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1. Analysis of Nurse and Patient Preferences for Pre-Filled Pen Devices for Self-Injection of Highly Purified Human Menopausal Gonadotropin (HP-hMG, MENOPUR®)

Author

De Mesmaeker G, Calles B, and Smith JA

Subjects
fertility, ovarian stimulation, patient preference, assisted reproductive technology, gonadotropin-injection pen, Medicine (General), R5-920
Abstract

Guy De Mesmaeker,1,* Brigitte Calles,2,* Judith A Smith3,* 1Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Brussels, Belgium; 2Ferring Pharmaceuticals, Gentilly, France; 3CARE Fertility Group, Nottingham, UK*These authors contributed equally to this workCorrespondence: Judith A Smith, CARE Fertility Nottingham, John Webster House, 6 Lawrence Drive, Nottingham Business Park, Nottingham, NG8 6PZ, UK, Tel + 44 0 115 852 8100, Email judith.smith@carefertility.comPurpose: This study aimed to identify the most important attributes for a gonadotropin pen as perceived by assisted reproductive technology (ART) patients and fertility nurses, and to examine how well a prototype HP-hMG (MENOPUR®) pen reflects these preferences.Patients and Methods: This market research study incorporated a two-part survey with respondents (N=221) from Poland, Spain and the UK. Respondents included patients (n=141) who consulted a fertility specialist in the previous 2 years, and fertility nurses (n=80) who assisted in at least 75 ART cycles/year. Patients were divided into two subgroups depending on their experience with ART (experienced and naïve). Key attributes for an injection pen, as perceived by patients and nurses, were assessed via an online survey and ranked by their relative importance using Anchored Maximum Difference Scaling. After performing a dummy injection, respondents compared the attributes of an unbranded prototype pen against the key attributes identified.Results: Across all survey respondents, the ability to correct the dialed dose was considered to be the most important product attribute of a gonadotropin pen. Confidence in the patient’s ability to inject correctly at home was also identified as a key attribute, considered by both nurses and naïve patients as extremely high. When considering the prototype pen device, almost all study respondents reported a positive experience (99%) with 72% rating it as “very good”. The prototype pen was perceived to possess the key attributes considered important for a gonadotropin pen by patients and nurses, including correcting the dose, the ability to self-inject safely and correctly, ease of preparation and use, and an injection which appeared to be as painless as possible.Conclusion: The prototype pen was found to perform well across all key attributes, especially those considered most important in gonadotropin pens, suggesting that it is a user-friendly option for patients undergoing ART.Graphical Abstract: Keywords: fertility, ovarian stimulation, patient preference, assisted reproductive technology, gonadotropin-injection pen

Published
2023

2. Diet, Diabetes Status, and Personal Experiences of Individuals with Type 2 diabetes Who Self-Selected and Followed a Low Carbohydrate High Fat diet

Author

Webster CC, Murphy TE, Larmuth KM, Noakes TD, and Smith JA

Subjects
carbohydrate restriction, diabetes remission, ketogenic diet, lchf, nutritional therapy, food addiction, Specialties of internal medicine, RC581-951
Abstract

Christopher C Webster, Tamzyn E Murphy, Kate M Larmuth, Timothy D Noakes, James A Smith Division of Exercise Science and Sports Medicine, University of Cape Town, Cape Town, South AfricaCorrespondence: Christopher C WebsterDivision of Exercise Science and Sports Medicine, University of Cape Town, Sports Science Institute of South Africa, Newlands, Cape Town 7700, South AfricaEmail wbschr002@myuct.ac.zaBackground: Low carbohydrate high fat (LCHF) diets are increasing in popularity amongst patients with type 2 diabetes (T2D), however it is unclear what constitutes a sustainable LCHF diet in a real-world setting.Methods: This descriptive multi-method study characterized the diets, T2D status, and personal experiences of individuals with T2D who claimed to have followed an LCHF diet for at least 6 months. Participants completed a medications history, mixed-method dietary assessment, provided a blood sample, and were interviewed in-depth about their experiences with the diet (First-Assessment). Past medical records were obtained corresponding to T2D diagnosis and prior to starting their LCHF diets. Additionally, participants were followed up 15 months later to assess T2D remission (Follow-Up).Results: Twenty-eight participants completed First-Assessment and 24 completed Follow-Up. Habitual carbohydrate intake was 20 to 50 g/d for 10 participants and 50 to 115 g/d for 17 participants. Commonly reported foods were full-fat dairy, non-starchy vegetables, coconut oil, eggs, nuts, olives and avocados, olive oil, and red meat and poultry with fat. Median (interquartile range) for HbA1c was 7.5 (6.5–9.5) % prior to starting their diets, 5.8 (5.4–6.2) % at First-Assessment and 5.9 (5.3–6.6) % at Follow-Up. Reported body weight and glucose-lowering medication requirements were considerably lower at both assessments than when starting the diet. At Follow-Up, 24 participants had been following their LCHF diets for 35 (26–53) months, the majority of which were in full or partial T2D remission. Participants perceived reduced hunger and cravings as one of the most important aspects of their diets. Of concern, many participants felt unsupported by their doctors.Conclusion: This study described the foods and characteristics of an LCHF “lifestyle” that was sustainable and effective for certain T2D patients in a real-world setting.Keywords: carbohydrate restriction, diabetes remission, ketogenic diet, LCHF, nutritional therapy, food addiction

Published
2019

3. Elevated fractional exhaled nitric oxide and blood eosinophil counts are associated with a 17q21 asthma risk allele in adult subjects

Author

Schwantes EA, Evans MD, Cuskey A, Burford A, Smith JA, Lemanske RF Jr, Jarjour NN, and Mathur SK

Subjects
asthma, eosinophils, exhaled nitric oxide (FeNO), 17q21, Immunologic diseases. Allergy, RC581-607
Abstract

Elizabeth A Schwantes,1 Michael D Evans,2 Alex Cuskey,1 Alex Burford,1 Judith A Smith,3 Robert F Lemanske Jr,3 Nizar N Jarjour,1 Sameer K Mathur1 1Division of Allergy, Pulmonary and Critical Care, Department of Medicine, 2Department of Biostatistics and Medical Informatics, 3Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Background and objectives: Genome-wide association studies identified single-nucleotide polymorphisms (SNPs) at the 17q21 locus conferring increased risk for childhood-onset asthma. Little is known about how these SNPs impact adult asthma patients. We sought to examine an adult population for associations between rs7216389 (17q21-associated SNP) and features of asthma including fractional exhaled nitric oxide (FeNO), eosinophil counts, and age of asthma onset. Methods: Subjects were genotyped at SNP rs7216389. The geometric mean of FeNO measurements and peripheral blood eosinophil counts from 2008 to 2015 were collected. Demographics and medical history were collected including self-reported allergy diagnoses and age of asthma onset. Eosinophils, monocytes, and peripheral blood mononuclear cells (PBMCs) were isolated for the examination of ORMDL3 expression. Results: FeNO levels from 157 genotyped subjects (31CC, 72CT, and 54TT) and peripheral eosinophil counts from 252 genotyped subjects (46CC, 122CT, and 84TT) were analyzed. In a sub-group analysis of asthma subjects, the number of attributable T alleles was associated with significantly lower age of asthma onset (P=0.03) and greater FeNO levels (geometric mean 30.0 ppb TT, 20.0 ppb CT, 20.0 ppb CC, P=0.02). In the total cohort of subjects, the T allele was associated with a higher percentage of individual eosinophil counts >200/mm3 (45% TT, 26% CT, 24% CC, P=0.005). Eosinophils expressed ORMDL3 mRNA and protein. Conclusion: In adult subjects, the number of T alleles at SNP rs7216389 corresponds to significantly greater FeNO levels and peripheral eosinophil counts. The expression of ORMDL3 in eosinophils suggests that they may participate in mediating the asthma risk associated with the 17q21 locus. Keywords: asthma, eosinophils, fractional exhaled nitric oxide, 17q21

Published
2017

4. Enhancing health and independent living for veterans with disabilities by leveraging community-based resources

Author

Hale-Gallardo J, Jia H, Delisle T, Levy CE, Osorio V, Smith JA, and Hannold EM

Subjects
independent living, veterans, disabilities, community, Medicine (General), R5-920
Abstract

