Publications by authors named "Linda Robinson"

83 Publications

Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain.

Sci Transl Med 2019 12;11(523)

Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.

Brain lesions composed of pathological tau help to drive neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Here, we identified the mammalian suppressor of tauopathy 2 () gene as a modifier of susceptibility to tau toxicity in two mouse models of tauopathy. Transgenic PS19 mice overexpressing tau, a model of AD, and lacking the gene exhibited decreased learning and memory deficits, reduced neurodegeneration, and reduced accumulation of pathological tau compared to PS19 tau transgenic mice expressing Conversely, overexpression in 4RTauTg2652 tau transgenic mice increased pathological tau deposition and promoted the neuroinflammatory response to pathological tau. MSUT2 is a poly(A) RNA binding protein that antagonizes the canonical nuclear poly(A) binding protein PABPN1. In individuals with AD, MSUT2 abundance in postmortem brain tissue predicted an earlier age of disease onset. Postmortem AD brain tissue samples with normal amounts of MSUT2 showed elevated neuroinflammation associated with tau pathology. We observed co-depletion of MSUT2 and PABPN1 in postmortem brain samples from a subset of AD cases with higher tau burden and increased neuronal loss. This suggested that MSUT2 and PABPN1 may act together in a macromolecular complex bound to poly(A) RNA. Although MSUT2 and PABPN1 had opposing effects on both tau aggregation and poly(A) RNA tail length, we found that increased poly(A) tail length did not ameliorate tauopathy, implicating other functions of the MSUT2/PABPN1 complex in tau proteostasis. Our findings implicate poly(A) RNA binding proteins both as modulators of pathological tau toxicity in AD and as potential molecular targets for interventions to slow neurodegeneration in tauopathies.
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http://dx.doi.org/10.1126/scitranslmed.aao6545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311111PMC
December 2019

Optimizing efficiency and skill utilization: Analysis of genetic counselors' attitudes regarding delegation in a clinical setting.

J Genet Couns 2020 02 13;29(1):67-77. Epub 2019 Nov 13.

Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.

This study assessed genetic counselors' (GCs) perceptions of delegation as a tool to increase workforce efficiency and help meet the current gap between the number of genetic service providers and the number of patients. GCs were recruited to participate via an online survey that assessed activities (categorized as typical genetic counseling, administrative, or professional development) performed by a clinical genetic counselor. Respondents indicated which activities represent their largest time consumers, their willingness to delegate these activities, and barriers to and perceived outcomes of delegation. Overall, respondents indicated that they spend 25% of their time performing administrative activities that they would largely be willing to delegate; however, respondents were generally unwilling to delegate many typical genetic counseling and professional development activities, citing concerns regarding accuracy and liability, and highlighting the belief that these activities constitute the core role of a genetic counselor. Respondents indicated that delegation of time-consuming administrative activities would increase access to genetic services and improve job satisfaction. Additionally, differences were identified among clinical specialties regarding which activities were selected as top time consumers, indicating that potential targets of re-allocation of time or delegation may be variable. This research indicates a need to reduce the number of administrative tasks in which GCs are directly involved to re-allocate time toward core responsibilities, direct patient care, and professional development, the result of which is more efficient use of the GC skill-set.
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http://dx.doi.org/10.1002/jgc4.1181DOI Listing
February 2020

Screening for Lynch Syndrome by Immunohistochemistry of Mismatch Repair Proteins: Significance of Indeterminate Result and Correlation With Mutational Studies.

Arch Pathol Lab Med 2019 10 27;143(10):1225-1233. Epub 2019 Mar 27.

From the Departments of Pathology (Dr Sarode) and Genetics (Dr Robinson), University of Texas Southwestern Medical Center, Dallas.

Context.—: Immunohistochemical expression of mismatch repair (MMR) protein is a well-accepted method for routine screening for Lynch syndrome with relatively high sensitivity and specificity. Occasionally, however, immunohistochemistry (IHC) can yield an equivocal result with poor reproducibility and the potential for misdiagnosis.

Objective.—: To determine the frequency and significance of indeterminate MMR IHC expression in patients routinely screened for Lynch syndrome and correlation with germline mutation studies.

Design.—: Semiquantitative scoring of MMR IHC was performed by image analysis in 479 cases, of which 380 were colorectal and 99 endometrial cancer. Scores of 10% or more, less than 10%, and 0% were used as cutoffs for retained, indeterminate, and loss of expression, respectively. Negative and indeterminate IHC results were confirmed by mutational studies.

Results.—: Four hundred eighteen of 479 cases (87.2%) were reported as retained expression, 45 (9.3%) as loss of expression, and 16 (3.3%) as indeterminate expression. Fifteen of 45 (33.3%) and 8 of 16 (50%) with loss and indeterminate expression, respectively, were found to have Lynch syndrome by germline studies. The overall frequency of Lynch syndrome in our patient population was 4.8% (23 of 479), and 34.7% of these (8 of 23) were associated with indeterminate IHC expression. In the indeterminate group, germline mutation was the most frequent (6 of 13; 46.2%), followed by MSH6 (4 of 13; 30.7%).

Conclusions.—: Our findings provide further evidence that indeterminate IHC should be further investigated for possible MMR germline mutation. Guidelines for interpretation of MMR IHC and the establishment of more objective criteria for defining indeterminate results are important to improve the sensitivity and specificity of the IHC assay.
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http://dx.doi.org/10.5858/arpa.2018-0201-OADOI Listing
October 2019

Public prescription drug plan coverage for antiretrovirals and the potential cost to people living with HIV in Canada: a descriptive study.

CMAJ Open 2018 Oct-Dec;6(4):E551-E560. Epub 2018 Nov 27.

Department of Pharmacy (Yoong), St. Michael's Hospital, Toronto, Ont.; Centre for Urban Health Solutions (Bayoumi), Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ont.; Department of Medicine (Bayoumi), University of Toronto, Toronto, Ont.; Department of Pharmacy (Robinson), Windsor Regional Hospital, Windsor, Ont.; Ontario HIV Treatment Network (Rachlis), Toronto, Ont.; Department of Family and Community Medicine (Antoniou), St. Michael's Hospital and University of Toronto, Toronto, Ont.; Li Ka Shing Knowledge Institute (Antoniou), St. Michael's Hospital, Toronto, Ont.

