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1. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

Author

Kathryn Westendorf, Stefanie Žentelis, Lingshu Wang, Denisa Foster, Peter Vaillancourt, Matthew Wiggin, Erica Lovett, Robin van der Lee, Jörg Hendle, Anna Pustilnik, J. Michael Sauder, Lucas Kraft, Yuri Hwang, Robert W. Siegel, Jinbiao Chen, Beverly A. Heinz, Richard E. Higgs, Nicole L. Kallewaard, Kevin Jepson, Rodrigo Goya, Maia A. Smith, David W. Collins, Davide Pellacani, Ping Xiang, Valentine de Puyraimond, Marketa Ricicova, Lindsay Devorkin, Caitlin Pritchard, Aoise O’Neill, Kush Dalal, Pankaj Panwar, Harveer Dhupar, Fabian A. Garces, Courtney A. Cohen, John M. Dye, Kathleen E. Huie, Catherine V. Badger, Darwyn Kobasa, Jonathan Audet, Joshua J. Freitas, Saleema Hassanali, Ina Hughes, Luis Munoz, Holly C. Palma, Bharathi Ramamurthy, Robert W. Cross, Thomas W. Geisbert, Vineet Menachery, Kumari Lokugamage, Viktoriya Borisevich, Iliana Lanz, Lisa Anderson, Payal Sipahimalani, Kizzmekia S. Corbett, Eun Sung Yang, Yi Zhang, Wei Shi, Tongqing Zhou, Misook Choe, John Misasi, Peter D. Kwong, Nancy J. Sullivan, Barney S. Graham, Tara L. Fernandez, Carl L. Hansen, Ester Falconer, John R. Mascola, Bryan E. Jones, and Bryan C. Barnhart

Subjects
CP: Microbiology, Biology (General), QH301-705.5
Abstract

Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants of concern (VOCs) have negatively affected therapeutic use of some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody. LY-CoV1404 potently neutralizes authentic SARS-CoV-2, B.1.1.7, B.1.351, and B.1.617.2. In pseudovirus neutralization studies, LY-CoV1404 potently neutralizes variants, including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved, except for N439 and N501. The binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The broad and potent neutralization activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants.

Published
2022
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2. Breath-synchronized electrical stimulation of the expiratory muscles in mechanically ventilated patients: a randomized controlled feasibility study and pooled analysis

Author

Annemijn H. Jonkman, Tim Frenzel, Euan J. McCaughey, Angus J. McLachlan, Claire L. Boswell-Ruys, David W. Collins, Simon C. Gandevia, Armand R. J. Girbes, Oscar Hoiting, Matthijs Kox, Eline Oppersma, Marco Peters, Peter Pickkers, Lisanne H. Roesthuis, Jeroen Schouten, Zhong-Hua Shi, Peter H. Veltink, Heder J. de Vries, Cyndi Shannon Weickert, Carsten Wiedenbach, Yingrui Zhang, Pieter R. Tuinman, Angélique M. E. de Man, Jane E. Butler, and Leo M. A. Heunks

Subjects
Functional electrical stimulation, Expiratory muscles, Mechanical ventilation, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Expiratory muscle weakness leads to difficult ventilator weaning. Maintaining their activity with functional electrical stimulation (FES) may improve outcome. We studied feasibility of breath-synchronized expiratory population muscle FES in a mixed ICU population (“Holland study”) and pooled data with our previous work (“Australian study”) to estimate potential clinical effects in a larger group. Methods Holland: Patients with a contractile response to FES received active or sham expiratory muscle FES (30 min, twice daily, 5 days/week until weaned). Main endpoints were feasibility (e.g., patient recruitment, treatment compliance, stimulation intensity) and safety. Pooled: Data on respiratory muscle thickness and ventilation duration from the Holland and Australian studies were combined (N = 40) in order to estimate potential effect size. Plasma cytokines (day 0, 3) were analyzed to study the effects of FES on systemic inflammation. Results Holland: A total of 272 sessions were performed (active/sham: 169/103) in 20 patients (N = active/sham: 10/10) with a total treatment compliance rate of 91.1%. No FES-related serious adverse events were reported. Pooled: On day 3, there was a between-group difference (N = active/sham: 7/12) in total abdominal expiratory muscle thickness favoring the active group [treatment difference (95% confidence interval); 2.25 (0.34, 4.16) mm, P = 0.02] but not on day 5. Plasma cytokine levels indicated that early FES did not induce systemic inflammation. Using a survival analysis approach for the total study population, median ventilation duration and ICU length of stay were 10 versus 52 (P = 0.07), and 12 versus 54 (P = 0.03) days for the active versus sham group. Median ventilation duration of patients that were successfully extubated was 8.5 [5.6–12.2] versus 10.5 [5.3–25.6] days (P = 0.60) for the active (N = 16) versus sham (N = 10) group, and median ICU length of stay was 10.5 [8.0–14.5] versus 14.0 [9.0–19.5] days (P = 0.36) for those active (N = 16) versus sham (N = 8) patients that were extubated and discharged alive from the ICU. During ICU stay, 3/20 patients died in the active group versus 8/20 in the sham group (P = 0.16). Conclusion Expiratory muscle FES is feasible in selected ICU patients and might be a promising technique within a respiratory muscle-protective ventilation strategy. The next step is to study the effects on weaning and ventilator liberation outcome. Trial registration: ClinicalTrials.gov, ID NCT03453944. Registered 05 March 2018—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03453944 .

Published
2020
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3. Recruitment strategies and lessons learned from a large genetic study of African Americans

Author

Rebecca J. Salowe, Roy Lee, Selam Zenebe-Gete, Marquis Vaughn, Harini V. Gudiseva, Maxwell Pistilli, Ava Kikut, Emily Becker, David W. Collins, Jie He, Sayaka Merriam, Kristen Mulvihill, Nora Laberee, Sara Lomax-Reese, Windell Murphy, Jeffrey Henderer, Venkata R. M. Chavali, Qi N. Cui, Ahmara G. Ross, Victoria Addis, Prithvi S. Sankar, Eydie Miller-Ellis, Maureen G. Maguire, and Joan M. O’Brien

Subjects
Public aspects of medicine, RA1-1270
Abstract

Genetic studies must enroll large numbers of participants to obtain adequate statistical power. Data are needed on how researchers can best use limited financial and practical resources to achieve these targets, especially in under-represented populations. This paper provides a retrospective analysis of the recruitment strategies for a large glaucoma genetics study in African Americans. The Primary Open-Angle African American Glaucoma Genetics study enrolled 10,192 African American subjects from the Philadelphia region. Major recruitment approaches included clinic enrollment from University of Pennsylvania (UPenn) sites, clinic enrollment from external sites, sampling of Penn Medicine Biobank (PMBB), and community outreach. We calculated the enrollment yield, cost per subject, and seasonal trends of these approaches. The majority (65%) of subject were enrolled from UPenn sites with an average cost of $133/subject. Over time, monthly case enrollment declined as the pool of eligible subjects was depleted. Expanding to external sites boosted case numbers ($129/subject) and the biobank provided additional controls at low cost ($5/subject), in large part due to the generosity of PMBB providing samples free of cost. Community outreach was costly with low return on enrollment ($978/subject for 220 subjects). Summer months (Jun-Aug) produced the highest recruitment yields (p

Published
2022

4. Abdominal functional electrical stimulation to assist ventilator weaning in critical illness: a double-blinded, randomised, sham-controlled pilot study

Author

Euan J. McCaughey, Annemijn H. Jonkman, Claire L. Boswell-Ruys, Rachel A. McBain, Elizabeth A. Bye, Anna L. Hudson, David W. Collins, Leo M. A. Heunks, Angus J. McLachlan, Simon C. Gandevia, and Jane E. Butler

Subjects
Critical illness, Electrical stimulation, Mechanical ventilation, Respiratory function, Respiratory muscles, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background For every day a person is dependent on mechanical ventilation, respiratory and cardiac complications increase, quality of life decreases and costs increase by > $USD 1500. Interventions that improve respiratory muscle function during mechanical ventilation can reduce ventilation duration. The aim of this pilot study was to assess the feasibility of employing an abdominal functional electrical stimulation (abdominal FES) training program with critically ill mechanically ventilated patients. We also investigated the effect of abdominal FES on respiratory muscle atrophy, mechanical ventilation duration and intensive care unit (ICU) length of stay. Methods Twenty critically ill mechanically ventilated participants were recruited over a 6-month period from one metropolitan teaching hospital. They were randomly assigned to receive active or sham (control) abdominal FES for 30 min, twice per day, 5 days per week, until ICU discharge. Feasibility was assessed through participant compliance to stimulation sessions. Abdominal and diaphragm muscle thickness were measured using ultrasound 3 times in the first week, and weekly thereafter by a blinded assessor. Respiratory function was recorded when the participant could first breathe independently and at ICU discharge, with ventilation duration and ICU length of stay also recorded at ICU discharge by a blinded assessor. Results Fourteen of 20 participants survived to ICU discharge (8, intervention; 6, control). One control was transferred before extubation, while one withdrew consent and one was withdrawn for staff safety after extubation. Median compliance to stimulation sessions was 92.1% (IQR 5.77%) in the intervention group, and 97.2% (IQR 7.40%) in the control group (p = 0.384). While this pilot study is not adequately powered to make an accurate statistical conclusion, there appeared to be no between-group thickness changes of the rectus abdominis (p = 0.099 at day 3), diaphragm (p = 0.652 at day 3) or combined lateral abdominal muscles (p = 0.074 at day 3). However, ICU length of stay (p = 0.011) and ventilation duration (p = 0.039) appeared to be shorter in the intervention compared to the control group. Conclusions Our compliance rates demonstrate the feasibility of using abdominal FES with critically ill mechanically ventilated patients. While abdominal FES did not lead to differences in abdominal muscle or diaphragm thickness, it may be an effective method to reduce ventilation duration and ICU length of stay in this patient group. A fully powered study into this effect is warranted. Trial registration The Australian New Zealand Clinical Trials Registry, ACTRN12617001180303. Registered 9 August 2017.

