Medicine and Health Sciences Commons^™

Cotrimoxazole Prophylaxis Increases Resistance Gene Prevalence And Α-Diversity But Decreases Β-Diversity In The Gut Microbiome Of Human Immunodeficiency Virus-Exposed, Uninfected Infants, Alaric W D'Souza, Eshia Moodley-Govender, Bertram Berla, Tejas Kelkar, Bin Wang, Xiaoqing Sun, Brodie Daniels, Anna Coutsoudis, Indi Trehan, Gautam Dantas

2020-Current year OA Pubs

BACKGROUND: Prophylactic cotrimoxazole treatment is recommended in human immunodeficiency virus (HIV)-exposed, uninfected (HEU) infants, but the effects of this treatment on developing HEU infant gut microbiotas and resistomes are largely undefined.

METHODS: We analyzed whole-metagenome sequencing data from 163 longitudinally collected stool samples from 63 HEU infants randomized to receive (n = 34; CTX-T) or to not receive (n = 29; CTX-N) prophylactic cotrimoxazole treatment. We generated taxonomic, functional pathway, and resistance gene profiles for each sample and compared microbiome signatures between the CTX-T and CTX-N infants.

RESULTS: Metagenomic analysis did not reveal significant differences in taxonomic or functional pathway …

Longitudinal Care Cascade Outcomes Among People Eligible For Antiretroviral Therapy Who Are Newly Linking To Care In Zambia: A Multistate Analysis, Aaloke Mody, David V Glidden, Ingrid Eshun-Wilson, Kombatende Sikombe, Sandra Simbeza, Njekwa Mukamba, Paul Somwe, Laura K Beres, Jake Pry, Carolyn Bolton-Moore, Nancy Padian, Charles B Holmes, Izukanji Sikazwe, Elvin H Geng

2020-Current year OA Pubs

BACKGROUND: Retention in human immunodeficiency virus (HIV) care is dynamic, with patients frequently transitioning in and out of care. Analytical approaches (eg, survival analyses) commonly used to assess HIV care cascade outcomes fail to capture such transitions and therefore incompletely represent care outcomes over time.

METHODS: We analyzed antiretroviral therapy (ART)-eligible adults newly linking to care at 64 clinics in Zambia between 1 April 2014 and 31 July 2015. We used electronic medical record data and supplemented these with updated care outcomes ascertained by tracing a multistage random sample of patients lost to follow-up (LTFU, >90 days late for last …

Approaches To Aggressive B-Cell Lymphomas In Less Fit Patients, Nancy L Bartlett

2020-Current year OA Pubs

Treating unfit patients with aggressive B-cell lymphoma poses the dilemma of balancing potential cure while minimizing toxicity because of frailty and comorbidities. Age greater than 80 years and common comorbidities such as cardiovascular disease and poorly controlled diabetes mellitus often preclude the use of full-dose anthracyclines and steroids, the backbones of standard regimens for aggressive B-cell lymphomas. Assessing patient fitness remains subjective, with no consensus on best practice or how to integrate assessment tools into decision making. Incorporation of prephase steroids for all unfit patients may markedly improve performance status with consideration of standard dose therapy, especially in patients less …

Comparing The Effects Of Hiv Self-Testing To Standard Hiv Testing For Key Populations: A Systematic Review And Meta-Analysis, T Charles Witzel, Ingrid Eshun-Wilson, Muhammad S Jamil, Nerissa Tilouche, Carmen Figueroa, Cheryl C Johnson, David Reid, Rachel Baggaley, Nandi Siegfried, Fiona M Burns, Alison J Rodger, Peter Weatherburn

2020-Current year OA Pubs

BACKGROUND: We update a previous systematic review to inform new World Health Organization HIV self-testing (HIVST) recommendations. We compared the effects of HIVST to standard HIV testing services to understand which service delivery models are effective for key populations.