Background: Antiretrovirals are expensive and people living with HIV may experience a range of financial burdens when accessing these medications. Our aim was to describe the policy of all Canadian public drug insurance programs for antiretroviral drugs and illustrated how these policies might affect patients' annual out-of-pocket expenditures.

Methods: In December 2017, we reviewed public drug programs offering antiretroviral coverage in Canada using government websites to summarize eligibility criteria. We estimated the annual out-of-pocket costs incurred by people living with HIV by applying the cost-sharing rules to 2 hypothetical cases, a single man and a married woman with a net household income of $39 000 and $80 000, respectively, receiving identical prescriptions in different jurisdictions.

Results: We observed substantial variation in the subsidy provided based mainly on geography, income and age. All 5 federal programs and 6 of 13 provincial and territorial jurisdictions offered universal coverage. In the remaining regions, patients spend up to several thousand dollars annually depending on income (Manitoba), age and income (Ontario, Saskatchewan) and age, income and drug costs (Quebec and Newfoundland and Labrador). We found the greatest variation for our higher income case, with out-of-pocket expenses ranging from 0 to over 50% of the antiretroviral cost.

Interpretation: There is considerable inter- and intra-jurisdiction heterogeneity in the cost-sharing policies for antiretrovirals across Canada's public drug programs. Policy reforms that either eliminate or set national standards for copayments, deductibles or premiums would minimize variation and could reduce the risk of cost-associated non-adherence to HIV therapy.
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http://dx.doi.org/10.9778/cmajo.20180058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276936PMC
November 2018

Genetic Counseling Assistants: an Integral Piece of the Evolving Genetic Counseling Service Delivery Model.

J Genet Couns 2017 Aug 10;26(4):716-727. Epub 2016 Nov 10.

University of Texas Southwestern Medical Center and Moncrief Cancer Institute, 5323 Harry Hines Blvd, Dallas, TX, 75390-9323, USA.

This study explores the potential impact of the genetic counseling assistant (GCA) position on the efficiency of the genetic counseling field, evaluates attitudes regarding expansion of the genetic counseling field to include the GCA, and presents data on GCA endeavors and GCA job tasks as reported by GCAs, certified genetic counselors (CGCs), and program directors (PDs). Data on GCA roles and attitudes toward different aspects of the GCA position were collected via surveys of CGCs who have worked with GCAs, PDs who have and have not had experience with GCAs in their programs, and GCAs. We analyzed responses from 63 individuals: 27 PDs, 22 CGCs, and 14 GCAs. GCAs' impact on efficiency was calculated via internal analysis of genetic patient volume per genetic counselor within the University of Texas Southwestern (UTSW) patient database prior to, and since the addition of, a GCA to the practice. The response rates for PDs, CGCs, and GCAs were 27 %, 79 %, and 61 %, respectively. Every CGC stated the GCA increased their efficiency. CGCs with a GCA reported a 60 % average increase in patient volume. This figure was congruent with internal data from the UTSW cancer genetics program (58.5 % increase). Appropriate responsibilities for GCAs as reported by CGCs and PDs (>90 %) include: data entry, shipping tests, administrative tasks, research, and ordering supplies. Regarding GCAs delivering test results, there was response variation whether this should be a job duty: 42 % of CGCs agreed to GCAs delivering negative results to patients, compared to 22 % of program directors. Twenty-two percent of PDs expressed concern about the job title "Genetic Counseling Assistant." Ninety percent of CGCs felt that GCA was a career path to becoming a CGC, compared to 42 % of PDs. Eighty-three percent of GCAs who decided to apply to CGC graduate programs were accepted. We conclude the addition of a GCA to a genetic counseling practice contributes to increased efficiency and is one way to expand the reach of the profession.
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http://dx.doi.org/10.1007/s10897-016-0039-6DOI Listing
August 2017

To stay or to go? Postretirement housing choices of single Baby Boomer women.

J Women Aging 2017 14;29(5):417-427. Epub 2016 Sep 14.

a School of Economics, Finance and Marketing , Royal Melbourne Institute of Technology University , Melbourne , Victoria , Australia.

Single women of the Baby Boomer generation are often financially disadvantaged in the retirement planning process due to their lower accumulated savings compared to male retirees. This disadvantage impacts significant consumption decisions such as postretirement housing choices. This study uses the theory of planned behavior to examine how certainty in intentions influences preparing and planning for postretirement housing. A typology of single Baby Boomer women is developed based on their financial, demographic, and psychological circumstances. Each segment likely requires different informational strategies and financial services to foster proactive planning for retirement. Significant implications exist for social policy and the financial services sector.
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http://dx.doi.org/10.1080/08952841.2016.1213109DOI Listing
May 2018

Prediction of Cancer Prevention: From Mammogram Screening to Identification of BRCA1/2 Mutation Carriers in Underserved Populations.

EBioMedicine 2015 Nov 21;2(11):1827-33. Epub 2015 Oct 21.

Department of Cancer Genetics, University of Texas Southwestern Medical Center's Harold Simmons Comprehensive Cancer Center, Dallas and Moncrief Cancer Institute, Fort Worth, TX, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: The US Preventative Service Task Force recommends that physicians perform a genetic risk assessment to identify women at risk for BRCA1/2 mutations associated with hereditary breast and ovarian cancer (HBOC) syndrome. However, outcomes data after a diagnosis of HBOC syndrome especially in diverse populations, are minimal. Here we asked if genetic screening of high-risk underserved women identified in the mammogram population reduces cancer incidence.

Methods: We evaluated 61,924 underserved women at screening mammography for family histories suggestive of HBOC syndrome over the course of 21 months. Data were collected retrospectively from patients at two safety net hospitals through chart review. A computer model was used to calculate the long-term effect of this screening on cancer incidence by assessing both the mutation detection rate and the completion of prophylactic surgeries in BRCA1/2 mutation carriers.

