Publications by authors named "Jennifer Malinowski"

16 Publications

  • Page 1 of 1

Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability.

Genet Med 2020 06 23;22(6):986-1004. Epub 2020 Mar 23.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Purpose: Exome and genome sequencing (ES/GS) are performed frequently in patients with congenital anomalies, developmental delay, or intellectual disability (CA/DD/ID), but the impact of results from ES/GS on clinical management and patient outcomes is not well characterized. A systematic evidence review (SER) can support future evidence-based guideline development for use of ES/GS in this patient population.

Methods: We undertook an SER to identify primary literature from January 2007 to March 2019 describing health, clinical, reproductive, and psychosocial outcomes resulting from ES/GS in patients with CA/DD/ID. A narrative synthesis of results was performed.

Results: We retrieved 2654 publications for full-text review from 7178 articles. Only 167 articles met our inclusion criteria, and these were primarily case reports or small case series of fewer than 20 patients. The most frequently reported outcomes from ES/GS were changes to clinical management or reproductive decision-making. Two studies reported on the reduction of mortality or morbidity or impact on quality of life following ES/GS.

Conclusion: There is evidence that ES/GS for patients with CA/DD/ID informs clinical and reproductive decision-making, which could lead to improved outcomes for patients and their family members. Further research is needed to generate evidence regarding health outcomes to inform robust guidelines regarding ES/GS in the care of patients with CA/DD/ID.
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http://dx.doi.org/10.1038/s41436-020-0771-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222126PMC
June 2020

The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis.

PLoS One 2018 25;13(7):e0200486. Epub 2018 Jul 25.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200486PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059436PMC
January 2019

Intellectual property considerations for molecular diagnostic development with emphasis on companion diagnostics.

Expert Opin Ther Pat 2018 Feb 9;28(2):123-128. Epub 2017 Dec 9.

b Godney, USVI , USA.

Introduction: The development of molecular diagnostics is a complex endeavor, with multiple regulatory pathways to consider and numerous approaches to development and commercialization. Companion diagnostics, devices which are "essential for the safe and effective use of a corresponding drug or diagnostic product" (see U.S. Food & Drug Administration, In Vitro Diagnostics - Companion Diagnostics, U.S. Dept. of Health & Human Services(2016), available at https://www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/ucm407297.htm ) and complementary diagnostics, which are more broadly associated with a class of drug, are becoming increasingly important as integral components of the implementation of precision medicine. Areas covered: The following article will highlight the intellectual property ('IP') considerations pertinent to molecular diagnostics development with special emphasis on companion diagnostics. Expert opinion/commentary Summary: For all molecular diagnostics, intellectual property (IP) concerns are of paramount concern, whether the device will be marketed only in the United States or abroad. Taking steps to protect IP at each stage of product development is critical to optimize profitability of a diagnostic product. Also the legal framework around IP protection of diagnostic technologies has been changing over the previous few years and can be expected to continue to change in the foreseeable near future, thus, a comprehensive IP strategy should take into account the fact that changes in the law can be expected.
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http://dx.doi.org/10.1080/13543776.2018.1409209DOI Listing
February 2018

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.