Jennifer Hale-Gallardo,1 Huanguang Jia,1 Tony Delisle,2 Charles E Levy,1,3–5 Valentina Osorio,1 Jennifer A Smith,1 Elizabeth M Hannold,1,† 1Center of Innovation on Disability and Rehabilitation Research, North Florida/South Georgia Veterans Health System, 2Center for Independent Living of North Central Florida, 3Physical Medicine and Rehabilitation Service, North Florida/South Georgia Veterans Health Service, 4The Department of Occupational Therapy, College of Public Health and Health Professions, 5The Center for the Arts in Medicine, College of the Arts, University of Florida, Gainesville, FL, USA †Elizabeth M Hannold passed away on September 28, 2015. Abstract: The number of US veterans with disabilities has increased in recent years as service members have returned home with extensive injuries and veterans from previous wars acquire functional limitations as a consequence of aging with chronic diseases. Veterans with severe disabilities need assistance and support to maintain independence at home and to avoid institutionalization. The US Department of Veterans Affairs (VA) strives to network with community organizations to achieve the best possible outcomes for veterans. Key community resources in the US for individuals with disabilities are Centers for Independent Living (CILs) that provide a wide range of services, promoting independent living and well-being for people across disabilities. The widespread availability and services of CILs nationwide suggest their potential as a community-based resource for veterans, particularly for those with limited access to VA care. In this article, we discuss long-term needs of veterans with disabilities, efforts to address veterans’ rehabilitation needs at the VA and opportunities for leveraging the strengths of community-based organizations for veterans. More research is warranted to investigate CIL services and potential for CIL–VA partnerships. Keywords: rehabilitation, community engagement, community reintegration, functional limitations

Published
2017

5. Validity of a screening tool for detecting subtle cognitive impairment in the middle-aged and elderly

Author

Bruce KM, Robinson SR, Smith JA, Yell, and GW

Subjects
Aging, Mild cognitive impairment, Neuropsychological test, Subtle Cognitive Impairment Test, Validation, Reliability, Geriatrics, RC952-954.6
Abstract

Kathryn M Bruce,1 Stephen R Robinson,2 Julian A Smith,1 Gregory W Yelland2,3 1Department of Surgery (MMC), Monash University, Clayton, 2School of Health Sciences, RMIT University, Bundoora, 3Central Clinical School, Monash University, Alfred Health, Melbourne, VIC, Australia Abstract: The present study tested 121 middle-aged and elderly community-dwelling individuals on the computer-based Subtle Cognitive Impairment Test (SCIT) and compared their performance with that on several neuropsychological tests. The SCIT had excellent internal consistency, as demonstrated by a high split-half reliability measure (0.88–0.93). Performance on the SCIT was unaffected by the confounding factors of sex, education level, and mood state. Many participants demonstrated impaired performance on one or more of the neuropsychological tests (Controlled Oral Word Association Task, Rey Auditory and Verbal Learning Task, Grooved Pegboard [GP], Complex Figures). Performance on SCIT subtests correlated significantly with performance on many of the neuropsychological subtests, and the best and worst performing quartiles on the SCIT subtest discriminated between good and poor performers on other subtests, collectively indicating concurrent validity of the SCIT. Principal components analysis indicated that SCIT performance does not cluster with performance on most of the other cognitive tests, and instead is associated with decision-making efficacy, and processing speed and efficiency. Thus, the SCIT is responsive to the processes that underpin multiple cognitive domains, rather than being specific for a single domain. Since the SCIT is quick and easy to administer, and is well tolerated by the elderly, it may have utility as a screening tool for detecting cognitive impairment in middle-aged and elderly populations. Keywords: aging, mild cognitive impairment, neuropsychological test, Subtle Cognitive Impairment Test, validation, reliability

Published
2014

6. Heterogeneous melting near the Thwaites Glacier grounding line

Author

Schmidt, BE, Washam, P, Davis, PED, Nicholls, KW, Holland, DM, Lawrence, JD, Riverman, KL, Smith, JA, Spears, A, Dichek, DJG, Mullen, AD, Clyne, E, Yeager, B, Anker, P, Meister, MR, Hurwitz, BC, Quartini, ES, Bryson, FE, Basinski-Ferris, A, Thomas, C, Wake, J, Vaughan, DG, Anandakrishnan, S, Rignot, E, Paden, J, and Makinson, K

Subjects
Earth Sciences, Oceanography, Physical Geography and Environmental Geoscience, Geology, Climate Action, General Science & Technology
Abstract

Thwaites Glacier represents 15% of the ice discharge from the West Antarctic Ice Sheet and influences a wider catchment1-3. Because it is grounded below sea level4,5, Thwaites Glacier is thought to be susceptible to runaway retreat triggered at the grounding line (GL) at which the glacier reaches the ocean6,7. Recent ice-flow acceleration2,8 and retreat of the ice front8-10 and GL11,12 indicate that ice loss will continue. The relative impacts of mechanisms underlying recent retreat are however uncertain. Here we show sustained GL retreat from at least 2011 to 2020 and resolve mechanisms of ice-shelf melt at the submetre scale. Our conclusions are based on observations of the Thwaites Eastern Ice Shelf (TEIS) from an underwater vehicle, extending from the GL to 3 km oceanward and from the ice-ocean interface to the sea floor. These observations show a rough ice base above a sea floor sloping upward towards the GL and an ocean cavity in which the warmest water exceeds 2 °C above freezing. Data closest to the ice base show that enhanced melting occurs along sloped surfaces that initiate near the GL and evolve into steep-sided terraces. This pronounced melting along steep ice faces, including in crevasses, produces stratification that suppresses melt along flat interfaces. These data imply that slope-dependent melting sculpts the ice base and acts as an important response to ocean warming.

Published
2023

7. Correction: Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Author

Liang, J, Le, TH, Velez Edwards, DR, Tayo, BO, Gaulton, KJ, Smith, JA, Lu, Y, Jensen, RA, Chen, G, Yanek, LR, Schwander, K, Tajuddin, SM, Sofer, T, Kim, W, Kayima, J, McKenzie, CA, Fox, E, Nalls, MA, Young, JH, Sun, YV, Lane, JM, Cechova, S, Zhou, J, Tang, H, Fornage, M, Musani, SK, Wang, H, Lee, J, Adeyemo, A, Dreisbach, AW, Forrester, T, Chu, P-L, Cappola, A, Evans, MK, Morrison, AC, Martin, LW, Wiggins, KL, Hui, Q, Zhao, W, Jackson, RD, Ware, EB, Faul, JD, Reiner, AP, Bray, M, Denny, JC, Mosley, TH, Palmas, W, Guo, X, Papanicolaou, GJ, Penman, AD, Polak, JF, Rice, K, Taylor, KD, Boerwinkle, E, Bottinger, EP, Liu, K, Risch, N, Hunt, SC, Kooperberg, C, Zonderman, AB, Laurie, CC, Becker, DM, Cai, J, Loos, RJF, Psaty, BM, Weir, DR, Kardia, SLR, Arnett, DK, Won, S, Edwards, TL, Redline, S, Cooper, RS, Rao, DC, Rotter, JI, Rotimi, C, Levy, D, Chakravarti, A, Zhu, X, and Franceschini, N

Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1006728.].

Published
2018

8. Ice sheet–free West Antarctica during peak early Oligocene glaciation

Author

Smith, H Jesse, Klages, Johann Philipp, Hillenbrand, C-D, Bohaty, SM, Salzmann, U, Bickert, T, Lohmann, G, Knahl, HS, Gierz, P, Niu, L, Titschack, J, Kuhn, G, Frederichs, T, Müller, J, Bauersachs, T, Larter, RD, Hochmuth, K, Ehrmann, W, Nehrke, G, Rodríguez-Tovar, FJ, Schmiedl, G, Spezzaferri, S, Läufer, A, Lisker, F, van de Flierdt, T, Eisenhauer, A, Uenzelmann-Neben, G, Esper, O, Smith, JA, Pälike, H, Spiegel, C, Dziadek, R, Ronge, TA, Freudenthal, T, Gohl, K, Smith, H Jesse, Klages, Johann Philipp, Hillenbrand, C-D, Bohaty, SM, Salzmann, U, Bickert, T, Lohmann, G, Knahl, HS, Gierz, P, Niu, L, Titschack, J, Kuhn, G, Frederichs, T, Müller, J, Bauersachs, T, Larter, RD, Hochmuth, K, Ehrmann, W, Nehrke, G, Rodríguez-Tovar, FJ, Schmiedl, G, Spezzaferri, S, Läufer, A, Lisker, F, van de Flierdt, T, Eisenhauer, A, Uenzelmann-Neben, G, Esper, O, Smith, JA, Pälike, H, Spiegel, C, Dziadek, R, Ronge, TA, Freudenthal, T, and Gohl, K

Abstract

One of Earth’s most fundamental climate shifts – the greenhouse-icehouse transition 34 Ma ago – initiated Antarctic ice-sheet build-up, influencing global climate until today. However, the extent of the ice sheet during the Early Oligocene Glacial Maximum (~33.7–33.2 Ma) that immediately followed this transition, a critical knowledge gap for assessing feedbacks between permanently glaciated areas and early Cenozoic global climate reorganization, is uncertain. Here, we present shallow-marine drilling data constraining earliest Oligocene environmental conditions on West Antarctica’s Pacific margin – a key region for understanding Antarctic ice sheet-evolution. These data indicate a cool-temperate environment, with mild ocean and air temperatures preventing West Antarctic Ice Sheet formation. Climate-ice sheet modeling corroborates a highly asymmetric Antarctic ice sheet, thereby revealing its differential regional response to past and future climatic change.