Findings: We identified 20 of the 85 (23.5%) expected BRCA1/2 mutation carriers in the underserved population. The frequencies of prophylactic mastectomies and oophorectomies in the mutation carriers were 25% and 40%, respectively. Using these data, our model predicted only an 8.8% reduction in both breast and ovarian cancer in the underserved patients. This contrasts with a 57% reduction in breast cancer and 51% reduction in ovarian cancer in an insured reference population. Our data indicate that underserved patients with HBOC syndrome are difficult to identify and when identified are limited in their ability to adhere to NCCN guidelines for cancer prevention.

Interpretation: Screening for women at risk for HBOC syndrome in mammogram populations will only prevent cancers if we can increase compliance with management guidelines. This study provides prototypic baseline data for step-wise analysis of the efficacy of the use of family history analysis in the mammography setting for detection and management of HBOC syndrome.
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http://dx.doi.org/10.1016/j.ebiom.2015.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740331PMC
November 2015

Expression of mutant bone morphogenetic protein receptor II worsens pulmonary hypertension secondary to pulmonary fibrosis.

Pulm Circ 2015 Dec;5(4):681-90

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Pulmonary fibrosis is often complicated by pulmonary hypertension (PH), and previous studies have shown a potential link between bone morphogenetic protein receptor II (BMPR2) and PH secondary to pulmonary fibrosis. We exposed transgenic mice expressing mutant BMPR2 and control mice to repetitive intraperitoneal injections of bleomycin for 4 weeks. The duration of transgene activation was too short for mutant BMPR2 mice to develop spontaneous PH. Mutant BMPR2 mice had increased right ventricular systolic pressure compared to control mice, without differences in pulmonary fibrosis. We found increased hypoxia-inducible factor (HIF)1-α stabilization in lungs of mutant-BMPR2-expressing mice compared to controls following bleomycin treatment. In addition, expression of the hypoxia response element protein connective tissue growth factor was increased in transgenic mice as well as in a human pulmonary microvascular endothelial cell line expressing mutant BMPR2. In mouse pulmonary vascular endothelial cells, mutant BMPR2 expression resulted in increased HIF1-α and reactive oxygen species production following exposure to hypoxia, both of which were attenuated with the antioxidant TEMPOL. These data suggest that expression of mutant BMPR2 worsens secondary PH through increased HIF activity in vascular endothelium. This pathway could be therapeutically targeted in patients with PH secondary to pulmonary fibrosis.
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http://dx.doi.org/10.1086/683811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671742PMC
December 2015

High copy wildtype human 1N4R tau expression promotes early pathological tauopathy accompanied by cognitive deficits without progressive neurofibrillary degeneration.

Acta Neuropathol Commun 2015 Jun 4;3:33. Epub 2015 Jun 4.

Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.

Introduction: Accumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer's disease (AD) and other tauopathies. In most AD subjects, wild-type (WT) tau aggregates and accumulates in neurofibrillary tangles and dystrophic neurites in the brain; however, in some familial tauopathy disorders, mutations in the gene encoding tau cause disease.

Results: We generated a mouse model, Tau4RTg2652, that expresses high levels of normal human tau in neurons resulting in the early stages of tau pathology. In this model, over expression of WT human tau drives pre-tangle pathology in young mice resulting in behavioral deficits. These changes occur at a relatively young age and recapitulate early pre-tangle stages of tau pathology associated with AD and mild cognitive impairment. Several features distinguish the Tau4RTg2652 model of tauopathy from previously described tau transgenic mice. Unlike other mouse models where behavioral and neuropathologic changes are induced by transgenic tau harboring MAPT mutations pathogenic for frontotemporal lobar degeneration (FTLD), the mice described here express the normal tau sequence.

Conclusions: Features of Tau4RTg2652 mice distinguishing them from other established wild type tau overexpressing mice include very early phenotypic manifestations, non-progressive tau pathology, abundant pre-tangle and phosphorylated tau, sparse oligomeric tau species, undetectable fibrillar tau pathology, stability of tau transgene copy number/expression, and normal lifespan. These results suggest that Tau4RTg2652 animals may facilitate studies of tauopathy target engagement where WT tau is driving tauopathy phenotypes.
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http://dx.doi.org/10.1186/s40478-015-0210-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453289PMC
June 2015

Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic.

EBioMedicine 2015 Jan;2(1):74-81

Department of Internal Medicine, UT Southwestern Medical Center, Dallas TX, 75390, USA ; Department of Cancer Genetics, UT Southwestern Medical Center, Dallas, TX, 75390, USA.

Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks.
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http://dx.doi.org/10.1016/j.ebiom.2014.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444225PMC
January 2015

Proactive case finding to improve concurrently curative and palliative care in patients with end-stage liver disease.

J Palliat Med 2015 Apr 10;18(4):378-81. Epub 2014 Dec 10.

1 Greater Los Angeles Veterans Affairs Healthcare System, David Geffen School of Medicine at University of California , Los Angeles, California.

Background: Palliative care and preparation for liver transplantation are often perceived as conflicting for patients with end-stage liver disease (ESLD). We sought to improve both simultaneously through a case finding and care coordination quality improvement intervention.

Methods: We identified patients with cirrhosis using validated ICD-9 codes and screened them for ESLD by assessing medical records at a VA hospital for either a model for end-stage liver disease (MELD) ≥14 or a diagnosis of hepatocellular carcinoma (HCC) between October 2012 and January 2013. A care coordinator followed veterans from the index hospitalization through April 2013 and encouraged treating physicians to submit liver transplant evaluation consults for all veterans with a MELD ≥14 and palliative care consults for all veterans with a MELD ≥20 or inoperable HCC.

Results: We compared rates of consultation for 49 hospitalized veterans and compared their outcomes to 61 pre-intervention veterans. Veterans were more likely to be considered for liver transplantation (77.6% versus 31.1%, p<0.001) and receive palliative care consultation during the intervention period, although the latter finding did not reach statistical significance (62.5% versus 47.1%, p=0.38).