Authors:
Gregory T Jones Gerard Tromp Helena Kuivaniemi Solveig Gretarsdottir Annette F Baas Betti Giusti Ewa Strauss Femke N G Van't Hof Thomas R Webb Robert Erdman Marylyn D Ritchie James R Elmore Anurag Verma Sarah Pendergrass Iftikhar J Kullo Zi Ye Peggy L Peissig Omri Gottesman Shefali S Verma Jennifer Malinowski Laura J Rasmussen-Torvik Kenneth M Borthwick Diane T Smelser David R Crosslin Mariza de Andrade Evan J Ryer Catherine A McCarty Erwin P Böttinger Jennifer A Pacheco Dana C Crawford David S Carrell Glenn S Gerhard David P Franklin David J Carey Victoria L Phillips Michael J A Williams Wenhua Wei Ross Blair Andrew A Hill Thodor M Vasudevan David R Lewis Ian A Thomson Jo Krysa Geraldine B Hill Justin Roake Tony R Merriman Grzegorz Oszkinis Silvia Galora Claudia Saracini Rosanna Abbate Raffaele Pulli Carlo Pratesi Athanasios Saratzis Ana R Verissimo Suzannah Bumpstead Stephen A Badger Rachel E Clough Gillian Cockerill Hany Hafez D Julian A Scott T Simon Futers Simon P R Romaine Katherine Bridge Kathryn J Griffin Marc A Bailey Alberto Smith Matthew M Thompson Frank M van Bockxmeer Stefan E Matthiasson Gudmar Thorleifsson Unnur Thorsteinsdottir Jan D Blankensteijn Joep A W Teijink Cisca Wijmenga Jacqueline de Graaf Lambertus A Kiemeney Jes S Lindholt Anne Hughes Declan T Bradley Kathleen Stirrups Jonathan Golledge Paul E Norman Janet T Powell Steve E Humphries Stephen E Hamby Alison H Goodall Christopher P Nelson Natzi Sakalihasan Audrey Courtois Robert E Ferrell Per Eriksson Lasse Folkersen Anders Franco-Cereceda John D Eicher Andrew D Johnson Christer Betsholtz Arno Ruusalepp Oscar Franzén Eric E Schadt Johan L M Björkegren Leonard Lipovich Anne M Drolet Eric L Verhoeven Clark J Zeebregts Robert H Geelkerken Marc R van Sambeek Steven M van Sterkenburg Jean-Paul de Vries Kari Stefansson John R Thompson Paul I W de Bakker Panos Deloukas Robert D Sayers Seamus C Harrison Andre M van Rij Nilesh J Samani Matthew J Bown

Circ Res 2017 Jan 29;120(2):341-353. Epub 2016 Nov 29.

For the author affiliations, please see the Appendix.

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA.

Objective: To identify additional AAA risk loci using data from all available genome-wide association studies.

Methods And Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9.

Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.308765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253231PMC
January 2017

Parathyroidectomy prior to kidney transplant decreases graft failure.

Surgery 2017 01 15;161(1):44-50. Epub 2016 Nov 15.

Department of Surgery, Section of Transplantation Surgery, Yale University School of Medicine, New Haven, CT.

Background: Uncorrected uremic hyperparathyroidism is associated with delayed graft function after kidney transplantation. The current guidelines of the Kidney Disease Improving Global Outcomes recommend maintaining parathyroid hormone ≤9x normal in patients pre-kidney transplantation. This study explores the effect of increased levels of serum parathyroid hormone and preoperative parathyroidectomy on outcomes after kidney transplantation.

Methods: A retrospective review was performed of adult patients who underwent kidney transplantation between January 1, 2005, and December 31, 2014, at a single institution. Biochemistries and outcomes were analyzed pre-kidney transplantation and at 30 days, 6 months, and 1 year post-kidney transplantation.

Results: A total of 913 patients underwent kidney transplantation from 2005-2014. Graft survival 1 year post-kidney transplantation was 97.8%. Overall, 462 (50.6%) patients had a pre-kidney transplantation diagnosis of uncorrected uremic hyperparathyroidism, which was associated with complications in the first year post-kidney transplantation (odds ratio 1.44; 95% confidence interval, 1.11-1.87); no statistical association with delayed graft function or graft failure was detected. Pre-kidney transplantation parathyroid hormone ≥6x normal was associated with post-kidney transplantation graft failure (P < .05). A total of 57 (6.2%) patients underwent pre-kidney transplantation parathyroidectomy, which was associated with lesser risk of graft failure (odds ratio: 0.547; 95% confidence interval, 0.327-0.913), but no statistically significant association with delayed graft function or complications were detected.

Conclusion: Pre-kidney transplantation parathyroidectomy decreases post-kidney transplantation graft failure and may benefit patients whose serum parathyroid hormone levels decrease into the target range of current Kidney Disease Improving Global Outcomes guidelines.
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http://dx.doi.org/10.1016/j.surg.2016.10.003DOI Listing
January 2017

Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms.

J Am Heart Assoc 2016 07 14;5(7). Epub 2016 Jul 14.

Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

Background: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs.