METHODS: We did a systematic review of randomised controlled trials (RCTs) which compared HIVST to standard HIV testing in key populations, published from 1 January 2006 to 4 June 2019 in PubMed, Embase, Global Index Medicus, Social Policy and Practice, PsycINFO, Health Management Information Consortium, EBSCO CINAHL Plus, Cochrane Library and Web of Science. We extracted study characteristic and outcome data …

Sequence Analysis In Bos Taurus Reveals Pervasiveness Of X-Y Arms Races In Mammalian Lineages, Jennifer F Hughes, Colin Kremitzki, Catrina Fronick, Tina A Graves-Lindsay, Lucinda Fulton, Wesley C Warren, Richard K Wilson, Et Al.

2020-Current year OA Pubs

Studies of Y Chromosome evolution have focused primarily on gene decay, a consequence of suppression of crossing-over with the X Chromosome. Here, we provide evidence that suppression of X-Y crossing-over unleashed a second dynamic: selfish X-Y arms races that reshaped the sex chromosomes in mammals as different as cattle, mice, and men. Using super-resolution sequencing, we explore the Y Chromosome of

The Impact Of Uncorrected Mild Aortic Insufficiency At The Time Of Left Ventricular Assist Device Implantation, Yuki Tanaka, Tomohiro Nakajima, Irene Fischer, Fei Wan, Kunal Kotkar, Marc R Moon, Ralph J Damiano Jr, Muhammad F Masood, Akinobu Itoh

2020-Current year OA Pubs

OBJECTIVE: The study objective was to investigate the progression of uncorrected mild aortic insufficiency and its impact on survival and functional status after left ventricular assist device implantation.

METHODS: We retrospectively reviewed 694 consecutive patients who underwent implantation of a continuous-flow left ventricular assist device between January 2006 and March 2018. Pre-left ventricular assist device transthoracic echocardiography identified 111 patients with mild aortic insufficiency and 493 patients with trace or no aortic insufficiency. To adjust for differences in preoperative factors, propensity score matching was used, resulting in 101 matched patients in each of the mild aortic insufficiency and no aortic …

A Randomized, Placebo-Controlled Trial Evaluating Effects Of Lebrikizumab On Airway Eosinophilic Inflammation And Remodelling In Uncontrolled Asthma (Clavier), Cary D Austin, Kaharu Sumino, Et Al.

2020-Current year OA Pubs

BACKGROUND: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling.

OBJECTIVE: To report safety and efficacy results from enrolled participants with available data from CLAVIER.

METHODS: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm

RESULTS: There was a baseline …

Carfilzomib, Lenalidomide, And Dexamethasone Plus Transplant In Newly Diagnosed Multiple Myeloma, Jagoda K Jasielec, Ravi Vij, Et Al.

2020-Current year OA Pubs

In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point …

Altered Capicua Expression Drives Regional Purkinje Neuron Vulnerability Through Ion Channel Gene Dysregulation In Spinocerebellar Ataxia Type 1, Ravi Chopra, David D Bushart, John P Cooper, Dhananjay Yellajoshyula, Logan M Morrison, Haoran Huang, Hillary P Handler, Luke J Man, Warunee Dansithong, Daniel R Scoles, Stefan M Pulst, Harry T Orr, Vikram G Shakkottai

2020-Current year OA Pubs

Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, …

Central Nervous System Pathology In Preclinical Mps Iiib Dogs Reveals Progressive Changes In Clinically Relevant Brain Regions, Martin T Egeland, Marta M Tarczyluk-Wells, Melissa M Asmar, Evan G Adintori, Roger Lawrence, Elizabeth M Snella, Jackie K Jens, Brett E Crawford, Jill C M Wait, Emma Mccullagh, Jason Pinkstaff, Jonathan D Cooper, N Matthew Ellinwood

2020-Current year OA Pubs

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B) is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase activity, leading to increased levels of nondegraded heparan sulfate (HS). A mouse model has been useful to evaluate novel treatments for MPS IIIB, but has limitations. In this study, we evaluated the naturally occurring canine model of MPS IIIB for the onset and progression of biochemical and neuropathological changes during the preclinical stages (onset approximately 24-30 months of age) of canine MPS IIIB disease. Even by 1 month of age, MPS IIIB dogs had elevated HS levels in brain …

Functional Genomic Analyses Uncover Apoe-Mediated Regulation Of Brain And Cerebrospinal Fluid Beta-Amyloid Levels In Parkinson Disease, Laura Ibanez, Jorge A Bahena, Chengran Yang, Umber Dube, Fabiana H G Farias, John P Budde, Kristy Bergmann, Carol Brenner-Webster, John C Morris, Richard J Perrin, Nigel J Cairns, John O'Donnell, Rebecca Miller, Albert A Davis, Paul Kotzbauer, Meghan C Campbell, Joel S Perlmutter, Oscar Harari, Carlos Cruchaga, Bruno A Benitez, Et Al.