Conclusions: Active case finding improved consideration for liver transplantation without decreasing palliative care consultation.
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http://dx.doi.org/10.1089/jpm.2014.0265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367526PMC
April 2015

Resistance to noise-induced hearing loss in 129S6 and MOLF mice: identification of independent, overlapping, and interacting chromosomal regions.

J Assoc Res Otolaryngol 2014 Oct 21;15(5):721-38. Epub 2014 Jun 21.

The V.M. Bloedel Hearing Research Center, Department of Otolaryngology-HNS, University of Washington, Seattle, WA, 98195, USA,

Noise-induced hearing loss (NIHL) is a prevalent health risk. Inbred mouse strains 129S6/SvEvTac (129S6) and MOLF/EiJ (MOLF) show strong NIHL resistance (NR) relative to CBA/CaJ (CBACa). In this study, we developed quantitative trait locus (QTL) maps for NR. We generated F1 animals by intercrossing (129S6 × CBACa) and (MOLF × CBACa). In each intercross, NR was recessive. N2 animals were produced by backcrossing F1s to their respective parental strain. The 232 N2-129S6 and 225 N2-MOLF progenies were evaluated for NR using auditory brainstem response. In 129S6, five QTL were identified on chromosomes (Chr) 17, 18, 14, 11, and 4, referred to as loci nr1, nr2, nr3, nr4, and nr5, respectively. In MOLF, four QTL were found on Chr 4, 17, 6, and 12, referred to as nr7, nr8, nr9, and nr10, respectively. Given that NR QTL were discovered on Chr 4 and 17 in both the N2-129S6 and N2-MOLF cross, we generated two consomic strains by separately transferring 129S6-derived Chr 4 and 17 into an otherwise CBACa background and a double-consomic strain by crossing the two strains. Phenotypic analysis of the consomic strains indicated that whole 129S6 Chr 4 contributes strongly to mid-frequency NR, while whole 129S6 Chr 17 contributes markedly to high-frequency NR. Therefore, we anticipated that the double-consomic strain containing Chr 4 and 17 would demonstrate NR across the mid- and high-frequency range. However, whole 129S6 Chr 17 masks the expression of mid-frequency NR from whole 129S6 Chr 4. To further dissect NR on 129S6 Chr 4 and 17, CBACa.129S6 congenic strains were generated for each chromosome. Phenotypic analysis of the Chr 17 CBACa.129S6 congenic strains further defined the NR region on proximal Chr 17, uncovered another NR locus (nr6) on distal Chr 17, and revealed an epistatic interaction between proximal and distal 129S6 Chr 17.
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http://dx.doi.org/10.1007/s10162-014-0472-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164691PMC
October 2014

State of inertia: psychological preparation of single Australian and UK baby boomer women for retirement housing change.

J Women Aging 2014 ;26(3):280-97

a School of Economics, Finance and Marketing , Royal Melbourne Institute of Technology University , Victoria , Australia.

The transition into retirement is an important life phase that presents significant challenges in respect to well-being, lifestyle, and consumption choices. This article examines the consumption context of housing after retirement, in particular for the low-resourced cohort of single baby boomer women. Utilizing an extended Theory of Planned Behavior model, we examine the relationship between intention and actual behavior, in this case financial advice seeking, as an important component of the psychological preparedness of single female baby boomer women. Our analysis showed both Australian and UK single baby boomer women display different behaviors in terms of seeking advice and their mental preparedness to adjust to a change in their living arrangements. The findings are discussed in terms of their implications for policy and further research.
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http://dx.doi.org/10.1080/08952841.2014.889447DOI Listing
September 2015

An internal performance assessment of CancerGene Connect: an electronic tool to streamline, measure and improve the genetic counseling process.

J Genet Couns 2014 Dec 12;23(6):1034-44. Epub 2014 Jun 12.

Department of Cancer Genetics, University of Texas Southwestern Medical Center's Simmons Comprehensive Cancer Center, Dallas and Moncrief Cancer Institute, Dallas, TX, USA.

CancerGene Connect (CGC) is a web-based program that combines the collection of family and medical history, cancer risk assessment, psychosocial assessment, report templates, a result tracking system, and a patient follow up system. The performance of CGC was assessed in several ways: pre-appointment completion data analyzed for demographic and health variables; a time study to assess overall time per case and to compare the data entry by the genetic counselor compared to the patient, and a measured quality assessment of the program via observation and interview of patients. Prior to their appointment, 52.3% of 2,414 patients completed the online patient questionnaire section of CGC. There were significant differences in completion rates among racial and ethnic groups. County hospital patients were less likely to complete the questionnaire than insured patients (p < 0.0001); and likewise uninsured patients and patients with Medicare/Medicaid were less likely to complete the questionnaire than private patients (p < 0.0001). The average genetic counseling time per case was 82 min, with no significant differences whether the counselor or the patient completed CGC. CGC reduces genetic counselor time by approximately 14-46% compared to average time per case using traditional risk assessment and documentation methods previously reported. All surveyed users felt the questionnaire was easy to understand. CGC is an effective tool that streamlines workflow, and provides a standardized data collection tool that can be used to evaluate and improve the genetic counseling process.
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http://dx.doi.org/10.1007/s10897-014-9732-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233159PMC
December 2014

Engagement with Care, Substance Use, and Adherence to Therapy in HIV/AIDS.

AIDS Res Treat 2014 3;2014:675739. Epub 2014 Apr 3.

University of Utah, 201 Presidents Circle, Salt Lake City, UT 84112, USA.

Engagement with care for those living with HIV is aimed at establishing a strong relationship between patients and their health care provider and is often associated with greater adherence to therapy and treatment (Flickinger, Saha, Moore, and Beach, 2013). Substance use behaviors are linked with lower rates of engagement with care and medication adherence (Horvath, Carrico, Simoni, Boyer, Amico, and Petroli, 2013). This study is a secondary data analysis using a cross-sectional design from a larger randomized controlled trial (n = 775) that investigated the efficacy of a self-care symptom management manual for participants living with HIV. Participants were recruited from countries of Africa and the US. This study provides evidence that substance use is linked with lower self-reported engagement with care and adherence to therapy. Data on substance use and engagement are presented. Clinical implications of the study address the importance of utilizing health care system and policy factors to improve engagement with care.
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http://dx.doi.org/10.1155/2014/675739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996287PMC
May 2014

Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations.

