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Recent documents in eScholarship@UMMS
Updated: 1 week 4 days ago

The Science and Psychology of Infertility

Fri, 06/27/2014 - 2:56pm

An evidence-based presentation on the science/etiologies of infertility and its psychological impact. Outline: Prevalence and Etiology of Infertility. Basic Evaluation. Treatment Options. Psychological Effects of Infertility. Depression/Anxiety. Social, Cultural, and Gender Issues. Relationship Issues. Patient Distress and Pregnancy Rates. Psychological Support. Evidence-Based Psychological Interventions.

Preoperative Pain and Function Profiles Reflect Consistent TKA Patient Selection Among US Surgeons

Fri, 06/27/2014 - 11:29am

BACKGROUND: As the number of primary total knee arthroplasties (TKAs) performed in the United States increases, policymakers have questioned whether the indications and timing of TKA have evolved so that surgery is offered earlier.

QUESTIONS/PURPOSES: We analyzed data from a US national TKA cohort to evaluate variation in surgeon selection criteria for elective unilateral TKA based on preoperative patient-reported pain and function scores.

METHODS: Preoperative SF-36 (Physical Component Summary [PCS]/physical function) scores and Knee Injury and Osteoarthritis Outcome Score (KOOS) (pain, activities of daily living/function) of 4900 patients undergoing elective unilateral TKA enrolled in this national database of prospectively followed patients from 22 states were evaluated. The 25(th), 50(th), and 75(th) percentile pain and function scores for patients cared for in 24 orthopaedic offices with 20 or more patients in the database were compared to assess whether consistent preoperative criteria are used in selecting patients undergoing TKA across settings.

RESULTS: The preoperative global function (PCS median, 32.6; national norm, 50; SD, 10) and knee-specific function (KOOS median, 51.5; maximum score, 100; SD, 17) percentile scores represented substantial patient disability, because both values approached 2 SDs below ideal. Consistency in patients across 24 surgeon offices, and more than 100 surgeons, was noted because site-specific medians varied from the national median by less than the minimum clinically important change.

CONCLUSIONS: These data suggest that despite the rapidly growing use of TKA, surgeons in the participating sites use consistent patient criteria in scheduling TKA. Today's patients report significant pain and disability, supporting the need for TKA.

Childhood maltreatment, emotional dysregulation, and psychiatric comorbidities

Thu, 06/26/2014 - 2:31pm

Affect dysregulation, defined as the impaired ability to regulate or tolerate negative emotional states, has been associated with interpersonal trauma and posttraumatic stress. Affect-regulation difficulties play a role in many psychiatric conditions, including anxiety and mood disorders, and especially major depression in youth and bipolar disorder throughout the life span. Exposure to traumatic events and interpersonal trauma in childhood is associated with wide-ranging psychosocial, developmental, and medical impairments in children, adolescents, and adults, with emotional dysregulation being a core feature that may help to account for this heightened risk. In order to understand how the developmental effects of childhood maltreatment contribute to emotional dysregulation and psychiatric sequelae, we review emotional regulation and its developmental neurobiology, and examine the research evidence of associations between childhood trauma, emotional dysregulation, and psychiatric comorbidities in children, adolescents, and adults.

Teaching tobacco dependence treatment and counseling skills during medical school: rationale and design of the Medical Students helping patients Quit tobacco (MSQuit) group randomized controlled trial

Wed, 06/25/2014 - 9:20am

INTRODUCTION: Physician-delivered tobacco treatment using the 5As is clinically recommended, yet its use has been limited. Lack of adequate training and confidence to provide tobacco treatment is cited as leading reasons for limited 5A use. Tobacco dependence treatment training while in medical school is recommended, but is minimally provided. The MSQuit trial (Medical Students helping patients Quit tobacco) aims to determine if a multi-modal and theoretically-guided tobacco educational intervention will improve tobacco dependence treatment skills (i.e. 5As) among medical students.

METHODS/DESIGN: 10 U.S. medical schools were pair-matched and randomized in a group-randomized controlled trial to evaluate whether a multi-modal educational (MME) intervention compared to traditional education (TE) will improve observed tobacco treatment skills. MME is primarily composed of TE approaches (i.e. didactics) plus a 1st year web-based course and preceptor-facilitated training during a 3rd year clerkship rotation. The primary outcome measure is an objective score on an Objective Structured Clinical Examination (OSCE) tobacco-counseling smoking case among 3rd year medical students from schools who implemented the MME or TE.

