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2. TGA + IVS + LVOTO: patterns of practice and outcomes

Author

Husain Esmaeil, Jeffrey P. Jacobs, Christo I. Tchervenkov, Andrzej Kansy, Bohdan Maruszewski, Zdzislaw Tobota, James D. St. Louis, James K. Kirklin, David M. Overman, Vladimiro Vida, Claudia Herbst, Awais Ashfaq, Zohair Al-Halees, and George E. Sarris

Subjects
Pediatrics, Perinatology and Child Health, General Medicine, Cardiology and Cardiovascular Medicine
Abstract

Purpose:Transposition of great arteries with intact ventricular septum and left ventricular outflow tract obstruction (TGA + IVS + LVOTO) is uncommon. We reviewed operations performed in patients with TGA + IVS + LVOTO in the European Congenital Heart Surgeons Association Congenital Database (ECHSA-CD).Methods:All 109 patients with a diagnosis of TGA + IVS + LVOTO in ECHSA-CD who underwent cardiac surgery during a 21-year period (01/2000-02/2021, inclusive) were included. Preoperative variables, operative data, and postoperative outcomes were collected.Results:These 109 patients underwent 176 operations, including 37 (21.0%) arterial switch operations (ASO), 26 (14.2%) modified Blalock-Taussig-Thomas shunts (MBTTS), 11 (6.2%) Rastelli operations, and 13 (7.3%) other palliative operations (8 superior cavopulmonary anastomosis[es], 4 Fontan, and 1 other palliative procedure). Of 37 patients undergoing ASO, 22 had a concomitant procedure.There were 68 (38.6%) reoperations, including 11 pacemaker procedures and 8 conduit operations. After a systemic-to-pulmonary artery shunt, reoperations included shunt reoperation (n = 4), Rastelli (n = 4), and superior cavopulmonary anastomosis (n = 3).Overall Operative Mortality was 8.2% (9 deaths), including three following ASO, two following “Nikaidoh, Kawashima, or LV-PA conduit” procedures, and two following Rastelli. Postoperative complications occurred after 36 operations (20.4%). The most common complications were delayed sternal closure (n = 11), postoperative respiratory insufficiency requiring mechanical ventilation >7 days (n = 9), and renal failure requiring temporary dialysis (n = 8).Conclusion:TGA + IVS + LVOTO is rare (109 patients in ECHSA-CD over 21 years). ASO, MBTTS, and Rastelli are the most common operations performed for TGA + IVS + LVOTO. Larger international studies with long-term follow-up are needed to better define the anatomy of the LVOTO and to determine the optimal surgical strategy.

Published
2023
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3. Proteomic analysis of canine vaccines

Author

Jackeline Franco, Uma K. Aryal, Harm HogenEsch, and George E. Moore

Subjects
General Veterinary, General Medicine
Abstract

OBJECTIVE To use proteomic analysis to identify qualitatively and quantitatively mammalian protein components of commercial veterinary vaccines against canine distemper, leptospirosis, borreliosis, and rabies. SAMPLE 25 licensed veterinary vaccines (from 4 different manufacturers) against canine distemper and leptospirosis, borreliosis, and rabies (3-year and 1-year durations of immunity). PROCEDURES Duplicate samples from a single-lot vial of each vaccine were prepared by acetone precipitation and proteolysis with trypsin and Lys-C protease mix. Peptides mixtures (1 μg) were analyzed by liquid chromatography-tandem mass spectrometry using an Orbitrap Fusion Lumos mass spectrometer. Liquid chromatography-tandem mass spectroscopy data were searched against a Bos taurus protein database using MaxQuant to identify and quantify mammalian proteins in the vaccines. Identified proteins were classified by function and network analysis to visualize interactions. RESULTS The largest number of mammalian proteins was identified in 3-year rabies vaccines (median, 243 proteins; range, 184 to 339 proteins) and 1-year rabies vaccines (median, 193 proteins; range, 169 to 350 proteins). Borrelia and leptospirosis-distemper (L&D) vaccines had the lowest number of proteins. Rabies vaccines had the highest number of identified proteins in common (n = 316); 33 were unique to 1-year products and 44 were found in 3-year products. Borrelia and L&D vaccines had 16 and 22 uniquely identified proteins, respectively. The protein classifications were primarily modulators of protein-binding activity, enzymes, transfer-carrier proteins, cytoskeletal proteins, defense-immunity proteins, calcium-binding proteins, and extracellular matrix proteins. CLINICAL RELEVANCE This study demonstrates proteomics application to evaluate quality differences among different vaccines, identifying potential stimulants of desirable and undesirable immune responses.

Published
2023
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4. A Conceptual Framework of a Detective Model for Social Bot Classification

Author

Emmanuel Etuh, George E. Okereke, Deborah U. Ebem, and Francis S. Bakpo

Subjects
General Medicine
Abstract

Social media platform has greatly enhanced human interactive activities in the virtual community. Virtual socialization has positively influenced social bonding among social media users irrespective of one’s location in the connected global village. Human user and social bot user are the two types of social media users. While human users personally operate their social media accounts, social bot users are developed software that manages a social media account for the human user called the botmaster. This botmaster in most cases are hackers with bad intention of attacking social media users through various attacking mode using social bots. The aim of this research work is to design an intelligent framework that will prevent attacks through social bots on social media network platforms.

Published
2022
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5. The Effect of Aqueous Extract of Gum Arabic on Hepato-renal Function During Ethanol Withdrawal Induced Stress in Wistar Rats

Author

Jeffrey I. Omoruyi, George E. Eriyamremu, Israel E. Ebhohimen, Oke. A. Emuedo, and Edwina O. Uzunuigbe

Subjects
General Medicine
Abstract

Background: Alcohol withdrawal syndrome (AWS) is a life-threatening condition affecting alcoholics who ceased or decreased their alcohol consumption. The synthetic drugs used to manage these consequences are not without undesirable effects; hence, the need for a natural and affordable approach is raised. Objectives: This study aimed at investigating the effect of aqueous extract of gum arabic (GA) on hepato-renal functions during ethanol withdrawal syndrome in Wistar rats. Methods: In phase I, dose-response for GA and alcohol for the study were determined. In phase II, the effect of GA on biomarkers during AWS was studied. A total of 60 male Wistar rats were used for the study. Blood and tissue samples were obtained at the end of stipulated periods of oral administration for biochemical and histological analysis, and biochemical parameters were analyzed by spectrophotometry. Results: In the dose-response study, there were no significant differences (P≥0.05) in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as well as in total bilirubin (TBIL), malondialdehyde (MDA), sodium ion (Na+), potassium ion (K+), and creatinine concentrations in groups treated with 200 mg/kg body weight (bw) and 400 mg/kg bw GA aqueous extract compared to the control group. However, significant alterations were observed in groups treated with 600 and 800 mg/kg bw GA extract. Furthermore, rats that received 5.5 mL/kg bw alcohol showed marked changes in biochemical parameters compared to the group that received 4.5 mL/kg bw and the control group. The results obtained in Phase II exhibited the hepato-renal protective effect of GA during ethanol withdrawal. Statistical analysis of the obtained results indicated a better response from the study groups that were pre-treated or co-administered with GA compared to the group that was post-treated. Conclusion: The result of this study suggests that GA aqueous extract offered better protection prophylactically than curatively.

Published
2022
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7. Obesity-induced inflammation exacerbates clonal hematopoiesis

Author

Santhosh Kumar Pasupuleti, Baskar Ramdas, Sarah S. Burns, Lakshmi Reddy Palam, Rahul Kanumuri, Ramesh Kumar, Taruni Reddy Pandhiri, Utpal P. Dave, Nanda Kumar Yellapu, Xinyu Zhou, Chi Zhang, George E. Sandusky, Zhi Yu, Michael C. Honigberg, Alexander G. Bick, Gabriel K. Griffin, Abhishek Niroula, Benjamin L. Ebert, Sophie Paczesny, Pradeep Natarajan, and Reuben Kapur

Subjects
General Medicine
Published
2023
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9. Reporting guideline for the early-stage clinical evaluation of decision support systems driven by artificial intelligence

Author

Vasey, Baptiste, Nagendran, Myura, Campbell, Bruce, Clifton, David A, Collins, Gary S., Denaxas, Spiros, Denniston, Alastair K., Faes, Livia, Geerts, Bart, Ibrahim, Mudathir, Liu, Xiaoxuan, Mateen, Bilal A., Mathur, Piyush, Mccradden, Melissa D., Morgan, Lauren, Ordish, Johan, Rogers, Campbell, Saria, Suchi, Ting, Daniel S. W., Watkinson, Peter, Weber, Wim, Wheatstone, Peter, Mcculloch, Peter, Lee, Aaron Y., Fraser, Alan G., Connell, Ali, Vira, Alykhan, Esteva, Andre, Althouse, Andrew D., Beam, Andrew L., de Hond, Anne, Boulesteix, Anne-Laure, Bradlow, Anthony, Ercole, Ari, Paez, Arsenio, Tsanas, Athanasios, Kirby, Barry, Glocker, Ben, Velardo, Carmelo, Park, Chang Min, Hehakaya, Charisma, Baber, Chris, Paton, Chris, Johner, Christian, Kelly, Christopher J., Vincent, Christopher J., Yau, Christopher, Mcgenity, Clare, Gatsonis, Constantine, Faivre-Finn, Corinne, Simon, Crispin, Sent, Danielle, Bzdok, Danilo, Treanor, Darren, Clifton, David A., Wong, David C., Steiner, David F., Higgins, David, Benson, Dawn, O’Regan, Declan P., Gunasekaran, Dinesh V., Danks, Dominic, Neri, Emanuele, Kyrimi, Evangelia, Schwendicke, Falk, Magrabi, Farah, Ives, Frances, Rademakers, Frank E., Fowler, George E., Frau, Giuseppe, Hogg, H. D. Jeffry, Marcus, Hani J., Chan, Heang-Ping, Xiang, Henry, Mcintyre, Hugh F., Harvey, Hugh, Kim, Hyungjin, Habli, Ibrahim, Fackler, James C., Shaw, James, Higham, Janet, Wohlgemut, Jared M., Chong, Jaron, Bibault, Jean-Emmanuel, Cohen, Jérémie F., Kers, Jesper, Morley, Jessica, Krois, Joachim, Monteiro, Joao, Horovitz, Joel, Fletcher, John, Taylor, Jonathan, Yoon, Jung Hyun, Singh, Karandeep, Moons, Karel G. M., Karpathakis, Kassandra, Catchpole, Ken, Hood, Kerenza, Balaskas, Konstantinos, Kamnitsas, Konstantinos, Militello, Laura, Wynants, Laure, Oakden-Rayner, Lauren, Lovat, Laurence B., Smits, Luc J. M., Hinske, Ludwig C., Elzarrad, M. Khair, van Smeden, Maarten, Giavina-Bianchi, Mara, Daley, Mark, Sendak, Mark P., Sujan, Mark, Rovers, Maroeska, Decamp, Matthew, Woodward, Matthew, Komorowski, Matthieu, Marsden, Max, Mackintosh, Maxine, Abramoff, Michael D., de la Hoz, Miguel Ángel Armengol, Hambidge, Neale, Daly, Neil, Peek, Niels, Redfern, Oliver, Ahmad, Omer F., Bossuyt, Patrick M., Keane, Pearse A., Ferreira, Pedro N. P., Schnell-Inderst, Petra, Mascagni, Pietro, Dasgupta, Prokar, Guan, Pujun, Barnett, Rachel, Kader, Rawen, Chopra, Reena, Mann, Ritse M., Sarkar, Rupa, Mäenpää, Saana M., Finlayson, Samuel G., Vollam, Sarah, Vollmer, Sebastian J., Park, Seong Ho, Laher, Shakir, Joshi, Shalmali, van der Meijden, Siri L., Shelmerdine, Susan C., Tan, Tien-En, Stocker, Tom J. W., Giannini, Valentina, Madai, Vince I., Newcombe, Virginia, Wei Yan, Ng, Rogers, Wendy A., Ogallo, William, Park, Yoonyoung, and Perkins, Zane B.

Subjects
Research Report, Consensus, Artificial Intelligence, Research Design, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Immunology, Humans, General Medicine, DECIDE-AI expert group, General Biochemistry, Genetics and Molecular Biology, 11 Medical and Health Sciences, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Checklist
Abstract

A growing number of artificial intelligence (AI)-based clinical decision support systems are showing promising performance in preclinical, in silico evaluation, but few have yet demonstrated real benefit to patient care. Early-stage clinical evaluation is important to assess an AI system’s actual clinical performance at small scale, ensure its safety, evaluate the human factors surrounding its use and pave the way to further large-scale trials. However, the reporting of these early studies remains inadequate. The present statement provides a multi-stakeholder, consensus-based reporting guideline for the Developmental and Exploratory Clinical Investigations of DEcision support systems driven by Artificial Intelligence (DECIDE-AI). We conducted a two-round, modified Delphi process to collect and analyze expert opinion on the reporting of early clinical evaluation of AI systems. Experts were recruited from 20 pre-defined stakeholder categories. The final composition and wording of the guideline was determined at a virtual consensus meeting. The checklist and the Explanation & Elaboration (E&E) sections were refined based on feedback from a qualitative evaluation process. In total, 123 experts participated in the first round of Delphi, 138 in the second round, 16 in the consensus meeting and 16 in the qualitative evaluation. The DECIDE-AI reporting guideline comprises 17 AI-specific reporting items (made of 28 subitems) and ten generic reporting items, with an E&E paragraph provided for each. Through consultation and consensus with a range of stakeholders, we developed a guideline comprising key items that should be reported in early-stage clinical studies of AI-based decision support systems in healthcare. By providing an actionable checklist of minimal reporting items, the DECIDE-AI guideline will facilitate the appraisal of these studies and replicability of their findings.

Published
2022
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10. Diet breadth of the aphid predator Chrysoperla rufilabris Burmeister (Neuroptera: Chrysopidae)

Author

Michela C. Batista, George E. Heimpel, Mariana Bulgarella, and Madelaine Venzon

Subjects
Insect Science, General Medicine, Agronomy and Crop Science
Abstract

The performance (development and reproduction) of generalist predators can vary greatly among the prey species that they use, and these differences can influence the ability of predatory insects to suppress pest populations. The aim of this study was to compare the performance of larvae of the green lacewing Chrysoperla rufilabris (Burmeister, 1839) by offering 16 species of aphids and by assessing the effects of each species on the survival, larval development time, prey consumption, pupal mass and egg load of adult Chr. rufilabris females taking aphid phylogeny into account. Chrysoperla rufilabris larvae preyed on individuals from all 16 aphid species, but complete development, adult emergence and egg load production were achieved only in seven species. As a general pattern, the best levels of performance were achieved for an aphid clade that includes the soybean aphid, Aphis glycines (Matsumara, 1917), and for a milkweed-feeding species, Myzocallis asclepiadis (Monell, 1879). We found significant phylogenetic clustering for most of the performance traits indicating the aspects of specialization in the diet breadth of Chr. rufilabris despite the fact that this species is considered a generalist aphid predator. These findings can help us to understand the interactions of this species in agroecological food webs, where it is commonly found, and provide insights into why natural, conservation biological control or augmentative releases may succeed or fail.

Published
2022
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13. The Edinburgh Claudication Questionnaire has poor diagnostic accuracy in people with intermittent claudication

Author

Saïd Ibeggazene, Andrew Stirrup, Sean Pymer, Joanne Palmer, Paris L Cai, George E Smith, and Ian C Chetter

Subjects
Radiology, Nuclear Medicine and imaging, Surgery, General Medicine, Cardiology and Cardiovascular Medicine
Abstract

Background The screening and diagnosis of intermittent claudication is a challenging process and often relies on the expertise of specialist vascular clinicians. We sought to investigate the diagnostic performance of the Edinburgh Claudication Questionnaire (ECQ) as a screening tool for referrals of suspected intermittent claudication from primary to secondary care. Method Prospectively, 100 referrals from primary care with a stated diagnosis or query regarding intermittent claudication were recruited. All participants who completed the ECQ, underwent an anklebrachial pressure index (ABPI) assessment and treadmill exercise testing. Outcomes of the ECQ were compared to clinical diagnoses of intermittent claudication. Results The ECQ had a sensitivity of 46.8% (95% CI: 27–65%), specificity of 63.2% (95% CI: 43–82%) and accuracy of 53.0% (95% CI: 43–63%). The diagnostic performance was not changed by combining the ECQ with a positive ABPI or post-exercise ABPI outcome for PAD. Conclusion The ECQ had a poor diagnostic performance in this cohort. Considering the results found here and in other recent studies, the utility of the ECQ as a screening tool and epidemiological survey tool must be questioned. Novel, low-resource diagnostic tools are needed in this population.