Published
2019
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5. Isolation of monoclonal antibodies from anti-synthetase syndrome patients and affinity maturation by recombination of independent somatic variants

Author

Luke Burman, Yeeting E. Chong, Sherie Duncan, Anders Klaus, Kaitlyn Rauch, Kristina Hamel, Karine Hervé, Stephanie Pfaffen, David W. Collins, Kevin Heyries, Leslie Nangle, Carl Hansen, and David J. King

Subjects
Aminoacyl tRNA synthetase, antibody, autoimmune disease, bioinformatics, cellular immune response, protein evolution, Therapeutics. Pharmacology, RM1-950, Immunologic diseases. Allergy, RC581-607
Abstract

The autoimmune disease known as Jo-1 positive anti-synthetase syndrome (ASS) is characterized by circulating antibody titers to histidyl-tRNA synthetase (HARS), which may play a role in modulating the non-canonical functions of HARS. Monoclonal antibodies to HARS were isolated by single-cell screening and sequencing from three Jo-1 positive ASS patients and shown to be of high affinity, covering diverse epitope space. The immune response was further characterized by repertoire sequencing from the most productive of the donor samples. In line with previous studies of autoimmune repertoires, these antibodies tended to have long complementarity-determining region H3 sequences with more positive-charged residues than average. Clones of interest were clustered into groups with related sequences, allowing us to observe different somatic mutations in related clones. We postulated that these had found alternate structural solutions for high affinity binding, but that mutations might be transferable between clones to further enhance binding affinity. Transfer of somatic mutations between antibodies within the same clonal group was able to enhance binding affinity in a number of cases, including beneficial transfer of a mutation from a lower affinity clone into one of higher affinity. Affinity enhancement was seen with mutation transfer both between related single-cell clones, and directly from related repertoire sequences. To our knowledge, this is the first demonstration of somatic hypermutation transfer from repertoire sequences to further mature in vivo derived antibodies, and represents an additional tool to aid in affinity maturation for the development of antibodies.

Published
2020
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6. Fit Factor Change on Quantitative Fit Testing of Duckbill N95 Respirators with the Use of Safety Goggles

Author

Sandy Kyaw, Yahya Shehabi, Moira Johns, Claudia M Whyte, Warren C Stewart, Solomon R Thambiraj, Rimen Lim, Sumesh Arora, and David W Collins

Subjects
business.product_category, Coronavirus disease 2019 (COVID-19), business.industry, Fit testing, HCW (Healthcare workers), N95 MASK, Critical Care and Intensive Care Medicine, Intervention studies, Occupational injury, Safety goggles, Quantitative measure, Eyeglasses, Intensive care, Personal protective equipment, Infectious diseases, Medicine, Optometry, Original Article, Safety, Respirator, business, N95 respirators
Abstract

N95 respirators and safety goggles are important components of personal protective equipment to reduce the spread of airborne infections, such as COVID-19, among healthcare workers. Poor N95 respirator seal may reduce its protective effect, thereby increasing transmission. Quantitative fit testing is an established way of assessing the N95 respirator fit, which provides a quantitative measure for seal, called the fit factor. Duckbill N95 respirators frequently fail the fit test. We hypothesized that using safety goggles with a wraparound elastic headband will increase their fit-factor by reinforcing the seal between the face and the upper margin of the respirator. We studied the effect of safety goggles with a wraparound elastic headband (3M™ Chemical Splash Resistant Goggles, ID 70006982741) on the fit factor of two types of Duckbill N95 respirators (Halyard FLUIDSHIELD*3, Model 99SA070M, and ProShield® N95 Model TN01-11) in 63 healthy volunteers in a nonrandomized, before-and-after intervention study design. The mean fit factor increased from 69.4 to 169.1 increased from 17/63 (27%) to 46/63 (73%) after the intervention (p

Published
2021

7. LY-CoV1404 potently neutralizes SARS-CoV-2 variants

Author

Kathryn Westendorf, Stefanie Žentelis, Lingshu Wang, Denisa Foster, Peter Vaillancourt, Matthew Wiggin, Erica Lovett, Robin van der Lee, Jörg Hendle, Anna Pustilnik, J. Michael Sauder, Lucas Kraft, Yuri Hwang, Robert W. Siegel, Jinbiao Chen, Beverly A. Heinz, Richard E. Higgs, Nicole L. Kallewaard, Kevin Jepson, Rodrigo Goya, Maia A. Smith, David W. Collins, Davide Pellacani, Ping Xiang, Valentine de Puyraimond, Marketa Ricicova, Lindsay Devorkin, Caitlin Pritchard, Aoise O’Neill, Kush Dalal, Pankaj Panwar, Harveer Dhupar, Fabian A. Garces, Courtney A. Cohen, John M. Dye, Kathleen E. Huie, Catherine V. Badger, Darwyn Kobasa, Jonathan Audet, Joshua J. Freitas, Saleema Hassanali, Ina Hughes, Luis Munoz, Holly C. Palma, Bharathi Ramamurthy, Robert W. Cross, Thomas W. Geisbert, Vineet Menacherry, Kumari Lokugamage, Viktoriya Borisevich, Iliana Lanz, Lisa Anderson, Payal Sipahimalani, Kizzmekia S. Corbett, Eun Sung Yang, Yi Zhang, Wei Shi, Tongqing Zhou, Misook Choe, John Misasi, Peter D. Kwong, Nancy J. Sullivan, Barney S. Graham, Tara L. Fernandez, Carl L. Hansen, Ester Falconer, John R. Mascola, Bryan E. Jones, and Bryan C. Barnhart

Subjects
chemistry.chemical_classification, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Antibodies, Monoclonal, Biology, Vaccine efficacy, Antibodies, Viral, Virology, Antibodies, Neutralizing, Epitope, Virus, General Biochemistry, Genetics and Molecular Biology, Article, COVID-19 Drug Treatment, Epitopes, chemistry, biology.protein, Potency, Humans, Symptom onset, Antibody, Glycoprotein
Abstract

SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization when administered early during COVID-19 disease. However, the emergence of variants of concern has negatively impacted the therapeutic use of some authorized mAbs. Using a high throughput B-cell screening pipeline, we isolated a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody called LY-CoV1404 (also known as bebtelovimab). LY-CoV1404 potently neutralizes authentic SARS-CoV-2 virus, including the prototype, B.1.1.7, B.1.351 and B.1.617.2). In pseudovirus neutralization studies, LY-CoV1404 retains potent neutralizing activity against numerous variants including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant and retains binding to spike proteins with a variety of underlying RBD mutations including K417N, L452R, E484K, and N501Y. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved with the exception of N439 and N501. Notably, the binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The breadth of reactivity to amino acid substitutions present among current VOC together with broad and potent neutralizing activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants causing COVID-19.In BriefLY-CoV1404 is a potent SARS-CoV-2-binding antibody that neutralizes all known variants of concern and whose epitope is rarely mutated.HighlightsLY-CoV1404 potently neutralizes SARS-CoV-2 authentic virus and known variants of concern including the B.1.1.529 (Omicron), the BA.2 Omicron subvariant, and B.1.617.2 (Delta) variantsNo loss of potency against currently circulating variantsBinding epitope on RBD of SARS-CoV-2 is rarely mutated in GISAID databaseBreadth of neutralizing activity and potency supports clinical development

Published
2021

8. The association of mitochondrial DNA haplogroups with POAG in African Americans

Author

Qi N. Cui, Rebecca Salowe, Prithvi S. Sankar, Douglas C. Wallace, Maxwell Pistilli, Harini V. Gudiseva, Gui-Shuang Ying, Larry N. Singh, Naira Khachataryan, David W. Collins, Jie He, Venkata R M Chavali, Sayaka Merriam, Jeffrey D Henderer, Brian S. Cole, Eydie Miller-Ellis, Joan M. O'Brien, and Victoria Addis

Subjects
Adult, Male, Functional role, Mitochondrial DNA, genetic structures, Biology, DNA, Mitochondrial, Article, Haplogroup, Cellular and Molecular Neuroscience, symbols.namesake, Odds Ratio, Humans, Genotyping, African american, Genetics, Middle Aged, eye diseases, Sensory Systems, Black or African American, Ophthalmology, Logistic Models, Bonferroni correction, Haplotypes, Cohort, symbols, Female, Glaucoma, Open-Angle, Human mitochondrial DNA haplogroup
Abstract

Mitochondrial dysfunction has been implicated in the pathogenesis of primary open-angle glaucoma (POAG). However, the potential significance of mitochondrial DNA (mtDNA) haplogroups to POAG has not been evaluated in the overaffected African American population. To investigate the association of mtDNA haplogroups with POAG and its phenotypic characteristics, genotyping data from 4081 African American subjects (1919 cases and 2162 controls) was analyzed using 1293 positions on mtDNA. The overall frequency of mtDNA haplogroups in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study cohort was 37% L3, 29% L2, 21% L1, 4% L0, and 10% non-African haplogroups (non-L). When all haplogroups (L0, L1, L2, and non-L) were compared against theL3 reference group, after adjusting by age and principal component of ancestry, the non-L3 haplogroups showed higher risk of POAG (OR-1.19, p = 0.02), with a particularly strong association among males (OR = 1.41, p = 0.003). More specifically the non-L group was associated with higher POAG risk than the L3 haplogroup (OR = 1.77, p = 0.007, Bonferroni adjusted p = 0.027) and to the L3e (n = 256, OR = 1.92, p = 0.007, Bonferroni adjusted p = 0.029). No significant association was found when genders were analyzed together or in female only analysis. There were no significant differences in various POAG endophenotypes across mtDNA haplogroups. This study expands our knowledge of mitochondrial genetics and mtDNA haplogroup associations in African American POAG. Further work is needed to better understand the functional role of mtDNA polymorphisms and their interactions with nuclear genes that affect POAG.