Published
2024

9. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author

Ibrahim-Verbaas, CA, Bressler, J, Debette, S, Schuur, M, Smith, AV, Bis, JC, Davies, G, Trompet, S, Smith, JA, Wolf, C, Chibnik, LB, Liu, Y, Vitart, V, Kirin, M, Petrovic, K, Polasek, O, Zgaga, L, Fawns-Ritchie, C, Hoffmann, P, Karjalainen, J, Lahti, J, Llewellyn, DJ, Schmidt, CO, Mather, KA, Chouraki, V, Sun, Q, Resnick, SM, Rose, LM, Oldmeadow, C, Stewart, M, Smith, BH, Gudnason, V, Yang, Q, Mirza, SS, Jukema, JW, deJager, PL, Harris, TB, Liewald, DC, Amin, N, Coker, LH, Stegle, O, Lopez, OL, Schmidt, R, Teumer, A, Ford, I, Karbalai, N, Becker, JT, Jonsdottir, MK, Au, R, Fehrmann, RSN, Herms, S, Nalls, M, Zhao, W, Turner, ST, Yaffe, K, Lohman, K, van Swieten, JC, Kardia, SLR, Knopman, DS, Meeks, WM, Heiss, G, Holliday, EG, Schofield, PW, Tanaka, T, Stott, DJ, Wang, J, Ridker, P, Gow, AJ, Pattie, A, Starr, JM, Hocking, LJ, Armstrong, NJ, McLachlan, S, Shulman, JM, Pilling, LC, Eiriksdottir, G, Scott, RJ, Kochan, NA, Palotie, A, Hsieh, Y-C, Eriksson, JG, Penman, A, Gottesman, RF, Oostra, BA, Yu, L, DeStefano, AL, Beiser, A, Garcia, M, Rotter, JI, Nöthen, MM, Hofman, A, Slagboom, PE, Westendorp, RGJ, Buckley, BM, Wolf, PA, Uitterlinden, AG, Psaty, BM, Grabe, HJ, Bandinelli, S, and Chasman, DI

Subjects
Biological Psychology, Clinical and Health Psychology, Psychology, Human Genome, Neurosciences, Genetics, Clinical Research, Aging, Aetiology, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Cell Adhesion Molecules, Cognition, Cohort Studies, Executive Function, Female, Genetic Association Studies, Genetic Variation, Genome-Wide Association Study, Genomics, Humans, Introns, Male, Middle Aged, Neuropsychological Tests, Polymorphism, Single Nucleotide, White People, gamma-Aminobutyric Acid, Generation Scotland, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Published
2016

11. Prolonged survival in patients >= 60 years with first relapsed/refractory acute myeloid leukemia treated with vosaroxin plus cytarabine vs placebo plus cytarabine: Results from the phase 3 VALOR study

Author

Krug, U, Ravandi, F, Ritchie, EK, Sayar, H, Lancet, JE, Craig, MD, Vey, N, Strickland, SA, Schiller, GJ, Jabbour, E, Erba, HP, Pigneux, A, Horst, H-A, Recher, C, Klimek, VM, Cortes, J, Roboz, GJ, Craig, AR, Fox, JA, Ward, R, Smith, JA, Acton, G, Mehta, C, Kantarjian, HM, and Stuart, RK

Published
2015

12. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

Author

Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, J, van der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Generation Scotland, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, J-C, Lee, T, Li, G, Li, S-C, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, and Wright, AF

Subjects
Generation Scotland, Humans, Genetic Predisposition to Disease, HMGN1 Protein, Cohort Studies, Cognition, Cognition Disorders, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Scotland, Female, Male, Atherosclerosis, Genome-Wide Association Study, and over, Polymorphism, Single Nucleotide, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Published
2015

14. Unilateral nevoid telangiectasia syndrome (UNTS) associated with chronic Hepatitis C virus and positive immunoreactivity for VEGF

Author

Smith, JA, Kamangar, F, Prakash, N, Fung, MA, Konia, T, and Fazel, N

Abstract

Unilateral Nevoid Telangectasia Syndrome (UNTS) is characterized by superficial telangiectasias in a unilateral distribution. Vascular endothelial growth factor (VEGF) may play a role in the pathogenesis of UNTS in patients with underlying hepatic disease.  We report a case of a patient with UNTS accompanied by chronic hepatitis C virus infection, with a normal serum estrogen profile and strong positive immunohistochemical staining of lesional skin with VEGF.

Published
2014

15. Genetics of coronary artery calcification among African Americans, a meta-analysis

Author

Wojczynski, MK, Li, M, Bielak, LF, Kerr, KF, Reiner, AP, Wong, ND, Yanek, LR, Qu, L, White, CC, Lange, LA, Ferguson, JF, He, J, Young, T, Mosley, TH, Smith, JA, Kral, BG, Guo, X, Wong, Q, Ganesh, SK, Heckbert, SR, Griswold, ME, O'Leary, DH, Budoff, M, Carr, JJ, Taylor, HA, Bluemke, DA, Demissie, S, Hwang, SJ, Paltoo, DN, Polak, JF, Psaty, BM, Becker, DM, Province, MA, Post, WS, O'Donnell, CJ, Wilson, JG, Harris, TB, Kavousi, M, Cupples, LA, Rotter, JI, Fornage, M, Becker, LC, Peyser, PA, Borecki, IB, and Reilly, MP

Abstract

Background: Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants.Methods: We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis.Results: Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region.Conclusions: While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations. © 2013 Wojczynski et al.; licensee BioMed Central Ltd.

Published
2013

16. Controlling anisotropic properties by manipulating the orientation of chiral small molecules

Author

Wade, J, Salerno, F, Kilbride, RC, Kim, DK, Schmidt, JA, Smith, JA, LeBlanc, LM, Wolpert, EH, Adeleke, AA, Johnson, ER, Nelson, J, Mori, T, Jelfs, KE, Heutz, S, and Fuchter, MJ

Subjects
General Chemical Engineering, Anisotropy, Electrons, General Chemistry
Abstract

Chiral π-conjugated molecules bring new functionality to technological applications and represent an exciting, rapidly expanding area of research. Their functional properties, such as the absorption and emission of circularly polarized light or the transport of spin-polarized electrons, are highly anisotropic. As a result, the orientation of chiral molecules critically determines the functionality and efficiency of chiral devices. Here we present a strategy to control the orientation of a small chiral molecule (2,2'-dicyano[6]helicene) by the use of organic and inorganic templating layers. Such templating layers can either force 2,2'-dicyano[6]helicene to adopt a face-on orientation and self-assemble into upright supramolecular columns oriented with their helical axis perpendicular to the substrate, or an edge-on orientation with parallel-lying supramolecular columns. Through such control, we show that low- and high-energy chiroptical responses can be independently 'turned on' or 'turned off'. The templating methodologies described here provide a simple way to engineer orientational control and, by association, anisotropic functional properties of chiral molecular systems for a range of emerging technologies.

Published
2022

17. Open-circuit and short-circuit loss management in wide-gap perovskite p-i-n solar cells

Author

Caprioglio, P, Smith, JA, Oliver, RDJ, Dasgupta, A, Choudhary, S, Farrar, MD, Ramadan, AJ, Lin, Y-H, Christoforo, MG, Ball, JM, Diekmann, J, Thiesbrummel, J, Zaininger, K-A, Shen, X, Johnston, MB, Neher, D, Stolterfoht, M, and Snaith, HJ

Subjects
Multidisciplinary, General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract

In this work, we couple theoretical and experimental approaches to understand and reduce the losses of wide bandgap Br-rich perovskite pin devices at open-circuit voltage (VOC) and short-circuit current (JSC) conditions. A mismatch between the internal quasi-Fermi level splitting (QFLS) and the external VOC is detrimental for these devices. We demonstrate that modifying the perovskite top-surface with guanidinium-Br and imidazolium-Br forms a low-dimensional perovskite phase at the n-interface, suppressing the QFLS-VOC mismatch, and boosting the VOC. Concurrently, the use of an ionic interlayer or a self-assembled monolayer at the p-interface reduces the inferred field screening induced by mobile ions at JSC, promoting charge extraction and raising the JSC. The combination of the n- and p-type optimizations allows us to approach the thermodynamic potential of the perovskite absorber layer, resulting in 1 cm2 devices with performance parameters of VOCs up to 1.29 V, fill factors above 80% and JSCs up to 17 mA/cm2, in addition to a thermal stability T80 lifetime of more than 3500 h at 85 °C.