DISCUSSION: MSQuit is the first randomized to evaluate whether a tobacco treatment educational intervention implemented during medical school will improve medical students' tobacco treatment skills. We hypothesize that the MME intervention will better prepare students in tobacco dependence treatment as measured by the OSCE. If a comprehensive tobacco treatment educational learning approach is effective, while also feasible and acceptable to implement, then medical schools may substantially influence skill development and use of the 5As among future physicians.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

A Qualitative Exploration of Smoking Influences and Quit Attempts among Nondaily Smokers

Wed, 06/25/2014 - 9:20am

Objectives: We examined social cognitive constructs in relation to nondaily smoking and cessation-related behaviors in a community sample of adult nondaily smokers (>24 years of age).

Methods: We conducted six focus groups using a semi-structured interview format. Participants were 28 African-American and 24 white nondaily smokers.

Results: Participants described a sense of control over their smoking but previous failed quit attempts had negative implications for self-efficacy. Participants perceived themselves as reducing their health risks relative to daily smokers. Potential impediments to quitting include social influences to smoke and skepticism of using smoking cessation medications.

Conclusions: Smoking cessation messaging should specifically address nondaily smoking. Targeted health communications may help increase relevance to nondaily smokers and increase treatment utilization.

Debi Lang and Sharon Grundel on Youth Program Ingredients: How to Measure Success and Tell the Story

Tue, 06/24/2014 - 3:59pm

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

Judy Savageau and Kathy Muhr on Working with Different Data Sources

Tue, 06/24/2014 - 3:59pm

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

Caenorhabditis elegans metabolic gene regulatory networks govern the cellular economy

Mon, 06/23/2014 - 3:50pm

Diet greatly impacts metabolism in health and disease. In response to the presence or absence of specific nutrients, metabolic gene regulatory networks sense the metabolic state of the cell and regulate metabolic flux accordingly, for instance by the transcriptional control of metabolic enzymes. Here, we discuss recent insights regarding metazoan metabolic regulatory networks using the nematode Caenorhabditis elegans as a model, including the modular organization of metabolic gene regulatory networks, the prominent impact of diet on the transcriptome and metabolome, specialized roles of nuclear hormone receptors (NHRs) in responding to dietary conditions, regulation of metabolic genes and metabolic regulators by miRNAs, and feedback between metabolic genes and their regulators.

Defining functional DNA elements in the human genome

Mon, 06/23/2014 - 3:50pm

With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.

Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription

Mon, 06/23/2014 - 3:49pm

A new level of chromosome organization, topologically associating domains (TADs), was recently uncovered by chromosome conformation capture (3C) techniques. To explore TAD structure and function, we developed a polymer model that can extract the full repertoire of chromatin conformations within TADs from population-based 3C data. This model predicts actual physical distances and to what extent chromosomal contacts vary between cells. It also identifies interactions within single TADs that stabilize boundaries between TADs and allows us to identify and genetically validate key structural elements within TADs. Combining the model's predictions with high-resolution DNA FISH and quantitative RNA FISH for TADs within the X-inactivation center (Xic), we dissect the relationship between transcription and spatial proximity to cis-regulatory elements. We demonstrate that contacts between potential regulatory elements occur in the context of fluctuating structures rather than stable loops and propose that such fluctuations may contribute to asymmetric expression in the Xic during X inactivation.

A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways

Mon, 06/23/2014 - 3:49pm

Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models.

Multiple transcription factors directly regulate Hox gene lin-39 expression in ventral hypodermal cells of the C. elegans embryo and larva, including the hypodermal fate regulators LIN-26 and ELT-6

Mon, 06/23/2014 - 3:49pm

BACKGROUND: Hox genes encode master regulators of regional fate specification during early metazoan development. Much is known about the initiation and regulation of Hox gene expression in Drosophila and vertebrates, but less is known in the non-arthropod invertebrate model system, C. elegans. The C. elegans Hox gene lin-39 is required for correct fate specification in the midbody region, including the Vulval Precursor Cells (VPCs). To better understand lin-39 regulation and function, we aimed to identify transcription factors necessary for lin-39 expression in the VPCs, and in particular sought factors that initiate lin-39 expression in the embryo.

