resembled those in a depressive episode on both indices. In contrast, SF-12 physical subscale scores showed no intergroup differences. These quality-of-life data provide further support for the conceptualization that mania and hypomania are syndromes characterized by reduced, rather than increased, sense of well-being and quality of life. Moreover, depressive symptoms appear to be the primary determinant of quality of life in bipolar disorder, although other factors may be associated with both depression and reduced quality of life in bipolar disorder., (Copyright 2001 by W.B. Saunders Company)

In a community-based cross-sectional study of 297 children aged 6 months to 6 years in an Indian city, the authors assessed the prevalence of elevated (> or = 10 microg/dL) blood lead (PbB) levels, their risk factors, and the lead contents in potential environmental sources. Mean PbB was 18.4 microg/dL +/- 16.5. The prevalence of elevated PbB was 67%. Anticipated risk factors for elevated PbB were living in houses painted with lead-based paint, odds ratio (OR) 6.42 (1.75, 23.6; p = 0.005), recent exposures to lead-based paint, OR 2.61 (1.07, 6.66; p = 0.03), and the use of the eye cosmetic ma," OR 2.63 (1.24, 5.56; p = 0.01). Unanticipated results were effect of upper caste as a risk factor, OR (adjusted) 1.85 (95% CI = 0.96, 3.57; p = 0.06), and the lack of effect of traffic, parental occupational exposure, or nutritional status. Analysis of various environmental sources such as paint, pencils, crayons, and clay revealed high lead levels. These results demonstrate the existence of a major environmental health problem in Indian children, with risk factors that differ from those in other countries.

Study Objective: To compare hospital length of stay (LOS), weekly discharges, and days of antibiotic treatment with linezolid (intravenous with oral follow-up) and vancomycin (intravenous only)., Design: Multinational, randomized, phase III trial., Settings: Hospitals in North America, Latin America, and Europe., Patients: Four hundred sixty hospitalized patients with infections of known or suspected methicillin-resistant Staphylococcus species., Intervention: Administration of linezolid or vancomycin., Measurements and Main Results: For linezolid recipients, median LOS was 5 and 8 days shorter (p=0.05 and 0.003) in the complicated skin and soft tissue infection intent-to-treat (230 patients) and clinically evaluable (144) samples, and slightly but not significantly shorter in the overall intent-to-treat (460) and clinically evaluable (254) samples. In all samples, linezolid recipients had more discharges in the first week of treatment and fewer days of intravenous therapy than vancomycin recipients., Conclusion: Our results support linezolid's ability to reduce medical resource use.

Objective: General health state classification systems, such as the EuroQol instrument, have been developed to improve the systematic measurement and comparability of health state preferences. In this paper we generate valuations for EuroQol health states using responses to this instrument's visual analogue scale made by patients enrolled in a randomized clinical trial evaluating tirilazad mesylate, a new drug used to treat subarachnoid haemorrhage. We then compare these valuations derived from patients with published valuations derived from responses made by a sample from the general public., Methods: The data were derived from two sources: (1) responses to the EuroQol instrument from 649 patients 3 months after enrollment in the clinical trial, and (2) from a published study reporting a scoring rule for the EuroQol instrument that was based upon responses made by the general public. We used a linear regression model to develop an additive scoring rule. This rule enables direct valuation of all 243 EuroQol health states using patients' scores for their own health states elicited using a visual analogue scale. We then compared predicted scores generated using our scoring rule with predicted scores derived from a sample from the general public., Results: The predicted scores derived using the additive scoring rules met convergent validity criteria and explained a substantial amount of the variation in visual analogue scale scores (R(2)=0.57). In the pairwise comparison of the predicted scores derived from the study sample with those derived from the general public, we found that the former set of scores were higher for 223 of the 243 states. Despite the low level of correspondence in the pairwise comparison, the overall correlation between the two sets of scores was 87%., Conclusions: The model presented in this paper demonstrated that scoring weights for the EuroQol instrument can be derived directly from patient responses from a clinical trial and that these weights can explain a substantial amount of variation in health valuations. Scoring weights based on patient responses are significantly higher than those derived from the general public. Further research is required to understand the source of these differences., (Copyright 2001 John Wiley & Sons, Ltd.)