J Thorac Oncol 2014 Apr;9(4):456-63

*Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX; †Department of Pathology, UT Southwestern Medical Center, Dallas, TX; ‡Cancer Genetics, Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX; §Department of Clinical Science and McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX; ‖Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; ¶Department of Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; #Department of Radiology, UT Southwestern Medical Center, Dallas, TX; **Department of Clinical Science and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX; ††Department of Cardiovascular and Thoracic Surgery, UT Southwestern Medical Center, Dallas, TX; and ‡‡Department of Medicine and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX.

Introduction: Hereditary lung cancer syndromes are rare, and T790M germline mutations of the epidermal growth factor receptor (EGFR) gene predispose to the development of lung cancer. The goal of this study was to determine the clinical features and smoking status of lung cancer cases and unaffected family members with this germline mutation and to estimate its incidence and penetrance.

Methods: We studied a family with germline T790M mutations over five generations (14 individuals) and combined our observations with data obtained from a literature search (15 individuals).

Results: T790M germline mutations occurred in approximately 1% of non-small-cell lung cancer cases and in less than one in 7500 subjects without lung cancer. Both sporadic and germline T790M mutations were predominantly adenocarcinomas, favored female gender, and were occasionally multifocal. Of lung cancer tumors arising in T790M germline mutation carriers, 73% contained a second activating EGFR gene mutation. Inheritance was dominant. The odds ratio that T790M germline carriers who are smokers will develop lung cancer compared with never smoker carriers was 0.31 (p = 6.0E-05). There was an overrepresentation of never smokers with lung cancer with this mutation compared with the general lung cancer population (p = 7.4E-06).

Conclusion: Germline T790M mutations result in a unique hereditary lung cancer syndrome that targets never smokers, with a preliminary estimate of 31% risk for lung cancer in never smoker carriers, and this risk may be lower for heavy smokers. The resultant cancers share several features and differences with lung cancers containing sporadic EGFR mutations.
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http://dx.doi.org/10.1097/JTO.0000000000000130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509739PMC
April 2014

BMP pathway regulation of and by macrophages.

PLoS One 2014 8;9(4):e94119. Epub 2014 Apr 8.

Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.

Pulmonary arterial hypertension (PAH) is a disease of progressively increasing pulmonary vascular resistance, associated with mutations of the type 2 receptor for the BMP pathway, BMPR2. The canonical signaling pathway for BMPR2 is through the SMAD family of transcription factors. BMPR2 is expressed in every cell type, but the impact of BMPR2 mutations affecting SMAD signaling, such as Bmpr2delx4+, had only previously been investigated in smooth muscle and endothelium. In the present study, we created a mouse with universal doxycycline-inducible expression of Bmpr2delx4+ in order to determine if broader expression had an impact relevant to the development of PAH. We found that the most obvious phenotype was a dramatic, but patchy, increase in pulmonary inflammation. We crossed these double transgenic mice onto an NF-κB reporter strain, and by luciferase assays on live mice, individual organs and isolated macrophages, we narrowed down the origin of the inflammatory phenotype to constitutive activation of tissue macrophages. Study of bone marrow-derived macrophages from mutant and wild-type mice suggested a baseline difference in differentiation state in Bmpr2 mutants. When activated with LPS, both mutant and wild-type macrophages secrete BMP pathway inhibitors sufficient to suppress BMP pathway activity in smooth muscle cells (SMC) treated with conditioned media. Functionally, co-culture with macrophages results in a BMP signaling-dependent increase in scratch closure in cultured SMC. We conclude that SMAD signaling through BMP is responsible, in part, for preventing macrophage activation in both live animals and in cells in culture, and that activated macrophages secrete BMP inhibitors in sufficient quantity to cause paracrine effect on vascular smooth muscle.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094119PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979749PMC
January 2015

American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.

J Clin Oncol 2014 Mar 3;32(8):833-40. Epub 2014 Feb 3.

Karen H. Lu, Molly Daniels, and Cathy Burke, MD Anderson Cancer Center, Houston; Linda Robinson, Simmons Comprehensive Cancer Center, Dallas, TX; Marie E. Wood, University of Vermont, Burlington, VT; James Ford, Stanford University Medical Center, Stanford, CA; Noah D. Kauff, Memorial Sloan-Kettering Cancer Center, New York, NY; Wendy Kohlmann, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Therese M. Mulvey, Southcoast Centers for Cancer Care, Fall River; Sapna Syngal, Dana-Farber Cancer Institute, Brigham and Women's Hospital; Kevin S. Hughes, Avon Comprehensive Breast Evaluation Center, Massachusetts General Hospital, Boston, MA; Wendy Rubinstein, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD; Elena M. Stoffel, University of Michigan, Ann Arbor, MI; Carrie Snyder, Creighton University, Omaha, NE; and Janette K. Merrill and Dana Swartzberg Wollins, American Society of Clinical Oncology, Alexandria, VA.

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http://dx.doi.org/10.1200/JCO.2013.50.9257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940540PMC
March 2014

The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience.

Genet Med 2014 May 10;16(5):407-12. Epub 2013 Oct 10.

Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Purpose: The advent of next-generation sequencing for cancer susceptibility genes holds promise for clinical genetics application, but the practical issues surrounding integration of this testing into the clinical setting have not been well addressed. This article describes the clinical experience of genetic counselors in an academic and community setting with next-generation sequencing cancer panels.

Methods: Between April 2012 and January 2013, 60 next-generation sequencing panels were ordered. A retrospective review was conducted to determine the indication for ordering the results of the tests and the patient management based on the results.

Results: Ten tests were canceled due to out-of-pocket costs or previously identified mutations. Among the 50 tests, 5 (10%) showed a positive result. Moreover, 15 of the 50 (30%) panels detected variant(s) of uncertain significance or variant(s) suspected benign.