RESULTS: We used the yeast one-hybrid (Y1H) method to screen for factors that bound to 13 fragments from the lin-39 region: twelve fragments contained sequences conserved between C. elegans and two other nematode species, while one fragment was known to drive reporter gene expression in the early embryo in cells that generate the VPCs. Sixteen transcription factors that bind to eight lin-39 genomic fragments were identified in yeast, and we characterized several factors by verifying their physical interactions in vitro, and showing that reduction of their function leads to alterations in lin-39 levels and lin-39::GFP reporter expression in vivo. Three factors, the orphan nuclear hormone receptor NHR-43, the hypodermal fate regulator LIN-26, and the GATA factor ELT-6 positively regulate lin-39 expression in the embryonic precursors to the VPCs. In particular, ELT-6 interacts with an enhancer that drives GFP expression in the early embryo, and the ELT-6 site we identified is necessary for proper embryonic expression. These three factors, along with the factors ZTF-17, BED-3 and TBX-9, also positively regulate lin-39 expression in the larval VPCs.

CONCLUSIONS: These results significantly expand the number of factors known to directly bind and regulate lin-39 expression, identify the first factors required for lin-39 expression in the embryo, and hint at a positive feedback mechanism involving GATA factors that maintains lin-39 expression in the vulval lineage. This work indicates that, as in other organisms, the regulation of Hox gene expression in C. elegans is complicated, redundant and robust.

Calmodulation meta-analysis: Predicting calmodulin binding via canonical motif clustering

Fri, 06/20/2014 - 2:52pm

The calcium-binding protein calmodulin (CaM) directly binds to membrane transport proteins to modulate their function in response to changes in intracellular calcium concentrations. Because CaM recognizes and binds to a wide variety of target sequences, identifying CaM-binding sites is difficult, requiring intensive sequence gazing and extensive biochemical analysis. Here, we describe a straightforward computational script that rapidly identifies canonical CaM-binding motifs within an amino acid sequence. Analysis of the target sequences from high resolution CaM-peptide structures using this script revealed that CaM often binds to sequences that have multiple overlapping canonical CaM-binding motifs. The addition of a positive charge discriminator to this meta-analysis resulted in a tool that identifies potential CaM-binding domains within a given sequence. To allow users to search for CaM-binding motifs within a protein of interest, perform the meta-analysis, and then compare the results to target peptide-CaM structures deposited in the Protein Data Bank, we created a website and online database. The availability of these tools and analyses will facilitate the design of CaM-related studies of ion channels and membrane transport proteins.

Amyotrophic Lateral Sclerosis Association

Thu, 06/19/2014 - 12:25pm

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, leading to muscular atrophy, progressive loss of muscle control, paralysis, and death. This is a review of the ALS Association web site. The site continues to provide ALS patients and caregivers with current resources for managing life with ALS, and it provides researchers and healthcare professionals with access to evidence-based information on the latest scholarship, and guidelines for the most effective therapies and treatments for ALS. The ALS Association website remains an authoritative resource for anyone seeking quality information about ALS.

The Effects of Vitamin D supplementation on Hepatic Dysfunction, Vitamin D Status, and Glycemic Control in Children and Adolescents with Vitamin D Deficiency and Either Type 1 or Type 2 Diabetes Mellitus

Thu, 06/19/2014 - 10:43am

BACKGROUND: The effects of vitamin D supplementation on mild hepatic dysfunction and glycemic control are unclear in children and adolescents with either type 1 (T1D) or type 2 diabetes (T2D).

HYPOTHESIS: Vitamin D supplementation will improve hepatic dysfunction and glycemic control.

AIM: To determine the effect of vitamin D supplementation on alanine transaminase (ALT), hemoglobin A1c (HbA1c), and serum 25-hydroxyvitamin D [25(OH)D] concentration.