Published
2022
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14. A review onin vitro/in vivoresponse of additively manufactured Ti–6Al–4V alloy

Author

Saeid Alipour, Shirin Nour, Seyyed Morteza Attari, Mohammad Mohajeri, Sogol Kianersi, Farzaneh Taromian, Mohammadparsa Khalkhali, George E. Aninwene, and Lobat Tayebi

Subjects
Biomedical Engineering, General Materials Science, General Chemistry, General Medicine
Abstract

This review paper introduced a novel 3B-based classification (Biofunctionality, Bioactivity, Biostability), which mainly governs native body response, to provide a comprehensive overview to examine thein vitroandin vivoresponses of additively manufactured Ti64 implants.

Published
2022
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15. On the role of reduction at the orienting stage of activity in planning disorders in schizophrenia

Author

Andrey A. Alekseev, George E. Rupchev, and Aleksandr Sh. Tkhostov

Subjects
Semi-structured interview, Near-death experience, Medical education, General Medicine, Psychology
Abstract

Background. _e present study is devoted to the analysis of the role of shortening in the orienting stage of activity in planning disorders in patients with schizophrenia. _is question, widely discussed in literature, is important and relevant in psychology, since it allows us to study various strategies applied to performing planning tasks in healthy subjects and patients with mental disorders. In the future, the obtained data can be used in the psycho-correction of planning disorders in patients with schizophrenia, as well as to improve the e`ciency of planning in healthy people. Objective. _e aim is to study the strategy for dealing with planning problems in patients with schizophrenia. Sample. Experimental group consisted of 40 patients with paranoid schizophrenia (age: 34.4±8.24 years; illness duration: 7.78±5.47 years). Control group included 40 healthy subjects (age: 32.5±7.28 years). Methods. _e “object” and “visual” versions of the Tower of London test (TOL-DX and TOL-BACS) were used to evaluate planning. TOL-DX provides the test subject with the opportunity to choose how to solve the problem: whether to plan actions in advance (before they are completed), or to build a plan as the tasks are completed. TOL-BACS limits the choice of subjects to planning actions before they are carried out. _e main indicator is the number of tasks solved correctly (optimally) (Alekseev, Rupchev, Katenko, 2012). Psychomotor speed was assessed by Schulte tables. Results. Patients with schizophrenia coped signiacantly worse with the “object” version of the test, but showed a productivity comparable to that of healthy subjects in the “visual” tasks. To analyze the dynamics of changes in the latent time (time to think on the tasks) depending on the number of moves in the “object” version of TOL patients with schizophrenia were divided into a group of patients with planning disorders and a group of patients without planning disorders. _e dynamics of changes in latent time in healthy subjects and patients without planning disorders was similar and was characterized by an increase in latent time with an increase in the number of moves required to solve tasks. At the same time, patients subering from schizophrenia with planning disorders showed approximately the same latent time, regardless of the complexity of tasks. _e amount of latent time in patients with planning disorders was lower than in healthy subjects at the level of statistical trend in tasks with 5 moves and statistically signiacantly lower in tasks with 6 and 7 moves. Conclusion. _e results obtained outline the role of reduction at the orienting stage of activity in planning disorders in patients with schizophrenia.

Published
2022
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16. Euthanasia Education in Veterinary Schools in the United States

Author

George E. Dickinson, Heath C. Hoffmann, and Kathleen Cooney

Subjects
Veterinary medicine, General Veterinary, Core competency, General Medicine, United States, Veterinarians, Education, Competence (law), Dogs, Euthanasia, Animal, Animal welfare, Animals, Humans, Curriculum, Horses, Education, Veterinary, Psychology, Schools, Veterinary
Abstract

Euthanasia of animals plays a significant role in veterinary practices and is a pivotal experience for veterinarians and their clients. It is good animal welfare to have a humane method of euthanasia, correctly applied, and a well-educated individual regarding such techniques. The purpose of this research was to determine how US veterinary medicine schools are preparing students to perform euthanasia. A survey of the 30 US veterinary schools was electronically mailed by the American Association of Veterinary Medical Colleges (AAVMC) in the fall of 2019, with a return rate of 10. Findings revealed that the average number of hours devoted to euthanasia methods and techniques was 2.8, yet euthanasia facilitation was considered a core competency by all schools responding. Not all veterinary students perform or are present for euthanasia. The most frequent method for teaching euthanasia was intracardiac and intravenous with dogs, cats, horses, livestock, and exotics. Whichever method of euthanasia is used, personnel performing euthanasia must be trained, knowledgeable, and proficient in the chosen techniques. The findings in this article suggest, however, that euthanasia techniques are inconsistent, and potentially incomplete, and that veterinary schools should consider incorporating more advanced euthanasia training programs into the curriculum.

Published
2021
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17. Predictors of future haemorrhage from cerebral cavernous malformations: a retrospective cohort study

Author

Conor S. Gillespie, Khalifa E. Alnaham, George E. Richardson, Mohammad A. Mustafa, Basel A. Taweel, Abdurrahman I. Islim, Cathal John Hannan, and Emmanuel Chavredakis

Subjects
Surgery, Neurology (clinical), General Medicine
Abstract

Cerebral cavernous malformations (CCMs) are commonly diagnosed, with a low reported rate of haemorrhage on long-term follow-up. The identification of factors predictive of future haemorrhage risk would assist in guiding the management of patients with CCM. The aim of this study was to identify variables associated with haemorrhage, and calculate haemorrhage risk in CCM. We conducted a retrospective study of patients diagnosed with a CCM, managed at a specialist tertiary neuroscience centre (2007–2019). The primary outcome was symptomatic haemorrhage, and secondary outcomes were variables associated with increased risk of haemorrhage, using multivariable Cox regression analysis. Included were 545 patients, with 734 confirmed cavernomas. Median age at diagnosis was 47 (interquartile range [IQR] 35–60), with a median follow-up duration after diagnosis of 46 months (IQR 19–85). Of the patients, 15.0% had multiple lesions (N = 82/545). Symptomatic presentation was observed in 52.5% of patients (N = 286/545). The annual haemorrhage rate was 1.00% per lesion-year (25 events in 2512 lesion-years), and higher in those with symptoms at presentation (1.50% per lesion-year, 22 events vs 0.29%, 3 events, P < 0.001). The variables associated with symptomatic haemorrhage were increased size (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.01–1.07, P = 0.004), eloquent location (HR 2.63, 95% CI 1.12–6.16, P = 0.026), and symptomatic haemorrhage at presentation (HR 5.37, 95% CI 2.40–11.99, P < 0.001). This study demonstrated that CCMs have a low haemorrhage rate. Increased size, eloquent location, and haemorrhage at presentation appear to be predictive of a higher risk of haemorrhage, and could be used to stratify management protocols.

Published
2023
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19. Respirasome Proteins Are Regulated by Sex-Hormone Interactions in the Brain

Author

Andrew J. McGovern, Maria Angeles Arevalo, Sergio Ciordia, Luis Miguel Garcia-Segura, George E. Barreto, Science Foundation Ireland, Agencia Estatal de Investigación (España), European Commission, Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), and Instituto de Salud Carlos III

Subjects
sex differences, proteome, Organic Chemistry, General Medicine, Catalysis, Computer Science Applications, mitochondria, Inorganic Chemistry, tibolone, Tibolone, respirasome, gonadectomy, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract

The existence of sex differences in disease incidence is attributed, in part, to sex differences in metabolism. Uncovering the precise mechanism driving these differences is an extraordinarily complex process influenced by genetics, endogenous hormones, sex-specific lifetime events, individual differences and external environmental/social factors. In fact, such differences may be subtle, but across a life span, increase susceptibility to a pathology. Whilst research persists in the hope of discovering an elegant biological mechanism to underpin sex differences in disease, here, we show, for the first time, that such a mechanism may be subtle in nature but influenced by multiple sex-specific factors. A proteomic dataset was generated from a gonadectomized mouse model treated with Tibolone, a menopausal hormone therapy. Following functional enrichment analysis, we identified that Alzheimer's disease and the electron transport chain-associated pathways were regulated by sex-hormone interactions. Specifically, we identified that the expression of three respirasome proteins, NDUFA2, NDUFA7 and UQCR10, is significantly altered by compounding factors that contribute to sex differences. These proteins function in bioenergetics and produce reactive oxygen species, which are each dysregulated in many diseases with sex differences in incidence. We show sex-specific reprogrammed responses to Tibolone following gonadectomy, which primarily influence the expression of proteins contributing to metabolic pathways. This further infers that metabolic differences may underpin the observed sex differences in disease, but also that hormone therapy research now has potential in exploring sex-specific interventions to produce an effective method of prevention or treatment., This work was partly supported by funding from Science Foundation Ireland under the Frontiers for the Future Programme (Grant #20/FFP-P/8649) to GEB. This work was also supported by grant PID2020-115019RB-I00, awarded to M.A.A., from Agencia Estatal de Investigación (AEI), co-funded by Fondo Europeo de Desarrollo Regional (FEDER) and by Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.

Published
2023
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20. The impact of curcumin on migraine: A comprehensive review

Author

Hajar Heidari, Mehrnaz Shojaei, Gholamreza Askari, Muhammed Majeed, Mohammad Bagherniya, George E. Barreto, and Amirhossein Sahebkar

Subjects
Pharmacology, Biological sciences, inflammation, 31 Biological sciences, FOS: Biological sciences, oxidative stress, curcumin, migraine, General Medicine
Abstract

Migraine, a neurovascular condition, is a chronic and lifelong disease that affects about 15% of the population worldwide. Although the exact pathophysiology and etiology of migraine are still unclear, oxidative stress, inflammation, and neuroendocrine imbalances are identified as the critical risk factors for migraine attacks. Curcumin is an active component and a polyphenolic diketone compound extracted from turmeric. Curcumin is a promising candidate for preventing and controlling migraine due to its anti‑inflammatory, antioxidative, anti-protein aggregate, and analgesic effects. In the present review, we have evaluated experimental and clinical studies investigating the impact of liposomal curcumin and nano-curcumin on the frequency and severity of migraine attacks in patients. Although the results are promising, more studies should be conducted in this area to show the exact efficacies of curcumin on clinical symptoms of migraine and investigate its potential mechanisms.

Published
2023
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21. Report of the 2021-2022 Strategic Engagement Standing Committee

Author

George E. MacKinnon, Kyle Turner, Brian Kawahara, Julie Akers, Grace Kuo, John Gums, Vasudha Gupta, and Jasey Cárdenas

Subjects
AACP Report, Education, Pharmacy, Schools, Pharmacy, Humans, General Medicine, General Pharmacology, Toxicology and Pharmaceutics, Faculty, Education
Published
2022

22. Effective refractive error coverage in adults aged 50 years and older: estimates from population-based surveys in 61 countries

Author

Rupert Richard Alexander Bourne, Maria Vittoria Cicinelli, Tabassom Sedighi, Ian H Tapply, Ian McCormick, Jost B Jonas, Nathan G Congdon, Jacqueline Ramke, Kovin S Naidoo, Timothy R Fricke, Matthew J Burton, Andreas Müller, Mukharram M Bikbov, João M Furtado, Fatima Kyari, Mingguang He, Ya Xing Wang, Lingam Vijaya, Vinay Nangia, Garry Brian, Mohammad Hassan Emamian, Akbar Fotouhi, Hassan Hashemi, Rajiv B Khandekar, Srinivas Marmamula, Solange Salomão, Ronnie George, Gyulli Kazakbaeva, Tasanee Braithwaite, Robert J Casson, Aiko Iwase, Noopur Gupta, Mohammad H Abdianwall, Rohit Varma, Tien Y Wong, Ningli Wang, Hugh R Taylor, Seth R Flaxman, Stuart Keel, Serge Resnikoff, Alain Bron, Ching-Yu Cheng, Arthur Fernandes, David Friedman, Andrew Gazzard, Rim Kahloun, John Kempen, Moncef Khairallah, Van C Lansingh, Janet Leasher, Nicolas Leveziel, Hans Limburg, Michal Nowak, Konrad Pesudovs, Tunde Peto, Luca Rossetti, Nina Tahhan, Wondu Alemayehu, Aries Arditi, Reza Dana, Monte Del Monte, jenny Deva, Laura Dreer, Josh Ehrlich, Leon Ellwein, Billy Hammond, Mary E Hartnett, April Ingram, Rohit Khanna, Judy Kim, Jennifer Lim, Alan Morse, David Musch, Maurizio B Parodi, Pradeep Ramulu, Alan Robin, Janet Serle, Tueng Shen, Rita S Sitorus, Dwight Stambolian, Fotis Topouzis, Miltiadis Tsilimbaris, Gianni Virgili, Sheila West, Jafer K Ababora, Heba AlSawahli, Hery Harimanitra Andriamanjato, Rosario Barrenechea, Juan F Batlle, Anthea M Burnett, Robert P Finger, Marcelo Gallarreta, Pedro A Gomez-Bastar, Reeta Gurung, Elesh Jain, George E Kabona, Khumbo Kalua, Levi Kandeke, Jefitha Karimurio, Susan A Kikira, Sucheta Kulkarni, Wanjiku Mathenge, Sailesh Kumar Mishra, Seyed Farzad Mohammadi, Manfred Mörchen, Nasiru Muhammad, Grace C Mutati, Maria Eugenia Nano, János Németh, Ala Paduca, Alexander Páez, M Mansur Rabiu, Lutfah Rif'ati, Mohamad Aziz Salowi, Yuddha D Sapkota, Nicholas Sargent, Ubeydulla Thoufeeq, Astrid V Villalobos, Biaxiang Xiao, Mariano Yee Melgar, and Xiu Juan Zhang

Subjects
Adult, Male, Europe, Humans, General Medicine, Middle Aged, Global Health, Refractive Errors, Africa South of the Sahara, Aged, Global Burden of Disease
Abstract

In 2021, WHO Member States endorsed a global target of a 40-percentage-point increase in effective refractive error coverage (eREC; with a 6/12 visual acuity threshold) by 2030. This study models global and regional estimates of eREC as a baseline for the WHO initiative.The Vision Loss Expert Group analysed data from 565 448 participants of 169 population-based eye surveys conducted since 2000 to calculate eREC (met need/[met need + undermet need + unmet need]). A binary logistic regression model was used to estimate eREC by Global Burden of Disease (GBD) Study super region among adults aged 50 years and older.In 2021, distance eREC was 79·1% (95% CI 72·4-85·0) in the high-income super region; 62·1% (54·7-68·8) in north Africa and Middle East; 49·5% (45·0-54·0) in central Europe, eastern Europe, and central Asia; 40·0% (31·7-48·2) in southeast Asia, east Asia, and Oceania; 34·5% (29·4-40·0) in Latin America and the Caribbean; 9·0% (6·5-12·0) in south Asia; and 5·7% (3·1-9·0) in sub-Saharan Africa. eREC was higher in men and reduced with increasing age. Global distance eREC increased from 2000 to 2021 by 19·0%. Global near vision eREC for 2021 was 20·5% (95% CI 17·8-24·4).Over the past 20 years, distance eREC has increased in each super region yet the WHO target will require substantial improvements in quantity and quality of refractive services in particular for near vision impairment.WHO, Sightsavers, The Fred Hollows Foundation, Fondation Thea, Brien Holden Vision Institute, Lions Clubs International Foundation.

Published
2022
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23. Cis-eQTL Analysis and Functional Validation of Candidate Genes for Carcass Yield Traits in Beef Cattle

Author

Tianzhen Wang, Qunhao Niu, Tianliu Zhang, Xu Zheng, Haipeng Li, Xue Gao, Yan Chen, Huijiang Gao, Lupei Zhang, George E. Liu, Junya Li, and Lingyang Xu

Subjects
Inorganic Chemistry, Organic Chemistry, cis-eQTL, GWAS, carcass yield traits, PON3, PRIM2, beef cattle, General Medicine, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Catalysis, Computer Science Applications
Abstract

Carcass yield traits are of considerable economic importance for farm animals, which act as a major contributor to the world’s food supply. Genome-wide association studies (GWASs) have identified many genetic variants associated with carcass yield traits in beef cattle. However, their functions are not effectively illustrated. In this study, we performed an integrative analysis of gene-based GWAS with expression quantitative trait locus (eQTL) analysis to detect candidate genes for carcass yield traits and validate their effects on bovine skeletal muscle satellite cells (BSCs). The gene-based GWAS and cis-eQTL analysis revealed 1780 GWAS and 1538 cis-expression genes. Among them, we identified 153 shared genes that may play important roles in carcass yield traits. Notably, the identified cis-eQTLs of PON3 and PRIM2 were significantly (p < 0.001) enriched in previous GWAS loci for carcass traits. Furthermore, overexpression of PON3 and PRIM2 promoted the BSCs’ proliferation, increased the expression of MYOD and downregulated the expression of MYOG, which indicated that these genes may inhibit myogenic differentiation. In contrast, PON3 and PRIM2 were significantly downregulated during the differentiation of BSCs. These findings suggested that PON3 and PRIM2 may promote the proliferation of BSCs and inhibit them in the pre-differentiation stage. Our results further contribute to the understanding of the molecular mechanisms of carcass yield traits in beef cattle.