Conclusion: We propose clinical guidelines for identifying high-risk patients who should be offered this testing. Our data support the National Comprehensive Cancer Network recommendations that next-generation sequencing be ordered as a second-tier test for high-risk individuals with cancer by trained cancer genetics providers. Literature review and expert knowledge should be used to create management plans for the identification of both positive and variants of uncertain significance results. Providers should be aware of limitations regarding reimbursement for testing and recommended management strategies.
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http://dx.doi.org/10.1038/gim.2013.160DOI Listing
May 2014

Hyperoxia synergizes with mutant bone morphogenic protein receptor 2 to cause metabolic stress, oxidant injury, and pulmonary hypertension.

Am J Respir Cell Mol Biol 2013 Nov;49(5):778-87

1 Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine.

Pulmonary arterial hypertension (PAH) has been associated with a number of different but interrelated pathogenic mechanisms. Metabolic and oxidative stresses have been shown to play important pathogenic roles in a variety of model systems. However, many of these relationships remain at the level of association. We sought to establish a direct role for metabolic stress and oxidant injury in the pathogenesis of PAH. Mice that universally express a disease-causing mutation in bone morphogenic protein receptor 2 (Bmpr2) were exposed to room air or to brief daily hyperoxia (95% oxygen for 3 h) for 6 weeks, and were compared with wild-type animals undergoing identical exposures. In both murine tissues and cultured endothelial cells, the expression of mutant Bmpr2 was sufficient to cause oxidant injury that was particularly pronounced in mitochondrial membranes. With the enhancement of mitochondrial generation of reactive oxygen species by hyperoxia, oxidant injury was substantially enhanced in mitochondrial membranes, even in tissues distant from the lung. Hyperoxia, despite its vasodilatory actions in the pulmonary circulation, significantly worsened the PAH phenotype (elevated right ventricular systolic pressure, decreased cardiac output, and increased pulmonary vascular occlusion) in Bmpr2 mutant animals. These experiments demonstrate that oxidant injury and metabolic stress contribute directly to disease development, and provide further evidence for PAH as a systemic disease with life-limiting cardiopulmonary manifestations.
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http://dx.doi.org/10.1165/rcmb.2012-0463OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931097PMC
November 2013

Implementation of routine screening for Lynch syndrome in university and safety-net health system settings: successes and challenges.

Genet Med 2013 Dec 18;15(12):925-32. Epub 2013 Apr 18.

Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Purpose: Routine screening for evidence of DNA mismatch repair abnormalities can identify colorectal cancer patients with Lynch syndrome, but impact in usual care settings requires study. After implementing routine screening at our university and safety-net health systems as usual practice, our aims were to determine outcomes, including screening process quality.

Methods: We conducted a retrospective cohort study from 1 May 2010 to 1 May 2011. Screening included reflexive immunohistochemistry to evaluate DNA mismatch repair protein expression for patients with colorectal cancer aged ≤70 years, with a cancer genetics team following up results. Screening outcomes, as well as challenges to a high-quality screening process were evaluated.

Results: We included 129 patients (mean age 56 years, 36% female); 100 had immunohistochemistry screening completed. Twelve patients had abnormal immunohistochemistry: four with definite Lynch syndrome, four with probable Lynch syndrome, and three without Lynch syndrome; one patient had an incomplete work-up. Lynch syndrome was confirmed for 6/13 asymptomatic relatives tested. Screening process quality was optimal for 77.5% of patients. Barriers to optimal quality screening included ensuring reflexive immunohistochemistry completion, complete follow-up of abnormal immunohistochemistry, and timely incorporation of results into clinical decision making.

Conclusion: Usual care implementation of routine screening for Lynch syndrome can result in significant rates of detection, even in a largely safety-net setting. To optimize implementation, challenges to high-quality Lynch syndrome screening, such as ensuring reflexive screening completion and clinically indicated genetic testing and follow-up for abnormal screens, must be identified and addressed.
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http://dx.doi.org/10.1038/gim.2013.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215584PMC
December 2013

The impact of stressful life events, symptom status, and adherence concerns on quality of life in people living with HIV.

J Assoc Nurses AIDS Care 2013 Nov-Dec;24(6):478-90. Epub 2013 Mar 7.

Studies concerning persons living with HIV (PLWH) report that stressful life events (SLEs) contribute to an exacerbation of symptoms and reduced antiretroviral (ARV) adherence and quality of life (QOL). Little is known about whether these findings are site-specific. Our study's aims were to characterize the type and frequency of SLEs for PLWH in Puerto Rico, South Africa, and the United States, and to assess the impact of SLEs by national site, symptoms, and ARV adherence concerns on QOL. The sample consisted of 704 participants. The total number of SLEs correlated significantly with the total number of symptoms, adherence concerns, and QOL (p ≤ .001). Overall, 27.2% of the variance in QOL was explained by the aforementioned variables. Although SLEs were of concern to PLWH, worries about ARV adherence were of even greater concern. Routine assessment of ARV concerns and SLEs can promote ongoing ARV adherence and improved QOL.
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http://dx.doi.org/10.1016/j.jana.2012.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681926PMC
March 2014

Genetic predisposition syndromes and their management.

Surg Clin North Am 2013 Apr 11;93(2):341-62. Epub 2013 Feb 11.

Department of Surgery, UT Southwestern Medical Center at Dallas, Dallas, TX, USA.

Apart from BRCA1, BRCA2, and TP53, more than a dozen breast cancer susceptibility genes have been identified. Recognizing affected individuals depends on evaluation of cancer family history and recognition of certain phenotypic markers on physical examination. Genetic testing provides a powerful tool for individualized risk stratification. Mutation carriers have several options for managing risk, including lifestyle alterations, enhanced surveillance, chemoprevention, and prophylactic surgery. Genetic counseling and testing should be considered in the initial evaluation of patients with newly diagnosed breast cancer because this information contributes to surgical decisions, radiation therapy options, and systemic therapy choices.
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http://dx.doi.org/10.1016/j.suc.2013.01.005DOI Listing
April 2013

Right ventricular systolic pressure measurements in combination with harvest of lung and immune tissue samples in mice.