Published
2023

19. Proactive breast cancer risk assessment in primary care: a review based on the principles of screening.

Author

Usher-Smith, JA, Hindmarch, S, French, DP, Tischkowitz, M, Moorthie, S, Walter, FM, Dennison, RA, Stutzin Donoso, F, Archer, S, Taylor, L, Emery, J, Morris, S, Easton, DF, Antoniou, AC, Usher-Smith, JA, Hindmarch, S, French, DP, Tischkowitz, M, Moorthie, S, Walter, FM, Dennison, RA, Stutzin Donoso, F, Archer, S, Taylor, L, Emery, J, Morris, S, Easton, DF, and Antoniou, AC

Abstract

In the UK, the National Institute for Health and Care Excellence (NICE) recommends that women at moderate or high risk of breast cancer be offered risk-reducing medication and enhanced breast screening/surveillance. In June 2022, NICE withdrew a statement recommending assessment of risk in primary care only when women present with concerns. This shift to the proactive assessment of risk substantially changes the role of primary care, in effect paving the way for a primary care-based screening programme to identify those at moderate or high risk of breast cancer. In this article, we review the literature surrounding proactive breast cancer risk assessment within primary care against the consolidated framework for screening. We find that risk assessment for women under 50 years currently satisfies many of the standard principles for screening. Most notably, there are large numbers of women at moderate or high risk currently unidentified, risk models exist that can identify those women with reasonable accuracy, and management options offer the opportunity to reduce breast cancer incidence and mortality in that group. However, there remain a number of uncertainties and research gaps, particularly around the programme/system requirements, that need to be addressed before these benefits can be realised.

Published
2023

20. Nonmitogenic anti-CD3 monoclonal antibodies deliver a partial T cell receptor signal and induce clonal anergy.

Author

Smith, JA, Tso, JY, Clark, MR, Cole, MS, and Bluestone, JA

Subjects
Lymph Nodes, T-Lymphocytes, Animals, Mice, Inbred BALB C, Mice, Inbred DBA, Mice, Phosphotyrosine, Receptors, Antigen, T-Cell, Antibodies, Monoclonal, Immunosuppression, Lymphocyte Activation, Signal Transduction, Receptor Aggregation, Clonal Anergy, Phosphorylation, ZAP-70 Protein-Tyrosine Kinase, Protein-Tyrosine Kinases, CD3 Complex, Antibodies, Monoclonal, Inbred BALB C, Inbred DBA, Receptors, Antigen, T-Cell, Medical and Health Sciences, Immunology
Abstract

Anti-CD3 monoclonal antibodies (mAbs) are potent immunosuppressive agents used in clinical transplantation. However, the activation-related adverse side effects associated with these mAbs have prompted the development of less toxic nonmitogenic anti-CD3 mAb therapies. At present, the functional and biochemical consequences of T cell exposure to nonmitogenic anti-CD3 is unclear. In this study, we have examined the early signaling events triggered by a nonmitogenic anti-CD3 mAb. Like the mitogenic anti-CD3 mAb, nonnmitogenic anti-CD3 triggered changes in the T cell receptor (TCR) complex, including zeta chain tyrosine phosphorylation and ZAP-70 association. However, unlike the mitogenic anti-CD3 stimulation, nonmitogenic anti-CD3 was ineffective at inducing the highly phosphorylated form of zeta (p23) and tyrosine phosphorylation of the associated ZAP-70 tyrosine kinase. This proximal signaling deficiency correlated with minimal phospholipase Cgamma-1 phosphorylation and failure to mobilize detectable Ca2+. Not only did biochemical signals delivered by nonmitogenic anti-CD3 resemble altered peptide ligand signaling, but exposure of Th1 clones to nonmitogenic anti-CD3 also resulted in functional anergy. Finally, a bispecific anti-CD3 X anti-CD4 F(ab)'2 reconstituted early signal transduction events and induced proliferation, suggesting that defective association of lck with the TCR complex may underlie the observed signaling differences between the mitogenic and nonmitogenic anti-CD3.

Published
1997

21. Seed banks, community dynamics and species persistence in 5 Tasmanian temporary wetlands

Author

Smith, JA

Subjects
Biogeography and phylogeography
Abstract

Water regime has been found to be the most important factor in determining vegetation patterns in wetlands. The present study investigates the short and long-term persistence of plant communities within 5 temporary Tasmanian lentic wetlands and- resistance and resilience of wetland communities to dry periods. Within each wetland an aquatic herbaceous and sedge-dominated zone were sampled seasonally between February, 1997 and November, 1998, to test difference between and within wetlands, and their relations to water depth. Four glasshouse experiments using sediments taken from 9 permanent quadrats per vegetation type per wetland (zone) were used to determine temporal and spatial differences in seed banks in relation to season, vegetation type, depth, germination treatment and water regime. The relationship between the seed bank and extant vegetation was investigated. A functional group classification generated similar groups to Brock and Casanova (1997). These were: a) submerged; b) amphibious fluctuation responder; c) amphibious fluctuation tolerator-emergent; d) amphibious fluctuation tolerator-saturated/mudflat; and e) terrestrial. The vegetation communities within the 5 temporary wetlands proved not resistant to changes in water level. Large differences in percentage cover were associated with hydrological changes over the 2 year period. However, the communities were able to resurrect relatively quickly after both short and long term dry periods. The seed bank experiments indicated that Tasmanian temporary wetlands have speciesrich persistent seed banks, and, therefore, the potential for future regeneration. In general, species in the seed bank could be related to species found in the extant vegetation. However, at any given time, species can be found in the seed bank and not present in the extant vegetation, or vice versa. Both seed banks and vegetative regeneration were important mechanisms for species persistence in the vegetation communities of the 5 wetlands.

Published
2023
Full Text
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22. Validation and Meaningful Change Thresholds for an Objective Cough Frequency Measurement in Chronic Cough

Author

Smith, Jaclyn, Schelfhout, J, Nguyen, AM, Birring, SS, Bacci, ED, Vernon, M, Muccino, DR, La, Rosa C, and Smith, JA

Subjects
Pulmonary and Respiratory Medicine, Clinically meaningful change, Patient-reported outcomes, Cough, ROC Curve, Objective cough frequency, Chronic cough, Cough monitoring, Humans, Patient Reported Outcome Measures, Plastic Surgery Procedures, Pain Measurement, Cough severity
Abstract

Purpose Objective cough frequency is used to assess efficacy of chronic cough (CC) treatments. The objective of this study was to explore the relationship between objective cough frequency and cough-specific patient-reported outcomes (PROs) and estimate a clinically meaningful change threshold (MCT) for objective cough frequency. Methods Data collected in a phase 2b study in participants with refractory or unexplained CC were used to investigate the relationship between 24-h cough frequency (measured using an ambulatory cough monitor) and cough-specific PROs (i.e., cough severity visual analog scale, cough severity diary, Leicester Cough Questionnaire). Convergent validity was assessed using Spearman ρ. An MCT for 24-h cough frequency was estimated using the patient global impression of change (PGIC) scale as an anchor. Results Correlations between 24-h cough frequency and cough-specific PROs at baseline, Week 4, and Week 12 were significant (P ρ = 0.30–0.58). Participants categorized as very much improved/much improved (i.e., PGIC of 1 or 2) or minimally improved (i.e., PGIC of 3) had mean 24-h cough frequency reductions of 55% and 30%, respectively. Receiver operating characteristic curve analysis suggested that a 24-h cough frequency reduction of 38% optimizes sensitivity and specificity for predicting a PGIC score of 1–3. Conclusion Objective 24-h cough frequency is significantly associated with cough-specific PROs, but cough frequency and PROs most likely capture distinct aspects of CC. A ≥ 30% reduction in 24-h cough frequency is a reasonable MCT to define treatment response in CC clinical trials.

Published
2022

23. Synergistic Surface Modification of Tin-Lead Perovskite Solar Cells

Author

Hu, S, Zhao, P, Nakano, K, Oliver, RDJ, Pascual, J, Smith, JA, Yamada, T, Truong, MA, Murdey, R, Shioya, N, Hasegawa, T, Ehara, M, Johnston, MB, Tajima, K, Kanemitsu, Y, Snaith, HJ, and Wakamiya, A

Subjects
Mechanics of Materials, Mechanical Engineering, General Materials Science
Abstract

Interfaces in thin-film photovoltaics play a pivotal role in determining device efficiency and longevity. Herein, we study the top surface treatment of mixed tin-lead (∼1.26 eV) halide perovskite films for p-i-n solar cells. We are able to promote charge extraction by treating the perovskite surface with piperazine. This compound reacts with the organic cations at the perovskite surface, modifying the surface structure and tuning the interfacial energy level alignment. In addition, the combined treatment with C60 pyrrolidine tris-acid (CPTA) reduces hysteresis and leads to efficiencies up to 22.7%, with open-circuit voltage values reaching 0.90 V, ∼92% of the radiative limit for the band gap of this material. The modified cells also show superior stability, with unencapsulated cells retaining 96% of their initial efficiency after >2000 hours of storage in N2 and encapsulated cells retaining 90% efficiency after >450 hours of storage in air. Intriguingly, CPTA preferentially binds to Sn2+ sites at film surface over Pb2+ due to the energetically favoured exposure of the former, according to first-principles calculations. This work provides new insights into the surface chemistry of perovskite films in terms of their structural, electronic, and defect characteristics and we use this knowledge to fabricate state-of-the-art solar cells.