2020-Current year OA Pubs

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta

A Phase 1b Study Of Afm13 In Combination With Pembrolizumab In Patients With Relapsed Or Refractory Hodgkin Lymphoma, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

In relapsed/refractory Hodgkin lymphoma (R/R HL), immunotherapies such as the anti-programmed death-1 inhibitor pembrolizumab have demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatment. The CD30/CD16A-bispecific antibody AFM13 is an innate immune cell engager, a first-in-class, tetravalent antibody, designed to create a bridge between CD30 on HL cells and the CD16A receptor on natural killer cells and macrophages, to induce tumor cell killing. Early studies of AFM13 have demonstrated signs of efficacy as monotherapy for patients with R/R HL and the combination of AFM13 with pembrolizumab represents a rational new treatment modality. Here, we describe a …

Anemocheck-Lrs: An Optimized, Color-Based Point-Of-Care Test To Identify Severe Anemia In Limited-Resource Settings, Marina S Perez-Plazola, Erika A Tyburski, Luke R Smart, Thad A Howard, Amanda Pfeiffer, Russell E Ware, Wilbur A Lam, Patrick T Mcgann

2020-Current year OA Pubs

BACKGROUND: Severe anemia is common and frequently fatal for hospitalized patients in limited-resource settings. Lack of access to low-cost, accurate, and rapid diagnosis of anemia impedes the delivery of life-saving care and appropriate use of the limited blood supply. The WHO Haemoglobin Colour Scale (HCS) is a simple low-cost test but frequently inaccurate. AnemoCheck-LRS (limited-resource settings) is a rapid, inexpensive, color-based point-of-care (POC) test optimized to diagnose severe anemia.

METHODS: Deidentified whole blood samples were diluted with plasma to create variable hemoglobin (Hb) concentrations, with most in the severe (≤ 7 g/dL) or profound (≤ 5 g/dL) anemia range. Each …

Non-Negative Data-Driven Mapping Of Structural Connections With Application To The Neonatal Brain, E Thompson, A R Mohammadi-Nejad, E C Robinson, J L R Andersson, S Jbabdi, M F Glasser, M Bastiani, S N Sotiropoulos

2020-Current year OA Pubs

Mapping connections in the neonatal brain can provide insight into the crucial early stages of neurodevelopment that shape brain organisation and lay the foundations for cognition and behaviour. Diffusion MRI and tractography provide unique opportunities for such explorations, through estimation of white matter bundles and brain connectivity. Atlas-based tractography protocols, i.e. a priori defined sets of masks and logical operations in a template space, have been commonly used in the adult brain to drive such explorations. However, rapid growth and maturation of the brain during early development make it challenging to ensure correspondence and validity of such atlas-based tractography approaches …

A Praziquantel Treatment Study Of Immune And Transcriptome Profiles In Schistosoma Haematobium-Infected Gabonese Schoolchildren, Lucja A Labuda, Ayola A Adegnika, Bruce A Rosa, John Martin, Ulysse Ateba-Ngoa, Abena Serwaa Amoah, Honorine Mbenkep Lima, Lynn Meurs, Moustapha Mbow, Mikhael D Manurung, Jeannot F Zinsou, Hermelijn H Smits, Peter G Kremsner, Makedonka Mitreva, Maria Yazdanbakhsh

2020-Current year OA Pubs

BACKGROUND: Although Schistosoma haematobium infection has been reported to be associated with alterations in immune function, in particular immune hyporesponsiveness, there have been only few studies that have used the approach of removing infection by drug treatment to establish this and to understand the underlying molecular mechanisms.

METHODS: Schistosoma haematobium-infected schoolchildren were studied before and after praziquantel treatment and compared with uninfected controls. Cellular responses were characterized by cytokine production and flow cytometry, and in a subset of children RNA sequencing (RNA-Seq) transcriptome profiling was performed.

