Digital Commons Network^™

Human Pluripotent Stem Cell-Derived Kidney Organoids With Improved Collecting Duct Maturation And Injury Modeling, Kohei Uchimura, Haojia Wu, Yasuhiro Yoshimura, Benjamin D Humphreys

Open Access Publications

Maximizing the potential of human kidney organoids for drug testing and regenerative medicine and to model development and disease requires addressing cell immaturity, the lack of a mature collecting system, and off-target cell types. By independently generating two kidney progenitor cell populations-metanephric mesenchyme and ureteric bud (UB)-like cells-we could generate kidney organoids with a collecting system. We also identify the hormones aldosterone and arginine vasopressin (AVP) as critical to promote differentiation of collecting duct cell types including both principal cells (PCs) and intercalated cells (ICs). The resulting PCs express aquaporin-2 (AQP2) protein, which undergoes translocation to the apical membrane after …

Comparative Evaluation Of Clinical Manifestations And Risk Of Death In Patients Admitted To Hospital With Covid-19 And Seasonal Influenza: Cohort Study, Yan Xie, Benjamin Bowe, Geetha Maddukuri, Ziyad Al-Aly

Open Access Publications

No abstract provided.

Protocol For The Prognosticating Delirium Recovery Outcomes Using Wakefulness And Sleep Electroencephalography (P-Drows-E) Study: A Prospective Observational Study Of Delirium In Elderly Cardiac Surgical Patients, S Kendall Smith, Thomas Nguyen, Alyssa K Labonte, Mohammadmehdi Kafashan, Orlandrea Hyche, Christian S Guay, Elizabeth Wilson, Courtney W Chan, Anhthi Luong, L Brian Hickman, Bradley A Fritz, Daniel Emmert, Thomas J Graetz, Spencer J Melby, Brendan P Lucey, Yo-El S Ju, Troy S Wildes, Michael S Avidan, Ben J A Palanca

Open Access Publications

INTRODUCTION: Delirium is a potentially preventable disorder characterised by acute disturbances in attention and cognition with fluctuating severity. Postoperative delirium is associated with prolonged intensive care unit and hospital stay, cognitive decline and mortality. The development of biomarkers for tracking delirium could potentially aid in the early detection, mitigation and assessment of response to interventions. Because sleep disruption has been posited as a contributor to the development of this syndrome, expression of abnormal electroencephalography (EEG) patterns during sleep and wakefulness may be informative. Here we hypothesise that abnormal EEG patterns of sleep and wakefulness may serve as predictive and diagnostic …

Yap And Taz Maintain Prox1 Expression In The Developing Lymphatic And Lymphovenous Valves In Response To Vegf-C Signaling, Boksik Cha, Yen-Chun Ho, Xin Geng, Md Riaj Mahamud, Lijuan Chen, Yeunhee Kim, Dongwon Choi, Tae Hoon Kim, Gwendalyn J Randolph, Xinwei Cao, Hong Chen, R Sathish Srinivasan

Open Access Publications

Lymphatic vasculature is an integral part of digestive, immune and circulatory systems. The homeobox transcription factor PROX1 is necessary for the development of lymphatic vessels, lymphatic valves (LVs) and lymphovenous valves (LVVs). We and others previously reported a feedback loop between PROX1 and vascular endothelial growth factor-C (VEGF-C) signaling. PROX1 promotes the expression of the VEGF-C receptor VEGFR3 in lymphatic endothelial cells (LECs). In turn, VEGF-C signaling maintains PROX1 expression in LECs. However, the mechanisms of PROX1/VEGF-C feedback loop remain poorly understood. Whether VEGF-C signaling is necessary for LV and LVV development is also unknown. Here, we report for the …

Autoregulation Of Yeast Ribosomal Proteins Discovered By Efficient Search For Feedback Regulation, Basab Roy, David Granas, Fredrick Bragg Jr, Jonathan A Y Cher, Michael A White, Gary D Stormo