Published
2022

27. Contribution of Common Genetic Variants to Risk of Early Onset Ischemic Stroke

Author

Jaworek, T, Xu, H, Gaynor, BJ, Cole, JW, Rannikmae, K, Stanne, TM, Tomppo, L, Abedi, V, Amouyel, P, Armstrong, ND, Attia, J, Bell, S, Benavente, OR, Boncoraglio, GB, Butterworth, A, Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium, Carcel-Marquez, J, Chen, Z, Chong, M, Cruchaga, C, Cushman, M, Danesh, J, Debette, S, Duggan, DJ, Durda, JP, Engstrom, G, Enzinger, C, Faul, JD, Fecteau, NS, Fernandez-Cadenas, I, Gieger, C, Giese, A-K, Grewal, RP, Grittner, U, Havulinna, AS, Heitsch, L, Hochberg, MC, Holliday, E, Hu, J, Ilinca, A, INVENT Consortium, Irvin, MR, Jackson, RD, Jacob, MA, Janssen, RR, Jimenez-Conde, J, Johnson, JA, Kamatani, Y, Kardia, SL, Koido, M, Kubo, M, Lange, L, Lee, J-M, Lemmens, R, Levi, CR, Li, J, Li, L, Lin, K, Lopez, H, Luke, S, Maguire, J, McArdle, PF, McDonough, CW, Meschia, JF, Metso, T, Muller-Nurasyid, M, O'Connor, TD, O'Donnell, M, Peddareddygari, LR, Pera, J, Perry, JA, Peters, A, Putaala, J, Ray, D, Rexrode, K, Ribases, M, Rosand, J, Rothwell, PM, Rundek, T, Ryan, KA, Sacco, RL, Salomaa, V, Sanchez-Mora, C, Schmidt, R, Sharma, P, Slowik, A, Smith, JA, Smith, NL, Wassertheil-Smoller, S, Soederholm, M, Stine, OC, Strbian, D, Sudlow, CL, Tatlisumak, T, Terao, C, Thijs, V, Torres-Aguila, NP, Tregouet, D-A, Tuladhar, AM, Veldink, JH, Walters, RG, Weir, DR, Woo, D, Worrall, BB, Hong, CC, Ross, O, Zand, R, Leeuw, F-ED, Lindgren, AG, Pare, G, Anderson, CD, Markus, HS, Jern, C, Malik, R, Dichgans, M, Mitchell, BD, Kittner, SJ, and Early Onset Stroke Genetics Consortium of the International Stroke Genetics Consortium (ISGC)

Subjects
Neurology & Neurosurgery, 1103 Clinical Sciences, 1109 Neurosciences, 1702 Cognitive Sciences
Abstract

BACKGROUND AND OBJECTIVES: Current genome-wide association studies of ischemic stroke have focused primarily on late onset disease. As a complement to these studies, we sought to identifythe contribution of common genetic variants to risk of early onset ischemic stroke. METHODS: We performed a meta-analysis of genome-wide association studies of early onset stroke (EOS), ages 18-59, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late onset stroke (LOS) and compared polygenic risk scores for venous thromboembolism between EOS and LOS. RESULTS: We observed genome-wide significant associations of EOS with two variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% CI: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to LOS (p=0.008). DISCUSSION: The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.

Published
2022

28. ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer

Author

Kim, E, Kim, Y-J, Ji, Z, Kang, JM, Wirianto, M, Paudel, KR, Smith, JA, Ono, K, Kim, J-A, Eckel-Mahan, K, Zhou, X, Lee, HK, Yoo, JY, Yoo, S-H, and Chen, Z

Subjects
0601 Biochemistry and Cell Biology, 1112 Oncology and Carcinogenesis
Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft experiments showed that NOB significantly inhibited TNBC cell proliferation and motility in vitro and in vivo. ROR loss- and gain-of-function studies showed concordant effects of the NOB–ROR axis on MDA-MB-231 cell growth. Mechanistically, we found that NOB activates ROR binding to the ROR response elements (RRE) of the IκBα promoter, and NOB strongly inhibited p65 nuclear translocation. Consistent with transcriptomic analysis indicating cancer and NF-κB signaling as major pathways altered by NOB, p65-inducible expression abolished NOB effects, illustrating a requisite role of NF-κB suppression mediating the anti-TNBC effect of NOB. Finally, in vivo mouse xenograft studies showed that NOB enhanced the antitumor efficacy in mammary fat pad implanted TNBC, as a single agent or in combination with the chemotherapy agent Docetaxel. Together, our study highlights an anti-TNBC mechanism of ROR-NOB via suppression of NF-κB signaling, suggesting novel preventive and chemotherapeutic strategies against this devastating disease.

Published
2022

29. Risk prediction models for symptomatic patients with bladder and kidney cancer: a systematic review

Author

Harrison, H, Usher-Smith, JA, Li, L, Roberts, L, Lin, Z, Thompson, RE, Rossi, SH, Stewart, GD, Walter, FM, Griffin, S, Zhou, Y, Harrison, H, Usher-Smith, JA, Li, L, Roberts, L, Lin, Z, Thompson, RE, Rossi, SH, Stewart, GD, Walter, FM, Griffin, S, and Zhou, Y

Abstract

BACKGROUND: Timely diagnosis of bladder and kidney cancer is key to improving clinical outcomes. Given the challenges of early diagnosis, models incorporating clinical symptoms and signs may be helpful to primary care clinicians when triaging at-risk patients. AIM: To identify and compare published models that use clinical signs and symptoms to predict the risk of undiagnosed prevalent bladder or kidney cancer. DESIGN AND SETTING: Systematic review. METHOD: A search identified primary research reporting or validating models predicting the risk of bladder or kidney cancer in MEDLINE and EMBASE. After screening identified studies for inclusion, data were extracted onto a standardised form. The risk models were classified using TRIPOD guidelines and evaluated using the PROBAST assessment tool. RESULTS: The search identified 20 661 articles. Twenty studies (29 models) were identified through screening. All the models included haematuria (visible, non-visible, or unspecified), and seven included additional signs and symptoms (such as abdominal pain). The models combined clinical features with other factors (including demographic factors and urinary biomarkers) to predict the risk of undiagnosed prevalent cancer. Several models (n = 13) with good discrimination (area under the receiver operating curve >0.8) were identified; however, only eight had been externally validated. All of the studies had either high or unclear risk of bias. CONCLUSION: Models were identified that could be used in primary care to guide referrals, with potential to identify lower-risk patients with visible haematuria and to stratify individuals who present with non-visible haematuria. However, before application in general practice, external validations in appropriate populations are required.

Published
2022

30. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Author

Howe, LJ, Nivard, MG, Morris, TT, Hansen, AF, Rasheed, H, Cho, Y, Chittoor, G, Ahlskog, R, Lind, PA, Palviainen, T, van der Zee, MD, Cheesman, R, Mangino, M, Wang, Y, Li, S, Klaric, L, Ratliff, SM, Bielak, LF, Nygaard, M, Giannelis, A, Willoughby, EA, Reynolds, CA, Balbona, JV, Andreassen, OA, Ask, H, Baras, A, Bauer, CR, Boomsma, DI, Campbell, A, Campbell, H, Chen, Z, Christofidou, P, Corfield, E, Dahm, CC, Dokuru, DR, Evans, LM, de Geus, EJC, Giddaluru, S, Gordon, SD, Harden, KP, Hill, WD, Hughes, A, Kerr, SM, Kim, Y, Kweon, H, Latvala, A, Lawlor, DA, Li, L, Lin, K, Magnus, P, Magnusson, PKE, Mallard, TT, Martikainen, P, Mills, MC, Njolstad, PR, Overton, JD, Pedersen, NL, Porteous, DJ, Reid, J, Silventoinen, K, Southey, MC, Stoltenberg, C, Tucker-Drob, EM, Wright, MJ, Hewitt, JK, Keller, MC, Stallings, MC, Lee, JJ, Christensen, K, Kardia, SLR, Peyser, PA, Smith, JA, Wilson, JF, Hopper, JL, Hagg, S, Spector, TD, Pingault, J-B, Plomin, R, Havdahl, A, Bartels, M, Martin, NG, Oskarsson, S, Justice, AE, Millwood, IY, Hveem, K, Naess, O, Willer, CJ, Asvold, BO, Koellinger, PD, Kaprio, J, Medland, SE, Walters, RG, Benjamin, DJ, Turley, P, Evans, DM, Smith, GD, Hayward, C, Brumpton, B, Hemani, G, Davies, NM, Howe, LJ, Nivard, MG, Morris, TT, Hansen, AF, Rasheed, H, Cho, Y, Chittoor, G, Ahlskog, R, Lind, PA, Palviainen, T, van der Zee, MD, Cheesman, R, Mangino, M, Wang, Y, Li, S, Klaric, L, Ratliff, SM, Bielak, LF, Nygaard, M, Giannelis, A, Willoughby, EA, Reynolds, CA, Balbona, JV, Andreassen, OA, Ask, H, Baras, A, Bauer, CR, Boomsma, DI, Campbell, A, Campbell, H, Chen, Z, Christofidou, P, Corfield, E, Dahm, CC, Dokuru, DR, Evans, LM, de Geus, EJC, Giddaluru, S, Gordon, SD, Harden, KP, Hill, WD, Hughes, A, Kerr, SM, Kim, Y, Kweon, H, Latvala, A, Lawlor, DA, Li, L, Lin, K, Magnus, P, Magnusson, PKE, Mallard, TT, Martikainen, P, Mills, MC, Njolstad, PR, Overton, JD, Pedersen, NL, Porteous, DJ, Reid, J, Silventoinen, K, Southey, MC, Stoltenberg, C, Tucker-Drob, EM, Wright, MJ, Hewitt, JK, Keller, MC, Stallings, MC, Lee, JJ, Christensen, K, Kardia, SLR, Peyser, PA, Smith, JA, Wilson, JF, Hopper, JL, Hagg, S, Spector, TD, Pingault, J-B, Plomin, R, Havdahl, A, Bartels, M, Martin, NG, Oskarsson, S, Justice, AE, Millwood, IY, Hveem, K, Naess, O, Willer, CJ, Asvold, BO, Koellinger, PD, Kaprio, J, Medland, SE, Walters, RG, Benjamin, DJ, Turley, P, Evans, DM, Smith, GD, Hayward, C, Brumpton, B, Hemani, G, and Davies, NM