Published
2022
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24. Effective cataract surgical coverage in adults aged 50 years and older: estimates from population-based surveys in 55 countries

Author

Ian McCormick, Robert Butcher, Jennifer R Evans, Islay Z Mactaggart, Hans Limburg, Emma Jolley, Yuddha D Sapkota, Joseph Enyegue Oye, Sailesh Kumar Mishra, Andrew Bastawrous, João M Furtado, Anagha Joshi, Baixiang Xiao, Thulasiraj D Ravilla, Rupert R A Bourne, Alarcos Cieza, Stuart Keel, Matthew J Burton, Jacqueline Ramke, Jafer K Ababora, Heba AlSawahli, Doris M Alvarado, Hery Harimanitra Andriamanjato, Ahmad Ashraf Amalius, Rosario Barrenechea, Juan F Batlle, Ileana Brea, Anthea M Burnett, Felipe A Chiriboga, Uranchimeg Davaatseren, Rainald Duerksen, Cristina I Eusebio, Robert P Finger, Pedro A Gomez-Bastar, César Gonzales, Reeta Gurung, Saad Hajar, Muhammad Zahid Jadoon, Elesh Jain, George E Kabona, Khumbo Kalua, Levi Kandeke, Ram P Kandel, Jefitha Karimurio, Sucheta Kulkarni, Van C Lansingh, Nor T Lepcha, Wanjiku Mathenge, Seyed Farzad Mohammadi, Manfred Mörchen, Nasiru Muhammad, Paddy B Musana, Grace C Mutati, Maria Eugenia Nano, János Németh, Ala Paduca, Alexander Páez, Sarah Polack, M Mansur Rabiu, Lutfah Rif'ati, Beatriz Natividad Rodríguez Rodríguez, Mohamad Aziz Salowi, Nicholas Sargent, Mansyur Syumarti, Ubeydulla Thoufeeq, Astrid V Villalobos, Joseph W Wachira, Min Wu, Biaxiang Xiao, Mariano Yee Melgar, and Xiu Juan Zhang

Subjects
Male, Adult, Prevalence, Humans, Female, Cataract Extraction, General Medicine, Middle Aged, Blindness, Global Health, Health Surveys, Cataract, Aged
Abstract

BackgroundCataract is the leading cause of blindness globally. Effective cataract surgical coverage (eCSC) measures the number of people in a population who have been operated on for cataract, and had a good outcome, as a proportion of all people operated on or requiring surgery. Therefore, eCSC describes service access (ie, cataract surgical coverage, [CSC]) adjusted for quality. The 74th World Health Assembly endorsed a global target for eCSC of a 30-percentage point increase by 2030. To enable monitoring of progress towards this target, we analysed Rapid Assessment of Avoidable Blindness (RAAB) survey data to establish baseline estimates of eCSC and CSC.MethodsIn this secondary analysis, we used data from 148 RAAB surveys undertaken in 55 countries (2003–21) to calculate eCSC, CSC, and the relative quality gap (% difference between eCSC and CSC). Eligible studies were any version of the RAAB survey conducted since 2000 with individual participant survey data and census population data for people aged 50 years or older in the sampling area and permission from the study's principal investigator for use of data. We compared median eCSC between WHO regions and World Bank income strata and calculated the pooled risk difference and risk ratio comparing eCSC in men and women.FindingsCountry eCSC estimates ranged from 3·8% (95% CI 2·1–5·5) in Guinea Bissau, 2010, to 70·3% (95% CI 65·8–74·9) in Hungary, 2015, and the relative quality gap from 10·8% (CSC: 65·7%, eCSC: 58·6%) in Argentina, 2013, to 73·4% (CSC: 14·3%, eCSC: 3·8%) in Guinea Bissau, 2010. Median eCSC was highest among high-income countries (60·5% [IQR 55·6–65·4]; n=2 surveys; 2011–15) and lowest among low-income countries (14·8%; [IQR 8·3–20·7]; n=14 surveys; 2005–21). eCSC was higher in men than women (148 studies pooled risk difference 3·2% [95% CI 2·3–4·1] and pooled risk ratio of 1·20 [95% CI 1·15–1·25]).InterpretationeCSC varies widely between countries, increases with greater income level, and is higher in men. In pursuit of 2030 targets, many countries, particularly in lower-resource settings, should emphasise quality improvement before increasing access to surgery. Equity must be embedded in efforts to improve access to surgery, with a focus on underserved groups.

Published
2022
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25. Initial Invasive or Conservative Strategy for Stable Coronary Disease