Published
2019

9. SNP located in an AluJb repeat downstream of TMCO1, rs4657473, is protective for POAG in African Americans

Author

Joan M. O'Brien, Ben T Trachtman, Sonika Rathi, Ian Danford, Harini V. Gudiseva, Maxwell Pistilli, David W. Collins, Gui-Shuang Ying, Lana Verkuil, Venkata R M Chavali, Naqi Haider, and Jie He

Subjects
Genetics, 0303 health sciences, education.field_of_study, business.industry, Population, Locus (genetics), Single-nucleotide polymorphism, Sensory Systems, 03 medical and health sciences, Cellular and Molecular Neuroscience, Ophthalmology, 0302 clinical medicine, Gene expression, Genotype, 030221 ophthalmology & optometry, Medicine, SNP, Electrophoretic mobility shift assay, education, business, Gene, 030304 developmental biology
Abstract

AimsTo determine the association of single nucleotide polymorphisms (SNPs) downstream from the TMCO1 gene with primary open-angle glaucoma (POAG) in African Americans (AA).MethodsAA subjects were recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study from the Scheie Eye Institute and its satellite sites in Philadelphia. A region containing an AluJb repeat and seven SNPs, including rs4656461 near the TMCO1 gene, were PCR-Sanger sequenced from POAAGG cases (n=1537) and controls (n=1570). Association between POAG and SNPs near TMCO1 was investigated by logistic regression analysis. Phenotypic trait associations with these SNPs were assessed by analysis of variance. Electrophoretic mobility shift assay (EMSA) was performed to assess the affinity of human T-box 5 (TBX5) protein for a predicted binding motif in the TMCO1 region. Dual Luciferase assays were performed by transfecting recombinant plasmids containing the region surrounding the above SNPs in HEK293T and trabecular meshwork cells.ResultsThe SNP rs4657473 (C>T) was associated with POAG; the TT genotype was protective (OR 0.20, 95% CI 0.09 to 0.42; pTMCO1 variants and phenotypic traits. EMSA confirmed the affinity of TBX5 for a predicted binding motif containing TMCO1 SNP rs4657475. Luciferase assays demonstrated a regulatory function for the genomic region around SNP rs4656561, located within AluJb repeat.ConclusionOur results demonstrate that a SNP downstream of TMCO1, rs4657473, is associated with POAG in an AA population. Our studies suggest a regulatory role for the previously POAG-associated locus near the TMCO1 gene that may affect gene expression.

Published
2019

10. Isolation of monoclonal antibodies from anti-synthetase syndrome patients and affinity maturation by recombination of independent somatic variants

Author

Karine Hervé, Carl L. Hansen, Yeeting E. Chong, Luke Burman, Kaitlyn Rauch, David W Collins, Leslie A. Nangle, Stephanie Pfaffen, Kevin A. Heyries, Anders Klaus, David J. King, Sherie Duncan, and Kristina Hamel

Subjects
medicine.drug_class, Somatic cell, Immunology, Antibody Affinity, Somatic hypermutation, autoimmune disease, Biology, Monoclonal antibody, medicine.disease_cause, Epitope, Histidine-tRNA Ligase, Affinity maturation, Report, antibody, medicine, Immunology and Allergy, Humans, protein evolution, cellular immune response, Autoantibodies, Genetics, Mutation, Myositis, repertoire, Antibodies, Monoclonal, bioinformatics, single cell, biology.protein, Immunologic Techniques, Somatic Hypermutation, Immunoglobulin, Aminoacyl tRNA synthetase, Antibody, Clone (B-cell biology)
Abstract

The autoimmune disease known as Jo-1 positive anti-synthetase syndrome (ASS) is characterized by circulating antibody titers to histidyl-tRNA synthetase (HARS), which may play a role in modulating the non-canonical functions of HARS. Monoclonal antibodies to HARS were isolated by single-cell screening and sequencing from three Jo-1 positive ASS patients and shown to be of high affinity, covering diverse epitope space. The immune response was further characterized by repertoire sequencing from the most productive of the donor samples. In line with previous studies of autoimmune repertoires, these antibodies tended to have long complementarity-determining region H3 sequences with more positive-charged residues than average. Clones of interest were clustered into groups with related sequences, allowing us to observe different somatic mutations in related clones. We postulated that these had found alternate structural solutions for high affinity binding, but that mutations might be transferable between clones to further enhance binding affinity. Transfer of somatic mutations between antibodies within the same clonal group was able to enhance binding affinity in a number of cases, including beneficial transfer of a mutation from a lower affinity clone into one of higher affinity. Affinity enhancement was seen with mutation transfer both between related single-cell clones, and directly from related repertoire sequences. To our knowledge, this is the first demonstration of somatic hypermutation transfer from repertoire sequences to further mature in vivo derived antibodies, and represents an additional tool to aid in affinity maturation for the development of antibodies.

Published
2020

11. Breath-synchronized electrical stimulation of the expiratory muscles in mechanically ventilated patients

Author

Cyndi Shannon Weickert, David W. Collins, Lisanne H Roesthuis, Jeroen Schouten, Carsten Wiedenbach, Matthijs Kox, Peter H. Veltink, Annemijn H. Jonkman, Peter Pickkers, Marco Peters, Euan J. McCaughey, Jane E. Butler, Yingrui Zhang, Zhong-Hua Shi, Angelique M E de Man, Leo M. A. Heunks, Heder J de Vries, Pieter R. Tuinman, Claire L. Boswell-Ruys, Tim Frenzel, Eline Oppersma, Oscar Hoiting, Simon C. Gandevia, A.J. McLachlan, Armand R. J. Girbes, Cardiovascular and Respiratory Physiology, Biomedical Signals and Systems, Intensive care medicine, ACS - Diabetes & metabolism, and ACS - Pulmonary hypertension & thrombosis

Subjects
Male, medicine.medical_treatment, Population, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], Medicare, Critical Care and Intensive Care Medicine, Cohort Studies, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Mechanical ventilation, Functional electrical stimulation, medicine, Respiratory muscle, Humans, Weaning, Hospital Mortality, education, Survival analysis, Aged, Proportional Hazards Models, Retrospective Studies, Aged, 80 and over, education.field_of_study, business.industry, Research, Other Research Radboud Institute for Health Sciences [Radboudumc 0], lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, Respiration, Artificial, Electric Stimulation, Respiratory Muscles, United States, Confidence interval, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030228 respiratory system, Anesthesia, Breathing, Feasibility Studies, Female, Expiratory muscles, business
Abstract

BackgroundExpiratory muscle weakness leads to difficult ventilator weaning. Maintaining their activity with functional electrical stimulation (FES) may improve outcome. We studied feasibility of breath-synchronized expiratory population muscle FES in a mixed ICU population (“Holland study”) and pooled data with our previous work (“Australian study”) to estimate potential clinical effects in a larger group.MethodsHolland:Patients with a contractile response to FES received active or sham expiratory muscle FES (30 min, twice daily, 5 days/week until weaned). Main endpoints were feasibility (e.g., patient recruitment, treatment compliance, stimulation intensity) and safety.Pooled:Data on respiratory muscle thickness and ventilation duration from the Holland and Australian studies were combined (N = 40) in order to estimate potential effect size. Plasma cytokines (day 0, 3) were analyzed to study the effects of FES on systemic inflammation.ResultsHolland:A total of 272 sessions were performed (active/sham: 169/103) in 20 patients (N = active/sham: 10/10) with a total treatment compliance rate of 91.1%. No FES-related serious adverse events were reported.Pooled:On day 3, there was a between-group difference (N = active/sham: 7/12) in total abdominal expiratory muscle thickness favoring the active group [treatment difference (95% confidence interval); 2.25 (0.34, 4.16) mm,P = 0.02] but not on day 5. Plasma cytokine levels indicated that early FES did not induce systemic inflammation. Using a survival analysis approach for the total study population, median ventilation duration and ICU length of stay were 10 versus 52 (P = 0.07), and 12 versus 54 (P = 0.03) days for the active versus sham group. Median ventilation duration of patients that were successfully extubated was 8.5 [5.6–12.2] versus 10.5 [5.3–25.6] days (P = 0.60) for the active (N = 16) versus sham (N = 10) group, and median ICU length of stay was 10.5 [8.0–14.5] versus 14.0 [9.0–19.5] days (P = 0.36) for those active (N = 16) versus sham (N = 8) patients that were extubated and discharged alive from the ICU. During ICU stay, 3/20 patients died in the active group versus 8/20 in the sham group (P = 0.16).ConclusionExpiratory muscle FES is feasible in selected ICU patients and might be a promising technique within a respiratory muscle-protective ventilation strategy. The next step is to study the effects on weaning and ventilator liberation outcome.Trial registration:ClinicalTrials.gov, ID NCT03453944. Registered 05 March 2018—Retrospectively registered,https://clinicaltrials.gov/ct2/show/NCT03453944.