RESULTS: Removal of S haematobium infection resulted in increased schistosome-specific cytokine responses that were …

Genetics And Geography Of Leukocyte Telomere Length In Sub-Saharan Africans, Steven C Hunt, Michael A Province, Et Al.

2020-Current year OA Pubs

Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To elucidate the roles of genetics and geography in LTL variability across humans, we compared LTL measured in 1295 sub-Saharan Africans (SSAs) with 559 African-Americans (AAms) and 2464 European-Americans (EAms). LTL differed significantly across SSAs (P = 0.003), with the San from Botswana (with the oldest genomic ancestry) having the longest LTL and populations from Ethiopia having the shortest LTL. SSAs had significantly longer LTL than AAms [P = 6.5(e-16)] whose LTL was significantly longer than EAms [P = 2.5(e-7)]. Genetic variation in SSAs explained 52% of …

Maternal Altitude And Risk Of Low Birthweight: A Systematic Review And Meta-Analyses, Lin Yang, Veronika Helbich-Poschacher, Chao Cao, Katrin Klebermass-Schrehof, Thomas Waldhoer

2020-Current year OA Pubs

BACKGROUND: Previous studies conducted in high altitude regions showed that maternal altitude was associated with low birth weight. The effect size of birth weight reduction is inclusive with unknown effects due to preterm birth. We systematically reviewed the literature and synthesize evidence on associations between altitude elevation from sea level and birth weight.

METHOD: We searched MEDLINE/PubMed, Embase, Scopus, Web of Science, and Cochrane database, from inception to May 5, 2020 for studies that reported maternal altitude and birth weight. Bayesian multilevel effect models were employed to estimate the effect size on birth weight (and gestational age) associated with altitude. …

Geff: Graph Embedding For Functional Fingerprinting, Kausar Abbas, Enrico Amico, Diana Otero Svaldi, Uttara Tipnis, Duy Anh Duong-Tran, Mintao Liu, Meenusree Rajapandian, Jaroslaw Harezlak, Beau M Ances, Joaquín Goñi

2020-Current year OA Pubs

It has been well established that Functional Connectomes (FCs), as estimated from functional MRI (fMRI) data, have an individual fingerprint that can be used to identify an individual from a population (subject-identification). Although identification rate is high when using resting-state FCs, other tasks show moderate to low values. Furthermore, identification rate is task-dependent, and is low when distinct cognitive states, as captured by different fMRI tasks, are compared. Here we propose an embedding framework, GEFF (Graph Embedding for Functional Fingerprinting), based on group-level decomposition of FCs into eigenvectors. GEFF creates an eigenspace representation of a group of subjects using one …

A Retrospective Analysis Of Clinical Use Of Alirocumab In Lipoprotein Apheresis Patients, Anne C Goldberg, Richard L Dunbar, Linda Hemphill, Stephan P Babirak, Gerald Wilson, Michael Wooten, Mohamed Iydroose, Kelley Dacus, Heather Minchew, Julie-Ann Dutton, Patrick M Moriarty

2020-Current year OA Pubs

BACKGROUND: The previously published ODYSSEY ESCAPE trial demonstrated a significant reduction in the use of lipoprotein apheresis for heterozygous familial hypercholesterolemia (HeFH) patients when placed on alirocumab 150 mg every 2 weeks. In patients with HeFH who have consistently elevated levels of low-density lipoprotein cholesterol (LDL-C) despite maximally tolerated statin therapy, current lipid guidelines recommend apheresis. Although apheresis reduces LDL-C levels by 50%-75%, it must be repeated, as frequently as every 1-2 weeks.

OBJECTIVE: To assess clinical experience with apheresis and alirocumab for patients in a real-world practice setting.

METHODS: This retrospective review included patients from 5 apheresis centers who …

Relationships Between Accelerometry And General Compensatory Movements Of The Upper Limb After Stroke, Jessica Barth, Joeseph W Klaesner, Catherine E Lang

2020-Current year OA Pubs

BACKGROUND: Standardized assessments are used in rehabilitation clinics after stroke to measure restoration versus compensatory movements of the upper limb. Accelerometry is an emerging tool that can bridge the gap between in- and out-of-clinic assessments of the upper limb, but is limited in that it currently does not capture the quality of a person's movement, an important concept to assess compensation versus restoration. The purpose of this analysis was to characterize how accelerometer variables may reflect upper limb compensatory movement patterns after stroke.