SUBJECTS AND METHODS: A retrospective study of 131 subjects with either T1D (n = 88∶46 females, 42 males), or T2D (n = 43∶26 females, 17 males) of ages 3-18 years between 2007-2013. All subjects had (1) a diagnosis of diabetes for >12 mo, (2) received vitamin D supplementation for the management of vitamin D deficiency (3) had baseline and subsequent simultaneous measurements of HbA1c, ALT, and 25(OH)D. Vitamin D deficiency was defined as 25(OH)D concentration of/L (20 ng/mL).

RESULTS: At baseline, vitamin D deficiency occurred in 72.1% of patients with T2D and in 37.5% of T1D patients (p

CONCLUSIONS: Vitamin D supplementation in subjects with T2D was associated with statistically significant decreases in BMI SDS, ALT, and a clinically-significant decrease in HbA1c.

Risk factors for radiation maculopathy and papillopathy after intraocular irradiation

Wed, 06/18/2014 - 11:01am

PURPOSE: To evaluate rates of occurrence and risk factors for radiation maculopathy and radiation papillopathy in patients with choroidal melanoma at high risk for these complications.

DESIGN: Cohort study.

PARTICIPANTS: A total of 558 patients treated with proton irradiation for choroidal melanoma between 1986 and 1996 with small to moderate sized tumors (less than 5 mm in height and 15 mm in diameter) located within 4 disc diameters of the macula or optic nerve and with a median ocular follow-up of 4 years.

METHODS: Annual and cumulative rates of each endpoint were estimated using life table approaches. Prognostic factors were evaluated using the Cox proportional hazards regression.

MAIN OUTCOME MEASURES: Radiation maculopathy, radiation papillopathy, and vision loss to worse than 20/100.

RESULTS: Cumulative 5-year rates for radiation maculopathy, radiation papillopathy, and vision loss were 64%, 35%, and 68%, respectively. Complication rates rose as a function of radiation exposure to the macula (P for trend = 0.04) or optic disc (P for trend < 0.001), although dose-response patterns were nonlinear. History of diabetes was a significant risk factor for maculopathy (P < 0.001) and optic neuropathy (P = 0.009).

CONCLUSIONS: The onset of radiation vasculopathy is determined primarily by the degree of irradiation exposure to the macula and optic disc. Risk may be enhanced among those with underlying vascular disorders.

Patterns of tumor initiation in choroidal melanoma

Wed, 06/18/2014 - 11:01am

This study attempts to document the occurrence of tumors with respect to clock hour location and distance from the macula and to evaluate tumor location in relation to retinal topography and light dose distribution on the retinal sphere. Analysis of patterns of tumor initiation may provide new evidence to clarify the controversy regarding the possible light-related etiology of choroidal melanoma. Incident cases of choroidal and ciliary body melanoma in Massachusetts residents diagnosed between 1984 and 1993 were the basis for analysis. Conventional fundus drawings and photos were used to assess the initiation site of each tumor. The initiation site was defined as the intersect between the largest tumor diameter and the largest perpendicular diameter of the tumor. Initiation sites were recorded using spherical coordinates. The retinal sphere was divided into 61 mutually exclusive sectors defined according to clock hour and anteroposterior distance from the macula. Rates of initiation were computed for each sector, overall, and according to gender and other clinical factors. Results were similar in left and right eyes; therefore, these were combined in analysis. Tumor initiation had a predilection for the macula (P < 0.0001). Overall, no significant clock hour preference was observed (P = 0.63). However, the parafoveal zone showed a strong circular trend (P < 0.01), with highest rates occurring in the temporal region, and the lowest rates occurring in the nasal region. Rates of occurrence in six progressively more anterior concentric zones (designated as the foveal, parafoveal, posterior, peripheral, anterior, and ciliary body zones) were 21.4, 14.2, 12.1, 8.9, 4.5, and 4.3 counts per spherical unit per 1000 eyes, respectively. Concentric zone location did not vary by gender (P = 0.93) or laterality (P = 0.78). However, posterior location was associated with light iris color (P = 0.01). Tumor diameters were largest in the peripheral region of the fundus and smallest in the macular and ciliary body zone (P < 0.001). Clock hour location was not influenced by gender (P = 0.74), laterality (P = 0.53), iris color (P = 0.84), or tumor diameter (P = 0.73). Results suggest that tumor initiation is not uniformly distributed, with rates of occurrence concentrated in the macular area and decreasing monotonically with distance from the macula to the ciliary body. This pattern is consistent with the retinal topography and correlates positively with the dose distribution of solar light on the retinal sphere.