Published
2020

12. Genome wide-association study identifies novel loci in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study

Author

Anita S. Bowman, Sayaka Merriam, Jie He, Khachataryan N, Scott M. Williams, Chavali Vrm, Weiner M, Rebecca Salowe, Amanda Lehman, Addis, Joan M. O'Brien, Gui-Shuang Ying, David W. Collins, Anastasia Lucas, Maxwell Pistilli, Harini V. Gudiseva, Ahmara G. Ross, Windell Murphy, Jeffrey D Henderer, Zody Mc, Sonika Rathi, Jason H. Moore, Eydie Miller-Ellis, Robert J. Lee, Prithvi S. Sankar, Rohit Varma, Qi N. Cui, Ebenezer Daniel, Caitlin P. McHugh, Shefali S. Verma, and Ritchie

Subjects
Genetics, 0303 health sciences, genetic structures, Open angle glaucoma, Glaucoma, Genome-wide association study, Single-nucleotide polymorphism, Disease, Biology, medicine.disease, Genetic analysis, eye diseases, 03 medical and health sciences, 0302 clinical medicine, 030221 ophthalmology & optometry, medicine, SNP, sense organs, Gene, 030304 developmental biology
Abstract

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects African Americans. Large-scale POAG genetic studies have focused on individuals of European and Asian ancestry, limiting our understanding of disease biology. Here we report genetic analysis of the largest-ever deeply phenotyped African American population (n=5950), identifying a novel POAG-associated SNP on chromosome 11 near the TRIM66 gene (rs112369934). POAG trait association also implicated SNPs in genes involved in trabecular meshwork homeostasis and retinal ganglion cell maintenance. These new loci deepen our understanding of the pathophysiology of POAG in African Americans.

Published
2020

13. Functional classification of long non-coding RNAs by k-mer content

Author

Megan D. Schertzer, Allison R Baker, Daniel Sprague, Qidi Chen, Jessime M. Kirk, Peter J. Mucha, Kevin M. Weeks, David W Collins, J. Mauro Calabrese, Joshua Wooten, Matthew J. Smola, Kaoru Inoue, David M Lee, Shuo Wang, Christopher R Horning, and Susan O Kim

Subjects
0301 basic medicine, Sequence analysis, Sequence alignment, Computational biology, Biology, Article, Homology (biology), Conserved sequence, Mice, 03 medical and health sciences, 0302 clinical medicine, Databases, Genetic, Genetics, Animals, Cluster Analysis, Humans, Nucleotide Motifs, Conserved Sequence, Base Sequence, Sequence Analysis, RNA, RNA, Molecular Sequence Annotation, Hep G2 Cells, 030104 developmental biology, Potassium Channels, Voltage-Gated, k-mer, Nucleic Acid Conformation, RNA, Long Noncoding, K562 Cells, Sequence motif, Sequence Alignment, Algorithms, 030217 neurology & neurosurgery
Abstract

The functions of most long non-coding RNAs (lncRNAs) are unknown. In contrast to proteins, lncRNAs with similar functions often lack linear sequence homology; thus, the identification of function in one lncRNA rarely informs the identification of function in others. We developed a sequence comparison method to deconstruct linear sequence relationships in lncRNAs and evaluate similarity based on the abundance of short motifs called k-mers. We found that lncRNAs of related function often had similar k-mer profiles despite lacking linear homology, and that k-mer profiles correlated with protein binding to lncRNAs and with their subcellular localization. Using a novel assay to quantify Xist-like regulatory potential, we directly demonstrated that evolutionarily unrelated lncRNAs can encode similar function through different spatial arrangements of related sequence motifs. K-mer-based classification is a powerful approach to detect recurrent relationships between sequence and function in lncRNAs.

Published
2018

14. Abdominal functional electrical stimulation to assist ventilator weaning in critical illness: a double-blinded, randomised, sham-controlled pilot study

Author

Annemijn H. Jonkman, Claire L. Boswell-Ruys, Anna L. Hudson, Rachel A. McBain, A.J. McLachlan, Elizabeth A Bye, Euan J. McCaughey, Jane E. Butler, Leo M. A. Heunks, Simon C. Gandevia, David W. Collins, Intensive care medicine, and ACS - Pulmonary hypertension & thrombosis

Subjects
Adult, Male, Critical Illness, medicine.medical_treatment, Rectus Abdominis, Pilot Projects, Critical Care and Intensive Care Medicine, law.invention, 03 medical and health sciences, Mechanical ventilation, 0302 clinical medicine, Double-Blind Method, law, Respiratory muscles, medicine, Respiratory muscle, Humans, Functional electrical stimulation, Respiratory function, APACHE, Aged, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, Length of Stay, Middle Aged, Intensive care unit, Electric Stimulation, 3. Good health, Diaphragm (structural system), Clinical trial, Intensive Care Units, Electrical stimulation, Anesthesia, Breathing, Female, business, Ventilator Weaning
Abstract

BACKGROUND: For every day a person is dependent on mechanical ventilation, respiratory and cardiac complications increase, quality of life decreases and costs increase by > $USD 1500. Interventions that improve respiratory muscle function during mechanical ventilation can reduce ventilation duration. The aim of this pilot study was to assess the feasibility of employing an abdominal functional electrical stimulation (abdominal FES) training program with critically ill mechanically ventilated patients. We also investigated the effect of abdominal FES on respiratory muscle atrophy, mechanical ventilation duration and intensive care unit (ICU) length of stay.METHODS: Twenty critically ill mechanically ventilated participants were recruited over a 6-month period from one metropolitan teaching hospital. They were randomly assigned to receive active or sham (control) abdominal FES for 30 min, twice per day, 5 days per week, until ICU discharge. Feasibility was assessed through participant compliance to stimulation sessions. Abdominal and diaphragm muscle thickness were measured using ultrasound 3 times in the first week, and weekly thereafter by a blinded assessor. Respiratory function was recorded when the participant could first breathe independently and at ICU discharge, with ventilation duration and ICU length of stay also recorded at ICU discharge by a blinded assessor.RESULTS: Fourteen of 20 participants survived to ICU discharge (8, intervention; 6, control). One control was transferred before extubation, while one withdrew consent and one was withdrawn for staff safety after extubation. Median compliance to stimulation sessions was 92.1% (IQR 5.77%) in the intervention group, and 97.2% (IQR 7.40%) in the control group (p = 0.384). While this pilot study is not adequately powered to make an accurate statistical conclusion, there appeared to be no between-group thickness changes of the rectus abdominis (p = 0.099 at day 3), diaphragm (p = 0.652 at day 3) or combined lateral abdominal muscles (p = 0.074 at day 3). However, ICU length of stay (p = 0.011) and ventilation duration (p = 0.039) appeared to be shorter in the intervention compared to the control group.CONCLUSIONS: Our compliance rates demonstrate the feasibility of using abdominal FES with critically ill mechanically ventilated patients. While abdominal FES did not lead to differences in abdominal muscle or diaphragm thickness, it may be an effective method to reduce ventilation duration and ICU length of stay in this patient group. A fully powered study into this effect is warranted.TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry, ACTRN12617001180303. Registered 9 August 2017.

Published
2019

15. Neuromuscular Electrical Stimulation Applied to the Abdominal Muscles to Assist Ventilator Weaning in Critically Ill Patients: An Assessor Blinded, Randomized, Sham-Controlled Pilot Study

Author

Anna L. Hudson, Annemijn H. Jonkman, Rachel A. McBain, Simon C. Gandevia, Euan J. McCaughey, Leo M. A. Heunks, A.J. McLachlan, Jane E. Butler, E. Bye, Claire L. Boswell-Ruys, David W. Collins, Intensive care medicine, and ACS - Pulmonary hypertension & thrombosis

Subjects
Ventilator weaning, Abdominal muscles, Critically ill, business.industry, Anesthesia, Medicine, Stimulation, business
Published
2019

16. Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study: gender and risk of POAG in African Americans

Author

Qi N. Cui, Ebenezer Daniel, Amanda Lehman, Prithvi S. Sankar, Maxwell Pistilli, Naira Khachatryan, Tanisha Moore, Victoria Addis, Jeffrey D Henderer, Harini V. Gudiseva, Eydie Miller-Ellis, Windell Murphy, Maureen G. Maguire, Rebecca Salowe, David W. Collins, Joan M. O'Brien, Venkata R M Chavali, and Raymond Fertig