Author

Maron D. J., Hochman J. S., Reynolds H. R., Bangalore S., O'Brien S. M., Boden W. E., Chaitman B. R., Senior R., Lopez-Sendon J., Alexander K. P., Lopes R. D., Shaw L. J., Berger J. S., Newman J. D., Sidhu M. S., Goodman S. G., Ruzyllo W., Gosselin G., Maggioni A. P., White H. D., Bhargava B., Min J. K., John Mancini G. B., Berman D. S., Picard M. H., Kwong R. Y., Ali Z. A., Mark D. B., Spertus J. A., Krishnan M. N., Elghamaz A., Moorthy N., Hueb W. A., Demkow M., Mavromatis K., Bockeria O., Peteiro J., Miller T. D., Szwed H., Doerr R., Keltai M., Selvanayagam J. B., Gabriel Steg P., Held C., Kohsaka S., Mavromichalis S., Kirby R., Jeffries N. O., Harrell F. E., Rockhold F. W., Broderick S., Bruce Ferguson T., Williams D. O., Harrington R. A., Stone G. W., Rosenberg Y, ISCHEMIA Research Group: Joseph Ricci, A Tello Montoliu, A I Robero Aniorte, Abbey Mulder, Abhay A Laddu, Abhinav Goyal, Abhishek Dubey, Abhishek Goyal, Abigail Knighton, Abraham Oomman, Adam J Jaskowiak, Adam Kolodziej, Adam Witkowski, Adnan Hameed, Adriana Anesini, Afshan Hussain, Agne Juceviciene, Agne Urboniene, Agnes Jakal, Agnieszka Szramowska, Ahmad Khairuddin, Ahmed Abdel-Latif, Ahmed Adel, Ahmed Aljzeeri, Ahmed Kamal, Ahmed Talaat, Aimee Mann, Aira Contreras, Ajit Kumar, V K Kumar, Akemi Furukawa, Akshay Bagai, Akvile Smigelskaite, Alain Furber, Alain Rheault, Alaine Melanie Loehr, Alan Rosen, Albert Varga, Albertina Qelaj, Alberto Barioli, Aldo Russo, Alec Moorman, Alejandro Gisbert, Aleksandra Fratczak, Aleksandras Laucevicius, Alena Kuleshova, Alessandro Sionis, Alexander A Sirker, Alexander M Chernyavskiy, Alexandra Craft, Alexandra Vazquez, Alexandre Ciappina Hueb, Alexandre S Colafranseschi, Alexandre Schaan de Quadros, Alexandre Tognon, Ali Alghamdi, Alice Manica Muller, Aline Nogueira Rabaça, Aline Peixoto Deiro, Alison Hallam, Allegra Stone, Allison Schley, Almudena Castro, Alvaro Rabelo Ales, Amanda Germann, Amanda O'Malley, Amar Uxa, Amarachi Ojajuni, Amarino C Oliveira Jr, Amber B Hull, Ambuj Roy, Amer Zarka, Amir Janmohamed, Ammani Brown, Ammy Malinay, Amparo Martinez Monzonis, Amy J Richards, Amy Iskandrian, Amy Ollinger, Ana D Djordjevic-Dikic, Ana Fernández Martínez, Ana Gomes Almeida, Ana Paula Batista, Ana Rita Francisco, Ana S Mladenovic, Ana Santana, Anam Siddiqui, Anastasia M Kuzmina-Krutetskaya, Andras Vertes, Andre S Sousa, Andre Gabriel, André Schmidt, Andrea M Lundeen, Andrea Bartykowszki, Andrea Lorimer, Andrea Mortara, Andrea Pascual, Andreia Coelho, Andreia Rocha, Andrés García-Rincón, Andrew G Howarth, Andrew J Moriarty, Andrew Docherty, Andrew Starovoytov, Andrew Zurick, Andrzej Łabyk, Andrzej Swiatkowski, Andy Lam, Anelise Kawakami, Angela Hoye, Angela Kim, Angelique Smit, Angelo Nobre, Anil V Shah, Anja Ljubez, Anjali Anand, Ankush Sachdeva, Ann Greenberg, Ann Luyten, Ann Ostrander, Anna Di Donato, Anna Cichocka-Radwan, Anna Fojt, Anna Plachcinska, Anna Proietti, Anna Teresinska, Anne Marie Webb, Anne Cartwright, Anne Heath, Anne Mackin, Anong Amaritakomol, Anong Chaiyasri, Anoop Chauhan, Anoop Mathew, Anthony Gemignani, Anto Luigi Andres, Antonia Vega, Antonietta Hansen, Antonino Ginel Iglesias, Antonio Carlos Carvalho, Antonio Di Chiara, Antonio Serra Peñaranda, Antonio Carvalho, Antonio Colombo, Antonio Fiarresga, Anupama Rao, Aquiles Valdespino-Estrada, Araceli Boan, Areef Ishani, Ariel Diaz, Arijit Ghosh, Arintaya Prommintikul, Arline Roberts, Arnold H Seto, Arnold P Good, Arshed Quyyumi, Arthur J Labovitz, Arthur Kerner, Arturo S Campos-Santaolalla, Arunima Misra, Ashok Mukherjee, Ashok Seth, Ashraf Seedhom, Asim N Cheema, Asker Ahmed, Atul Mathur, Atul Verma, Audrey W Leong, Axel Åkerblom, Axelle Fuentes, Aynun Naher, Badhma Valaiyapathi, Baljeet Kaur, Bandula Guruge, Barbara Brzezińska, Barbara Nardi, Bartosz Czarniak, Bebek Singh, Begoña Igual, Bela Merkely, Belen Cid Alvarez, Benjamin J Spooner, Benjamin J W Chow, Benjamin Cheong, Benoy N Shah, Bernard de Bruyne, Bernardas Valecka, Bernhard Jäger, Beth A Archer, Beth Abramson, Beth Jorgenson, Bethany Harvey, Betsy O'Neal, Bev Atkinson, Bev Bozek, Bevin Lang, Bijulal Sasidharan, Bin Yang, Bin Zhang, Binoy Mannekkattukudy Kurian, Bjoern Goebel, Bob Hu, Bogdan A Popescu, Bogdan Crnokrak, Bolin Zhu, Bonnie J Kirby, Brandi D Zimbelman, Brandy Starks, Branko D Beleslin, Brenda Hart, Brian P Shapiro, Brian McCandless, Brianna Wisniewski, Brigham R Smith, Brooks Mirrer, Bruce McManus, Bruce Rutkin, Bruna Edilena Paulino, Bruna Maria Ascoli, Bryn Smith, Byron J Allen, C Michael Gibson, C Noel Bairey Merz, Calin Pop, Cameron Hague, Camila Thais de Ormundo, Candace Gopaul, Candice P Edillo, Carísi A Polanczyk, Carita Krannila, Carla Vicente, Carl-Éric Gagné, Carlo Briguori, Carlos Peña Gil, Carlos Alvarez, Carly Ohmart, Carmen C Beladan, Carmen Ginghina, Carol M Kartje, Caroline Alsweiler, Caroline Brown, Caroline Callison, Caroline Pinheiro, Caroline Rodgers, Caroline Spindler, Carolyn Corbett, Carrie Drum, Casey Riedberger, Catherine Bone, Catherine Fleming, Catherine Gordon, Catherine Jahrsdorfer, Catherine Lemay, Catherine Weick, Cathrine Patten, Cecilia Goletto, Cezary Kepka, Chandini Suvarna, Chang Xu, Chantale Mercure, Charle A Viljoen, Charlene Wiyarand, Charles Jia-Yin Hou, Charles Y Lui, Charles Cannan, Charles Cornet, Charlotte Pirro, Chataroon Rimsukcharoenchai, Chen Wang, Cheng-Ting Tsai, Chen-Yen Chien, Cheryl A Allardyce, Chester M Hedgepeth, Chetan Patel, Chiara Attanasio, Chih-Hsuan Yen, Chi-Ming Chow, Ching Min Er, Ching-Ching Ong, Cholenahally Nanjappa Manjunath, Chris Beck, Chris Buller, Christel Vassaliere, Christian Hamm, Christiano Caldeira, Christie Ballantyne, Christina Björklund, Christine R Hinton, Christine Bergeron, Christine Masson, Christine Roraff, Christine Shelley, Christophe Laure, Christophe Thuaire, Christopher Kinsey, Christopher McFarren, Christopher Spizzieri, Christopher Travill, Chun-Chieh Liu, Chung-Lieh Hung, Chunguang Li, Chun-Ho Yun, Chunli Xia, Ciarra Heard, Cidney Schultz, Clare Venn-Edmonds, Claudia P Hochberg, Claudia Wegmayr, Claudia Cortés, Claudia Escobar, Cláudia Freixo, Claudio T Mesquita, Clemens T Kadalie, Colin Berry, Constance Philander, Corine Thobois, Costantino Costantini, Courtney Page, Craig Atkinson, Craig Barr, Craig Paterson, Cristina Bare, Cynthia Baumann, Cynthia Burman, Dalisa Espinosa, Damien Collison, Dan Deleanu, Dan Elian, Dan Gao, Dana Oliver, Daniel P Vezina, Daniel O'Rourke, Daniele Komar, Danielle Schade, Darrel P Francis, Dastan Malaev, David A Bull, David E Winchester, David P Faxon, David Booth, David Cohen, David DeMets, David Foo, David Schlichting, David Taggart, David Waters, David Wohns, Davis Vo, Dawid Teodorczyk, Dawn Shelstad, Dawn Turnbull, Dayuan Li, Dean Kereiakes, Deborah O'Neill, Deborah Yip, Debra K Johnson, Debra Dees, Deepak L Bhatt, Deepika Gopal, Deepti Kumar, Deirdre Mattina, Deirdre Murphy, Delano R Small, Delsa K Rose, Dengke Jiang, Denis Carl Phaneuf, Denise Braganza, Denise Fine, Derek Cyr, Desiree Tobin, Diana Cukali, Diana Parra, Diane Camara, Diane Minshall Liu, Diego Adrián Vences, Diego Franca de Cunha, Dimitrios Stournaras, Dipti Patel, Dongze Li, Donna Exley, Dorit Grahl, Dragana Stanojevic, Duarte Cacela, Dwayne S G Conway, E Pinar Bermudez, Eapen Punnoose, Edgar L Tay, Edgar Karanjah, Edoardo Verna, Eduardo Hernandez-Rangel, Edward D Nicol, Edward O McFalls, Edward T Martin, Edyta Kaczmarska, Ekaterina I Lubinskaya, Elena A Demchenko, Elena Refoyo Salicio, Eli Feen, Elihú Durán-Cortés, Elisabeth M Janzen, Elise L Hannemann, Elise van Dongen, Elissa Restelli Piloto, Eliza Kaplan, Elizabeta Srbinovska Kostovska, Elizabeth Capasso-Gulve, Elizabeth Congdon, Elizabeth Ferguson, Elizaveta V Zbyshevskaya, Ellen Magedanz, Ellie Fridell, Ellis W Lader, Elvin Kedhi, Emanuela Racca, Emilie Tachot, Emily DeRosa, Encarnación Alonso-Álvarez, Eric Nicollet, Eric Peterson, Erick Alexánderson Rosas, Erick Donato Morales, Erin Orvis, Ermina Moga, Estelle Montpetit, Estevao Figueiredo, Eugene Passamani, Eugenia Nikolsky, Eunice Yeoh, Evgeniy I Kretov, Ewa Szczerba, Ewelina Wojtala, Expedito Eustáquio Ribeiro Silva, F Marin Ortuño, Fabio R Farias, Fabio Fimiani, Fabrizio Rolfo, Fa-Chang Yu, Fadi Hage, Fadi Matar, Fahim Haider Jafary, Fang Feng, Fang Liu, Fatima Ranjbaran, Fatima Rodriguez, Fausto J Pinto, Fauzia Rashid, Federica Ramani, Fei Wang, Fernanda Igansi, Filipa Silva, Filippo Ottani, Fiona Haines, Firas Al Solaiman, Flávia Egydio, Flavio Lyra, Florian Egger, Fran Farquharson, Frances Laube, Francesc Carreras Costa, Francesca de Micco, Francesca Bianchini, Francesca Pezzetta, Francesca Pietrucci, Francesco Orso, Francesco Pisano, Francis Burt, Francisca Patuleia Figueiras, Francisco Fernandez-Aviles, Francois Pierre Mongeon, Frans Van de Werf, Franziska Guenther, Fraser N Witherow, Fred Mohr, Frederico Dall'Orto, Fumiyuki Otsuka, G De La Morena, G Karthikeyan, Gabor Dekany, Gabor Kerecsen, Gabriel Galeote, Gabriel Grossmann, Gabriel Vorobiof, Gabriela Sanchez de Souza, Gabriela Guzman, Gabriela Zeballos, Gabriele Gabrielli, Gabriele Jakl-Kotauschek, Gail A Shammas, Gail Brandt, Gang Chen, Gary E Lane, Gary J Luckasen, Gautam Sharma, Gelmina Mikolaitiene, Gennie Yee, Georg Nickenig, George E Revtyak, George J Juang, Gerald Fletcher, Gerald Leonard, Gerard Patrick Devlin, Gerard Esposito, Gergely Ágoston, Gervasio Lamas, Geza Fontos, Ghada Mikhail, Gia Cobb, Gian Piero Perna, Gianpiero Leone, Giles Roditi, Gilles Barone-Rochette, Girish Mishra, Giuseppe Tarantini, Glenda Wong, Glenn S Hamroff, Glenn Rayos, Gong Cheng, Gonzalo Barge-Caballero, Goran Davidović, Goran Stankovic, Gordana Stevanovic, Grace Jingyan Wang, Grace M Young, Graceanne Wayser, Graciela Scaro, Graham S Hillis, Graham Wong, Grazyna Anna Szulczyk, Gregor Simonis, Gregory Kumkumian, Gretchen Ann Peichel, Grzegorz Gajos, Gudrun Steinmaurer, Guilherme G Rucatti, Guilherme Portugal, Guilhermina Cantinho Lopes, Guillem Pons Lladó, Gunnar Frostfelt, Gurpreet S Wander, Gurpreet Gulati, Gustavo Pucci, Hafidz Abd Hadi, Haibo Zhang, Haitao Wang, Halina Marciniak, Han Chen, Hanan Kerr, Hani Najm, Hanna Douglas, Hannah Phillips, Hao Dai, Haojian Dong, Haqeel Jamil, Harikrishnan Sivadasanpillai, Harry Suryapranata, Hassan Reda, Hayley Pomeroy, Heather Barrentine, Heather Golden, Heather Hurlburt, Heidi Wilson, Helen C Tucker, Helene Abergel, Hemalata Siddaram, Hermine Osseni, Herwig Schuchlenz, Hesong Zeng, Hicham Skali, Hilda Solomon, Hollie Horton, Holly Hetrick, Holly Little, Holly Park, Hongjie Chi, Hossam Mahrous, Howard A Levite, Hristo Pejkov, Huajun Li, Hugo Bloise-Adames, Hugo Marques, Hui Zhong, Hui-Min Zhang, Humayrah Hashim, Hung-I Yeh, Hussien El Fishawy, Ian Webb, Iftikhar Kullo, Igor O Grazhdankin, Ihab Hamzeh, Ikraam Hassan, Ikuko Ueda, Ileana L Pina, Ilona Tamasauskiene, Ilse Bouwhuis, Imran Arif, Ina Wenzelburger, Inês Zimbarra Cabrita, Ines Rodrigues, Inga H Robbins, Inga Soveri, Ingela Schnittger, Iqbal Karimullah, Ira M Dauber, Iram Rehman, Irena Peovska Mitevska, Irene Marthe Lang, Irina Subbotina, Irma Kalibataite-Rutkauskiene, Irni Yusnida, Isabel Estela Carvajal, Isabella C Palazzo, Isabelle Hogan, Isabelle Roy, Ishba Syed, Ishita Tejani, Ivan A Naryshkin, Ivana Jankovic, Iwona Niedzwiecka, J David Knight, Jacek Kusmierek, Jackie M White, Jackie Chow, Jacob Udell, Jacqueline E Tamis-Holland, Jacqueline Fannon, Jacquelyn A Quin, Jacquelyn Do, Jaekyeong Heo, Jakub Maksym, James E Davies, James H O'Keefe Jr, James J Jang, James Cha, James Harrison, James Hirsch, James Stafford, James Tatoulis, Jamie Rankin, Jan Henzel, Jan Orga, Jana Tancredi, Janaina Oliveira, Jane Burton, Jane Eckstein, Jane Marucci, Janet P Knight, Janet Blount, Janet Halliday, Janetta Kourzenkova, Janitha Raj, Jan-Malte Sinning, Jaqueline Pozzibon, Jaroslaw Drozdz, Jaroslaw Karwowski, Jason D Glover, Jason Loh Kwok, Jason T Call, Jason Linefsky, Jassira Gomes, Jati Anumpa, Javier J Garcia, Javier Courtis, Jay Meisner, K Jayakumar, Jayne Scales, Jean E Denaro, Jean Michel Juliard, Jean Ho, Jeanette K Stansborough, Jean-Michel Juliard, Jeanne Russo, Jeannette J M Schoep, Jeet Thambyrajah, Jeff Leimberger, Jeffery A Breall, Jeffrey A Kohn, Jeffrey C Milliken, Jeffrey Anderson, Jeffrey Blume, Jeffrey Kanters, Jeffrey Lorin, Jeffrey Moses, Jelena J Stepanovic, Jelena Celutkiene, Jelena Djokic, Jelena Stojkovic, Jenne M Jose, Jenne Manchery, Jennifer A Mull, Jennifer H Czerniak, Jennifer L Stanford, Jennifer Gillis, Jennifer Horst, Jennifer Isaacs, Jennifer Langdon, Jennifer Thomson, Jennifer Tomfohr, Jennifer White, Jen-Yuan Kuo, Jeremy Rautureau, Jerome Fleg, Jessica Berg, Jessica Rodriguez, Jessica Waldron, Jhina Patro, Jia Li, Jiajia Mao, Jiamin Liu, Jian'an Wang, Jianhua Li, Jianxin Zhang, Jie Qi, Jihyun Lyo, Jill Marcus, Jim Blankenship, Jing Zhang, Jingjing Liu, Jing-Yao Fan, Jiun-Yi Li, Jiwan Pradhan, Jiyan Chen, J M Rivera Caravaca, Jo Evans, Joan Garcia Picart, Joan Hecht, Joanna Jaroch, Joanna Zalewska, Joanne Kelly, Joanne Taaffe, João Reynaldo Abbud, João V Vitola, Joaquín V Peñafiel, Jocelyne Benatar, Jody Bindeman, Joe Sabik, Joel Klitch, Johann Christopher, Johannes Aspberg, John D Friedman, John F Beltrame, John F Heitner, John Joseph Graham, John R Davies, John Doan, John Kotter, John Kurian, John Mukai, John Pownall, Jolanta Sobolewska, Jon Kobashigawa, Jonathan L Goldberg, Jonathan W Bazeley, Jonathan Byrne, Jonathan Himmelfarb, Jonathan Leipsic, Jonean Thorsen, Jorge F Trejo Gutierrez, Jorge Escobedo, Jorik Timmer, José A Ortega-Ramírez, José Antonio Marin-Neto, Jose D Salas, Jose Enrique Castillo, Jose Francisco Saraiva, José J Cuenca-Castillo, Jose L Diez, José Luis Narro Villanueva, José Luiz da Vieira, José M Flores-Palacios, Jose Ramon Gonzalez, Jose Seijas Amigo, Jose Fragata, Josep Maria Padró, Josheph F X McGarvey Jr, Joseph Hannan, Joseph Sacco, Joseph Sweeny, Joseph Wiesel, Josephine D Abraham, Joshua P Loh, Joy Burkhardt, Joyce R White, Joyce Riestenberg-Smith, Judit Sebo, Judith L Meadows, Judith Wright, Judy Mae Foltz, Judy Hung, Judy Otis, Juergen Stumpf, Jui-Peng Tsai, Julia S Dionne, Julia de Aveiro Morata, Julie Bunke, Julie Morrow, Julio César Figal, Jun Fujita, Jun Jiang, Junhua Li, Junqing Yang, Juntima Euathrongchit, Jyotsna Garg, K Manjula Rani, K Preethi, Kaatje Goetschalckx, Kai Eggers, Kamalakar Surineni, Kanae Hirase, T R Kapilamoorthy, Karen Calfas, Karen Gratrix, Karen Hallett, Karen Hultberg, Karen Nugent, Karen Petrosyan, Karen Swan, Karolina Kryczka, Karolina Wojtczak-Soska, Karolina Wojtera, Karsten Lenk, Karthik Ramasamy, Katarzyna Łuczak, Katarzyna Malinowska, Kate Pointon, Kate Robb, Katherine Martin, Kathleen Claes, Kathryn Carruthers, Kathy E Siegel, Katia Drouin, Katie Fowler-Lehman, Kavita Rawat, Kay Rowe, Keiichi Fukuda, Keith A A Fox, Ken Mahaffey, Kendra Unterbrink, Kenneth Giedd, Kerrie Van Loo, Kerry Lee, Kerstin Bonin, Kevin R Bainey, Kevin T Harley, Kevin Anstrom, Kevin Chan, Kevin Croce, Kevin Landolfo, Kevin Marzo, Keyur Patel, Khaled Abdul-Nour, Khaled Alfakih, Khaled Dajani, Khaled Ziada, Khaula Baloch, Khrystyna Kushniriuk, Kian-Keong Poh, Kim F Ireland, Kim Holland, Kimberly Ann Byrne, Kimberly E Halverson, Kimberly Elmore, Kimberly Miller-Cox, Kiran Reddy, Kirsten J Quiles, Kirsty Abercrombie, Klaus Matschke, Konrad Szymczyk, Koo Hui Chan, Kotiboinna Preethi, Kozhaya Sokhon, Krissada Meemuk, Kristian Thygesen, Kristin M Salmi, Kristin Newby, Kristina Wippler, Kristine Arges, Kristine Teoh, Krystal Etherington, Krystyna Łoboz-Grudzień, Krzysztof W Reczuch, Krzysztof Bury, Krzysztof Drzymalski, Krzysztof Kukuła, Kuo-Tzu Sung, Kurt Huber, Ladda Douangvila, Lance Sullenberger, Larissa Miranda Trama, Laszlone Matics, Laura Drew, Laura Flint, Laura Keinaite, Laura Sarti, Laurel Kolakaluri, Lawrence M Phillips, Lawrence Friedman, Lawrence Phillips, Lazar Velicki, Leah Howell, Leandro C Maranan, Leanne Cox, Ledjalem Daba, Lei Zhang, Lekshmi Dharmarajan, Leo Bockeria, Leonardo Pizzol Caetano, Leonardo Bridi, Leonid L Bershtein, Leszek Sokalski, Li Hai Yan, Li Li, Lia Nijmeijer, Lidia Sousa, Lihong Xu, Lihua Zhang, Lili Zhang, Lilia Schiavi, Lilian Mazza Barbosa, Lillian L Khor, Lina Felix-Stern, Linda L Hall, Linda M Hollenweger, Linda Arcand, Linda Davidson-Ray, Linda Schwarz, Lindsey N Sikora, Lingping Chi, Lino Patricio, Liping Zhang, Lisa Chaytor, Lisa Hatch, Lisa McCloy, Lisa Wong, Liselotte Persson, Lixin Jiang, Liz Low, Ljiljana Pupic, Loïc Bière, Lorenzo Monti, Lori Christensen, Lori Pritchard, Loriane Black, Lori-Ann Desimone, Lori-Ann Larmand, Lorraine McGregor, Louise Morby, Louise Thomson, Luc Harvey, Luciana de Pádua Baptista, Lucilla Garcia, Ludivine Eliahou, Ludmila Helmer, Luis F Smidt, Luis Bernanrdes, Luis Guzman, Luiz A Carvalho, Luyang Xiong, Lynette L Teo, Lynn M Neeson, Lynne Winstanley, M Barbara Srichai-Parsia, M Quintana Giner, M Sowjanya Reddy, M Valdés Chávarri, M Grazia Rossi, Maarten Simoons, Maayan Konigstein, Maciej Lesiak, Maciej Olsowka, Mafalda Selas, Magalie Corfias, Magdalena Madero Rovalo, Magdalena Łanocha, Magdalena Miller, Magdalena Misztal-Teodorczyk, Magdalena Rantinella, Magdy Abdelhamid, Magnolia Jimenez, Mahboob Alam, Mahevamma Mylarappa, Mahfouz El Shahawy, Mahmoud Mohamed, Mahmud Al-Bustami, Majo X Joseph, Malgorzata Frach, Małgorzta Celińska-Spodar, Malte Helm, Manas Chacko, Mandy Murphy, Manitha Vinod, Manjula Rani, Manu Dhawan, Manuela Mombelli, Marcel Weber, Marcello Galvani, Marcelo Jamus Rodrigues, Marcia F Dubin, Marcia F Werner Bayer, Marcin Szkopiak, Marco Antonio Monsalve, Marco Bizzaro Santos, Marco Magnoni, Marco Marini, Marco Sicuro, Marco Zenati, Marcos Valério Coimbra Resende, Marek Roik, Margalit Bentzvi, Margaret Gilsenan, Margaret Iraola, Margot C Quinn, Maria A Alfonso, Maria Antonieta Pereira Moraes, María Dolores Martínez-Ruíz, María Fernanda Canales, Maria Inês Caetano, Maria P Corral, Maria Pérez García, Maria Victoria Actis, Maria Aguirre, Maria Andreasson, Maria Aprile, Maria Colton, Maria Eugenia Martin, Maria Lasala, Maria Lorenzo, Maria Posada, Maria Shier, Maria Thottam, Mariana V Furtado, Mariana Yumi Okada, Marianna D A Dracoulakis, Marianne De Andrade, Mariano Rubio, Marie Essermark, Marielle Scherrer-Crosbie, Marija T Petrovic, Marija Zdravkovic, Marilyn Black, Marina Garcia, Mario J Garcia, Mariola Szulik, Marisa Orgera, Mark A de Belder, Mark Harbinson, Mark Hyun, Mark Peterson, Mark Xavier, Marlowe Mosley, Marta Capinha, Marta Marcinkiewicz-Siemion, Marta Swiderek, Martha Meyer, Martina Ceseri, Martina Tricoli, Marvin Kronenberg, Mary Williams, Mary Ann Champagne, Mary Colleen Rogge, Mary R Soltau, Mary Streif, Massimo Villella, Massoud Leesar, Matei Claudia, Mateusz Solecki, Matías Nicolás Mungo, Matthew Wall Jr, Matthew Budoff, Matthew Jezior, Matthew Luckie, Matthias Friedrich, Mauren P Haeffner, Maximilian Tscharre, Max-Paul Winter, Mayana Almeida, Mayil S Krishnam, Mayuri Patel, Meenakshi Mishra, Megan Manocchia, Meghana Kakade, Melanie J Munro, Melissa D Chaplin, Melissa LeFevre, Mervyn Andiapen, Michael A Gibson, Michael B Rubens, Michael C Turner, Michael D Shapiro, Michael W Lee, Michael Berlowitz, Michael Davidson, Michael Mack, Michael McDaniel, Michael Mumma, Michal Wlodarczyk, Michel G Khouri, Michel S Slama, Michele Rawlins, Michelle M Bonner, Michelle M Seib, Michelle Chang, Michelle Crowder, Michelle Dixon, Michelle Mayon, Michelle McEvoy, Michelle Yee, Miguel M Fernandes, Miguel Nobre Menezes, Miguel Souto Bayarri, Miguel Barrero, Mikhail T Torosoff, Milan R Dobric, Milan Dobric, Milica Nikola Dekleva, Milind Avdhoot Gadkari, Millie Gomez, Min Tun Kyaw, Miriam Brooks, Miroslav Stevo Martinovic, Mitchel B Lustre, Mohammad Tariq Vakani, Mohammad El-Hajjar, Mohammed Al-Amoodi, 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Riezebos, Robert M Donnino, Robert Bojar, Robert Chilton, Robert Guyton, Robert Henderson, Robert Kornberg, Robert Leber, Robert Mao, Robert Stenberg, Roberta P Santos, Roberto René Favaloro, Roberto Amati, Rodolfo G S D Lima, Rodrigo J Cerci, Rogerio Tumelero, Rohit Tandon, Roma Tewari, Romalisa Miranda-Peats, Ron Wald, Ronald A Mastouri, Ronald G Morford, Ronald G Schwartz, Ronald P Pedalino, Rongrong Hu, Ronnell A Hansen, Ronny A Cohen, Rory Hachamovitch, Rosa Homem, Rosa Sandonato, Rosane Laimer, Rosann Gans, Roxanne Yost, Roy Mathew, Rubén Baleón-Espinosa, Ruben Ramos, Rubine Gevorgyan, Rui Ferreira, Rui Jing, Ruth Pérez-Fernández, S K Dwivedi, S Ramakrishnan, Saadat Khan, Sabahat Bokhari, Sabu Thomas, Sadath Lubna, Sajeeda Parveen Khan, Sajeev Chakanalil Govindan, Saket Girotra, Saleem Kassam, Sallie Canada, Salvador Cruz-Flores, Samaa Mohamed, Samantha Ly, Sameh El Kaffas, Samia Massalha, Sampoornima Setty, Samuel Nwosu, Sandeep Seth, Sandeep Singh, Sander R Niehe, Sandra M 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Craig Barr, Craig Paterson, Cristina Bare, Cynthia Baumann, Cynthia Burman, Dalisa Espinosa, Damien Collison, Dan Deleanu, Dan Elian, Dan Gao, Dana Oliver, Daniel P Vezina, Daniel O'Rourke, Daniele Komar, Danielle Schade, Darrel P Francis, Dastan Malaev, David A Bull, David E Winchester, David P Faxon, David Booth, David Cohen, David DeMets, David Foo, David Schlichting, David Taggart, David Waters, David Wohns, Davis Vo, Dawid Teodorczyk, Dawn Shelstad, Dawn Turnbull, Dayuan Li, Dean Kereiakes, Deborah O'Neill, Deborah Yip, Debra K Johnson, Debra Dees, Deepak L Bhatt, Deepika Gopal, Deepti Kumar, Deirdre Mattina, Deirdre Murphy, Delano R Small, Delsa K Rose, Dengke Jiang, Denis Carl Phaneuf, Denise Braganza, Denise Fine, Derek Cyr, Desiree Tobin, Diana Cukali, Diana Parra, Diane Camara, Diane Minshall Liu, Diego Adrián Vences, Diego Franca de Cunha, Dimitrios Stournaras, Dipti Patel, Dongze Li, Donna Exley, Dorit Grahl, Dragana Stanojevic, Duarte Cacela, Dwayne S G Conway, E Pinar 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George J Juang, Gerald Fletcher, Gerald Leonard, Gerard Patrick Devlin, Gerard Esposito, Gergely Ágoston, Gervasio Lamas, Geza Fontos, Ghada Mikhail, Gia Cobb, Gian Piero Perna, Gianpiero Leone, Giles Roditi, Gilles Barone-Rochette, Girish Mishra, Giuseppe Tarantini, Glenda Wong, Glenn S Hamroff, Glenn Rayos, Gong Cheng, Gonzalo Barge-Caballero, Goran Davidović, Goran Stankovic, Gordana Stevanovic, Grace Jingyan Wang, Grace M Young, Graceanne Wayser, Graciela Scaro, Graham S Hillis, Graham Wong, Grazyna Anna Szulczyk, Gregor Simonis, Gregory Kumkumian, Gretchen Ann Peichel, Grzegorz Gajos, Gudrun Steinmaurer, Guilherme G Rucatti, Guilherme Portugal, Guilhermina Cantinho Lopes, Guillem Pons Lladó, Gunnar Frostfelt, Gurpreet S Wander, Gurpreet Gulati, Gustavo Pucci, Hafidz Abd Hadi, Haibo Zhang, Haitao Wang, Halina Marciniak, Han Chen, Hanan Kerr, Hani Najm, Hanna Douglas, Hannah Phillips, Hao Dai, Haojian Dong, Haqeel Jamil, Harikrishnan Sivadasanpillai, Harry Suryapranata, Hassan Reda, Hayley Pomeroy, Heather Barrentine, Heather Golden, Heather Hurlburt, Heidi Wilson, Helen C Tucker, Helene Abergel, Hemalata Siddaram, Hermine Osseni, Herwig Schuchlenz, Hesong Zeng, Hicham Skali, Hilda Solomon, Hollie Horton, Holly Hetrick, Holly Little, Holly Park, Hongjie Chi, Hossam Mahrous, Howard A Levite, Hristo Pejkov, Huajun Li, Hugo Bloise-Adames, Hugo Marques, Hui Zhong, Hui-Min Zhang, Humayrah Hashim, Hung-I Yeh, Hussien El Fishawy, Ian Webb, Iftikhar Kullo, Igor O Grazhdankin, Ihab Hamzeh, Ikraam Hassan, Ikuko Ueda, Ileana L Pina, Ilona Tamasauskiene, Ilse Bouwhuis, Imran Arif, Ina Wenzelburger, Inês Zimbarra Cabrita, Ines Rodrigues, Inga H Robbins, Inga Soveri, Ingela Schnittger, Iqbal Karimullah, Ira M Dauber, Iram Rehman, Irena Peovska Mitevska, Irene Marthe Lang, Irina Subbotina, Irma Kalibataite-Rutkauskiene, Irni Yusnida, Isabel Estela Carvajal, Isabella C Palazzo, Isabelle Hogan, Isabelle Roy, Ishba Syed, Ishita Tejani, Ivan A Naryshkin, Ivana Jankovic, Iwona Niedzwiecka, J David Knight, Jacek Kusmierek, Jackie M White, Jackie Chow, Jacob Udell, Jacqueline E Tamis-Holland, Jacqueline Fannon, Jacquelyn A Quin, Jacquelyn Do, Jaekyeong Heo, Jakub Maksym, James E Davies, James H O'Keefe Jr, James J Jang, James Cha, James Harrison, James Hirsch, James Stafford, James Tatoulis, Jamie Rankin, Jan Henzel, Jan Orga, Jana Tancredi, Janaina Oliveira, Jane Burton, Jane Eckstein, Jane Marucci, Janet P Knight, Janet Blount, Janet Halliday, Janetta Kourzenkova, Janitha Raj, Jan-Malte Sinning, Jaqueline Pozzibon, Jaroslaw Drozdz, Jaroslaw Karwowski, Jason D Glover, Jason Loh Kwok, Jason T Call, Jason Linefsky, Jassira Gomes, Jati Anumpa, Javier J Garcia, Javier Courtis, Jay Meisner, K Jayakumar, Jayne Scales, Jean E Denaro, Jean Michel Juliard, Jean Ho, Jeanette K Stansborough, Jean-Michel Juliard, Jeanne Russo, Jeannette J M Schoep, Jeet Thambyrajah, Jeff Leimberger, Jeffery A Breall, Jeffrey A Kohn, Jeffrey C Milliken, Jeffrey Anderson, Jeffrey Blume, Jeffrey Kanters, Jeffrey Lorin, Jeffrey Moses, Jelena J Stepanovic, Jelena Celutkiene, Jelena Djokic, Jelena Stojkovic, Jenne M Jose, Jenne Manchery, Jennifer A Mull, Jennifer H Czerniak, Jennifer L Stanford, Jennifer Gillis, Jennifer Horst, Jennifer Isaacs, Jennifer Langdon, Jennifer Thomson, Jennifer Tomfohr, Jennifer White, Jen-Yuan Kuo, Jeremy Rautureau, Jerome Fleg, Jessica Berg, Jessica Rodriguez, Jessica Waldron, Jhina Patro, Jia Li, Jiajia Mao, Jiamin Liu, Jian'an Wang, Jianhua Li, Jianxin Zhang, Jie Qi, Jihyun Lyo, Jill Marcus, Jim Blankenship, Jing Zhang, Jingjing Liu, Jing-Yao Fan, Jiun-Yi Li, Jiwan Pradhan, Jiyan Chen, J M Rivera Caravaca, Jo Evans, Joan Garcia Picart, Joan Hecht, Joanna Jaroch, Joanna Zalewska, Joanne Kelly, Joanne Taaffe, João Reynaldo Abbud, João V Vitola, Joaquín V Peñafiel, Jocelyne Benatar, Jody Bindeman, Joe Sabik, Joel Klitch, Johann Christopher, Johannes Aspberg, John D Friedman, John F Beltrame, John F Heitner, John Joseph Graham, John R Davies, John Doan, John Kotter, John Kurian, John Mukai, John Pownall, Jolanta Sobolewska, Jon Kobashigawa, Jonathan L Goldberg, Jonathan W Bazeley, Jonathan Byrne, Jonathan Himmelfarb, Jonathan Leipsic, Jonean Thorsen, Jorge F Trejo Gutierrez, Jorge Escobedo, Jorik Timmer, José A Ortega-Ramírez, José Antonio Marin-Neto, Jose D Salas, Jose Enrique Castillo, Jose Francisco Saraiva, José J Cuenca-Castillo, Jose L Diez, José Luis Narro Villanueva, José Luiz da Vieira, José M Flores-Palacios, Jose Ramon Gonzalez, Jose Seijas Amigo, Jose Fragata, Josep Maria Padró, Josheph F X McGarvey Jr, Joseph Hannan, Joseph Sacco, Joseph Sweeny, Joseph Wiesel, Josephine D Abraham, Joshua P Loh, Joy Burkhardt, Joyce R White, Joyce Riestenberg-Smith, Judit Sebo, Judith L Meadows, Judith Wright, Judy Mae Foltz, Judy Hung, Judy Otis, Juergen Stumpf, Jui-Peng Tsai, Julia S Dionne, Julia de Aveiro Morata, Julie Bunke, Julie Morrow, Julio César Figal, Jun Fujita, Jun Jiang, Junhua Li, Junqing Yang, Juntima 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Stephanie M Lane, Stephanie Ferket, Stephanie Kelly, Stephanie Wasmiller, Stephen H McKellar, Stephen P Hoole, Stephen Fremes, Stephen Preston, Steve Leung, Steven A Fein, Steven J Lindsay, Steven P Sedlis, Steven Giovannone, Steven Michael, Steven Weitz, Stijn van Vugt, Subhash Banerjee, Sudhir Naik, Suellen Hosino, Sukie Desire, Sukit Yamwong, Suku T Thambar, Sulagna Mookherjee, Suman Singh, Sundeep Mishra, Sunil Kumar Verma, Supap Kulthawong, Supatchara Khwakhong, Surendra Naik, Suresh Babu, Surin Woragidpoonpol, Suryaprakash Narayanappa, Susan Derbyshire, Susan Gent, Susan Mathus, Susan Milbrandt, Susan Moore, Susan Regan, Susan Stinson, Susan Webber, Susana Silva, Susanna Stevens, Susanne Gruensfelder, Suthara Aramcharoen, Suvarna Kolhe, Suzana Tavares, Suzanne Arnold, Suzanne Welsh, Svetlana Apostolovic, Swapna Kunhunny, Ta-Chuan Hung, Taissa Zappernick, Tali Sharir, Talita Silva, Tamara Colaiácovo Soares, Tapan Umesh Pillay, Tarun K Mittal, Tatiana Trifonova, Tauane Bello 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Wu, Yu Kunwu, Yu Zhao, Yudong Peng, Yueh-Hung Lin, Yulan Zhao, Yumei Dong, Yunhai Zhao, Yutthaphan Wannasopha, Yvonne Taul, Zakir Sahul, Zalina Kudzoeva, Zbigniew Kalarus, Zeljko Z Markovic, Zhen Huang, Zheng Ji, Zhenyu Liu, Zhou Yue, Zhulin Zhang, Zhuxi Li, Zile Singh Meharwal, Ziliang Bai, Zixiang Yu, Zohra Huda, Zoltan Davidovits