Open Access Publications

Post-transcriptional autoregulation of gene expression is common in bacteria but many fewer examples are known in eukaryotes. We used the yeast collection of genes fused to GFP as a rapid screen for examples of feedback regulation in ribosomal proteins by overexpressing a non-regulatable version of a gene and observing the effects on the expression of the GFP-fused version. We tested 95 ribosomal protein genes and found a wide continuum of effects, with 30% showing at least a 3-fold reduction in expression. Two genes, RPS22B and RPL1B, showed over a 10-fold repression. In both cases the cis-regulatory segment resides in the …

Single-Arm Prospective Interventional Study Assessing Feasibility Of Using Gallium-68 Ventilation And Perfusion Pet/Ct To Avoid Functional Lung In Patients With Stage Iii Non-Small Cell Lung Cancer, Nicholas Bucknell, Amir Iravani, Et Al

Open Access Publications

BACKGROUND: In the curative-intent treatment of locally advanced lung cancer, significant morbidity and mortality can result from thoracic radiation therapy. Symptomatic radiation pneumonitis occurs in one in three patients and can lead to radiation-induced fibrosis. Local failure occurs in one in three patients due to the lungs being a dose-limiting organ, conventionally restricting tumour doses to around 60 Gy. Functional lung imaging using positron emission tomography (PET)/CT provides a geographic map of regional lung function and preclinical studies suggest this enables personalised lung radiotherapy. This map of lung function can be integrated into Volumetric Modulated Arc Therapy (VMAT) radiotherapy planning …

Macrophage-Derived Vascular Endothelial Growth Factor-A Is Integral To Neuromuscular Junction Reinnervation After Nerve Injury, Chuieng-Yi Lu, Katherine B. Santosa, Albina Jablonka-Shariff, Bianca Vannucci, Anja Fuchs, Isaiah Turnbull, Deng Pan, Matthew D. Wood, Alison K. Snyder-Warwick

Open Access Publications

Functional recovery in the end target muscle is a determinant of outcome after peripheral nerve injury. The neuromuscular junction (NMJ) provides the interface between nerve and muscle and includes non-myelinating terminal Schwann cells (tSCs). After nerve injury, tSCs extend cytoplasmic processes between NMJs to guide axon growth and NMJ reinnervation. The mechanisms related to NMJ reinnervation are not known. We used multiple mouse models to investigate the mechanisms of NMJ reinnervation in both sexes, specifically whether macrophage-derived vascular endothelial growth factor-A (Vegf-A) is crucial to establishing NMJ reinnervation at the end target muscle. Both macrophage number and Vegf-A expression increased …

The Key Glycolytic Enzyme Phosphofructokinase Is Involved In Resistance To Antiplasmodial Glycosides, Gillian M Fisher, Simon A Cobbold, Andrew Jezewski, Emma F Carpenter, Megan Arnold, Annie N Cowell, Erick T Tjhin, Kevin J Saliba, Tina S Skinner-Adams, Marcus C S Lee, Audrey Odom John, Elizabeth A Winzeler, Malcolm J Mcconville, Sally-Ann Poulsen, Katherine T Andrews

Open Access Publications

No abstract provided.

Impact Of A 2-Year Trial Of Nutritional Ketosis On Indices Of Cardiovascular Disease Risk In Patients With Type 2 Diabetes, Shaminie J Athinarayanan, Sarah J Hallberg, Amy L Mckenzie, Katharina Lechner, Sarah King, James P Mccarter, Jeff S Volek, Stephen D Phinney, Ronald M Krauss

Open Access Publications

BACKGROUND: We have previously reported that in patients with type 2 diabetes (T2D) consumption of a very low carbohydrate diet capable of inducing nutritional ketosis over 2 years (continuous care intervention, CCI) resulted in improved body weight, glycemic control, and multiple risk factors for cardiovascular disease (CVD) with the exception of an increase in low density lipoprotein cholesterol (LDL-C). In the present study, we report the impact of this intervention on markers of risk for atherosclerotic cardiovascular disease (CVD), with a focus on lipoprotein subfraction particle concentrations as well as carotid-artery intima-media thickness (CIMT).