Subjects
Male, Eye Diseases, Physiology, Epidemiology, Visual Acuity, Glaucoma, Blood Pressure, Logistic regression, Vascular Medicine, Body Mass Index, 0302 clinical medicine, Endocrinology, Risk Factors, Medicine and Health Sciences, Ethnicities, Mass index, African American people, Genetics, Aged, 80 and over, Philadelphia, 030219 obstetrics & reproductive medicine, Multidisciplinary, Incidence (epidemiology), Incidence, Middle Aged, Population groupings, Physiological Parameters, Hypertension, Medicine, Female, Glaucoma, Open-Angle, Research Article, Endocrine Disorders, Science, 03 medical and health sciences, Diabetes mellitus, medicine, Diabetes Mellitus, Humans, Aged, business.industry, Body Weight, Case-control study, Biology and Life Sciences, Anthropometry, medicine.disease, Black or African American, Ophthalmology, Case-Control Studies, Metabolic Disorders, Medical Risk Factors, 030221 ophthalmology & optometry, Women's Health, People and places, business, Body mass index
Abstract

The purpose of this study was to investigate the association between gender and primary open-angle glaucoma (POAG) among African Americans and to assess demographic, systemic, and behavioral factors that may contribute to differences between genders. The Primary Open-Angle African American Glaucoma Genetics (POAAGG) study had a case-control design and included African Americans 35 years and older, recruited from the greater Philadelphia, Pennsylvania. Diagnosis of POAG was based on evidence of both glaucomatous optic nerve damage and characteristic visual field loss. Demographic and behavioral information, history of systemic diseases and anthropometric measurements were obtained at study enrollment. Gender differences in risk of POAG were examined using multivariate logistic regression. A total of 2,290 POAG cases and 2,538 controls were included in the study. The percentage of men among cases was higher than among controls (38.6% vs 30.3%, P

Published
2018

17. SNP located in an

Author

Lana, Verkuil, Ian, Danford, Maxwell, Pistilli, David W, Collins, Harini V, Gudiseva, Ben T, Trachtman, Jie, He, Sonika, Rathi, Naqi, Haider, Gui-Shuang, Ying, Venkata R M, Chavali, and Joan Marie, O'Brien

Subjects
Male, primary open-angle glaucoma, genetic structures, Genotyping Techniques, Electrophoretic Mobility Shift Assay, Transfection, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Alu Elements, Trabecular Meshwork, Humans, genetics, Intraocular Pressure, Aged, Aged, 80 and over, AluJb repeat, Middle Aged, eye diseases, Black or African American, Laboratory Science, HEK293 Cells, TMCO1, Case-Control Studies, Female, pathology, Calcium Channels, Glaucoma, Open-Angle, Plasmids
Abstract

Aims To determine the association of single nucleotide polymorphisms (SNPs) downstream from the TMCO1 gene with primary open-angle glaucoma (POAG) in African Americans (AA). Methods AA subjects were recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study from the Scheie Eye Institute and its satellite sites in Philadelphia. A region containing an AluJb repeat and seven SNPs, including rs4656461 near the TMCO1 gene, were PCR-Sanger sequenced from POAAGG cases (n=1537) and controls (n=1570). Association between POAG and SNPs near TMCO1 was investigated by logistic regression analysis. Phenotypic trait associations with these SNPs were assessed by analysis of variance. Electrophoretic mobility shift assay (EMSA) was performed to assess the affinity of human T-box 5 (TBX5) protein for a predicted binding motif in the TMCO1 region. Dual Luciferase assays were performed by transfecting recombinant plasmids containing the region surrounding the above SNPs in HEK293T and trabecular meshwork cells. Results The SNP rs4657473 (C>T) was associated with POAG; the TT genotype was protective (OR 0.20, 95% CI 0.09 to 0.42; p

Published
2018

18. The Primary Open-Angle African American Glaucoma Genetics Study

Author

Meredith Regina, Michael Chua, Rohit Varma, William T. Merritt, Charles W. Nichols, Rebecca Salowe, Raymond Fertig, David W. Collins, Joan M. O'Brien, Gui-Shuang Ying, Julia Salinas, Venkata R M Chavali, Allison Rhodes, Maxwell Pistilli, Eydie Miller-Ellis, Harini V. Gudiseva, Jeffrey D Henderer, Eric Jorgenson, Prithvi S. Sankar, Benjamin T. Trachtman, and Emily S. Charlson

Subjects
Genetics, education.field_of_study, Intraocular pressure, genetic structures, medicine.diagnostic_test, business.industry, Cross-sectional study, Population, Glaucoma, Diabetic retinopathy, medicine.disease, eye diseases, Ophthalmology, Eye examination, Cohort, medicine, Gonioscopy, sense organs, business, education
Abstract

Purpose To describe the baseline characteristics of the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study cohort, the largest African American population with primary open-angle glaucoma (POAG) recruited at a single institution (University of Pennsylvania [UPenn], Department of Ophthalmology, Scheie Eye Institute) to date. Design Population-based, cross-sectional, case-control study. Participants A total of 2520 African American subjects aged 35 years or more who were recruited from the greater Philadelphia, Pennsylvania area. Methods Each subject underwent a detailed interview and eye examination. The interview assessed demographic, behavioral, medical, and ocular risk factors. Current ZIP codes surrounding UPenn were recorded and US census data were queried to infer socioeconomic status. The eye examination included measurement of visual acuity (VA) and intraocular pressure, and a detailed anterior and posterior segment examination, including gonioscopy, dilated fundus and optic disc examination, visual fields, stereo disc photography, optical coherence tomography, and measurement of central corneal thickness. Main Outcome Measures The baseline characteristics of gender, age, and glaucoma diagnosis were collected. Body mass index (BMI), hypertension, diabetes, alcohol and tobacco use, ocular conditions (including blindness, cataract, nonproliferative diabetic retinopathy, and age-related macular degeneration), and use of ocular medication and surgery were examined. Median population density, income, education level, and other socioeconomic measures were determined for the study cohort. Results Of the 2520 African Americans recruited to the POAAGG study to date, 2067 (82.0%), including 807 controls and 1260 POAG cases, met all inclusion criteria and completed the detailed clinical ocular examination. Cases were more likely to have a lower BMI ( P P P P = 0.02), and be female ( P Conclusions The POAAGG study has currently recruited more than 2000 African Americans eligible for a POAG genetics study. Blindness and low BMI were significantly associated with POAG. This population was predominantly recruited from neighborhoods whose population income exists at or near the federal poverty level.

Published
2015

19. Characterizing the 'POAGome': A bioinformatics-driven approach to primary open-angle glaucoma

Author

David W. Collins, Levi N. Kanu, Harini V. Gudiseva, Daniel J. Choi, Katherine E. Uyhazi, Joan M. O'Brien, Marisa K. Lau, Ian D. Danford, Venkata R M Chavali, Lana D. Verkuil, and Gregory R. Grant

Subjects
0301 basic medicine, Senescence, Retinal Ganglion Cells, Open angle glaucoma, genetic structures, Ocular hypertension, Glaucoma, Disease, Biology, Bioinformatics, Article, 03 medical and health sciences, Normal tension glaucoma, medicine, Humans, Intraocular Pressure, Neurodegeneration, Computational Biology, medicine.disease, Phenotype, Sensory Systems, eye diseases, Ophthalmology, 030104 developmental biology, sense organs, Glaucoma, Open-Angle
Abstract

Primary open-angle glaucoma (POAG) is a genetically, physiologically, and phenotypically complex neurodegenerative disorder. This study addressed the expanding collection of genes associated with POAG, referred to as the "POAGome." We used bioinformatics tools to perform an extensive, systematic literature search and compiled 542 genes with confirmed associations with POAG and its related phenotypes (normal tension glaucoma, ocular hypertension, juvenile open-angle glaucoma, and primary congenital glaucoma). The genes were classified according to their associated ocular tissues and phenotypes, and functional annotation and pathway analyses were subsequently performed. Our study reveals that no single molecular pathway can encompass the pathophysiology of POAG. The analyses suggested that inflammation and senescence may play pivotal roles in both the development and perpetuation of the retinal ganglion cell degeneration seen in POAG. The TGF-β signaling pathway was repeatedly implicated in our analyses, suggesting that it may be an important contributor to the manifestation of POAG in the anterior and posterior segments of the globe. We propose a molecular model of POAG revolving around TGF-β signaling, which incorporates the roles of inflammation and senescence in this disease. Finally, we highlight emerging molecular therapies that show promise for treating POAG.

Published
2017

20. Central venous Oxygen Saturation during High-Risk General Surgical Procedures—Relationship to Complications and Clinical Outcomes

Author

Keogh Gw, G Flynn, David W. Collins, Maureen O’Brien, Michael H Bennett, Martin Boyle, and D Bihari

Subjects
Adult, Male, Multivariate analysis, Critical Care and Intensive Care Medicine, Postoperative Complications, Blood loss, Humans, Medicine, Prospective Studies, Aged, Aged, 80 and over, business.industry, Odds ratio, Perioperative, Length of Stay, Middle Aged, Surgical procedures, Confidence interval, Oxygen, Logistic Models, Treatment Outcome, Anesthesiology and Pain Medicine, Surgical Procedures, Operative, Intraoperative management, Anesthesia, Female, business, Complication
Abstract

Major non-cardiac surgery is associated with postoperative morbidity, and perioperative central venous oxygen saturation (ScvO2) may be a predictor of morbidity. This pilot study aimed to define intraoperative ScvO2 and to identify factors associated with postoperative complications. ScvO2 (reflection spectrophotometry) was recorded continuously in a convenience sample of adults undergoing high-risk general surgery. Demographics, intraoperative management, surgery duration, postoperative complications and deaths within 28 days were recorded. Data from 51 patients were analysed. Two (4%) died and 24 (47%) had at least one complication (range 1 to 5). The hospital length-of-stay and duration of surgery were longer in those with complications (22.1±6.1 versus 9.6±3.6 days, P >0.0001, and 328±162 minutes versus 241±94 minutes, P=0.02, respectively). Overall, the ScvO2 was 82±8% and ranged from 40% to 97% with 17 (33%) patients having at least one episode of ScvO2 >70%. Hospital length-of-stay (P >0.0001), time ScvO2 >90% (P=0.003), surgery duration (P=0.005) and blood loss (P=0.02) were correlated with the number of complications. Using multivariate analysis, surgery duration (odds ratio 1.008 [95% confidence interval 1.002 to 1.013]; P=0.006) and change in oxygen extraction ratio (O2ER) at the end of surgery compared to the beginning (odds ratio 1.13 [95% confidence interval 1.001 to 1.28]; P=0.04) were independently associated with complications. The surgery duration and an increased O2ER are factors related to the development of postoperative complications.