Metastatic melanoma death rates by anatomic site after proton beam irradiation for uveal melanoma

Wed, 06/18/2014 - 11:01am

BACKGROUND: Ciliary body location is an established prognostic factor for metastasis-related death from uveal melanoma. We evaluated alternative approaches for classifying this covariate when constructing predictive models of patient survival.

METHODS AND DESIGN: The analyses were based on a consecutive series of 1848 primary choroidal and/or ciliary body melanoma patients treated with proton beam irradiation (70 cobalt gray equivalent in 5 fractions) at the Harvard Cyclotron Laboratory, Boston, Mass, between July 1975 and December 1995. For each patient, the anatomic site of the tumor was classified according to an estimate of the proportion of the tumor base lying anterior to the ora serrata. Using proportional hazards regression, we estimated relative risk ratios and death rates from melanoma metastasis according to the extent of ciliary body involvement. All estimates were adjusted for other established prognostic factors.

RESULTS: Patients were followed up through April 30, 1998; none were lost to follow-up. Of 1848 patients analyzed, 378 died of melanoma metastasis. The median follow-up period among survivors was 9.5 years. Ciliary body origin (>50% of tumor base anterior to the ora serrata) was positively associated with tumor pigmentation (P<.001), tumor height (P<.001), and extrascleral extension of the tumor (P<.001). Compared with tumors involving only the choroid, melanoma-associated death rates increased with the proportion of the tumor base lying within the ciliary body (P =. 006); the multivariate-adjusted relative risk ratio for greater than 75% involvement was 2.30 (95% confidence interval [CI], 1.26-4.23). The covariate-adjusted 5-year death rates for ciliary body origin and choroidal origin were 15.9% (95% CI, 11.3%-21.2%) and 9.8% (95% CI, 8.3%-11.7%), respectively.

CONCLUSION: Patients with melanomas of presumed ciliary body origin seem to be subject to a higher risk of death resulting from melanoma metastasis. Arch Ophthalmol. 2000;118:1066-1070

Adaptational process of parents of pediatric oncology patients

Wed, 06/18/2014 - 11:01am

This study, based on grounded theory, explores the adaptational process of parents of pediatric oncology patients. Thirty-two Taiwanese parents (26 mothers and 6 fathers) were interviewed. Data were collected through individual in-depth and focus group interviews, observations, medical chart review, nurses' note, and researchers' reflexive journals. The findings suggest that parents adapt to their children's cancer by a dynamic process; i.e., they modify their coping tasks and related strategies as clinical events (e.g., diagnosis, side effects, relapses, or death) occur. This adaptational process consisted of five components: confronting treatment, maintaining family integrity, establishing support, maintaining emotional well-being, and searching for spiritual meaning. Related factors such as coping tasks are described.

Use of alternative therapy among pediatric oncology patients in Taiwan

Wed, 06/18/2014 - 11:01am

Both alternative medicine and western medicine have been commonly used to treat pediatric cancer patients in Taiwan. Each has its own intrinsic strengths and weaknesses and they can be complementary. Little is known about medical help-seeking behaviors of parents of pediatric cancer patients, especially those related to alternative therapies. This study investigated the extent and parental expectations on use of alternative therapies. All primary caregivers of 63 eligible patients were interviewed. Use of alternative therapies, regardless of education level or social status of their families, is prevalent (n = 46, 73%) in Taiwan. Commonly used alternative therapies included, in order of popularity, formulated functional food (n = 22, 48%), temple worship/shamanism (n = 19, 40%), traditional Chinese medicine (n = 9, 20%), secret recipes/herbs (n = 13, 28%), and diet supplements (n = 9, 19%). Such practices generally occur without medical guidance from oncologists, largely because of poor interactions between parents and oncologists. Future efforts should be made to encourage both parents and oncologists to discuss this issue. Nurses may serve as mediators by developing mutual trust and a sharing relationship between these groups.