METHODS: Analyses were performed in patients …

Activation Of The Archaeal Ion Channel Mthk Is Exquisitely Regulated By Temperature, Yihao Jiang, Vinay Idikuda, Sandipan Chowdhury, Baron Chanda

Open Access Publications

Physiological response to thermal stimuli in mammals is mediated by a structurally diverse class of ion channels, many of which exhibit polymodal behavior. To probe the diversity of biophysical mechanisms of temperature-sensitivity, we characterized the temperature-dependent activation of MthK, a two transmembrane calcium-activated potassium channel from thermophilic archaebacteria. Our functional complementation studies show that these channels are more efficient at rescuing K

Frequency And Risk Factors Of Acute Kidney Injury During Diabetic Ketoacidosis In Children And Association With Neurocognitive Outcomes, Sage R. Myers, Kimberly S. Quayle, Et Al

Open Access Publications

Importance: Acute kidney injury (AKI) occurs commonly during diabetic ketoacidosis (DKA) in children, but the underlying mechanisms and associations are unclear.

Objective: To investigate risk factors for AKI and its association with neurocognitive outcomes in pediatric DKA.

Design, Setting, and Participants: This cohort study was a secondary analysis of data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in DKA Study, a prospective, multicenter, randomized clinical trial comparing fluid protocols for pediatric DKA in 13 US hospitals. Included DKA episodes occurred among children age younger than 18 years with blood glucose 300 mg/dL or greater and …

Humoral Immune Responses Mediate The Development Of A Restrictive Phenotype Of Chronic Lung Allograft Dysfunction, Keizo Misumi, David S Wheeler, Yoshiro Aoki, Michael P Combs, Russell R Braeuer, Ryuji Higashikubo, Wenjun Li, Daniel Kreisel, Ragini Vittal, Jeffrey Myers, Amir Lagstein, Natalie M Walker, Carol F Farver, Vibha N Lama

Open Access Publications

Understanding the distinct pathogenic mechanisms that culminate in allograft fibrosis and chronic graft failure is key in improving outcomes after solid organ transplantation. Here, we describe an F1 → parent orthotopic lung transplant model of restrictive allograft syndrome (RAS), a particularly fulminant form of chronic lung allograft dysfunction (CLAD), and identify a requisite pathogenic role for humoral immune responses in development of RAS. B6D2F1/J (H2-b/d) donor lungs transplanted into the parent C57BL/6J (H2-b) recipients demonstrated a spectrum of histopathologic changes, ranging from lymphocytic infiltration, fibrinous exudates, and endothelialitis to peribronchial and pleuroparenchymal fibrosis, similar to those noted in the human …

Stem Cell And Niche Regulation In Human Short Bowel Syndrome, Vered A Gazit, Elzbieta A Swietlicki, Miranda U Liang, Adam Surti, Raechel Mcdaniel, Mackenzie Geisman, David M Alvarado, Matthew A Ciorba, Grant Bochicchio, Obeid Ilahi, John Kirby, William J Symons, Nicholas O Davidson, Marc S. Levin, Deborah C Rubin

Open Access Publications

Loss of functional small bowel surface area following surgical resection for disorders such as Crohn's disease, intestinal ischemic injury, radiation enteritis, and in children, necrotizing enterocolitis, atresia, and gastroschisis, may result in short bowel syndrome, with attendant high morbidity, mortality, and health care costs in the United States. Following resection, the remaining small bowel epithelium mounts an adaptive response, resulting in increased crypt cell proliferation, increased villus height, increased crypt depth, and enhanced nutrient and electrolyte absorption. Although these morphologic and functional changes are well described in animal models, the adaptive response in humans is less well understood. Clinically the …