Published
2014

21. Saliva DNA quality and genotyping efficiency in a predominantly elderly population

Author

Lana D. Verkuil, Linda Gutierrez, Ian D. Danford, Prithvi S. Sankar, Anita S. Bowman, Eydie Miller-Ellis, Amanda Lehman, Rebecca Salowe, Harini V. Gudiseva, Anna Sagaser, David W. Collins, Mark Hansen, Jie He, and Joan M. O'Brien

Subjects
Male, 0301 basic medicine, Genotyping, Saliva, Genotyping Techniques, Microarrays, Concordance, African-Americans, Biology, Polymerase Chain Reaction, law.invention, Andrology, 03 medical and health sciences, symbols.namesake, Elderly, 260/280 absorbance, 0302 clinical medicine, law, Genetics, GWAS, Humans, Genetics(clinical), Genetics (clinical), Polymerase chain reaction, Aged, Demography, Oligonucleotide Array Sequence Analysis, Sanger sequencing, Glaucoma, DNA, Sequence Analysis, DNA, Call rates, Molecular biology, SNP genotyping, Blood, 030104 developmental biology, 030220 oncology & carcinogenesis, symbols, Population study, Female, Research Article, SNPs
Abstract

Background The question of whether DNA obtained from saliva is an acceptable alternative to DNA from blood is a topic of considerable interest for large genetics studies. We compared the yields, quality and performance of DNAs from saliva and blood from a mostly elderly study population. Methods Two thousand nine hundred ten DNAs from primarily elderly subjects (mean age ± standard deviation (SD): 65 ± 12 years), collected for the Primary Open-Angle African-American Glaucoma Genetics (POAAGG) study, were evaluated by fluorometry and/or spectroscopy. These included 566 DNAs from blood and 2344 from saliva. Subsets of these were evaluated by Sanger sequencing (n = 1555), and by microarray SNP genotyping (n = 94) on an Illumina OmniExpress bead chip platform. Results The mean age of subjects was 65, and 68 % were female in both the blood and saliva groups. The mean ± SD of DNA yield per ml of requested specimen was significantly higher for saliva (17.6 ± 17.8 μg/ml) than blood (13.2 ± 8.5 μg/ml), but the mean ± SD of total DNA yield obtained per saliva specimen (35 ± 36 μg from 2 ml maximum specimen volume) was approximately three-fold lower than from blood (106 ± 68 μg from 8 ml maximum specimen volume). The average genotyping call rates were >99 % for 43 of 44 saliva DNAs and >99 % for 50 of 50 for blood DNAs. For 22 of 23 paired blood and saliva samples from the same individuals, the average genotyping concordance rate was 99.996 %. High quality PCR Sanger sequencing was obtained from ≥ 98 % of blood (n = 297) and saliva (n = 1258) DNAs. DNA concentrations ≥10 ng/μl, corresponding to total yields ≥ 2 μg, were obtained for 94 % of the saliva specimens (n = 2344). Conclusions In spite of inferior purity, the performance of saliva DNAs for microarray genotyping was excellent. Our results agree with other studies concluding that saliva collection is a viable alternative to blood. The potential to boost study enrollments and reduce subject discomfort is not necessarily offset by a reduction in genotyping efficiency. Saliva DNAs performed comparably to blood DNAs for PCR Sanger sequencing. Electronic supplementary material The online version of this article (doi:10.1186/s12920-016-0172-y) contains supplementary material, which is available to authorized users.

Published
2016

22. Association of primary open-angle glaucoma with mitochondrial variants and haplogroups common in African Americans

Author

David W, Collins, Harini V, Gudiseva, Benjamin, Trachtman, Anita S, Bowman, Anna, Sagaser, Prithvi, Sankar, Eydie, Miller-Ellis, Amanda, Lehman, Victoria, Addis, and Joan M, O'Brien

Subjects
Aged, 80 and over, Male, genetic structures, Gene Amplification, Mutation, Missense, Sequence Analysis, DNA, Middle Aged, DNA, Mitochondrial, Polymerase Chain Reaction, eye diseases, Mitochondria, Black or African American, Genes, Mitochondrial, Haplotypes, Risk Factors, Humans, Female, Glaucoma, Open-Angle, Aged, Research Article
Abstract

Purpose To estimate the population frequencies of all common mitochondrial variants and ancestral haplogroups among 1,999 subjects recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study, including 1,217 primary open-angle glaucoma (POAG) cases and 782 controls, and to identify ancestral subpopulations and mitochondrial mutations as potential risk factors for POAG susceptibility. Methods Subject classification by characteristic glaucomatous optic nerve findings and corresponding visual field defects, as defined by enrolling glaucoma specialists, stereo disc photography, phlebotomy, extraction of total DNA from peripheral blood or saliva, DNA quantification and normalization, PCR amplification of whole mitochondrial genomes, Ion Torrent deep semiconductor DNA sequencing on DNA pools (“Pool-seq”), Sanger sequencing of 3,479 individual mitochondrial DNAs, and bioinformatic analysis. Results The distribution of common African haplogroups within the POAAGG study population was broadly similar to prior surveys of African Americans. However, the POAG case population was found to be enriched in L1c2 haplogroups, which are defined in part by missense mutations m.6150G>A (Val83Ile, odds ratio [OR] 1.8, p=0.01), m.6253C>T (Met117Thr, rs200165736, OR 1.6, p=0.04), and m.6480G>A (Val193Ile, rs199476128, OR 4.6, p=0.04) in the cytochrome c oxidase subunit 1 (MT-CO1) gene and by a variant, m.2220A>G (OR 2.0, p=0.01), in MT-RNR2, which encodes the mitochondrial ribosomal 16s RNA gene. L2 haplogroups were predicted to be overrepresented in the POAG case population by Pool-seq, and the difference was confirmed to be significant with Sanger sequencing, that targeted the L2-associated variants m.2416T>C (rs28358580, OR 1.2, p=0.02) and m.2332C>T (OR 1.2, p=.02) in MT-RNR2. Another variant within MT-RNR2, m.3010G>A (rs3928306), previously implicated in sensitivity to the optic neuropathy-associated antibiotic linezolid, and arising on D4 and J1 lineages, associated with Leber hereditary optic neuropathy (LHON) severity, was confirmed to be common (>5%) but was not significantly enriched in the POAG cases. Two variants linked to the composition of the gut microbiome, m.15784T>C (rs527236194, haplogroup L2a1) and m.16390G>A (rs41378955, L2 haplogroups), were also enriched in the case DNA pools. Conclusions These results implicate African mtDNA haplogroups L1c2, L1c2b, and L2 as risk factors for POAG. Approximately one in four African Americans have these mitochondrial ancestries, which may contribute to their elevated glaucoma risk. These haplogroups are defined in part by ancestral variants in the MT-RNR2 and/or MT-CO1 genes, several of which have prior disease associations, such as MT-CO1 missense variants that have been implicated in prostate cancer.

Published
2015

23. The MT-CO1 V83I Polymorphism is a Risk Factor for Primary Open-Angle Glaucoma in African American Men

Author

Victoria Addis, Joan M. O'Brien, Prithvi S. Sankar, Amanda Lehman, William T. Merritt, Eydie Miller-Ellis, Rebecca A. Rossi, David W. Collins, Meera Ramakrishnan, Stephanie Blachon, Benjamin T. Trachtman, Venkata R M Chavali, Maxwell Pistilli, and Harini V. Gudiseva

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Open angle glaucoma, DNA Mutational Analysis, Mutation, Missense, Autophagy-Related Proteins, Glaucoma, Cell Cycle Proteins, Enzyme-Linked Immunosorbent Assay, mitochondrial DNA, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Haplogroup, open-angle glacuoma, Electron Transport Complex IV, 03 medical and health sciences, symbols.namesake, genetic diseases, Risk Factors, Polymorphism (computer science), Internal medicine, Genetics, medicine, Humans, Missense mutation, Adaptor Proteins, Signal Transducing, Aged, Sanger sequencing, Sex Characteristics, Amyloid beta-Peptides, business.industry, Wild type, Sequence Analysis, DNA, Odds ratio, medicine.disease, Mitochondria, Black or African American, glaucoma, 030104 developmental biology, Endocrinology, Case-Control Studies, haplogroups, symbols, Female, Carrier Proteins, business, Glaucoma, Open-Angle
Abstract