METHODS: This study was a secondary analysis of an existing data set from a Phase II, single-blind, …

Brain Function Distinguishes Female Carriers And Non-Carriers Of Familial Risk For Autism, Adam T Eggebrecht, Ally Dworetsky, Zoë Hawks, Rebecca Coalson, Babatunde Adeyemo, Savannah Davis, Daniel Gray, Alana Mcmichael, Steven E Petersen, John N Constantino, John R Pruett

2020-Current year OA Pubs

BACKGROUND: Autism spectrum disorder (ASD) is characterized by high population-level heritability and a three-to-one male-to-female ratio that occurs independent of sex linkage. Prior research in a mixed-sex pediatric sample identified neural signatures of familial risk elicited by passive viewing of point light motion displays, suggesting the possibility that both resilience and risk of autism might be associated with brain responses to biological motion. To confirm a relationship between these signatures and inherited risk of autism, we tested them in families enriched for genetic loading through undiagnosed ("carrier") females.

METHODS: Using functional magnetic resonance imaging, we examined brain responses to passive …

Splicing Factor Sf3b1 Promotes Endometrial Cancer Progression Via Regulating Ksr2 Rna Maturation, Pooja Popli, Megan M Richters, Sangappa B Chadchan, Tae Hoon Kim, Eric Tycksen, Obi Griffith, Premal H Thaker, Malachi Griffith, Ramakrishna Kommagani

2020-Current year OA Pubs

Although endometrial cancer is the most common cancer of the female reproductive tract, we have little understanding of what controls endometrial cancer beyond the transcriptional effects of steroid hormones such as estrogen. As a result, we have limited therapeutic options for the ~62,000 women diagnosed with endometrial cancer each year in the United States. Here, in an attempt to identify new prognostic and therapeutic targets, we focused on a new area for this cancer-alternative mRNA splicing-and investigated whether splicing factor, SF3B1, plays an important role in endometrial cancer pathogenesis. Using a tissue microarray, we found that human endometrial tumors expressed …

Trem2 Activation On Microglia Promotes Myelin Debris Clearance And Remyelination In A Model Of Multiple Sclerosis, Francesca Cignarella, Fabia Filipello, Bryan Bollman, Claudia Cantoni, Alberto Locca, Robert Mikesell, Melissa Manis, Adiljan Ibrahim, Li Deng, Bruno A Benitez, Carlos Cruchaga, Danilo Licastro, Kathie Mihindukulasuriya, Oscar Harari, Michael Buckland, David M Holtzman, Arnon Rosenthal, Tina Schwabe, Ilaria Tassi, Laura Piccio

2020-Current year OA Pubs

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the …

Assessment Of Postoperative Nausea And Vomiting After Bariatric Surgery Using A Validated Questionnaire, Bradley S Kushner, Dawn Freeman, Jayme Sparkman, Arghavan Salles, J Christopher Eagon, Shaina R Eckhouse

2020-Current year OA Pubs

BACKGROUND: Postoperative nausea and vomiting (PONV) is known to occur after bariatric surgery, with over two thirds of patients affected. However, variability exists in how to objectively measure PONV.

OBJECTIVES: The goals of the present study were to use a validated, patient-centered scoring tool, the Rhodes Index of Nausea, Vomiting, and Retching to measure the severity of PONV after bariatric surgery, to directly compare PONV between patients who underwent laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB), and to identify risk factors for the development of PONV after bariatric surgery.

SETTING: Barnes-Jewish Hospital/Washington University School of Medicine, St. …

Oral Leukoplakia And Risk Of Progression To Oral Cancer: A Population-Based Cohort Study, Anil K Chaturvedi, Natalia Udaltsova, Eric A Engels, Jed A Katzel, Elizabeth L Yanik, Hormuzd A Katki, Mark W Lingen, Michael J Silverberg

2020-Current year OA Pubs

BACKGROUND: The optimal clinical management of oral precancer remains uncertain. We investigated the natural history of oral leukoplakia, the most common oral precancerous lesion, to estimate the relative and absolute risks of progression to cancer, the predictive accuracy of a clinician's decision to biopsy a leukoplakia vis-à-vis progression, and histopathologic predictors of progression.