Functional Partitioning Of A Liquid-Like Organelle During Assembly Of Axonemal Dyneins, Chanjae Lee, Rachael M. Cox, Ophelia Papoulas, Amjad Horani, Kevin Drew, Caitlin C. Devitt, Steven L. Brody, Edward M. Marcotte, John B. Wallingford

Open Access Publications

Ciliary motility is driven by axonemal dyneins that are assembled in the cytoplasm before deployment to cilia. Motile ciliopathy can result from defects in the dyneins themselves or from defects in factors required for their cytoplasmic pre-assembly. Recent work demonstrates that axonemal dyneins, their specific assembly factors, and broadly-acting chaperones are concentrated in liquid-like organelles in the cytoplasm called DynAPs (Dynein Axonemal Particles). Here, we use

Laparoscopic Cytoreductive Nephrectomy Is Associated With Significantly Improved Survival Compared With Open Cytoreductive Nephrectomy Or Targeted Therapy Alone, Kaidong Zhao, Eric H Kim, Joel M Vetter, James J Hsieh, Ramakrishna Venkatesh, Sam B Bhayani, R Sherburne Figenshau

Open Access Publications

The aim of the present study was to compare the survival outcomes for patients with metastatic renal cell carcinoma (mRCC) who underwent laparoscopic cytoreductive nephrectomy (CN) vs. open CN vs. targeted therapy (TT) alone at our institution. A retrospective chart review was performed at our institution for patients who underwent CN prior to TT (laparoscopic, n=48; open, n=48) or who were deemed unfit for surgery and received TT alone (n=36), between January 2007 and December 2012. Kaplan-Meier estimated survival and Cox proportional hazards analyses were performed. Laparoscopic CN was associated with significantly longer survival compared with open CN or TT …

Arginine Kinetics Are Altered In A Pilot Sample Of Adolescents And Young Adults With Barth Syndrome, W Todd Cade, Kathryn L Bohnert, Adam J Bittel, Shaji J Chacko, Bruce W Patterson, Christina A Pacak, Barry J Byrne, Hilary J Vernon, Dominic N Reeds

Open Access Publications

Barth syndrome (BTHS) is a rare, X-linked cardiomyopathy that is characterized by abnormalities in glucose and lipid metabolism, with less known regarding amino acid metabolism. This pilot study characterized whole-body arginine kinetics and found lower arginine rate of appearance into plasma (0.69 ± 0.09 vs. 0.88 ± 0.06 μmol/kgFFM/min,

The Quest For The Optimal Surgical Management Of Tricuspid Valve Endocarditis In The Current Era: A Narrative Review, Francesco Nappi, Cristiano Spadaccio, Christos Mihos, Kasra Shaikhrezai, Christophe Acar, Marc R. Moon

Open Access Publications

Tricuspid valve endocarditis (TVE) is a growing concern with increasing rates and mortality burden. The currently changing etiology, the antibiotic resistance and the raise in iatrogenic causes as with implantable cardiac devices [cardiac implantable electronic device (CIED)], represent a challenge for the management of these patients. The progressively widespread use of CIEDs is adding to the more commonly known intravenous (IV) drug abuse in the list of causes. Treatment strategies include medical therapy alone or surgery. From the surgical standpoint tricuspid valve repair, replacement or the staged procedure of valvectomy as bridge to replacement are available options. Treatment of endocarditis …

A Narrative Review Of The Interpretation Of Guidelines For The Treatment Of Infective Endocarditis, Umberto Benedetto, Sanjeet Singh Avtaar Singh, Cristiano Spadaccio, Marc R. Moon, Francesco Nappi