Abstract

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Published
2022

31. Intra-operative and early post-operative prediction of cardiac surgery-associated acute kidney injury: Urinary oxygen tension compared with plasma and urinary biomarkers

Author

Noe, KM, Ngo, JP, Martin, A, Zhu, MZL, Cochrane, AD, Smith, JA, Thrift, AG, Singh, H, Evans, RG, Noe, KM, Ngo, JP, Martin, A, Zhu, MZL, Cochrane, AD, Smith, JA, Thrift, AG, Singh, H, and Evans, RG

Abstract

Acute kidney injury (AKI) is a common and serious post-operative complication of cardiac surgery. The value of a predictive biomarker is determined not only by its predictive efficacy, but also by how early this prediction can be made. For a biomarker of cardiac surgery-associated AKI, this is ideally during the intra-operative period. Therefore, in 82 adult patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB), we prospectively compared the predictive efficacy of various blood and urinary biomarkers with that of continuous measurement of urinary oxygen tension (UPO2) at pre-determined intra- and post-operative time-points. None of the blood or urine biomarkers we studied showed predictive efficacy for post-operative AKI when measured intra-operatively. When treated as a binary variable (≤ or > median for the whole cohort), the earliest excess risk of AKI was predicted by an increase in urinary neutrophil gelatinase-associated lipocalin (NGAL) at 3 h after entry into the intensive care unit (odds ratio [95% confidence limits], 2.86 [1.14–7.21], p = 0.03). Corresponding time-points were 6 h for serum creatinine (3.59 [1.40–9.20], p = 0.008), and 24 h for plasma NGAL (4.54 [1.73–11.90], p = 0.002) and serum cystatin C (6.38 [2.35–17.27], p = 0.001). In contrast, indices of intra-operative urinary hypoxia predicted AKI after weaning from CPB, and in the case of a fall in UPO2 to ≤10 mmHg, during the rewarming phase of CPB (3.00 [1.19–7.56], p = 0.02). We conclude that continuous measurement of UPO2 predicts AKI earlier than plasma or urinary NGAL, serum cystatin C, or early post-operative changes in serum creatinine.

Published
2022

32. Donor Cardiac Troponin for Prognosis of Adverse Outcomes in Cardiac Transplantation Recipients: a Systematic Review and Meta-analysis

Author

Liu, Z, Perry, LA, Penny-Dimri, JC, Handscombe, M, Overmars, I, Plummer, M, Segal, R, Smith, JA, Liu, Z, Perry, LA, Penny-Dimri, JC, Handscombe, M, Overmars, I, Plummer, M, Segal, R, and Smith, JA

Abstract

BACKGROUND: Cardiac troponin is a highly specific and widely available marker of myocardial injury, and elevations in cardiac transplant donors may influence donor selection. We aimed to investigate whether elevated donor troponin has a role as a prognostic biomarker in cardiac transplantation. METHODS: In a systematic review and meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library, without language restriction, from inception to December 2020. We included studies reporting the association of elevated donor troponin with recipient outcome after cardiac transplant. We generated summary odds ratios and hazard ratios for the association of elevated donor troponin with short- and long-term adverse outcomes. Methodological quality was monitored using the Quality In Prognosis Studies tool, and interstudy heterogeneity was assessed using a series of sensitivity and subgroup analyses. RESULTS: We included 17 studies involving 15 443 patients undergoing cardiac transplantation. Elevated donor troponin was associated with increased odds of graft rejection at 1 y (odds ratio, 2.54; 95% confidence interval, 1.22-5.28). No significant prognostic relationship was found between donor troponin and primary graft failure, short- to long-term mortality, cardiac allograft vasculopathy, and pediatric graft loss. CONCLUSIONS: Elevated donor troponin is not associated with an increased short- or long-term mortality postcardiac transplant despite increasing the risk of graft rejection at 1 y. Accordingly, an elevated donor troponin in isolation should not exclude donation.

Published
2022

33. Elevated Cardiac Troponin to Detect Acute Cellular Rejection After Cardiac Transplantation: A Systematic Review and Meta-Analysis

Author

Liu, Z, Perry, LA, Penny-Dimri, JC, Handscombe, M, Overmars, I, Plummer, M, Segal, R, Smith, JA, Liu, Z, Perry, LA, Penny-Dimri, JC, Handscombe, M, Overmars, I, Plummer, M, Segal, R, and Smith, JA

Abstract

Cardiac troponin is well known as a highly specific marker of cardiomyocyte damage, and has significant diagnostic accuracy in many cardiac conditions. However, the value of elevated recipient troponin in diagnosing adverse outcomes in heart transplant recipients is uncertain. We searched MEDLINE (Ovid), Embase (Ovid), and the Cochrane Library from inception until December 2020. We generated summary sensitivity, specificity, and Bayesian areas under the curve (BAUC) using bivariate Bayesian modelling, and standardised mean differences (SMDs) to quantify the diagnostic relationship of recipient troponin and adverse outcomes following cardiac transplant. We included 27 studies with 1,684 cardiac transplant recipients. Patients with acute rejection had a statistically significant late elevation in standardised troponin measurements taken at least 1 month postoperatively (SMD 0.98, 95% CI 0.33-1.64). However, pooled diagnostic accuracy was poor (sensitivity 0.414, 95% CrI 0.174-0.696; specificity 0.785, 95% CrI 0.567-0.912; BAUC 0.607, 95% CrI 0.469-0.723). In summary, late troponin elevation in heart transplant recipients is associated with acute cellular rejection in adults, but its stand-alone diagnostic accuracy is poor. Further research is needed to assess its performance in predictive modelling of adverse outcomes following cardiac transplant. Systematic Review Registration: identifier CRD42021227861.

Published
2022

34. The prognostic significance of postoperative hyperbilirubinemia in cardiac surgery: systematic review and meta-analysis

Author

Raveendran, D, Penny-Dimri, JC, Segal, R, Smith, JA, Plummer, M, Liu, Z, Perry, LA, Raveendran, D, Penny-Dimri, JC, Segal, R, Smith, JA, Plummer, M, Liu, Z, and Perry, LA

Abstract

BACKGROUND: Hyperbilirubinemia following cardiac surgery is a common phenomenon and is of emerging interest in prognostic factor research. This systematic review and meta-analysis evaluated the association between post-operative hyperbilirubinemia (PH) and mortality and morbidity in cardiac surgery patients. METHODS: Ovid Medline and Ovid Embase were searched from inception to July 2020 for studies evaluating the prognostic significance of PH following cardiac surgery. Maximally adjusted odds ratios (OR) with associated confidence intervals were obtained from each study and pooled using random effects inverse variance modelling to assess in-hospital mortality. Standardised mean differences were pooled to assess Intensive Care Unit (ICU) and hospital length of stay (LOS). Qualitative analysis was performed to assess ventilation requirements and long-term mortality. Meta-regression was used to assess inter- and intra-study heterogeneity. RESULTS: 3251 studies satisfied the selection criteria, from which 12 studies incorporating 3876 participants were included. PH significantly predicted in-hospital mortality with a pooled OR of 7.29 (95% CI 3.53, 15.09). Multiple pre-defined covariates contributed to the prognostic significance of PH, however only aortic cross-clamp time (p < 0.0001) and number of transfusions (p = 0.0001) were significant effect modifiers. PH significantly predicted both ICU LOS (Mean difference 1.32 [95% CI 0.04-2.6]) and hospital LOS (Mean difference 1.79 [95% CI 0.36-3.21]). Qualitative analysis suggested PH is associated with increased post-operative ventilation requirements and reduced long-term survival rates. CONCLUSIONS: Hyperbilirubinemia is a cost-effective, widely available prognostic marker of adverse outcomes following cardiac surgery, albeit with residual sources of heterogeneity.