Subjects
Male, Cardiac Catheterization, Computed Tomography Angiography, medicine.medical_treatment, Myocardial Ischemia, Coronary Disease, Coronary Artery Disease, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Coronary Angiography, ISCHEMIA Research Group, law.invention, Angina, Coronary artery disease, 0302 clinical medicine, Randomized controlled trial, law, Cardiovascular Disease, Myocardial Revascularization, 030212 general & internal medicine, Coronary Artery Bypass, 11 Medical and Health Sciences, Cardiac catheterization, General Medicine, Middle Aged, humanities, Cardiovascular Diseases, Cardiology, Female, Human, medicine.medical_specialty, Ischemia, Article, 03 medical and health sciences, Geriatric cardiology, Percutaneous Coronary Intervention, General & Internal Medicine, Internal medicine, medicine, Humans, Angina, Unstable, Aged, business.industry, Coronary Artery Bypa, Percutaneous coronary intervention, Bayes Theorem, medicine.disease, Heart failure, Quality of Life, business
Abstract

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Published
2020
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26. Lower calcium levels in hair of Parkinson’s disease patients are associated with presence of sleeping disturbances

Author

George E. Barreto, Marcelo Eça Rocha, Altair Brito dos Santos, Marcos A. Bezerra, and Kristi A. Kohlmeier

Subjects
Sleep Wake Disorders, Sleep disorder, education.field_of_study, Nutrition and Dietetics, Parkinson's disease, General Neuroscience, Population, Medicine (miscellaneous), Physiology, Excessive daytime sleepiness, Parkinson Disease, Disorders of Excessive Somnolence, General Medicine, medicine.disease, REM sleep behavior disorder, Sleep in non-human animals, Zinc, medicine, Humans, Biomarker (medicine), Calcium, medicine.symptom, education, Somnolence, Hair
Abstract

Objectives: To investigate the correlation between sleep disorders and the concentrations of three metals analyzed from hair samples of PD patients.The hypothesis of an involvement of an imbalance of metals in the development of Parkinson's Disease (PD) has been strengthened by several clinical chemistry studies. Interestingly, while sparse, some studies have correlated the imbalance of metals in PD patients with comorbidities present in this disease. Although not all PD sufferers present sleep disturbances, significant disorders of sleep are common in this population. Methods: Sleep evaluation was divided into three parameters: sleep quality, excessive daytime sleepiness and clinically probable REM Sleep Behavior Disorder. Flame atomic absorption spectrometry (F AAS) was used to assess the concentrations of calcium, iron and zinc in hair samples collected from a population of PD patients registered in a Brazilian city and from controls (a total of 53 subjects). All subjects lived within a restricted geographical region and were exposed to similar environmental conditions. Results: PD patients with poor sleep quality and excessive daytime sleepiness exhibited significant differences in concentrations of calcium, but not iron or zinc when compared to levels found in controls and PD patients who do not report these sleeping problems. Discussion: Our data suggest that different subgroups of PD patients exist, and clinical chemistry could be useful as a biomarker for these subgroups, which needs to be confirmed in a larger patient population. Further, our data raise the question regarding whether normalization of calcium levels could improve the sleep quality and somnolence in PD patients.

Published
2021
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27. The early effect of dapagliflozin on strain and tissue Doppler parameters of diastolic function in diabetic patients with heart failure with reduced ejection fraction

Author

Labrini Tsigkriki, Fragkiskos Parthenakis, Vasiliki Katsi, Alexandros P. Patrianakos, Maria Mamaloukaki, Spyridon Maragkoudakis, George E. Kochiadakis, Kostas Tsioufis, and Maria Marketou

Subjects
medicine.medical_specialty, Ejection fraction, strain and tissue Doppler parameters, business.industry, diastolic function, Diastole, General Medicine, dapagliflozin, medicine.disease, Sacubitril, chemistry.chemical_compound, chemistry, Valsartan, Clinical Research, Internal medicine, Heart failure, Cardiology, Medicine, Enalapril, Dapagliflozin, business, Prospective cohort study, medicine.drug
Abstract

IntroductionHeart failure (HF) with reduced ejection fraction (HFrEF) remains a challenging problem due to its high mortality rate. The PARADIGM HF trial and a new class of drugs – angiotensin receptor–neprilysin inhibitors (ARNIs) – managed to change the current perception of HF treatment by reducing cardiovascular mortality and morbidity as well as HF hospitalizations compared with enalapril and have emerged as an evidence-based therapy for HFrEF. Another novelty in HF therapy is dapagliflozin, a sodium-glucose transporter-2 inhibitor (SGLT2i) which decreased the rates of cardiac death and worsening of HF in the DAPA-HF trial, when added in other guideline recommended therapy. A recent study evaluated the potency of dapagliflozin in terms of mortality and deterioration of HF, in patients taking sacubitril/valsartan and in patients who were naive.Material and methodsA prospective cohort study of 30 symptomatic HF patients with EF < 35% (aged 65 ±10 years) was conducted. Diabetic (2TDM) patients of NYHA status II–III, previously treated with ARNI, -blocker, and mineralocorticoid receptor antagonists (MRA) were included. Dapagliflozin was added to their therapy.ResultsEchocardiographic evaluation revealed improvement of both conventional tissue Doppler and diastolic strain parameters by dapagliflozin addition on HF therapy.ConclusionsDapagliflozin impact on diastolic function may explain the symptom amelioration and the improvement of quality of life. And more specifically, the ratio of early diastolic transmitral flow velocity to global strain rate at the early filling phase of diastole (E/SRE)may be considered a reliable index of HF therapy responders.