Methods And Results: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10(-3)).

Conclusions: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.
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http://dx.doi.org/10.1161/JAHA.115.002603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015357PMC
July 2016

Dissection of Levels II Through V Is Required for Optimal Outcomes in Patients with Lateral Neck Lymph Node Metastasis from Papillary Thyroid Carcinoma.

J Am Coll Surg 2016 06 19;222(6):1066-73. Epub 2016 Feb 19.

Department of Surgery, Section of Endocrine Surgery, Yale University School of Medicine, New Haven, CT. Electronic address:

Background: Completeness of surgical resection is an important determinant of outcomes in patients with papillary thyroid carcinoma and regional lymph node metastasis. The extent of therapeutic lateral neck dissection remains controversial. This study aims to assess the impact of modified radical neck dissection of levels II to V in a large patient series.

Study Design: Retrospective analysis of consecutive patients with papillary thyroid carcinoma who underwent lateral neck dissection at a single institution from June 1, 2006 to December 31, 2014 was performed.

Results: A total of 241 lateral neck dissections were performed in 191 patients (118 [62%] women; median age 46 years [range 6 to 87 years]; median follow-up 14.3 months [range 0.1 to 107 months]). Overall, 202 initial neck dissections (195 modified radical neck dissections and 7 less extensive dissections) were performed. Among these initial dissections, 137 (68.8%), 132 (65.7%), 105 (52.0%), and 33 (16.9%) had positive lymph nodes in levels II, III, IV, and V, respectively. Ipsilateral lymph node persistence or recurrence occurred after 22 (10.9%) initial dissections, at level II in 10 (45.5%), level III in 8 (36.4%), level IV in 7 (31.8%), and level V in 3 (13.6%). Thirty-nine reoperative lateral neck dissection were performed, including 18 cases of persistence and recurrence after our initial dissections. In reoperative dissections, positive lymph nodes were confirmed in levels II, III, IV, and V in 18 (46.2%), 10 (25.6%), 13 (33.3%), and 5 (12.8%) dissections, respectively. Temporary nerve injury occurred in 6 (3.0%) initial and 4 (10.3%) reoperative dissections, respectively. There were no permanent nerve injuries.

Conclusions: Omitting levels II and V during lateral neck dissection for papillary thyroid carcinoma potentially misses level II disease in two-thirds of patients and level V disease in one-fifth of patients. Formal modified radical neck dissection is necessary to avoid the morbidity of reoperative surgery.
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http://dx.doi.org/10.1016/j.jamcollsurg.2016.02.006DOI Listing
June 2016

Cryptic relatedness in epidemiologic collections accessed for genetic association studies: experiences from the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study and the National Health and Nutrition Examination Surveys (NHANES).

Front Genet 2015 26;6:317. Epub 2015 Oct 26.

Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland OH, USA.

Epidemiologic collections have been a major resource for genotype-phenotype studies of complex disease given their large sample size, racial/ethnic diversity, and breadth and depth of phenotypes, traits, and exposures. A major disadvantage of these collections is they often survey households and communities without collecting extensive pedigree data. Failure to account for substantial relatedness can lead to inflated estimates and spurious associations. To examine the extent of cryptic relatedness in an epidemiologic collection, we as the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study accessed the National Health and Nutrition Examination Surveys (NHANES) linked to DNA samples ("Genetic NHANES") from NHANES III and NHANES 1999-2002. NHANES are population-based cross-sectional surveys conducted by the National Center for Health Statistics at the Centers for Disease Control and Prevention. Genome-wide genetic data is not yet available in NHANES, and current data use agreements prohibit the generation of GWAS-level data in NHANES samples due issues in maintaining confidentiality among other ethical concerns. To date, only hundreds of single nucleotide polymorphisms (SNPs) genotyped in a variety of candidate genes are available for analysis in NHANES. We performed identity-by-descent (IBD) estimates in three self-identified subpopulations of Genetic NHANES (non-Hispanic white, non- Hispanic black, and Mexican American) using PLINK software to identify potential familial relationships from presumed unrelated subjects. We then compared the PLINKidentified relationships to those identified by an alternative method implemented in Kinship-based INference for Genome-wide association studies (KING). Overall, both methods identified familial relationships in NHANES III and NHANES 1999-2002 for all three subpopulations, but little concordance was observed between the two methods due in major part to the limited SNP data available in Genetic NHANES. Despite the lack of genome-wide data, our results suggest the presence of cryptic relatedness in this epidemiologic collection and highlight the limitations of restricted datasets such as NHANES in the context of modern day genetic epidemiology studies.
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http://dx.doi.org/10.3389/fgene.2015.00317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620157PMC
November 2015