Purpose We investigate the function of the V83I polymorphism (m.6150G>A, rs879053914) in the mitochondrial cytochrome c oxidase subunit 1 (MT-CO1) gene and its role in African American (AA) primary open-angle glaucoma (POAG). Methods This study used Sanger sequencing (1339 cases, 850 controls), phenotypic characterization of Primary Open-Angle African American Glaucoma Genetics study (POAAGG) cases, a masked chart review of CO1 missense cases (V83I plus M117T, n = 29) versus wild type cases (n = 29), a yeast 2-hybrid (Y2H) cDNA library screen, and quantification of protein–protein interactions by Y2H and ELISA. Results The association of V83I with POAG in AA was highly significant for men (odds ratio [OR] 6.5; 95% confidence interval [CI] 2.0–21.3, P = 0.0001), but not for women (OR 1.1; 95% CI, 0.62–2.00, P = 0.78). POAG cases having CO1 double missense mutation (V83I + M117T, L1c2 haplogroup) had a higher cup-to-disc ratio (0.77 vs. 0.71, P = 0.04) and significantly worse visual function (average pattern standard deviation, 6.5 vs. 4.3, P = 0.009; average mean deviation −10.4 vs. −4.5, P = 0.006) when compared to matched wild type cases (L1b haplogroup). Interaction of the V83I region of CO1 with amyloid beta peptide (Aβ) was confirmed by ELISA assay, and this interaction was abrogated by V83I. A Y2H screen of an adult human brain cDNA library with the V83 region of CO1 as bait retrieved the UBQLN1 gene. Conclusions The V83I polymorphism was associated strongly with POAG in AA men and disrupts Aβ-binding to CO1. This region also interacts with a neuroprotective protein, UBQLN1.

Published
2018

24. Promotion of Homologous Recombination and Genomic Stability by RAD51AP1 via RAD51 Recombinase Enhancement

Author

Patrick Sung, Miaw Sheue Tsai, Gareth J. Williams, Eloise Dray, Idina Shi, Björn Rydberg, David Schild, David W. Collins, Claudia Wiese, Torsten Groesser, and Joseph San Filippo

Subjects
Genome instability, DNA Repair, DNA repair, DNA damage, genetic processes, RAD51, Electrophoretic Mobility Shift Assay, Chromatids, Biology, Genomic Instability, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, XRCC3, Humans, Molecular Biology, 030304 developmental biology, Recombination, Genetic, 0303 health sciences, DNA Breaks, RNA-Binding Proteins, Life Sciences, Cell Biology, Molecular biology, DNA-Binding Proteins, enzymes and coenzymes (carbohydrates), chemistry, 030220 oncology & carcinogenesis, Mutation, health occupations, Nucleic Acid Conformation, Chromatid, Rad51 Recombinase, biological phenomena, cell phenomena, and immunity, Homologous recombination, DNA, DNA Damage, HeLa Cells
Abstract

Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand pairing step in HR. RAD51AP1 (RAD51 Associated Protein 1) is a RAD51-interacting protein whose function has remained elusive. Knockdown of RAD51AP1 in human cells by RNA interference engenders sensitivity to different types of genotoxic stress, and RAD51AP1 is epistatic to the HR protein XRCC3. Moreover, RAD51AP1-depleted cells are impaired for the recombinational repair of a DNA double-strand break and exhibit chromatid breaks both spontaneously and upon DNA damaging treatment. Purified RAD51AP1 binds both dsDNA and a D-loop structure, and, only when able to interact with RAD51, greatly stimulates the RAD51-mediated D-loop reaction. Biochemical and cytological results show that RAD51AP1 functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Our findings provide evidence that RAD51AP1 helps maintain genomic integrity via RAD51 recombinase enhancement.

Published
2007
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25. Disparate requirements for the Walker A and B ATPase motifs of human RAD51D in homologous recombination

Author

Salustra S. Urbin, Robert S. Tebbs, John M. Hinz, Peter B. Nham, Larry H. Thompson, David W. Collins, Claudia Wiese, and David Schild

Subjects
DNA Repair, DNA repair, Amino Acid Motifs, Molecular Sequence Data, RAD51, CHO Cells, Biology, Article, XRCC2, 03 medical and health sciences, Cricetulus, 0302 clinical medicine, XRCC3, Cricetinae, Two-Hybrid System Techniques, Genetics, Animals, Humans, Immunoprecipitation, Amino Acid Sequence, 030304 developmental biology, Adenosine Triphosphatases, Recombination, Genetic, 0303 health sciences, Chinese hamster ovary cell, Genetic Complementation Test, Walker motifs, Life Sciences, DNA-Binding Proteins, nucleic acids, 030220 oncology & carcinogenesis, Mutation, RAD51C, Rad51 Recombinase, Homologous recombination, DNA Damage
Abstract

In vertebrates, homologous recombinational repair (HRR) requires RAD51 and five RAD51 paralogs (XRCC2, XRCC3, RAD51B, RAD51C and RAD51D) that all contain conserved Walker A and B ATPase motifs. In human RAD51D we examined the requirement for these motifs in interactions with XRCC2 and RAD51C, and for survival of cells in response to DNA interstrand crosslinks (ICLs). Ectopic expression of wild-type human RAD51D or mutants having a non-functional A or B motif was used to test for complementation of a rad51d knockout hamster CHO cell line. Although A-motif mutants complement very efficiently, B-motif mutants do not. Consistent with these results, experiments using the yeast two- and three-hybrid systems show that the interactions between RAD51D and its XRCC2 and RAD51C partners also require a functional RAD51D B motif, but not motif A. Similarly, hamster Xrcc2 is unable to bind to the non-complementing human RAD51D B-motif mutants in co-immunoprecipitation assays. We conclude that a functional Walker B motif, but not A motif, is necessary for RAD51D's interactions with other paralogs and for efficient HRR. We present a model in which ATPase sites are formed in a bipartite manner between RAD51D and other RAD51 paralogs. peerReviewed

Published
2006

26. The primary open-angle african american glaucoma genetics study: baseline demographics

Author

Emily S, Charlson, Prithvi S, Sankar, Eydie, Miller-Ellis, Meredith, Regina, Raymond, Fertig, Julia, Salinas, Maxwell, Pistilli, Rebecca J, Salowe, Allison L, Rhodes, William T, Merritt, Michael, Chua, Benjamin T, Trachtman, Harini V, Gudiseva, David W, Collins, Venkata Ramana Murthy, Chavali, Charles, Nichols, Jeffrey, Henderer, Gui-Shuang, Ying, Rohit, Varma, Eric, Jorgenson, and Joan M, O'Brien

Subjects
Male, Corneal Pachymetry, Gonioscopy, Visual Acuity, Middle Aged, Article, Body Mass Index, Black or African American, Cross-Sectional Studies, Social Class, Risk Factors, Case-Control Studies, Surveys and Questionnaires, Humans, Visual Field Tests, Female, Gene-Environment Interaction, Visual Fields, Glaucoma, Open-Angle, Intraocular Pressure, Tomography, Optical Coherence, Aged, Genome-Wide Association Study
Abstract

To describe the baseline characteristics of the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study cohort, the largest African American population with primary open-angle glaucoma (POAG) recruited at a single institution (University of Pennsylvania [UPenn], Department of Ophthalmology, Scheie Eye Institute) to date.Population-based, cross-sectional, case-control study.A total of 2520 African American subjects aged 35 years or more who were recruited from the greater Philadelphia, Pennsylvania area.Each subject underwent a detailed interview and eye examination. The interview assessed demographic, behavioral, medical, and ocular risk factors. Current ZIP codes surrounding UPenn were recorded and US census data were queried to infer socioeconomic status. The eye examination included measurement of visual acuity (VA) and intraocular pressure, and a detailed anterior and posterior segment examination, including gonioscopy, dilated fundus and optic disc examination, visual fields, stereo disc photography, optical coherence tomography, and measurement of central corneal thickness.The baseline characteristics of gender, age, and glaucoma diagnosis were collected. Body mass index (BMI), hypertension, diabetes, alcohol and tobacco use, ocular conditions (including blindness, cataract, nonproliferative diabetic retinopathy, and age-related macular degeneration), and use of ocular medication and surgery were examined. Median population density, income, education level, and other socioeconomic measures were determined for the study cohort.Of the 2520 African Americans recruited to the POAAGG study to date, 2067 (82.0%), including 807 controls and 1260 POAG cases, met all inclusion criteria and completed the detailed clinical ocular examination. Cases were more likely to have a lower BMI (P0.01) and report a history of blindness (VA of ≤20/200; P0.001), whereas controls were more likely to have diabetes (P0.001), have nonproliferative diabetic retinopathy (P = 0.02), and be female (P0.001). Study participants were drawn largely from predominantly African American neighborhoods of low income, high unemployment, and lower education surrounding UPenn.The POAAGG study has currently recruited more than 2000 African Americans eligible for a POAG genetics study. Blindness and low BMI were significantly associated with POAG. This population was predominantly recruited from neighborhoods whose population income exists at or near the federal poverty level.