Published
2021

28. Meningioma systematic reviews and meta-analyses: an assessment of reporting and methodological quality

Author

Alan M. George, Shubhi Gupta, Sumirat M. Keshwara, Mohammad A. Mustafa, Conor S. Gillespie, George E. Richardson, Amy C. Steele, Amir H. Zamanipoor Najafabadi, Linda Dirven, Anthony G. Marson, Abdurrahman I. Islim, Michael D. Jenkinson, and Christopher P. Millward

Subjects
ROBIS, systematic review, AMSTAR 2, Surgery, PRISMA, Neurology (clinical), General Medicine, Meningioma
Abstract

Introduction: Systematic reviews (SR) and systematic reviews with meta-analysis (SRMA) can constitute the highest level of research evidence. Such evidence syntheses are relied upon heavily to inform the clinical knowledge base and to guide clinical practice for meningioma. This review evaluates the reporting and methodological quality of published meningioma evidence syntheses to date. Methods: Eight electronic databases/registries were searched to identify eligible meningioma SRs with and without meta-analysis published between January 1990 and December 2020. Articles concerning spinal meningioma were excluded. Reporting and methodological quality were assessed against the following tools: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), A MeaSurement Tool to Assess systematic Reviews (AMSTAR 2), and Risk Of Bias in Systematic reviews (ROBIS). Results: 116 SRs were identified, of which 57 were SRMAs (49.1%). The mean PRISMA score for SRMA was 20.9 out of 27 (SD 3.9, 77.0% PRISMA adherence) and for SR without meta-analysis was 13.8 out of 22 (SD 3.4, 63% PRISMA adherence). Thirty-eight studies (32.8%) achieved greater than 80% adherence to PRISMA. Methodological quality assessment against AMSTAR 2 revealed that 110 (94.8%) studies were of critically low quality. Only 21 studies (18.1%) were judged to have a low risk of bias against ROBIS. Conclusion: The reporting and methodological quality of meningioma evidence syntheses was poor. Established guidelines and critical appraisal tools may be used as an adjunct to aid methodological conduct and reporting of such reviews, in order to improve the validity and transparency of research which may influence clinical practice.

Published
2022

29. Superficial digital flexor tendon graft augmentation improves the tensile strength and resistance to gap formation following primary gastrocnemius tendon repair in dogs

Author

Julianna K, DiMichele, Daniel J, Duffy, Yi-Jen, Chang, and George E, Moore

Subjects
Tendons, Dogs, General Veterinary, Tendon Injuries, Tensile Strength, Suture Techniques, Cadaver, Animals, Humans, Dog Diseases, General Medicine, Biomechanical Phenomena
Abstract

OBJECTIVE To evaluate the influence of superficial digital flexor tendon (SDFT) graft augmentation on the biomechanical properties and resistance to gap formation in a canine gastrocnemius tendon repair model. SAMPLE POPULATION 28 canine cadaveric hind limbs. PROCEDURES Respective hindlimbs from each dog were randomized to one of two groups (n = 14/group) using a 3-loop–pulley (3LP) pattern alone or 3LP + SDFT graft augmentation. Biomechanical parameters evaluated included yield, peak, and failure loads; tensile loads required to create 1- and 3-mm gap formations; and mode of construct failure. RESULTS Mean yield and failure loads for the 3LP + SDFT graft group were 483.6 ± 148.0 N and 478.3 ± 147.9 N, respectively, and were greater compared to the 3LP group (34.2 ± 6.7 N and 34.0 ± 8.0 N, P < .0001). Loads to both 1- and 3-mm gap formations for the 3LP + SDFT graft group were greater compared to 3LP alone (P < .001). Failure modes did not differ between groups (P = .120), with constructs failing most commonly by suture pulling through opposed tendinous tissues whereas SDFT grafts remained intact. CLINICAL RELEVANCE SDFT graft augmentation increased yield, peak, and failure forces 14-fold across all examined biomechanical variables compared to the 3LP group. The 3LP + SDFT graft group required 3.6X and 6.5X greater loads to cause a 1- and 3-mm gap, respectively, between tendon ends. These data support the biomechanical advantages of SDFT graft augmentation to increase repair-site strength and to promote resistance to gap formation of the tenorrhaphy. Additional in vivo studies are required to determine the effect of SDFT augmentation on clinical function and active limb use after graft harvest in dogs.

Published
2022
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30. Loop diameter of a modified Kessler locking-loop suture affects in vitro tensile strength and gapping characteristics of canine flexor tendon repairs

Author

Yi-Jen, Chang, Daniel J, Duffy, and George E, Moore

Subjects
Dogs, General Veterinary, Tendon Injuries, Tensile Strength, Suture Techniques, Cadaver, Animals, General Medicine, Biomechanical Phenomena
Abstract

OBJECTIVE To evaluate effects of loop diameter of a modified Kessler locking-loop (LL) suture on in vitro tensile strength and gapping characteristics of canine flexor tendon repairs. SAMPLE 48 cadaveric superficial digital flexor tendons from 24 adult medium- to large-breed dogs. PROCEDURES Flexor tendons were randomly assigned to 4 groups (n = 12/group) and repaired with 2-0 polypropylene in a LL pattern with loops measuring 1, 2, 3, or 4 mm in diameter. Biomechanical loads, gap formation between tendon ends, and failure modes were evaluated and compared between groups. RESULTS Increasing loop diameter from 1 to 4 mm significantly increased yield (P = .048), peak (P < .001), and failure (P < .001) loads. There were no significant differences in yield, peak, and failure loads between 1- and 2-mm loops. Load to 3-mm gap formation was significantly (P < .001) greater for 4-mm loops, compared with 1-, 2-, and 3-mm loops. Failure mode did not differ significantly among experimental groups, with 46 of 48 (96%) of constructs failing because of suture breakage. CLINICAL RELEVANCE Loop diameter of a LL suture pattern is an important biomechanical variable that influences construct biomechanics of canine tendon suture repairs. Loop diameters > 3 mm are recommended when the size of the tendon allows. Further studies are necessary to determine the in vivo effect of these findings, particularly the effects on tendon blood supply.

Published
2022
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31. Investigation of the Effects of Two-, Four-, Six- and Eight-Strand Suture Repairs on the Biomechanical Properties of Canine Gastrocnemius Tenorrhaphy Constructs

Author

Yi-Jen Chang, George E. Moore, and Daniel J. Duffy

Subjects
Orthodontics, Polypropylene suture, Sutures, General Veterinary, business.industry, medicine.medical_treatment, Suture Techniques, Tenotomy, General Medicine, Repair site, Tendon, Tendons, Dogs, medicine.anatomical_structure, Suture (anatomy), Animals, Medicine, Blood supply, Gastrocnemius tendon, Cadaveric spasm, business
Abstract

OBJECTIVE To determine the effects of 2-, 4-, 6- and 8-strand suture repairs on the biomechanical properties of canine gastrocnemius tenorrhaphy constructs in an ex vivo model. SAMPLE 56 cadaveric gastrocnemius musculotendinous units from 28 adult large-breed dogs. PROCEDURES Tendons were randomly assigned to 4 repair groups (2-, 4-, 6- or 8-strand suture technique; n = 14/group). Following tenotomy, repairs were performed with the assigned number of strands of 2-0 polypropylene suture in a simple interrupted pattern. Biomechanical testing was performed. Yield, peak, and failure loads, the incidence of 1- and 3-mm gap formation, forces associated with gap formation, and failure modes were compared among groups. RESULTS Yield, peak, and failure forces differed significantly among groups, with significantly greater force required as the number of suture strands used for tendon repair increased. The force required to create a 1- or 3-mm gap between tendon ends also differed among groups and increased significantly with number of strands used. All constructs failed by mode of suture pull-through. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that increasing the number of suture strands crossing the repair site significantly increases the tensile strength of canine gastrocnemius tendon repair constructs and their resistance to gap formation. Future studies are needed to assess the effects of multistrand suture patterns on tendon glide function, blood supply, healing, and long-term clinical function in dogs to inform clinical decision-making.

Published
2022
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32. Inter-laboratory automation of the in vitro micronucleus assay using imaging flow cytometry and deep learning

Author

John W. Wills, Ruby Buckley, Catherine A. Thornton, Claire M. Barnes, Paul Rees, George E. Johnson, Julia Kenny, Rachel E. Hewitt, Danielle S.G. Harte, Anne E. Carpenter, James G. Cronin, Minh Doan, Huw D. Summers, Andrew Filby, Benjamin J. Rees, Rachel E. Barnes, Jatin R. Verma, Qiellor Haxhiraj, Matthew A. Rodrigues, Anthony M. Lynch, Wills, John W. [0000-0002-4347-5394], Apollo - University of Cambridge Repository, and Wills, John W [0000-0002-4347-5394]

Subjects
0301 basic medicine, Imaging flow cytometry, Computer science, Health, Toxicology and Mutagenesis, Genotoxicity and Carcinogenicity, Image analysis, Toxicology, Cell Line, 03 medical and health sciences, Deep Learning, 0302 clinical medicine, Micronucleus test, Machine learning, High throughput, Humans, Inter-laboratory, Safety testing, Cytokinesis, Automation, Laboratory, Micronucleus Tests, Dose-Response Relationship, Drug, Contextual image classification, business.industry, Deep learning, Pattern recognition, General Medicine, Flow Cytometry, Methyl Methanesulfonate, Automation, Compound screening, 030104 developmental biology, 030220 oncology & carcinogenesis, Benzimidazoles, Genetic toxicology, Carbamates, Artificial intelligence, business, Micronucleus, DNA Damage, Mutagens
Abstract

The in vitro micronucleus assay is a globally significant method for DNA damage quantification used for regulatory compound safety testing in addition to inter-individual monitoring of environmental, lifestyle and occupational factors. However, it relies on time-consuming and user-subjective manual scoring. Here we show that imaging flow cytometry and deep learning image classification represents a capable platform for automated, inter-laboratory operation. Images were captured for the cytokinesis-block micronucleus (CBMN) assay across three laboratories using methyl methanesulphonate (1.25–5.0 μg/mL) and/or carbendazim (0.8–1.6 μg/mL) exposures to TK6 cells. Human-scored image sets were assembled and used to train and test the classification abilities of the “DeepFlow” neural network in both intra- and inter-laboratory contexts. Harnessing image diversity across laboratories yielded a network able to score unseen data from an entirely new laboratory without any user configuration. Image classification accuracies of 98%, 95%, 82% and 85% were achieved for ‘mononucleates’, ‘binucleates’, ‘mononucleates with MN’ and ‘binucleates with MN’, respectively. Successful classifications of ‘trinucleates’ (90%) and ‘tetranucleates’ (88%) in addition to ‘other or unscorable’ phenotypes (96%) were also achieved. Attempts to classify extremely rare, tri- and tetranucleated cells with micronuclei into their own categories were less successful (≤ 57%). Benchmark dose analyses of human or automatically scored micronucleus frequency data yielded quantitation of the same equipotent concentration regardless of scoring method. We conclude that this automated approach offers significant potential to broaden the practical utility of the CBMN method across industry, research and clinical domains. We share our strategy using openly-accessible frameworks. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03113-0.

Published
2021
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33. Effect of epitendinous suture caliber on the tensile strength of repaired canine flexor tendons

Author

Yi-Jen Chang, George E. Moore, Aidan R Chambers, Matthew B. Fisher, and Daniel J. Duffy

Subjects
musculoskeletal diseases, Tendons, Dogs, Suture (anatomy), Tendon Injuries, Cadaver, Tensile Strength, Ultimate tensile strength, Animals, Medicine, Dog Diseases, Sutures, General Veterinary, Flexor tendon, business.industry, Suture Techniques, General Medicine, Anatomy, musculoskeletal system, Biomechanical Phenomena, body regions, surgical procedures, operative, Caliber, Cadaveric spasm, business
Abstract

OBJECTIVE To determine the effect of epitendinous suture (ES) caliber on the tensile strength of flexor tendon repairs in cadaveric specimens from dogs. SAMPLE 60 cadaveric superficial digital flexor tendons (SDFTs) from 30 skeletally mature dogs. PROCEDURES Specimens were randomly assigned to 5 suture caliber groups (n = 12 SDFTs/group). After sharp transection, SDFTs were repaired by placement of a simple continuous circumferential ES created with size-0, 2-0, 3-0, 4-0, or 5-0 polypropylene suture. Constructs were preloaded to 2 N and load tested to failure. Loads at yield, peak, and failure and mode of failure were compared among groups by statistical methods. RESULTS Yield, peak, and failure loads for SDFT repair constructs were positively correlated with ES caliber and did not differ between the size-0 and 2-0 groups on pairwise comparisons. Yield load was significantly greater for size-0, 2-0, and 3-0 groups than for the 4-0 and 5-0 groups. Peak and failure loads were significantly greater for the size-0 and 2-0 groups than for the remaining groups. Most size-0 (12/12), 2-0 (12/12), and 3-0 (10/12) group constructs failed because of ES pull-through; several constructs in the 4-0 group (5/12) and most in the 5-0 group (11/12) failed because of ES breakage. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested size-0 and 2-0 sutures should be considered when placing an ES for flexor tendon repairs in dogs. However, in vivo studies are needed determine the effects of increasing ES caliber on clinical outcomes for dogs undergoing these procedures.

Published
2021
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34. Efonidipine Exerts Cerebroprotective Effect by Down-regulation of TGF-β/SMAD-2-Dependent Signaling Pathway in Diabetic Rats

Author

Ghulam Md Ashraf, Vishal Chavda, George E. Barreto, Snehal S. Patel, and Rashmi Rajput

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.drug_class, Efonidipine, Calcium channel blocker, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Diabetes mellitus, Internal medicine, medicine, Stroke, Voltage-dependent calcium channel, business.industry, Calcium channel, General Medicine, Streptozotocin, medicine.disease, Malondialdehyde, 030104 developmental biology, Endocrinology, chemistry, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Calcium overload and hyperglycemia are risks of stroke onset in diabetics. Our study was designed to elucidate the beneficial role of calcium channel blockers by targeting voltage-gated calcium channels in diabetes-associated cerebrovascular complications. Diabetes was induced using the neonatal streptozotocin rat model. After confirmation of diabetes, middle cerebral artery occlusion (MCAO) was carried out. The pre-treatment with 1 mg/kg/day efonidipine was administered for the period of 4 weeks. After 24 h of ischemic induction surgery, the neurological score was determined, and blood was collected for determination of biochemical parameters. Treatment with efonidipine showed a significant reduction in post-ischemic brain infract volume, brain hemisphere weight difference, neurological score, Na+-K+ ATPase activity, serum CK-MB, and LDH levels in normoglycemic and hyperglycemic MCAO-induced animals. While no significant changes in glucose and lipid levels were observed by treatment, efonidipine significantly decreased the levels of malondialdehyde, acetylcholine esterase, and nitrite levels and increased the levels of antioxidant markers in both normoglycemic and hyperglycemic MCAO animals. TGF-β and VEGF were found to be down-regulated after treatment with efonidipine in gene expression study. In conclusion, the study data supports the cerebroprotective role of efonidipine in diabetic animals possibly through TGF-β/SMAD-2 signaling pathway.