Genetic variants associated with serum thyroid stimulating hormone (TSH) levels in European Americans and African Americans from the eMERGE Network.

PLoS One 2014 1;9(12):e111301. Epub 2014 Dec 1.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States of America; Center for Human Genetics Research, Vanderbilt University, Nashville, TN, United States of America.

Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10-17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10-6, β = -0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = -0.09), VEGFA (rs11755845 p = 0.01, β = -0.13), and NFIA (rs334699 p = 1.50×10-3, β = -0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111301PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249871PMC
February 2016

Cross-cancer pleiotropic analysis of endometrial cancer: PAGE and E2C2 consortia.

Carcinogenesis 2014 Sep 15;35(9):2068-73. Epub 2014 May 15.

Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.

Genome-wide association studies (GWAS) have identified a large number of cancer-associated single nucleotide polymorphisms (SNPs), several of which have been associated with multiple cancer sites suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs associated with other cancers may be additionally associated with endometrial cancer. We examined 213 SNPs previously associated with 14 other cancers for their associations with endometrial cancer in 3758 endometrial cancer cases and 5966 controls of European ancestry from two consortia: Population Architecture Using Genomics and Epidemiology and the Epidemiology of Endometrial Cancer Consortium. Study-specific logistic regression estimates adjusted for age, body mass index and the most significant principal components of genetic ancestry were combined using fixed-effect meta-analysis to evaluate the association between each SNP and endometrial cancer risk. A Bonferroni-corrected P value of 2.35×10(-4) was used to determine statistical significance of the associations. SNP rs7679673, ~6.3kb upstream of TET2 and previously reported to be associated with prostate cancer risk, was associated with endometrial cancer risk in the direction opposite to that for prostate cancer [meta-analysis odds ratio = 0.87 (per copy of the C allele), 95% confidence interval = 0.81, 0.93; P = 7.37×10(-5)] with no evidence of heterogeneity across studies (P heterogeneity = 0.66). This pleiotropic analysis is the first to suggest TET2 as a susceptibility locus for endometrial cancer.
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http://dx.doi.org/10.1093/carcin/bgu107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146418PMC
September 2014

Development of a data-mining algorithm to identify ages at reproductive milestones in electronic medical records.

Pac Symp Biocomput 2014 :376-87

Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 519 Light Hall, Nashville, TN 37232, USA.

Electronic medical records (EMRs) are becoming more widely implemented following directives from the federal government and incentives for supplemental reimbursements for Medicare and Medicaid claims. Replete with rich phenotypic data, EMRs offer a unique opportunity for clinicians and researchers to identify potential research cohorts and perform epidemiologic studies. Notable limitations to the traditional epidemiologic study include cost, time to complete the study, and limited ancestral diversity; EMR-based epidemiologic studies offer an alternative. The Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, as part of the Population Architecture using Genomics and Epidemiology (PAGE) I Study, has genotyped more than 15,000 patients of diverse ancestry in BioVU, the Vanderbilt University Medical Center's biorepository linked to the EMR (EAGLE BioVU). We report here the development and performance of data-mining techniques used to identify the age at menarche (AM) and age at menopause (AAM), important milestones in the reproductive lifespan, in women from EAGLE BioVU for genetic association studies. In addition, we demonstrate the ability to discriminate age at naturally-occurring menopause (ANM) from medically-induced menopause. Unusual timing of these events may indicate underlying pathologies and increased risk for some complex diseases and cancer; however, they are not consistently recorded in the EMR. Our algorithm offers a mechanism by which to extract these data for clinical and research goals.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905575PMC
August 2014

Genetic variation and reproductive timing: African American women from the Population Architecture using Genomics and Epidemiology (PAGE) Study.