METHODS: We conducted a retrospective cohort study (1996-2012) of patients with oral leukoplakia (n = 4886), identified using electronic medical records within Kaiser Permanente Northern California. Among patients with leukoplakia who received a biopsy (n = 1888), we conducted a case-cohort study to investigate histopathologic predictors of …

Phase 1 Study Of The Mdm2 Antagonist Ro6839921 In Patients With Acute Myeloid Leukemia, Geoffrey L Uy, Sarit Assouline, Anne-Marie Young, Steven Blotner, Brian Higgins, Lin-Chi Chen, Karen Yee

2020-Current year OA Pubs

In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) …

Safety And Immunogenicity Of Fc-Eda, A Recombinant Ectodysplasin A1 Replacement Protein, In Human Subjects, Iris Körber, Ophir D Klein, Patrick Morhart, Florian Faschingbauer, Dorothy K Grange, Angus Clarke, Christine Bodemer, Silvia Maitz, Kenneth Huttner, Neil Kirby, Caroline Durand, Holm Schneider

2020-Current year OA Pubs

In X-linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather or febrile illness. Fc-EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc-EDA and efficacy if …

Comprehensive Pulmonary Safety Review Of Inhaled Technosphere® Insulin In Patients With Diabetes Mellitus, Janet B Mcgill, Anne Peters, John B Buse, Susanne Steiner, Tiffany Tran, Frank M Pompilio, David M Kendall

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVE: Technosphere

METHODS: Pooled data from 13 phase 2/3 clinical studies in 5505 patients with T1DM or T2DM treated with TI, Technosphere inhalation powder without insulin (TP; placebo), or active-comparator treatment were analyzed for incidences of respiratory treatment-emergent adverse events (TEAEs), changes in pulmonary function, and lung malignancies. Radiographic changes in the lungs were monitored in a subset of 229 patients.

RESULTS: Among 3017 patients receiving TI, the median duration of TI exposure was 168 days; median active-comparator and TP exposure durations were 363 and 149 days for 2198 and 290 patients, respectively. Respiratory TEAEs were comparable across …

Phenotypic Diversity In An International Cure Vcp Disease Registry, Chiseko Ikenaga, Andrew R Findlay, Michelle Seiffert, Allison Peck, Nathan Peck, Nicholas E Johnson, Jeffrey M Statland, Conrad C Weihl

2020-Current year OA Pubs

BACKGROUND: Dominant mutations in valosin-containing protein (VCP) gene cause an adult onset inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia also termed multisystem proteinopathy (MSP). The genotype-phenotype relationships in VCP-related MSP are still being defined; in order to understand this better, we investigated the phenotypic diversity and patterns of weakness in the Cure VCP Disease Patient Registry.

METHODS: Cure VCP Disease, Inc. was founded in 2018 for the purpose of connecting patients with VCP gene mutations and researchers to help advance treatments and cures. Cure VCP Disease Patient Registry is maintained by Coordination of Rare Diseases at Sanford. …

Gadobutrol-Enhanced Cardiac Magnetic Resonance Imaging For Detection Of Coronary Artery Disease, Andrew E Arai, Pamela K Woodard, Et Al.

2020-Current year OA Pubs

BACKGROUND: Gadolinium-based contrast agents were not approved in the United States for detecting coronary artery disease (CAD) prior to the current studies.

OBJECTIVES: The purpose of this study was to determine the sensitivity and specificity of gadobutrol for detection of CAD by assessing myocardial perfusion and late gadolinium enhancement (LGE) imaging.

METHODS: Two international, single-vendor, phase 3 clinical trials of near identical design, "GadaCAD1" and "GadaCAD2," were performed. Cardiovascular magnetic resonance (CMR) included gadobutrol-enhanced first-pass vasodilator stress and rest perfusion followed by LGE imaging. CAD was defined by quantitative coronary angiography (QCA) but computed tomography coronary angiography could exclude significant …