Objective: The Internal State Scale (ISS) is a self-report instrument that has been validated for discriminating mood states in patients with bipolar disorder. This study a) extends investigation to a multisite public sector sample and b) tests a revised scoring algorithm that formally identifies patients in mixed states., Methods: Eighty-six patients with bipolar disorder from four Veterans Affairs medical centers were assessed in a cross-sectional design. Physician-conducted semi-structured interviews used DSM-IV criteria to identify subjects as meeting criteria for euthymia, mania or hypomania, depression, or mixed state (mania or hypomania plus depression). A revised ISS scoring algorithm independently assigned mood state. Mean subscale scores were analyzed across groups. Receiver-operating characteristic (ROC) curve analysis was conducted to determine optimal algorithm structure., Results: Analysis of mean scores for the ISS subscales replicated original results for Activation, Well-Being, and Perceived Conflict, but indicated differences from the original results for the Depression Index. The ROC curve analysis identified optimal cut-off scores for the revised algorithm. The overall kappa score indicated moderate agreement between ISS and physician ratings of mood state, including mixed states., Limitations: The study used a sample consisting primarily of male veterans. Mood state was assigned by experts using expert clinician diagnosis, not structured interviews., Conclusion: The performance of the ISS in this multisite, public sector sample was similar to the performance in the initial research clinic sample. This finding confirms the validity of the ISS as a discriminator of mood states in bipolar disorder. The development of a revised scoring algorithm makes feasible formal identification of mixed episodes with the ISS.

Objective: To describe the types and costs of care received for 10 years after the identification of an older person with suspected Alzheimer's disease (AD) by using data from 3254 patients with suspected AD who participated in the National Long Term Care Survey (NLTCS)., Methods: By using a Markov model derived using grade of membership techniques, the following were determined: survival probabilities at 10 years; years of survival during the 10 years; years in institutions; years with two or more impairments in basic activities of daily living; hours of paid and informal care while the older person lived in the community; and costs of paid community, institutional, and medical care., Results: Greater degrees of cognitive impairment present when AD was identified were associated with reduced predicted probability of surviving 10 years, increased predicted number of years spent in institutions, increased hours of care required while affected individuals remained in the community, and increased costs of paid community, institutional, and medical care. Substantial differences between men and women were seen: severity-adjusted 10-year costs were almost two times higher for women with AD than for men ($75,000 compared with $44,000); according to sensitivity analysis, average 10-year costs might be as high as $109,000 for women and $67,000 for men., Conclusions: AD imposes a substantial burden on older persons. Interventions that slow the progression of the disease may therefore affect community survival as well as healthcare costs.

Background: Although surrogate markers such as CD4 counts and viral burden (HIV-1 RNA) are predictive of AIDS-related disease progression, little is known about the relationship between changes in surrogate markers and health-related quality of life (HRQOL) outcomes. This study investigated how changes in CD4/mm3 and viral burden (RNA copies/mL) are related to changes in HRQOL as indexed by the Medical Outcomes Study HIV Health Survey (MOS-HIV-30)., Methods: Subjects were HIV-1-infected patients with CD4 counts <300/mm3 enrolled in a double-blind, randomized clinical trial of delavirdine. As part of the clinical protocol, patients completed the MOS-HIV-30, from which the Physical Health (PHS) and Mental Health (MHS) summary scores were used for analyses. HRQOL and surrogate marker data assessed up to 2 years after randomization were analyzed for a total of 1,112 patients., Results: Individual patients' initial status (intercepts) and rates of change (slopes) over time for log CD4, log RNA, PHS, and MHS were estimated with the use of empirical Bayes. Early response to treatment correlated with HRQOL better for RNA than for CD4. However, the relationship between weekly change and HRQOL was stronger for CD4 than for RNA., Conclusions: Surrogate markers are significantly associated with HRQOL outcomes. Improvements in HRQOL over time are associated with lower initial viral load and with increases in CD4 counts. Limitations concerning the restricted variability of the change scores are addressed.

Objective: Amid changes in the organization and financing of health care, health care decision makers are increasingly interested in episodes of care. We sought to determine an episode of care for diabetic foot ulcer using an administrative claims database., Research Design and Methods: We used 1993-1995 claims data to assess resource utilization for privately insured patients with diabetic foot ulcers. Over a 26-week period, we determined the episode length by comparing differences in average daily charges and proportion of patients with charges before and after foot ulcer diagnosis. All 13 weeks before diagnosis were used to calculate baseline values. Significance was determined by CIs, which were calculated by a nonparametric bootstrap technique. Costs associated with the episode were also calculated. A sensitivity analysis using weeks with highest and lowest values as baseline was also conducted., Results: Based on average daily charges, the episode of care for diabetic foot ulcer was 5 weeks. Using proportion of patients with charges, the episode was longer than 13 weeks. The cost for an episode of care ranged from $900 to $2,600. In the sensitivity analyses, episodes of care ranged from 1 to 13 weeks., Conclusions: Episodes of care can be defined by the period beginning with increased resource consumption and ending when resource consumption returns to baseline levels. With the growth of managed care and disease management programs, episode-of-care analysis may have an increasingly important role in health care provision and delivery.