PLoS One 2013 12;8(2):e55258. Epub 2013 Feb 12.

Department of Biology and Environmental Science, Heidelberg University, Tiffin, Ohio, United States of America.

Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (n = 161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/CENPW, and two variants for ANM, rs897798/BRSK1 and rs769450/APOE, to our African American cohort. Overall, generalization of the majority of previously-identified variants for AM and ANM, including LIN28B and MCM8, was not observed in this African American sample. We identified three novel loci associated with ANM that reached significance after multiple testing correction (LDLR rs189596789, p = 5×10⁻⁰⁸; KCNQ1 rs79972789, p = 1.9×10⁻⁰⁷; COL4A3BP rs181686584, p = 2.9×10⁻⁰⁷). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p = 1.6×10⁻⁰⁶). While most associations were identified in either AM or ANM, we did identify genes suggestively associated with both: PHACTR1 and ARHGAP42. The lack of generalization coupled with the potentially novel associations identified here emphasize the need for additional genetic discovery efforts for AM and ANM in diverse populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570525PMC
August 2013

Phytosterols for dyslipidemia.

Am J Health Syst Pharm 2010 Jul;67(14):1165-73

Pharmacy Practice, Nesbitt College of Pharmacy and Nursing, Wilkes University, Wilkes-Barre, PA 18766, USA.

Purpose: The efficacy and safety of phytosterols for the management of dyslipidemia are reviewed.

Summary: Phytosterols have been evaluated in over 40 clinical trials. The incorporation of 2 g of phytosterols daily into margarine, mayonnaise, orange juice, olive oil, low-fat milk, yogurt, and tablets is associated with significant reductions in low-density-lipoprotein (LDL) cholesterol from baseline over 1-12 months in adults with normal or high cholesterol, in children, and in patients with type 2 diabetes mellitus. Phytosterol dosages of 1.6-3 g daily have been shown to reduce LDL cholesterol by 4.1-15% versus placebo within the first month of therapy. One meta-analysis found mean reductions of 10-11%, but results vary. Several placebo-controlled trials found that the addition of phytosterols to statin therapy was associated with reductions of 7-20% in LDL cholesterol for up to 1.5 years. Overall, phytosterols are useful for reducing LDL cholesterol in patients who cannot reach their treatment goal by diet alone or who are taking maximum tolerated doses of statins. These products offer an alternative to statins in patients who cannot take statins or whose statin dosage is restricted because of potential drug interactions or concomitant diseases. Commonly reported adverse effects are primarily gastrointestinal in nature.

Conclusion: Phytosterol therapy produces an average 10-11% reduction in LDL cholesterol concentration, but it is unknown whether this effect persists beyond two years. Phytosterol products are well tolerated and have few drug interactions, but their long-term safety has not been established. Current evidence is sufficient to recommend phytosterols for lowering LDL cholesterol in adults.
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http://dx.doi.org/10.2146/ajhp090427DOI Listing
July 2010

Vasopressor choice for hypotension in elective Cesarean section: ephedrine or phenylephrine?

Arch Med Sci 2010 Apr;6(2):257-63

Krishna Rajendra Hospital and Cheluvamba Hospital, Mysore Medical College, Rajiv Gandhi University, India.

Introduction: Hypotensive episodes are a common complication of spinal anesthesia during Cesarean section. The purpose of this study was to compare the effectiveness and the side effects of vasopressors, ephedrine and phenylephrine, administered for hypotension during elective Cesarean section under spinal anesthesia.

Material And Methods: The study consisted of 100 selected ASA I/II females scheduled for elective Cesarean section under spinal anesthesia. Each patient was randomly assigned to one of the two double-blind study groups. Group E received 1 ml ephedrine (5 mg/ml) with normal saline if hypotension was present (n=50). Group P received 1 ml phenylephrine (100 µg/ml) with normal saline if hypotension developed (n=50). Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) were compared within and between groups to basal levels at time increments of 0, 2, 4, 6, 8, 10, 15, 20, 25, 30, 45, and 60 min from start of surgery. Incidence of side effects and neonatal outcomes were studied between groups.