Published
2022

35. Machine learning to predict adverse outcomes after cardiac surgery: A systematic review and meta-analysis

Author

Penny-Dimri, JC, Bergmeir, C, Perry, L, Hayes, L, Bellomo, R, Smith, JA, Penny-Dimri, JC, Bergmeir, C, Perry, L, Hayes, L, Bellomo, R, and Smith, JA

Abstract

BACKGROUND: Machine learning (ML) models are promising tools for predicting adverse postoperative outcomes in cardiac surgery, yet have not translated to routine clinical use. We conducted a systematic review and meta-analysis to assess the predictive performance of ML approaches. METHODS: We conducted an electronic search to find studies assessing ML and traditional statistical models to predict postoperative outcomes. Our primary outcome was the concordance (C-) index of discriminative performance. Using a Bayesian meta-analytic approach we pooled the C-indices with the 95% credible interval (CrI) across multiple outcomes comparing ML methods to logistic regression (LR) and clinical scoring tools. Additionally, we performed critical difference and sensitivity analysis. RESULTS: We identified 2792 references from the search of which 51 met inclusion criteria. Two postoperative outcomes were amenable for meta-analysis: 30-day mortality and in-hospital mortality. For 30-day mortality, the pooled C-index and 95% CrI were 0.82 (0.79-0.85), 0.80 (0.77-0.84), 0.78 (0.74-0.82) for ML models, LR, and scoring tools respectively. For in-hospital mortality, the pooled C-index was 0.81 (0.78-0.84) and 0.79 (0.73-0.84) for ML models and LR, respectively. There were no statistically significant results indicating ML superiority over LR. CONCLUSION: In cardiac surgery patients, for the prediction of mortality, current ML methods do not have greater discriminative power over LR as measured by the C-index.

Published
2022

36. Health literacy measurement: embracing diversity in a strengths-based approach to promote health and equity, and avoid epistemic injustice

Author

Osborne, RH, Cheng, CC, Nolte, S, Elmer, S, Besancon, S, Budhathoki, SS, Debussche, X, Dias, S, Kolarcik, P, Loureiro, MI, Maindal, H, do O, DN, Smith, JA, Wahl, A, Elsworth, GR, Hawkins, M, Osborne, RH, Cheng, CC, Nolte, S, Elmer, S, Besancon, S, Budhathoki, SS, Debussche, X, Dias, S, Kolarcik, P, Loureiro, MI, Maindal, H, do O, DN, Smith, JA, Wahl, A, Elsworth, GR, and Hawkins, M

Abstract

Definitions of health literacy have evolved from notions of health-related literacy to a multidimensional concept that incorporates the importance of social and cultural knowledge, practices and contexts. This evolution is evident in the development of instruments that seek to measure health literacy in different ways. Health literacy measurement is important for global health because diverse stakeholders, including the WHO, use these data to inform health practice and policy, and to understand sources of inequity. In this Practice paper, we explore the potential for negative consequences, bias and epistemic injustice to occur when health literacy instruments are used across settings without due regard for the lived experiences of people in various contexts from whom data are collected. A health literacy measurement approach that is emic-sensitive, strengths based and solution oriented is needed to minimise biased data interpretation and use and to avoid epistemic injustice.

Published
2022

37. A saturated map of common genetic variants associated with human height

Author

Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, Hirschhorn, JN, Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, and Hirschhorn, JN

Abstract

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Published
2022

38. Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

Author

Lahti, J, Tuominen, S, Yang, Q, Pergola, G, Ahmad, S, Amin, N, Armstrong, NJ, Beiser, A, Bey, K, Bis, JC, Boerwinkle, E, Bressler, J, Campbell, A, Campbell, H, Chen, Q, Corley, J, Cox, SR, Davies, G, De Jager, PL, Derks, EM, Faul, JD, Fitzpatrick, AL, Fohner, AE, Ford, I, Fornage, M, Gerring, Z, Grabe, HJ, Grodstein, F, Gudnason, V, Simonsick, E, Holliday, EG, Joshi, PK, Kajantie, E, Kaprio, J, Karell, P, Kleineidam, L, Knol, MJ, Kochan, NA, Kwok, JB, Leber, M, Lam, M, Lee, T, Li, S, Loukola, A, Luck, T, Marioni, RE, Mather, KA, Medland, S, Mirza, SS, Nalls, MA, Nho, K, O'Donnell, A, Oldmeadow, C, Painter, J, Pattie, A, Reppermund, S, Risacher, SL, Rose, RJ, Sadashivaiah, V, Scholz, M, Satizabal, CL, Schofield, PW, Schraut, KE, Scott, RJ, Simino, J, Smith, AV, Smith, JA, Stott, DJ, Surakka, I, Teumer, A, Thalamuthu, A, Trompet, S, Turner, ST, van der Lee, SJ, Villringer, A, Voelker, U, Wilson, RS, Wittfeld, K, Vuoksimaa, E, Xia, R, Yaffe, K, Yu, L, Zare, H, Zhao, W, Ames, D, Attia, J, Bennett, DA, Brodaty, H, Chasman, DI, Goldman, AL, Hayward, C, Ikram, MA, Jukema, JW, Kardia, SLR, Lencz, T, Loeffler, M, Mattay, VS, Palotie, A, Psaty, BM, Ramirez, A, Ridker, PM, Riedel-Heller, SG, Sachdev, PS, Saykin, AJ, Scherer, M, Schofield, PR, Sidney, S, Starr, JM, Trollor, J, Ulrich, W, Wagner, M, Weir, DR, Wilson, JF, Wright, MJ, Weinberger, DR, Debette, S, Eriksson, JG, Mosley, TH, Launer, LJ, van Duijn, CM, Deary, IJ, Seshadri, S, Raikkonen, K, Lahti, J, Tuominen, S, Yang, Q, Pergola, G, Ahmad, S, Amin, N, Armstrong, NJ, Beiser, A, Bey, K, Bis, JC, Boerwinkle, E, Bressler, J, Campbell, A, Campbell, H, Chen, Q, Corley, J, Cox, SR, Davies, G, De Jager, PL, Derks, EM, Faul, JD, Fitzpatrick, AL, Fohner, AE, Ford, I, Fornage, M, Gerring, Z, Grabe, HJ, Grodstein, F, Gudnason, V, Simonsick, E, Holliday, EG, Joshi, PK, Kajantie, E, Kaprio, J, Karell, P, Kleineidam, L, Knol, MJ, Kochan, NA, Kwok, JB, Leber, M, Lam, M, Lee, T, Li, S, Loukola, A, Luck, T, Marioni, RE, Mather, KA, Medland, S, Mirza, SS, Nalls, MA, Nho, K, O'Donnell, A, Oldmeadow, C, Painter, J, Pattie, A, Reppermund, S, Risacher, SL, Rose, RJ, Sadashivaiah, V, Scholz, M, Satizabal, CL, Schofield, PW, Schraut, KE, Scott, RJ, Simino, J, Smith, AV, Smith, JA, Stott, DJ, Surakka, I, Teumer, A, Thalamuthu, A, Trompet, S, Turner, ST, van der Lee, SJ, Villringer, A, Voelker, U, Wilson, RS, Wittfeld, K, Vuoksimaa, E, Xia, R, Yaffe, K, Yu, L, Zare, H, Zhao, W, Ames, D, Attia, J, Bennett, DA, Brodaty, H, Chasman, DI, Goldman, AL, Hayward, C, Ikram, MA, Jukema, JW, Kardia, SLR, Lencz, T, Loeffler, M, Mattay, VS, Palotie, A, Psaty, BM, Ramirez, A, Ridker, PM, Riedel-Heller, SG, Sachdev, PS, Saykin, AJ, Scherer, M, Schofield, PR, Sidney, S, Starr, JM, Trollor, J, Ulrich, W, Wagner, M, Weir, DR, Wilson, JF, Wright, MJ, Weinberger, DR, Debette, S, Eriksson, JG, Mosley, TH, Launer, LJ, van Duijn, CM, Deary, IJ, Seshadri, S, and Raikkonen, K

Abstract

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Published
2022

39. The cardiac distress inventory: A new measure of psychosocial distress associated with an acute cardiac event

Author

Jackson, AC, Le Grande, MR, Rogerson, MC, Ski, CF, Amerena, J, Smith, JA, Hoover, V, Alvarenga, ME, Higgins, RO, Thompson, DR, Murphy, BM, Jackson, AC, Le Grande, MR, Rogerson, MC, Ski, CF, Amerena, J, Smith, JA, Hoover, V, Alvarenga, ME, Higgins, RO, Thompson, DR, and Murphy, BM