J Vis Exp 2013 Jan 16(71):e50023. Epub 2013 Jan 16.

Department of Environmental Medicine, New York University School of Medicine, Tuxedo, USA.

The function of the right heart is to pump blood through the lungs, thus linking right heart physiology and pulmonary vascular physiology. Inflammation is a common modifier of heart and lung function, by elaborating cellular infiltration, production of cytokines and growth factors, and by initiating remodeling processes. Compared to the left ventricle, the right ventricle is a low-pressure pump that operates in a relatively narrow zone of pressure changes. Increased pulmonary artery pressures are associated with increased pressure in the lung vascular bed and pulmonary hypertension. Pulmonary hypertension is often associated with inflammatory lung diseases, for example chronic obstructive pulmonary disease, or autoimmune diseases. Because pulmonary hypertension confers a bad prognosis for quality of life and life expectancy, much research is directed towards understanding the mechanisms that might be targets for pharmaceutical intervention. The main challenge for the development of effective management tools for pulmonary hypertension remains the complexity of the simultaneous understanding of molecular and cellular changes in the right heart, the lungs and the immune system. Here, we present a procedural workflow for the rapid and precise measurement of pressure changes in the right heart of mice and the simultaneous harvest of samples from heart, lungs and immune tissues. The method is based on the direct catheterization of the right ventricle via the jugular vein in close-chested mice, first developed in the late 1990s as surrogate measure of pressures in the pulmonary artery. The organized team-approach facilitates a very rapid right heart catheterization technique. This makes it possible to perform the measurements in mice that spontaneously breathe room air. The organization of the work-flow in distinct work-areas reduces time delay and opens the possibility to simultaneously perform physiology experiments and harvest immune, heart and lung tissues. The procedural workflow outlined here can be adapted for a wide variety of laboratory settings and study designs, from small, targeted experiments, to large drug screening assays. The simultaneous acquisition of cardiac physiology data that can be expanded to include echocardiography and harvest of heart, lung and immune tissues reduces the number of animals needed to obtain data that move the scientific knowledge basis forward. The procedural workflow presented here also provides an ideal basis for gaining knowledge of the networks that link immune, lung and heart function. The same principles outlined here can be adapted to study other or additional organs as needed.
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http://dx.doi.org/10.3791/50023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582655PMC
January 2013

The clinical consequences of hemizygosity across 2 MB of 10q23 are restricted to Cowden syndrome.

Breast Cancer Res Treat 2012 Dec 7;136(3):911-8. Epub 2012 Nov 7.

Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8548, USA.

Cowden syndrome is caused by germline mutations in PTEN and clinically characterized by hamartomas, macrocephaly, classic dermatologic stigmata, and an estimated 85 % lifetime risk of female breast cancer. A young woman with macrocephaly, tricholemmomas, AV malformations, and mammary papillomatosis was found to be hemizygous for PTEN in her germline DNA. Using MLPA, comparative genomic hybridization, and DNA sequencing, we identified a 2-Mb deletion in chromosome 10 spanning 344-kb centromeric and 1.7-Mb telomeric of PTEN. Her father who has a clinical history including macrocephaly, Hashimoto's thyroiditis, colonic polyposis, acral keratoses, and goiter was also found to have the same deletion. In benign breast tissue from the hemizygous female, PTEN protein expression was significantly reduced in luminal and stromal cells but present in the myoepithelium. Compared with a typical papilloma of the breast which had intense cytoplasmic PTEN staining, the majority of the patient's papilloma had significantly decreased PTEN expression while some cells had mislocalized perinuclear PTEN expression. In addition to PTEN, 22 other protein-coding genes were deleted including two predicted haploinsufficient genes and five additional genes that have previously been associated with hereditary predispositions to certain diseases. However, because all significant clinical features of the proband and her father are common to patients with genetic alterations in PTEN, the other 22 hemizygous protein-coding genes appear to be haplosufficient.
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http://dx.doi.org/10.1007/s10549-012-2322-zDOI Listing
December 2012

Minimizing side reactions in chemoenzymatic dynamic kinetic resolution: organometallic and material strategies.

Dalton Trans 2012 Nov;41(43):13423-8

School of Chemistry and Chemical Engineering, Queen's University Belfast, David Keir Building, Belfast, BT9 5AG, UK.

Chemoenzymatic dynamic kinetic resolution (DKR) of rac-1-phenyl ethanol into R-1-phenylethanol acetate was investigated with emphasis on the minimization of side reactions. The organometallic hydrogen transfer (racemization) catalyst was varied, and this was observed to alter the rate and extent of oxidation of the alcohol to form ketone side products. The performance of highly active catalyst [(pentamethylcyclopentadienyl)IrCl(2)(1-benzyl,3-methyl-imidazol-2-ylidene)] was found to depend on the batch of lipase B used. The interaction between the bio- and chemo-catalysts was reduced by employing physical entrapment of the enzyme in silica using a sol-gel process. The nature of the gelation method was found to be important, with an alkaline method preferred, as an acidic method was found to initiate a further side reaction, the acid catalyzed dehydration of the secondary alcohol. The acidic gel was found to be a heterogeneous solid acid.
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http://dx.doi.org/10.1039/c2dt31781hDOI Listing
November 2012

General surgery and otolaryngology resident perspectives on obtaining competency in thyroid surgery.

J Surg Educ 2012 Sep-Oct;69(5):593-8. Epub 2012 Jul 15.

Department of Surgery, Inova Fairfax Hospital, Falls Church, VA 22042, USA.

Objective: General surgery (GS) and otolaryngology (OTO) do not require a minimum number of thyroidectomies to qualify for board certification. No standardized criteria exist for declaring competence in this procedure. A survey was created to assess GS and OTO resident perspectives on becoming competent in thyroid surgery.

Design: A survey was electronically mailed to all GS and OTO residents assessing their competence in thyroid surgery.

Setting: National survey of general surgery and otolaryngology residents.

Participants: National general surgery and otolaryngology residents.