Results: All patients required vasopressor therapy for hypotension. Administration of phenylephrine was associated with significant drop in HR. Changes in SBP, DBP, and MAP were similar in both groups for most observed times. The incidences of nausea/vomiting and tachycardia were significantly higher in the ephedrine group.

Conclusions: Phenylephrine and ephedrine are acceptable choices to combat maternal hypotension related to spinal anesthesia in elective Cesarean section. Complications of intra-operative nausea and vomiting, tachycardia and bradycardia should be considered when choosing a vasopressor, suggesting phenylephrine may be more appropriate when considering maternal well-being.
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http://dx.doi.org/10.5114/aoms.2010.13905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281349PMC
April 2010

Elevation of low-density lipoprotein cholesterol concentration with over-the-counter fish oil supplementation.

Ann Pharmacother 2007 Jul 3;41(7):1296-300. Epub 2007 Jul 3.

Nesbitt School of Pharmacy and Nursing, Wilkes University, Wilkes-Barre, PA 18766, USA.

Objective: To report a case of elevated low-density lipoprotein cholesterol (LDL-C) concentration in a patient taking fish oil supplements for hypertriglyceridemia.

Case Summary: A 63-year-old white woman had been taking 2.7 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) daily in 9 g of over-the-counter (OTC) fish oil capsules for triglyceride lowering. Prior to the adverse event, she had baseline fasting triglyceride (TG) and LDL-C concentrations of 278 mg/dL and 106 mg/dL, respectively. After 6 weeks of treatment with fish oil, fasting TG levels decreased by 47.5% (-132 mg/dL) and the LDL-C increased by 75% (+80 mg/dL). Discontinuation of therapy for 6 weeks resulted in TG returning to high concentrations (334 mg/dL; +56 mg/dL change from baseline) and LDL-C decreasing toward baseline (143 mg/dL; +37 mg/dL change from baseline).

Discussion: Fish oil, an omega-3 polyunsaturated fatty acid, consists of EPA and DHA. EPA and DHA are thought to inhibit the synthesis of triglycerides in the liver. Type IV dyslipidemic patients may develop increased LDL-C levels while taking fish oil to lower triglycerides due to possible down-regulation of the LDL-C receptor in hepatic cells and formation of larger LDL particles. Use of the Naranjo probability scale indicates a probable relationship between elevations in LDL-C from baseline and initiation of fish oil treatment for hypertriglyceridemia. It is unknown whether any component within this particular product could have contributed to such an unusual elevation in LDL-C.

Conclusions: This case documents a much higher LDL-C elevation associated with OTC fish oil supplementation than has been previously identified in the literature. Healthcare providers should be advised that LDL-C levels may increase with use of OTC fish oil and should monitor patients periodically for such elevations. The significance of this increase on clinical outcomes is not known.
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http://dx.doi.org/10.1345/aph.1H695DOI Listing
July 2007

Possible mesalamine-induced pericarditis: case report and literature review.

Pharmacotherapy 2002 Mar;22(3):391-4

Department of Pharmacy Practice, Nesbitt School of Pharmacy, Wilkes University, Wilkes-Barre, Pennsylvania 18766, USA.

Pericarditis should be considered in any patient complaining of chest pain and/or dyspnea who is taking a product that contains mesalamine or sulfasalazine. A 41-year-old woman was taking mesalamine 800 mg 3 times/day for 3 weeks before hospital admission. She complained of sharp, pleuritic chest pain that radiated down both arms and increased in intensity when lying down. She was diagnosed with pericarditis based on clinical presentation and electrocardiogram findings. Differential diagnoses for myocardial infarction, systemic lupus erythematosus, and viral or bacterial causes were ruled out based on subjective and objective data. Mesalamine-induced pericarditis was considered on hospital day 2, and the drug was discontinued at discharge on day 3. Clinicians should be aware of this potential drug-related complication, as the relationship between mesalamine or sulfasalazine and pericarditis has been reported rarely in the literature.
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http://dx.doi.org/10.1592/phco.22.5.391.33188DOI Listing
March 2002