Abstract

BACKGROUND: Many challenges are posed by the experience of a heart attack or heart surgery which can be characterised as 'cardiac distress'. It spans multiple psychosocial domains incorporating patients' responses to physical, affective, cognitive, behavioural and social symptoms and experiences related to their cardiac event and their recovery. Although some measures of the psychological and emotional impacts of a cardiac event exist, none provides a comprehensive assessment of cardiac distress. To address this gap, the study aimed to develop a Cardiac Distress Inventory (CDI) using best practice in instrument design. METHOD: An item pool was generated through analysis of cognate measures, mostly in relation to other health conditions and through focus group and individual review by a multidisciplinary development team, cardiac patients, and end-users including cardiac rehabilitation co-ordinators. The resulting 144 items were reduced through further reviews to 74 for testing. The testing was carried out with 405 people recruited from three hospitals, through social media and by direct enrolment on the study website. A two-stage psychometric evaluation of the 74 items used exploratory factor analysis to extract the factors followed by Rasch analysis to confirm dimensionality within factors. RESULTS: Psychometric analysis resulted in the identification of 55 items comprising eight subscales, to form the CDI. The subscales assess fear and uncertainty, disconnection and hopelessness, changes to roles and relationships, overwhelm and depletion, cognitive challenges, physical challenges, health system challenges, and death concerns. Validation against the Kessler 6 supports the criterion validity of the CDI. CONCLUSION: The CDI reflects a nuanced understanding of cardiac distress and should prove to be a useful clinical assessment tool, as well as a research instrument. Individual subscales or the complete CDI could be used to assess or monitor specific areas of distres

Published
2022

40. Dynamic responses of renal oxygenation at the onset of cardiopulmonary bypass in sheep and man

Author

Evans, RG, Cochrane, AD, Hood, SG, Iguchi, N, Marino, B, Bellomo, R, McCall, PR, Okazaki, N, Smith, JA, Zhu, MZL, Ngo, JP, Noe, KM, Martin, A, Thrift, AG, Lankadeva, YR, May, CN, Evans, RG, Cochrane, AD, Hood, SG, Iguchi, N, Marino, B, Bellomo, R, McCall, PR, Okazaki, N, Smith, JA, Zhu, MZL, Ngo, JP, Noe, KM, Martin, A, Thrift, AG, Lankadeva, YR, and May, CN

Abstract

INTRODUCTION: The renal medulla is susceptible to hypoxia during cardiopulmonary bypass (CPB), which may contribute to the development of acute kidney injury. But the speed of onset of renal medullary hypoxia remains unknown. METHODS: We continuously measured renal medullary oxygen tension (MPO2) in 24 sheep, and urinary PO2 (UPO2) as an index of MPO2 in 92 patients, before and after induction of CPB. RESULTS: In laterally recumbent sheep with a right thoracotomy (n = 20), even before CPB commenced MPO2 fell from (mean ± SEM) 52 ± 4 to 41 ±5 mmHg simultaneously with reduced arterial pressure (from 108 ± 5 to 88 ± 5 mmHg). In dorsally recumbent sheep with a medial sternotomy (n = 4), MPO2 was even more severely reduced (to 12 ± 12 mmHg) before CPB. In laterally recumbent sheep in which a crystalloid prime was used (n = 7), after commencing CPB, MPO2 fell abruptly to 24 ±6 mmHg within 20-30 minutes. MPO2 during CPB was not improved by adding donor blood to the prime (n = 13). In patients undergoing cardiac surgery, UPO2 fell by 4 ± 1 mmHg and mean arterial pressure fell by 7 ± 1 mmHg during the 30 minutes before CPB. UPO2 then fell by a further 12 ± 2 mmHg during the first 30 minutes of CPB but remained relatively stable for the remaining 24 minutes of observation. CONCLUSIONS: Renal medullary hypoxia is an early event during CPB. It starts to develop even before CPB, presumably due to a pressure-dependent decrease in renal blood flow. Medullary hypoxia during CPB appears to be promoted by hypotension and is not ameliorated by increasing blood hemoglobin concentration.

Published
2022

41. The trophic basis of fish assemblages in temperate estuarine and coastal ecosystems

Author

Goddard, BK, Becker, A, Harasti, D, Smith, JA, Subramaniam, RC, Suthers, IM, Goddard, BK, Becker, A, Harasti, D, Smith, JA, Subramaniam, RC, and Suthers, IM

Abstract

More than half of the fish biomass of coastal rocky reefs depends on zooplankton however the trophic basis of estuarine fish assemblages remains unknown We quantified the trophic basis i e basal energy sources of fish community biomass inhabiting three habitat types seagrass natural reef and artificial reef in two estuaries compared with two coastal rocky reef sites Fish assemblages were surveyed with Baited Remote Underwater Video BRUVs and the species abundance richness and biomass of fish were classified into nine functional feeding groups 6 teleost and 3 elasmobranch Comparable metrics for coastal fish assemblages were obtained from published surveys using BRUVs Using the functional feeding group biomass and the group specific diet composition the breakdown of energy sources was calculated using a food web analysis Estuarine reef habitats had different species and different functional feeding group composition than seagrass habitat The majority of fish biomass in the seagrass habitat was supported by detritus 51 in Botany Bay or macrophytes 58 in Lake Macquarie In contrast zooplankton supported most fish biomass 45 59 at the coastal reef locations and in reef habitat in one estuary 35 43 but not the other estuary 33 34 Trophic pathways which support fish assemblages are key in identifying mitigation measures which can help conserve these populations with growing urbanisation of estuaries and coasts 2022 The Author s under exclusive licence to Springer Verlag GmbH Germany part of Springer Nature

Published
2022

42. Bioprocess decision support tool for scalable manufacture of extracellular vesicles

Author

Ng, KS, Smith, JA, McAteer, MP, Mead, BE, Ware, J, Jackson, FO, Carter, A, Ferreira, L, Bure, K, Rowley, JA, Reeve, B, Brindley, DA, Karp, JM, Ng, KS, Smith, JA, McAteer, MP, Mead, BE, Ware, J, Jackson, FO, Carter, A, Ferreira, L, Bure, K, Rowley, JA, Reeve, B, Brindley, DA, and Karp, JM

Abstract

© 2018 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. Newly recognized as natural nanocarriers that deliver biological information between cells, extracellular vesicles (EVs), including exosomes and microvesicles, provide unprecedented therapeutic opportunities. Large-scale and cost-effective manufacturing is imperative for EV products to meet commercial and clinical demands; successful translation requires careful decisions that minimize financial and technological risks. Here, we develop a decision support tool (DST) that computes the most cost-effective technologies for manufacturing EVs at different scales, by examining the costs of goods associated with using published protocols. The DST identifies costs of labor and consumables during EV harvest as key cost drivers, substantiating a need for larger-scale, higher-throughput, and automated technologies for harvesting EVs. Importantly, we highlight a lack of appropriate technologies for meeting clinical demands, and propose a potentially cost-effective solution. This DST can facilitate decision-making very early on in development and be used to predict, and better manage, the risk of process changes when commercializing EV products.

Published
2022

44. Gas-Assisted Spray Coating of Perovskite Solar Cells Incorporating Sprayed Self-Assembled Monolayers

Author

Cassella, EJ, Spooner, ELK, Thornber, T, O'Kane, ME, Catley, TE, Bishop, JE, Smith, JA, Game, OS, and Lidzey, DG

Subjects
General Chemical Engineering, General Engineering, General Physics and Astronomy, Medicine (miscellaneous), General Materials Science, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract

Self-assembled monolayers (SAMs) are becoming widely utilized as hole-selective layers in high-performance p-i-n architecture perovskite solar cells. Ultrasonic spray coating and airbrush coating are demonstrated here as effective methods to deposit MeO-2PACz; a carbazole-based SAM. Potential dewetting of hybrid perovskite precursor solutions from this layer is overcome using optimized solvent rinsing protocols. The use of air-knife gas-quenching is then explored to rapidly remove the volatile solvent from an MAPbI3 precursor film spray-coated onto an MeO-2PACz SAM, allowing fabrication of p-i-n devices with power conversion efficiencies in excess of 20%, with all other layers thermally evaporated. This combination of deposition techniques is consistent with a rapid, roll-to-roll manufacturing process for the fabrication of large-area solar cells.

Published
2022

46. P59 Baseline characteristics and medical history of patients with refractory or unexplained chronic cough participating in two global phase 3 clinical trials

Author

McGarvey, L, primary, Birring, SS, additional, Dicpinigaitis, P, additional, Morice, A, additional, Pavord, I, additional, Smith, JA, additional, Iskold, B, additional, Li, Q, additional, Martin Nguyen, A, additional, Schelfhout, J, additional, Tzontcheva, A, additional, La Rosa, C, additional, and Muccino, D, additional

Published
2021
Full Text
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49. P60 Patient-reported improvements with gefapixant, a P2X3-receptor antagonist, over 52 weeks in two phase 3 clinical trials for refractory or unexplained chronic cough

Author

Birring, SS, primary, Dicpinigaitis, P, additional, Morice, A, additional, Smith, JA, additional, McGarvey, L, additional, Pavord, I, additional, Martin Nguyen, A, additional, Schelfhout, J, additional, Tzontcheva, A, additional, Li, Q, additional, La Rosa, C, additional, and Muccino, D, additional

Published
2021
Full Text
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