Published
2021
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35. Current Status of Training and Certification for Congenital Heart Surgery Around the World: Proceedings of the Meetings of the Global Council on Education for Congenital Heart Surgery of the World Society for Pediatric and Congenital Heart Surgery

Author

Morten Helvind, Bohdan Maruszewski, Emile A. Bacha, Kisaburo Sakamoto, Christo I. Tchervenkov, Susan Vosloo, Cheul Lee, James S. Tweddell, Christian Kreutzer, Attilio A. Lotto, Hani K. Najm, Giovanni Stellin, Nguyen Ly Thinh Truong, Piya Samankatiwat, Jeffrey P. Jacobs, Joseph A. Dearani, Drissi Boumzebra, Miguel Arboleda, Krishna S Iyer, Pedro Becker, Tae-Gook Jun, James D St Louis, Valdano Manuel, Claudia Herbst, Bistra Zheleva, George E. Sarris, Richard A. Jonas, Frank Edwin, Kirsten Finucane, Sivakumar Sivalingam, Hafil B Abdulgani, Hao Zhang, David M. Overman, Marcelo B. Jatene, Vladimiro L. Vida, David J. Barron, Zohair Al-Halees, José Fragata, Adel Elgamal, Budi Rahmat, Elizabeth H. Stephens, Jorge Cervantes, Nestor Sandoval, Darshan Reddy, James K. Kirklin, and Justin T. Tretter

Subjects
Heart Defects, Congenital, Nonprofit organization, medicine.medical_specialty, Certification, Heart disease, education, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Cardiac Surgical Procedures, Quality of care, Child, Societies, Medical, business.industry, Thoracic Surgery, General Medicine, medicine.disease, Surgery, Cardiac surgery, 030228 respiratory system, Cardiothoracic surgery, Pediatrics, Perinatology and Child Health, Cardiology and Cardiovascular Medicine, business
Abstract

The optimal training of the highly specialized congenital heart surgeon is a long and complex process, which is a significant challenge in most parts of the world. The World Society for Pediatric and Congenital Heart Surgery (WSPCHS) has established the Global Council on Education for Congenital Heart Surgery as a nonprofit organization with the goal of assessing current training and certification and ultimately establishing standardized criteria for the training, evaluation, and certification of congenital heart surgeons around the world. The Global Council and the WSPCHS have reviewed the present status of training and certification for congenital cardiac surgery around the world. There is currently lack of consensus and standardized criteria for training in congenital heart surgery, with significant disparity between continents and countries. This represents significant obstacles to international job mobility of competent congenital heart surgeons and to the efforts to improve the quality of care for patients with Congenital Heart Disease worldwide. The purpose of this article is to summarize and document the present state of training and certification in congenital heart surgery around the world.

Published
2021
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36. Development and validation of a flow cytometric assay for detecting reactive oxygen species in the erythrocytes of healthy dogs

Author

George E. Moore, Andrea Pires dos Santos, John A. Christian, Andrew D Woolcock, and Priscila Beatriz da Silva Serpa

Subjects
chemistry.chemical_classification, Reactive oxygen species, Erythrocytes, Chromatography, General Veterinary, Hydrogen Peroxide, General Medicine, Flow Cytometry, Fluoresceins, chemistry.chemical_compound, Dogs, chemistry, Animals, Fluorescein, Reactive Oxygen Species, Hydrogen peroxide
Abstract

OBJECTIVE To validate the use of a flow cytometric assay that uses 2‘,7‘-dichlorodihydrofluorescein diacetate (DCFH-DA) to measure reactive oxygen species in the erythrocytes of healthy dogs. ANIMALS 50 healthy adult dogs. PROCEDURES Erythrocytes were incubated with DCFH-DA or a vehicle control (dimethyl sulfoxide), then incubated with (stimulated) or without (unstimulated) hydrogen peroxide. The flow cytometric assay was evaluated for specificity with increasing concentrations of DCFH-DA and hydrogen peroxide, and a polynomial regression line was applied to determine optimal concentrations. For precision, samples were analyzed 5 consecutive times for determination of intra- and interassay variability. Stability of samples stored at 4°C for up to 48 hours after blood collection was determined with flow cytometric analysis. Coefficient of variation (CV) was considered acceptable at 20%. Baseline measurements were used to determine an expected range of median fluorescence intensity for unstimulated erythrocytes incubated with DCFH-DA. RESULTS Erythrocytes were successfully isolated, and stimulated samples demonstrated higher median fluorescence intensity, compared with unstimulated samples. The intra-assay CV was 11.9% and 8.9% and interassay CV was 11.9% and 9.1% for unstimulated and stimulated samples, respectively. Unstimulated samples were stable for up to 24 hours, whereas stimulated samples were stable for up to 48 hours. CONCLUSIONS AND CLINICAL RELEVANCE Flow cytometry for the measurement of reactive oxygen species in the erythrocytes of healthy dogs by use of DCFH-DA had acceptable specificity, precision, and stability. Flow cytometry is a promising technique for evaluating intraerythrocytic oxidative stress for healthy dogs.

Published
2021
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37. Curcumin: A small molecule with big functionality against amyloid aggregation in neurodegenerative diseases and type 2 diabetes

Author

Shabnam Radbakhsh, Amirhossein Sahebkar, Abigail R. Bland, and George E. Barreto

Subjects
0301 basic medicine, Curcumin, Clinical Biochemistry, tau Proteins, Type 2 diabetes, Pharmacology, Protein aggregation, Biochemistry, Creutzfeldt-Jakob Syndrome, Protein Aggregates, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Alzheimer Disease, medicine, Humans, Hypoglycemic Agents, Clinical Trials as Topic, Amyloid beta-Peptides, Chemistry, Amyloidosis, Type 2 Diabetes Mellitus, Parkinson Disease, General Medicine, medicine.disease, Small molecule, In vitro, Mitochondria, Oxidative Stress, Huntington Disease, Neuroprotective Agents, 030104 developmental biology, Diabetes Mellitus, Type 2, 030220 oncology & carcinogenesis, Amyloid aggregation, alpha-Synuclein, Molecular Medicine
Abstract

Amyloidosis is a concept that implicates disorders and complications that are due to abnormal protein accumulation in different cells and tissues. Protein aggregation-associated diseases are classified according to the type of aggregates and deposition sites, such as neurodegenerative disorders and type 2 diabetes mellitus. Polyphenolic phytochemicals such as curcumin and its derivatives have anti-amyloid effects both in vitro and in animal models; however, the underlying mechanisms are not understood. In this review, we summarized possible mechanisms by which curcumin could interfere with self-assembly processes and reduce amyloid aggregation in amyloidosis. Furthermore, we discuss clinical trials in which curcumin is used as a therapeutic agent for the treatment of diseases linking to protein aggregates.

Published
2021
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38. Evaluation of a continuous locking novel epitendinous suture pattern with and without a core locking-loop suture on the biomechanical properties of tenorrhaphy constructs in an ex vivo model of canine superficial digital flexor tendon laceration

Author

Matthew B. Fisher, Daniel J. Duffy, Yi-Jen Chang, George E. Moore, and Lewis Gaffney

Subjects
Core (anatomy), Materials science, Sutures, General Veterinary, Flexor tendon, Suture Techniques, General Medicine, Lacerations, Biomechanical Phenomena, Tendons, Loop (topology), Dogs, Suture (anatomy), Tendon Injuries, Tensile Strength, Cadaver, Animals, Dog Diseases, Ex vivo, Biomedical engineering
Abstract

OBJECTIVE To evaluate the effect of a continuous locking novel epitendinous suture (nES) pattern with and without a core locking-loop (LL) suture on the biomechanical properties of ex vivo canine superficial digital flexor tendon (SDFT) tenorrhaphy constructs. SAMPLE 54 cadaveric forelimb SDFTs from 27 musculoskeletally normal adult dogs. PROCEDURES Tendons were assigned to 3 groups (18 SDFTs/group): sharply transected and repaired with a core LL suture alone (group 1), an nES pattern alone (group 2), or a combination of a core LL suture and nES pattern (group 3). All constructs underwent a single load-to-failure test. Yield, peak, and failure loads; gap formation incidence; and mode of failure were compared among the 3 groups. RESULTS Mean yield, peak, and failure loads differed significantly among the 3 groups and were greatest for group 3 and lowest for group 1. Mean yield, peak, and failure loads for group 3 constructs were greater than those for group 1 constructs by 50%, 47%, and 44%, respectively. None of the group 3 constructs developed 3-mm gaps. The most common mode of failure was suture pulling through the tendon for groups 1 (12/18) and 2 (12/18) and suture breakage for group 3 (13/18). CONCLUSIONS AND CLINICAL RELEVANCE Results suggested augmentation of a core LL suture with an nES pattern significantly increased the strength of and prevented 3-mm gap formation at the tenorrhaphy site in ex vivo canine SDFTs. In vivo studies are necessary to assess the effectiveness and practicality of the nES pattern for SDFT repair in dogs.

Published
2021
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39. Navigated transcranial magnetic stimulation mapping in patients with language-eloquent brain lesions

Author

George E. D. Petrescu, Roxana Radu, Andrei Giovani, Cristina Gorgan, Felix M. Brehar, and Radu M. Gorgan

Subjects
brain tumours, language areas cortical mapping, navigated transcranial magnetic stimulation, General Medicine, lcsh:Neurology. Diseases of the nervous system, lcsh:RC346-429
Abstract

Introduction: The surgical resection of brain lesions located in language-eloquent areas harbours a great risk for determining new functional deficits. Navigated transcranial magnetic stimulation represents a novel non-invasive cortical mapping method that can be used preoperative to determine language-eloquent areas. Materials and methods: We retrospectively reviewed a prospectively maintained database of patients that underwent preoperative cortical mapping using nTMS between March 2017 and June 2020. Patients older than 18 years old with brain lesions situated in a presumed language eloquent area, that underwent surgical resection of the brain lesion were included in the study. Various parameters such as error rate, number of language-negative sites were assessed. Results: Fourteen patients were included in the study. There were 10 males and 4 females in total. Most of the tumours were in the temporal and frontal lobes (five and four cases, respectively). The histopathological diagnosis was glioblastoma in seven cases, in one case there was an anaplastic astrocytoma and there were two cases of low-grade gliomas. There were three cases of brain metastasis and one cavernoma. The median (range) tumor volume was 25.01 cm3 (0.89 – 86.55 cm3). Gross-total resection (GTR) was achieved in seven cases. The error rate was significantly higher in patients that continued to have an impaired language function after surgical resection (p = 0.016), while the perilesional error rate was higher in patients with preoperative aphasia (p = 0.019). Conclusion: Our findings suggest that a lower tumour volume to perilesional negative stimuli ratio is associated with an extended surgical resection of brain tumours located in language-eloquent areas and that patients that presented with aphasia and have a high error rate have a worse functional prognosis. Through nTMS preoperative cortical mapping of language-eloquent areas, the neurosurgeon has more insight regarding the cortical function and can maximize the surgical resection, while avoiding the onset of new functional deficits.

Published
2021
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40. Apolipoprotein E genotype-dependent nutrigenetic effects to prebiotic inulin for modulating systemic metabolism and neuroprotection in mice via gut-brain axis

Author

Lucille M. Yanckello, Stefan J. Green, George E. Chlipala, Penghui Lin, Anika M.S. Hartz, Andrew T. Yackzan, Scott McCulloch, Ya-Hsuan Chang, Andrew N. Lane, Tyler C. Hammond, Ai-Ling Lin, Geetika Nehra, and Jared D. Hoffman

Subjects
0301 basic medicine, Apolipoprotein E, Genotype, medicine.medical_treatment, Apolipoprotein E4, Gut–brain axis, Inulin, Medicine (miscellaneous), Pharmacology, Biology, Blood–brain barrier, Neuroprotection, Nutrigenetics, Mice, 03 medical and health sciences, chemistry.chemical_compound, Apolipoproteins E, Nutrigenomics, 0302 clinical medicine, Brain-Gut Axis, medicine, Animals, Humans, 030109 nutrition & dietetics, Nutrition and Dietetics, General Neuroscience, Prebiotic, General Medicine, Metabolism, Disease Models, Animal, Prebiotics, medicine.anatomical_structure, chemistry, lipids (amino acids, peptides, and proteins), 030217 neurology & neurosurgery
Abstract

The goal of the study was to identify the potential nutrigenetic effects to inulin, a prebiotic fiber, in mice with different human apolipoprotein E (APOE) genetic variants. Specifically, we compared responses to inulin for the potential modulation of the systemic metabolism and neuroprotection via gut-brain axis in mice with humanWe performed experiments with young mice expressing the humanIn bothWe found that inulin had many similar beneficial effects in the gut and brain for both

Published
2021
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41. 33 Diagnostic Test Accuracy of the 4AT for Delirium Detection: Systematic Review and Meta-Analysis

Author

Damien Ryan, George E. Taffet, Susan D. Shenkin, Alasdair M.J. MacLullich, Zoë Tieges, Atul Anand, Terry J Quinn, Thomas Saller, Yue Chang, Margaret O'Connor, M Cassaroni, Rakesh C. Arora, Rose Galvin, and Kathryn Agarwal

Subjects
Aging, medicine.medical_specialty, Evidence-based practice, business.industry, MEDLINE, Diagnostic test, General Medicine, Meta-analysis, Ischemic stroke, medicine, Delirium, Geriatrics and Gerontology, medicine.symptom, business, Intensive care medicine, Reference standards
Abstract

Introduction Detection of delirium in hospitalised older adults is recommended in national and international guidelines. The 4 ‘A’s Test (4AT; www.the4AT.com) is a short ( Methods We searched the following electronic databases through Ovid: MEDLINE, Embase, and PsycINFO. Additional databases were searched: CINAHL (EBSCOhost), clinicaltrials.gov and Cochrane Central Register of Controlled Trials from 2011 (4AT publication) until 21 December 2019. Inclusion criteria: older adults (≥65) across any setting of care except critical care; validation study of the 4AT against a delirium reference standard (standard diagnostic criteria or validated tool). Two reviewers independently screened abstracts and papers and performed the data extraction. Pooled estimates of sensitivity and specificity were generated from a bivariate random effects model. Results 17 studies (n = 3,701 observations) were included. Various settings including acute medicine, surgery, stroke wards and the emergency department were represented. The overall prevalence of delirium was 24.2% (95% CI 17.8–32.1%; range 10.5–61.9%). The pooled sensitivity was 0.88 (95% CI 0.80–0.93) and the pooled specificity was 0.88 (95% CI 0.82–0.92). The methodological quality of studies was mostly good. Conclusions The 4AT is now supported by a substantial evidence base comparable to other well-studied tools such as the Confusion Assessment Method (CAM). The strong pooled sensitivity and specificity findings for the 4AT in this meta-analysis along with its brevity and lack of need for specific training provide support for its use as an effective assessment tool for delirium.

Published
2021
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42. Differentially CTCF-Binding Sites in Cattle Rumen Tissue during Weaning

Author

Clarissa Boschiero, Yahui Gao, Ransom L. Baldwin, Li Ma, Cong-jun Li, and George E. Liu

Subjects
Binding Sites, Genome, Rumen, Organic Chemistry, General Medicine, Weaning, Animal Feed, Catalysis, Computer Science Applications, Diet, Inorganic Chemistry, Transforming Growth Factor beta, Animals, Cattle, Physical and Theoretical Chemistry, cattle, ChIP-seq, CTCF, epithelial tissue, regulatory elements, rumen development, weaning, Molecular Biology, Spectroscopy
Abstract

The weaning transition in calves is characterized by major structural changes such as an increase in the rumen capacity and surface area due to diet changes. Studies evaluating rumen development in calves are vital to identify genetic mechanisms affected by weaning. This study aimed to provide a genome-wide characterization of CTCF-binding sites and differentially CTCF-binding sites (DCBS) in rumen tissue during the weaning transition of four Holstein calves to uncover regulatory elements in rumen epithelial tissue using ChIP-seq. Our study generated 67,280 CTCF peaks for the before weaning (BW) and 39,891 for after weaning (AW). Then, 7401 DCBS were identified for the AW vs. BW comparison representing 0.15% of the cattle genome, comprising ~54% of induced DCBS and ~46% of repressed DCBS. Most of the induced and repressed DCBS were in distal intergenic regions, showing a potential role as insulators. Gene ontology enrichment revealed many shared GO terms for the induced and the repressed DCBS, mainly related to cellular migration, proliferation, growth, differentiation, cellular adhesion, digestive tract morphogenesis, and response to TGFβ. In addition, shared KEGG pathways were obtained for adherens junction and focal adhesion. Interestingly, other relevant KEGG pathways were observed for the induced DCBS like gastric acid secretion, salivary secretion, bacterial invasion of epithelial cells, apelin signaling, and mucin-type O-glycan biosynthesis. IPA analysis further revealed pathways with potential roles in rumen development during weaning, including TGFβ, Integrin-linked kinase, and Integrin signaling. When DCBS were further integrated with RNA-seq data, 36 putative target genes were identified for the repressed DCBS, including KRT84, COL9A2, MATN3, TSPAN1, and AJM1. This study successfully identified DCBS in cattle rumen tissue after weaning on a genome-wide scale and revealed several candidate target genes that may have a role in rumen development, such as TGFβ, integrins, keratins, and SMADs. The information generated in this preliminary study provides new insights into bovine genome regulation and chromatin landscape.