Open Access Publications

The recommendations of the current guidelines and the position papers of professional societies from the European Society of Cardiology/European Society of Cardiothoracic Surgeons (ESC), the American College of Cardiology/American Heart Association/Society of Thoracic Surgeon (ACC/AHA/STS) and American Association of Thoracic Surgeon (AATS) regarding management of patients with valvular heart endocarditis were updated over the past decade. However, some of the recommendations appear to contradict one another. Given the changing paradigms on how the disease manifests, our aim was to review the respective guidelines and highlight these differences whilst drawing attention to the subsequent studies from which they were derived. In …

Incidence And Survival For Oropharynx And Non-Oropharynx Head And Neck Cancers Among Veterans Living With Hiv, Angela L Mazul, Christine Hartman, Jennifer Kramer, Donna L White, Kathryn Royse, Suchismita Raychaudhury, Vlad Sandulache, Sarah T Ahmed, Peter Richardson, Andrew G Sikora, Elizabeth Chiao

Open Access Publications

BACKGROUND: People living with HIV/AIDS (PLWH) have an excess risk for head and neck squamous cell carcinoma (HNSCC) compared to the general U.S. population, but little is known about HIV-specific risk factors associated with the incidence and outcomes HNSCC. We aim to identify clinical and HIV-specific risk factors associated with oropharyngeal and non-oropharyngeal HNSCC incidence and outcomes separately.

METHODS: We constructed a retrospective cohort study of 45,052 PLWH aged 18 or above from the national Veteran Affairs (VA) Corporate Data from 1999 to 2015. We extracted demographic data and risk factor information, including history of alcohol abuse, smoking, CD4 count …

Perspectives On Patient Experience: A National Survey Of Hospitalists, Rafina Khateeb, Angela Keniston, Amber Moore, Christine Hrach, Kimberly A Indovina, Patrick Kneeland, Mark Rudolph, Marisha Burden

Open Access Publications

Despite efforts to improve patient experience (PX), little is known about the perspective of hospitalists regarding PX initiatives and priorities. A survey was distributed to hospitalist groups across the country assessing involvement in PX initiatives and their perceived effectiveness, what PX means to providers, and facilitators/barriers in improving PX. Ninety-nine percent of respondents had encountered some improvement activity around PX. The most prevalent were communication training, group Hospital Consumer Assessment of Healthcare Providers and Systems data, and interdisciplinary bedside rounding. Respondents rated most initiatives a 5 to 6 out of 10 for their effectiveness, with the perception of effectiveness increasing …

Prenatal Stress Exposure And Multimodal Assessment Of Amygdala-Medial Prefrontal Cortex Connectivity In Infants, Kathryn L Humphreys, M C Camacho, Marissa C Roth, Elizabeth C Estes

Open Access Publications

Stressful experiences are linked to neurodevelopment. There is growing interest in the role of stress in the connectivity between the amygdala and medial prefrontal cortex (mPFC), a circuit that subserves automatic emotion regulation. However, the specific timing and mechanisms that underlie the association between stress and amygdala-mPFC connectivity are unclear. Many factors, including variations in fetal exposure to maternal stress, appear to affect early developing brain circuitry. However, few studies have examined the associations of stress and amygdala-mPFC connectivity in early life, when the brain is most plastic and sensitive to environmental influence. In this longitudinal pilot study, we characterized …

A Narrative Review Of Early Surgery Versus Conventional Treatment For Infective Endocarditis: Do We Have An Answer?, Umberto Benedetto, Cristiano Spadaccio, Federico Gentile, Marc R. Moon, Francesco Nappi

Open Access Publications

The most appropriate strategy and timing for surgery in infective endocarditis (IE) remains an argument of debate. Despite some authors promote the adoption of an early surgical approach (within 48 hours) to limit mortality and complications, no robust randomized trials are available on this argument and the evidence on this subject remain at the "expert opinion" level. Additionally, the different messages promulgated by the American and European guidelines contributed to fuel confusion regarding the relative priority of the surgical over medical therapy in IE. The European Society of Cardiology (ESC) guidelines individuates three level of urgency: emergency surgery, to be …