Published
2014

27. Evidence for Simultaneous Protein Interactions between Human Rad51 Paralogs

Author

David W. Collins, Tswakai Tsomondo, Yi Ching Lio, David J. Chen, and David Schild

Subjects
Genetics, Saccharomyces cerevisiae Proteins, RAD51, Saccharomyces cerevisiae, Cell Biology, Biology, Biochemistry, Recombinant Proteins, Yeast, Protein–protein interaction, DNA-Binding Proteins, XRCC2, XRCC3, Two-Hybrid System Techniques, Humans, RAD51C, Rad51 Recombinase, Baculoviridae, Molecular Biology, Protein Binding
Abstract

In yeast, the Rad51-related proteins include Rad55 and Rad57, which form a heterodimer that interacts with Rad51. Five human Rad51 paralogs have been identified (XRCC2, XRCC3, Rad51B/Rad51L1, Rad51C/Rad51L2, and Rad51D/Rad51L3), and each interacts with one or more of the others. Previously we reported that HsRad51 interacts with XRCC3, and Rad51C interacts with XRCC3, Rad51B, and HsRad51. Here we report that in the yeast two-hybrid system, Rad51D interacts with XRCC2 and Rad51C. No other interactions, including self-interactions, were found, indicating that the observed interactions are specific. The yeast Rad51 interacts with human Rad51 and XRCC3, suggesting Rad51 conservation since the human yeast divergence. Data from yeast three-hybrid experiments indicate that a number of the pairs of interactions between human Rad51 paralogs can occur simultaneously. For example, Rad51B expression enhances the binding of Rad51C to XRCC3 and to HsRad51D, and Rad51C expression allows the indirect interaction of Rad51B with Rad51D. Experiments using 6xHis-tagged proteins in the baculovirus system confirm several of our yeast results, including Rad51B interaction with Rad51D only when Rad51C is simultaneously expressed and Rad51C interaction with XRCC2 only when Rad51D is present. These results suggest that these proteins may participate in one complex or multiple smaller ones.

Published
2000

28. Isolation and characterization of RAD51C, a new human member of the RAD51 family of related genes

Author

David W. Collins, David Schild, Gregory G. Lennon, Manjit K. Dosanjh, Wufang Fan, Joanna S. Albala, and Zhiyuan Shen

Subjects
TBX1, DNA, Complementary, Saccharomyces cerevisiae Proteins, DNA Repair, Protein family, Genes, Fungal, Molecular Sequence Data, RAD51, Gene Expression, Saccharomyces cerevisiae, Biology, Fungal Proteins, XRCC2, Genetics, Humans, Tissue Distribution, Amino Acid Sequence, Cloning, Molecular, Gene, Recombination, Genetic, Base Sequence, Sequence Homology, Amino Acid, Molecular biology, DNA-Binding Proteins, RAD51C, DMC1, Rad51 Recombinase, Homologous recombination, Research Article
Abstract

The yeast and human RAD51 genes encode strand-transfer proteins that are thought to be involved in both recombinational repair of DNA damage and meiotic recombination. In yeast, the Rad51 family of related proteins also includes Rad55, Rad57 and Dmc1. In mammalian cells, five genes in this family have been identified (HsRAD51, XRCC2, XRCC3, RAD51B/hREC2 and HsDMC1), and here we report the isolation of the sixth member, RAD51C. RAD51C was originally identified by a computer screen of the EST database. A full-length approximately 1.3 kb cDNA clone has been isolated that encodes a protein of 376 aa, having a 18-26% aa identity with other human Rad51 family members. RAD51C includes a previously mapped sequenced-tagged site location near the end of chromosome 17q. The RAD51C transcript is expressed in various human tissues, with highest level of expression in testis, followed by heart muscle, spleen and prostate. Yeast two-hybrid experiments indicate that the Rad51C protein binds to two other members of the Rad51 protein family (Xrcc3 and Rad51B) but not to itself. These findings suggest that Rad51C may function similarly to the yeast Rad55 or Rad57 proteins, rather than as a Rad51 functional homolog.

Published
1998

30. Mitochondrial sequence variation in African-American primary open-angle glaucoma patients

Author

Benjamin T. Trachtman, Thomasine Gorry, Eydie Miller-Ellis, Joan M. O'Brien, Meredith Regina, Prithvi S. Sankar, Matthew Jerrehian, William T. Merritt, Harini V. Gudiseva, David W. Collins, and Allison Rhodes

Subjects
Nonsynonymous substitution, Mitochondrial DNA, genetic structures, lcsh:Medicine, Biology, DNA, Mitochondrial, Haplogroup, Deep sequencing, symbols.namesake, Databases, Genetic, Genetic variation, Humans, Genetic Predisposition to Disease, lcsh:Science, Phylogeny, Aged, Demography, Sanger sequencing, Genetics, Multidisciplinary, Base Sequence, Haplotype, lcsh:R, Genetic Variation, Reproducibility of Results, Sequence Analysis, DNA, Amplicon, eye diseases, Black or African American, Haplotypes, Case-Control Studies, symbols, lcsh:Q, sense organs, Glaucoma, Open-Angle, Research Article
Abstract

Primary open-angle glaucoma (POAG) is a major cause of blindness and results from irreversible retinal ganglion cell damage and optic nerve degeneration. In the United States, POAG is most prevalent in African-Americans. Mitochondrial genetics and dysfunction have been implicated in POAG, and potentially pathogenic sequence variations, in particular novel transversional base substitutions, are reportedly common in mitochondrial genomes (mtDNA) from POAG patient blood. The purpose of this study was to ascertain the spectrum of sequence variation in mtDNA from African-American POAG patients and determine whether novel nonsynonymous, transversional or other potentially pathogenic sequence variations are observed more commonly in POAG cases than controls. mtDNA from African-American POAG cases (n = 22) and age-matched controls (n = 22) was analyzed by deep sequencing of a single 16,487 base pair PCR amplicon by Ion Torrent, and candidate novel variants were validated by Sanger sequencing. Sequence variants were classified and interpreted using the MITOMAP compendium of polymorphisms. 99.8% of the observed variations had been previously reported. The ratio of novel variants to POAG cases was 7-fold lower than a prior estimate. Novel mtDNA variants were present in 3 of 22 cases, novel nonsynonymous changes in 1 of 22 cases and novel transversions in 0 of 22 cases; these proportions are significantly lower (p

Published
2013

31. Antivenom

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

32. Acinetobacter Bacteremia

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

33. AKI, Epidemiology of

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

34. Angiotensin II

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

35. Anti-glomerular Basement Membrane (GBM) Disease

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

36. Antibiotics: Resistance Mechanisms and Clinical Relevance

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

37. Acute Calculous Cholecystitis

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

38. Acinetobacter Urosepsis

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

39. Anti-arrhythmic Therapy

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

40. Acinetobacter Skin Infection

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

41. Acinetobacter ICU-Acquired Infection

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

42. Anterior Scalene Syndrome

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

43. Alkaline Phosphatase

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

44. Acute Care Surgery

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

45. Acute Ischemic Stroke

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

46. Acute Quadriplegic Myopathy

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

47. Arterial Blood Gas Analysis

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

48. Arterial Hypoxemia

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

49. Acute Coronary Syndrome: Risk Stratification

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

50. Acute Respiratory Failure, Mechanisms of

Author

Howard R. Champion, Nova L. Panebianco, Jan J. De Waele, Lewis J. Kaplan, Manu L. N. G. Malbrain, Annie L. Slaughter, Walter L. Biffl, Clay Cothren Burlew, Ernest E. Moore, Parita Bhuva, Barnett R. Nathan, Michael E. Silverman, Richard D. Shih, Luciano Gattinoni, E. Carlesso, Pietro Caironi, Argyris Michalopoulos, Matthew E. Falagas, Angela M. Mills, Anthony J. Dean, Christopher R. Wyatt, Chadwick D. Miller, Karina M. Soto-Ruiz, Joseph Varon, W. Frank Peacock, Prasad Devarajan, Arun Jeyabalan, Joan R. Badia, José A. Lorente, Nicolás Nin, Ramsey J. Daher, Mark D. Okusa, Rui P. Moreno, Djillali Annane, Brenna M. Farmer, Claudio Ronco, Zaccaria Ricci, Jameel Ali, Richard D. Branson, Bryce R. H. Robinson, Lara Wijayasiri, Andrew Rhodes, Maurizio Cecconi, Stuart F. Reynolds, Peter G. Brindley, John A. Kellum, Nattachai Srisawat, Patrick D. Brophy, Michelle Baack, Eric A. J. Hoste, Edward T. Dickinson, Alexander L. Colonna, J. Wayne Meredith, Ali El-Solh, Brian H. Rowe, Howard L. Corwin, Joel M. Bartfield, Thomas M. Scalea, Kareem R. AbdelFattah, Joseph P. Minei, Patrick T. Murray, Caitlin W. Hicks, Peter Q. Eichacker, S. Uddin, Susanna Price, Joseph P. Lynch, Anne-Cornélie J. M. Pont, Tyler W. Barrett, Brett F. Bechtel, David F. Gaieski, Munish Goyal, Mette M. Berger, Lucas Liaudet, Pascal Vranckx, Marco Valgimigli, P. W. Serruys, Ian Loftus, Charles S. Brudney, Srini Pyati, Juan B. Ochoa, Mary K. Miranowski, Rebecca M. Dodson, Sandra L. Kavalukas, Adrian Barbul, Jonathan R. Egan, Marino S. Festa, Samir H. Haddad, Yaseen M. Arabi, David W. Collins, Yahya Shehabi, Steven E. Carsons, Wouter Meersseman, Daniel K. Resnick, Basheal M. Agrawal, and Griet Thielen

Published
2012

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