Published
2022
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43. Effect of epitendinous suture augmentation to a double Krackow suture pattern for canine gastrocnemius tendon repair

Author

Amy C. Downey, Daniel J. Duffy, Yi-Jen Chang, Matthew B. Fisher, and George E. Moore

Subjects
Tendons, Dogs, General Veterinary, Sutures, Tendon Injuries, Tensile Strength, Suture Techniques, Cadaver, Animals, General Medicine, Dog Diseases, Biomechanical Phenomena
Abstract

OBJECTIVE To evaluate the effect of a double Krackow suture pattern (DK), with and without epitendinous suture augmentation (ES), in a canine gastrocnemius tendon (GT) model. SAMPLE Paired GTs from 12 adult dog cadavers and 4 control GT. PROCEDURES GTs were assigned to 2 groups (n = 12/group). Transverse tenotomy was performed and repaired with a DK or DK + ES. Yield, peak, and failure force, stiffness, occurrence of 1-and 3-mm gapping, and failure mode were examined. RESULTS Yield, peak, and failure loads were greater for DK + ES. Yield force was 48% greater for DK + ES (mean ± SD, 149.56 ± 53.26 N) versus DK (101.27 ± 37.17 N; P = 0.017). Peak force was 45% greater for DK + ES P < 0.001). Failure force was 47% greater for DK + ES (193.752 ± 31.43 N) versus DK (131.54 ± 22.28 N; P < 0.001). Construct stiffness was 36% greater for DK + ES (P = 0.04). All 12 DK and 10 of 12 DK + ES repairs produced a 1-mm gap, with all DK and 4 DK + ES repairs producing a 3-mm gap (P < 0.001). Loads required to create a 3-mm gap were significantly greater for DK + ES (P < 0.013). Suture breakage occurred in all DK repairs, which differed from DK + ES, where suture breakage (7/12) and tissue failure (5/12; P = 0.037) predominated. CLINICAL RELEVANCE Augmentation of a primary DK repair with an ES significantly improved construct strength in canine GT constructs while increasing loads required to cause 1- and 3-mm gap formation, respectively. ES augmentation is a simple technique modification that can be used to significantly increase construct strength, compared with DK alone.

Published
2022

44. A tale of two plasmids: contributions of plasmid associated phenotypes to epidemiological success among Shigella

Author

P. Malaka De Silva, George E. Stenhouse, Grace A. Blackwell, Rebecca J. Bengtsson, Claire Jenkins, James P.J. Hall, and Kate S. Baker

Subjects
Phenotype, Gene Transfer, Horizontal, General Immunology and Microbiology, Drug Resistance, Bacterial, Shigella, General Medicine, General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology, Anti-Bacterial Agents, Plasmids, General Environmental Science
Abstract

Dissemination of antimicrobial resistance (AMR) genes by horizontal gene transfer (HGT) mediated through plasmids is a major global concern. Genomic epidemiology studies have shown varying success of different AMR plasmids during outbreaks, but the underlying reasons for these differences are unclear. Here, we investigated two Shigella plasmids (pKSR100 and pAPR100) that circulated in the same transmission network but had starkly contrasting epidemiological outcomes to identify plasmid features that may have contributed to the differences. We used plasmid comparative genomics to reveal divergence between the two plasmids in genes encoding AMR, SOS response alleviation and conjugation. Experimental analyses revealed that these genomic differences corresponded with reduced conjugation efficiencies for the epidemiologically successful pKSR100, but more extensive AMR, reduced fitness costs, and a reduced SOS response in the presence of antimicrobials, compared with the less successful pAPR100. The discrepant phenotypes between the two plasmids are consistent with the hypothesis that plasmid-associated phenotypes contribute to determining the epidemiological outcome of AMR HGT and suggest that phenotypes relevant in responding to antimicrobial pressure and fitness impact may be more important than those around conjugation in this setting. Plasmid phenotypes could thus be valuable tools in conjunction with genomic epidemiology for predicting AMR dissemination.

Published
2022
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45. Loop modification of the traditional three-loop pulley pattern improves the biomechanical properties and resistance to 3-mm gap formation in a canine common calcanean teno-osseous avulsion model

Author

Daniel J. Duffy, Weston L. Beamon, Yi-Jen Chang, and George E. Moore

Subjects
Tendons, Dogs, Sutures, General Veterinary, Tendon Injuries, Tensile Strength, Suture Techniques, Cadaver, Animals, Dog Diseases, General Medicine, Biomechanical Phenomena
Abstract

OBJECTIVE To compare the biomechanical properties and gapping characteristics following loop modification of a 3-loop-pulley (3LP) pattern in an ex vivo canine common calcaneal tendon (CCT) avulsion repair model. SAMPLE 56 skeletally mature hindlimbs from 28 canine cadavers. PROCEDURES The CCTs were randomized to 1 of 4 experimental groups (n = 14/group) then sharply transected at the teno-osseous junction. Groups consisted of a 3LP, 4-loop-pulley (4LP), 5-loop-pulley (5LP), or 6-loop-pulley (6LP) pattern with loops placed 60° apart using size-0 polypropylene. Yield, peak, and failure loads, construct stiffness, loads to produce a 3-mm teno-osseous gap, and failure mode were evaluated and compared between groups. RESULTS Yield (P = 0.001), peak (P < 0.001), and failure loads (P < 0.001), construct stiffness (P < 0.001), and loads to 3-mm gap formation (P = 0.005) were all significantly greater for 6LP compared to all other groups. Mode of failure did not differ among groups (P = 0.733) with 75% (42/56) of repairs failing by mechanism of core sutures pulling through the tendinous tissue. Pattern modification by increasing the number of loops increased the repair site strength by 1.4, 1.6, and 1.8 times for 4LP, 5LP, and 6LP compared to 3LP, respectively. CLINICAL RELEVANCE Increasing the number of suture loops compared to a traditional 3LP repair is a relatively simple technique modification that significantly increases teno-osseous repair site strength and loads required to cause 3-mm gap formation. The results of this study justify further focused investigation of increasing the number of suture loops in vivo for teno-osseous CCT repair in dogs.

Published
2022
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46. Tibolone Pre-Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid-Induced Lipotoxicity in Human Astrocytes: A Label-Free MS-Based Proteomics and Network Analysis

Author

Diego Julián Vesga-Jiménez, Cynthia A. Martín-Jiménez, Adriana Grismaldo Rodríguez, Andrés Felipe Aristizábal-Pachón, Andrés Pinzón, George E. Barreto, David Ramírez, and Janneth González

Subjects
Proteomics, Norpregnenes, 31 Biological sciences, Organic Chemistry, Fatty Acids, Palmitic Acid, mass spectrometry, human astrocytes, tibolone, palmitic acid, obesity, neuroprotection, proteomics, network analysis, General Medicine, Catalysis, Computer Science Applications, Inorganic Chemistry, Biological sciences, Astrocytes, Protein Biosynthesis, FOS: Biological sciences, Humans, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract

Excessive accumulation and release of fatty acids (FAs) in adipose and non-adipose tissue are characteristic of obesity and are associated with the leading causes of death worldwide. Chronic exposure to high concentrations of FAs such as palmitic acid (pal) is a risk factor for developing different neurodegenerative diseases (NDs) through several mechanisms. In the brain, astrocytic dysregulation plays an essential role in detrimental processes like metabolic inflammatory state, oxidative stress, endoplasmic reticulum stress, and autophagy impairment. Evidence shows that tibolone, a synthetic steroid, induces neuroprotective effects, but its molecular mechanisms upon exposure to pal remain largely unknown. Due to the capacity of identifying changes in the whole data-set of proteins and their interaction allowing a deeper understanding, we used a proteomic approach on normal human astrocytes under supraphysiological levels of pal as a model to induce cytotoxicity, finding changes of expression in proteins related to translation, transport, autophagy, and apoptosis. Additionally, tibolone pre-treatment showed protective effects by restoring those same pal-altered processes and increasing the expression of proteins from cell survival processes. Interestingly, ARF3 and IPO7 were identified as relevant proteins, presenting a high weight in the protein-protein interaction network and significant differences in expression levels. These proteins are related to transport and translation processes, and their expression was restored by tibolone. This work suggests that the damage caused by pal in astrocytes simultaneously involves different mechanisms that the tibolone can partially revert, making tibolone interesting for further research to understand how to modulate these damages.

Published
2022
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47. Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19

Author

Julian M. Hopkin, Richard Quinton, Sreedhar Subramanian, Rose Anne Kenny, George E. Griffin, Martin Hewison, Jonathan M. Rhodes, and David R Thickett

Subjects
Fibroblast growth factor 23, Physiology, Rickets, 030204 cardiovascular system & hematology, vitamin D deficiency, 03 medical and health sciences, 0302 clinical medicine, medicine, Vitamin D and neurology, Humans, 030212 general & internal medicine, Dosing, Vitamin D, Pandemics, Respiratory Tract Infections, Respiratory tract infections, SARS-CoV-2, business.industry, COVID-19 rapid report, COVID-19, Respiratory infection, General Medicine, Vitamin D Deficiency, medicine.disease, Dietary Supplements, Bolus (digestion), business
Abstract

The value of vitamin D supplementation in the treatment or prevention of various conditions is often viewed with scepticism as a result of contradictory results of randomised trials. It is now becoming apparent that there is a pattern to these inconsistencies. A recent large trial has shown that high-dose intermittent bolus vitamin D therapy is ineffective at preventing rickets – the condition that is most unequivocally caused by vitamin D deficiency. There is a plausible biological explanation since high-dose bolus replacement induces long-term expression of the catabolic enzyme 24-hydroxylase and fibroblast growth factor 23, both of which have vitamin D inactivating effects. Meta-analyses of vitamin D supplementation in prevention of acute respiratory infection and trials in tuberculosis and other conditions also support efficacy of low dose daily maintenance rather than intermittent bolus dosing. This is particularly relevant during the current COVID-19 pandemic given the well-documented associations between COVID-19 risk and vitamin D deficiency. We would urge that clinicians take note of these findings and give strong support to widespread use of daily vitamin D supplementation.

Published
2021
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48. Commercial amniotic membrane extract for treatment of corneal ulcers in adult horses

Author

George E. Moore, Victoria N. Lyons, Wendy M. Townsend, and Siqi Liang

Subjects
medicine.medical_specialty, genetic structures, 040301 veterinary sciences, medicine.drug_class, Antibiotics, Corneal ulceration, Cornea, 0403 veterinary science, chemistry.chemical_compound, Healing rate, Ophthalmology, Mixed linear model, Animals, Medicine, Amnion, Horses, Fluorescein, Corneal Ulcer, Wound Healing, Plant Extracts, business.industry, Significant difference, 0402 animal and dairy science, Horse, 04 agricultural and veterinary sciences, General Medicine, 040201 dairy & animal science, eye diseases, medicine.anatomical_structure, chemistry, Horse Diseases, sense organs, business
Abstract

Background Amniotic membrane extract enhances the rate of epithelialisation after corneal ulceration in several species but has not been studied in the equine cornea. Objectives To evaluate the effect of amniotic membrane extract on re-epithelialisation of equine corneal ulcers compared to ulcers treated with antibiotic, antifungal, and mydriatic medical therapy alone; to evaluate equine corneal healing after experimentally induced superficial ulceration. Study design Masked, randomised, controlled experimental trial. Methods Superficial, 8 mm corneal ulcers were created bilaterally in each horse. One eye was treated with amniotic membrane extract; the opposite was control. Both eyes were treated with medical therapy. Treatment eyes received amniotic membrane extract, and control eyes received the amniotic membrane extract vehicle. Ulcers were stained with fluorescein and photographed in 12-hour increments until completely healed. Ulcer surface area was determined by analysing photographs with ImageJ. A mixed linear model was used to compare ulcer surface area and hours until healing between treatment groups. A regression model was also used to calculate corneal re-epithelialisation rate over time. Results Regardless of therapy, healing occurred in two phases: an initial rapid phase of 0.88 mm2 /hr (95% CI: 0.81 - 0.94 mm2 /hr) for approximately 48-54 hours followed by a second, slow phase of 0.07 mm2 /hr (95% CI: 0.04 - 0.09 mm2 /hr). Most eyes healed within 135.5 ± 48.5 hours. Treatment (amniotic membrane extract vs. control) was not significantly associated with size of ulcers over time (P=0.984). Discomfort was minimal to absent in all horses. Main limitations Results achieved experimental studies may differ from outcomes in the clinical setting. Conclusions There was no significant difference in healing rate with addition of amniotic membrane extract to medical therapy for equine superficial corneal ulcers. A biphasic corneal healing process was observed, with an initial rapid phase followed by a slow phase. Further study will be needed to determine if amniotic membrane extract will be helpful for infected or malacic equine corneal ulcers.

Published
2021
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49. Racial disparities in analgesic use amongst patients presenting to the emergency department for kidney stones in the United States

Author

Courtney Rowe, Benjamin I. Chung, Alexandra Berger, George E. Haleblian, Steven L. Chang, and Ye Wang

Subjects
medicine.medical_specialty, business.industry, Analgesic, Chronic pain, 030208 emergency & critical care medicine, General Medicine, Emergency department, medicine.disease, Ketorolac, 03 medical and health sciences, 0302 clinical medicine, Opioid, Internal medicine, Cohort, Emergency Medicine, medicine, Kidney stones, Renal colic, medicine.symptom, business, medicine.drug
Abstract

Introduction We sought quantify racial disparities in use of analgesia amongst patients seen in Emergency Departments for renal colic. Methods We identified all individuals presenting to the Emergency Department with urolithiasis from 2003 to 2015 in the nationally representative Premier Hospital Database. We included patients discharged in ≤1 day and excluded those with chronic pain or renal insufficiency. We assessed the relationship between race/ethnicity and opioid dosage in morphine milligram equivalents (MME), and ketorolac, through multivariable regression models adjusting for patient and hospital characteristics. Results The cohort was 266,210 patients, comprised of White (84%), Black (6%) and Hispanic (10%) individuals. Median opioid dosage was 20 MME and 55.5% received ketorolac. Our adjusted model showed Whites had highest median MME (20 mg) with Blacks (−3.3 mg [95% CI: −4.6 mg to −2.1 mg]) and Hispanics (−6.0 mg [95% CI: −6.9 mg to −5.1 mg]) receiving less. Blacks were less likely to receive ketorolac (OR: 0.72, 95% CI: 0.62–0.84) while there was no difference between Whites and Hispanics. Conclusions Black and Hispanic patients in American Emergency Departments with acute renal colic receive less opioid medication than White patients; Black patients are also less likely to receive ketorolac.

Published
2021
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50. AE37: a HER2-targeted vaccine for the prevention of breast cancer recurrence

Author

Patrick M. McCarthy, Timothy J. Vreeland, Anne E O'Shea, G. Travis Clifton, Alexandra M Adams, and George E. Peoples

Subjects
Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Receptor, ErbB-2, medicine.medical_treatment, Breast Neoplasms, Cancer Vaccines, 03 medical and health sciences, 0302 clinical medicine, Immune system, Breast cancer, Immunity, Internal medicine, medicine, Overall survival, Humans, Pharmacology (medical), skin and connective tissue diseases, Pharmacology, Breast cancer recurrence, business.industry, Growth factor, Prostatic Neoplasms, Cancer, General Medicine, medicine.disease, Invariant chain, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Immunotherapy, Neoplasm Recurrence, Local, business
Abstract

HER2 is a prevalent growth factor in a variety of malignancies, most prominently breast cancer. Over-expression has been correlated with the poorest overall survival and has been the target of successful therapies such as trastuzumab. AE37 is a novel, HER2-directed vaccine based on the AE36 hybrid peptide (aa776-790), which is derived from the intracellular portion of the HER2 protein, and the core portion of the MHC Class II invariant chain (the Ii-Key peptide). This hybrid peptide is given with GM-CSF immunoadjuvant as the AE37 vaccine.This article describes in detail the preclinical science leading to the creation of the AE37 vaccine and examines use of this agent in multiple clinical trials for breast and prostate cancer. The safety profile of AE37 is discussed and opinions on the potential of the vaccine in breast and prostate cancer patient subsets along with other malignancies, are offered.Future trials utilizing the AE37 vaccine to treat other HER2-expressing malignancies are likely to see similar success, and this will be enhanced by combination immunotherapy. Ii-Key modification of other peptides of interest across oncology and virology could yield impressive results over the longer term.

Published
2020
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