Results: A convenience sample of 526 residents responded (246/280 = GS/OTO). The mean clinical year of training was 3.3 (3.1/3.5). Most residents (50%/41%) performed between 1 and 10 thyroid operations. Residents believed 13 and 25 (GS/OTO) thyroidectomies were required by their respective Boards. Both groups felt that 30 (27/33) thyroid operations were necessary to obtain competence (p < 0.01). The most important feature was operative volume with graduated responsibility, followed by guidance under an expert mentor. Analysis of residents PGY4 and greater showed no significant differences.

Conclusions: While residents of both specialties generally agree on learning methods, the perception of readiness to perform thyroid surgery after training is variable. A disconnect is present between the number of cases required for Board certification, the number of cases residents believe are required, and the number of cases residents believe it takes to achieve competency.
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http://dx.doi.org/10.1016/j.jsurg.2012.06.008DOI Listing
January 2013

A randomized controlled trial of an HIV/AIDS Symptom Management Manual for depressive symptoms.

AIDS Care 2013 13;25(4):391-9. Epub 2012 Aug 13.

College of Nursing, Rutgers, The State University of New Jersey, Newark, NJ, USA.

Abstract Depressive symptoms are highly prevalent, underdiagnosed, and undertreated in people living with HIV/AIDS (PLWH), and are associated with poorer health outcomes. This randomized controlled trial examined the effects of the HIV/AIDS Symptom Management Manual self-care symptom management strategies compared with a nutrition manual on depressive symptoms in an international sample of PLWH. The sample consisted of a sub-group (N=222) of participants in a larger study symptom management study who reported depressive symptoms. Depressive symptoms of the intervention (n=124) and control (n=98) groups were compared over three months: baseline, one-month, and two-months. Use and effectiveness of specific strategies were examined. Depressive symptom frequency at baseline varied significantly by country (χ (2) 12.9; p=0.04). Within the intervention group there were significant differences across time in depressive symptom frequency [F(2, 207) = 3.27, p=0.05], intensity [F(2, 91) = 4.6, p=0.01], and impact [F(2, 252) = 2.92, p= 0.05), and these were significantly lower at one month but not at two months, suggesting that self-care strategies are effective in reducing depressive symptoms, however effects may be short term. Most used and most effective self-care strategies were distraction techniques and prayer. This study suggests that people living with HIV can be taught and will employ self-care strategies for management of depressive symptoms and that these strategies are effective in reducing these symptoms. Self-care strategies are noninvasive, have no side-effects, and can be readily taught as an adjunct to other forms of treatment. Studies are needed to identify the most effective self-care strategies and quantify optimum dose and frequency of use as a basis for evidence-based practice.
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http://dx.doi.org/10.1080/09540121.2012.712662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561506PMC
September 2013

Metabolomic analysis of bone morphogenetic protein receptor type 2 mutations in human pulmonary endothelium reveals widespread metabolic reprogramming.

Pulm Circ 2012 Apr-Jun;2(2):201-13

Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee, USA.

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease of the lung vasculature for which the molecular etiologies are unclear. Specific metabolic alterations have been identified in animal models and in PAH patients, though existing data focus mainly on abnormalities of glucose homeostasis. We hypothesized that analysis of the entire metabolome in PAH would reveal multiple other metabolic changes relevant to disease pathogenesis and possible treatment. Layered transcriptomic and metabolomic analyses of human pulmonary microvascular endothelial cells (hPMVEC) expressing two different disease-causing mutations in the bone morphogenetic protein receptor type 2 (BMPR2) confirmed previously described increases in aerobic glycolysis but also uncovered significant upregulation of the pentose phosphate pathway, increases in nucleotide salvage and polyamine biosynthesis pathways, decreases in carnitine and fatty acid oxidation pathways, and major impairment of the tricarboxylic acid (TCA) cycle and failure of anaplerosis. As a proof of principle, we focused on the TCA cycle, predicting that isocitrate dehydrogenase (IDH) activity would be altered in PAH, and then demonstrating increased IDH activity not only in cultured hPMVEC expressing mutant BMPR2 but also in the serum of PAH patients. These results suggest that widespread metabolic changes are an important part of PAH pathogenesis, and that simultaneous identification and targeting of the multiple involved pathways may be a more fruitful therapeutic approach than targeting of any one individual pathway.
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http://dx.doi.org/10.4103/2045-8932.97606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401874PMC
August 2012

Exploring the contribution of general self-efficacy to the use of self-care symptom management strategies by people living with HIV infection.

AIDS Patient Care STDS 2012 Jun 21;26(6):335-43. Epub 2012 May 21.

School of Nursing, MGH Institute of Health Professions, Boston, Massachusetts, USA.

General self-efficacy (GSE), the expectation that one is able to perform a behavior successfully, may differentiate those who are able to successfully utilize self-care symptom management strategies (SCSMS). This subanalysis (n=569) of an international 12 site longitudinal randomized controlled trial (RCT) (n=775), investigated GSE as an important factor determining symptom burden, SCSMS, engagement with the provider, and medication adherence over time, and identified differences in those with high and low GSE ratings concerning these variables. Parametric and nonparametric repeated-measures tests were employed to assess GSE and the perceived effectiveness of SCSMS for anxiety, depression, diarrhea, fatigue, nausea, and neuropathy. Symptom burden, engagement with the provider, and antiretroviral adherence were analyzed with regard to GSE. Our data indicated that there were differences in the perceived symptom burden over time of HIV infected individuals by GSE. Those individuals with higher GSE had fewer symptoms and these symptoms were perceived to be less intense than those experienced by the low GSE group. There were few meaningful differences in the SCSMS used by those with high versus low GSE other than the use of illicit substances in the low GSE group. The low GSE group was also significantly (p= < 0.001) less engaged with their healthcare providers. Given the difference in substance use by perceived GSE, and the importance of engagement with the healthcare provider, more attention to the resolution of the concerns of those with low GSE by healthcare providers is warranted.
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http://dx.doi.org/10.1089/apc.2011.0404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155925PMC
June 2012
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