Positive Information Facilitates Response Inhibition In Older Adults Only When Emotion Is Task-Relevant, Samantha E Williams, Eric J Lenze, Jill D Waring

Open Access Publications

Emotional information is integral to everyday life and impacts a variety of cognitive abilities including response inhibition, a critical skill for maintaining appropriate and flexible behaviour. However, reported effects of emotion on response inhibition are inconsistent in younger adults, and very limited in older adults. Effects of aging are especially relevant because emotion regulation improves with aging despite declining inhibitory control over neutral information. Across three studies, we assessed the impact of emotional facial expressions on response inhibition in younger and older adults while manipulating attention to task stimuli. Emotional faces (versus neutral faces) altered response inhibition only when task …

Final 5-Year Findings From The Phase 3 Helios Study Of Ibrutinib Plus Bendamustine And Rituximab In Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Graeme A M Fraser, Nancy L. Bartlett, Et Al

Open Access Publications

No abstract provided.

Intact Microstructure Of The Right Corticostriatal Pathway Predicts Creative Ability In Healthy Adults, Farzaneh Rahmani, Hossein Sanjari Moghaddam, Mohammad Hadi Aarabi

Open Access Publications

INTRODUCTION: Creativity is one of the most complex functions of the human brain. The corticostriatal pathways have been implicated in creative thinking, yet few studies have addressed the microstructural underpinnings of creative ability, especially those related to the corticostriatal dopaminergic circuitry. We hypothesized that performance in creativity tests can be predicted based on diffusion metrics of the corticostriatal pathways and basal ganglia.

METHODS: A total of 37 healthy adults were included. Neuropsychological tests of creativity, including the alternative uses task (AUT), test of creative imagery abilities (TCIA), remote associates test (RAT), and creative achievement questionnaire (CAQ), as well as diffusion …

The Effects Of Early-Treated Phenylketonuria On Volumetric Measures Of The Cerebellum, Kristina Aldridge, Kimberly K Cole, Amanda J Moffitt Gunn, Dawn Peck, Desirée A White, Shawn E Christ

Open Access Publications

Past murine studies of phenylketonuria (PKU) have documented significant effects on cerebellum at both the gross and cellular levels. The profile of neurocognitive and motor difficulties associated with early-treated PKU (ETPKU) is also consistent with potential cerebellar involvement. Previous neuroanatomical studies of cerebellum in patients with PKU, however, have yielded mixed results. The objective of the present study was to further examine potential differences in cerebellar morphometry between individuals with and without ETPKU. To this end, we analyzed high resolution T1-weighted MR images from a sample of 20 individuals with ETPKU and an age-matched comparison group of 20 healthy individuals …

Rev-Erbα Mediates Complement Expression And Diurnal Regulation Of Microglial Synaptic Phagocytosis, Percy Griffin, Patrick W. Sheehan, Julie M. Dimitry, Chun Guo, Michael F. Kanan, Jiyeon Lee, Jinsong Zhang, Erik S. Musiek

Open Access Publications

The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including

A Management Framework For Left Sided Endocarditis: A Narrative Review, Francesco Nappi, Cristiano Spadaccio, Marc R. Moon

Open Access Publications

Left sided endocarditis (LSE) can include the entirety or portion of mitral and/or aortic valve and the structures in their anatomical contiguity and represent a significant portion of emergency surgical activity. Literature and guidelines on the management of LSE relies mainly on observational studies given the difficulty in designing randomized trials in emergency settings. Heart teams (HT) are often called in to difficult decisions on the most appropriate strategy to adopted in case of LSE. Decision-making should take into account the localization and the extension of the infection, patient preoperative status and comorbidities, presence of a previous valve prosthesis and …

Effect Of Ulnar Collateral Ligament Reconstruction On Pitch Accuracy, Velocity, And Movement In Major League Baseball Pitchers, Braden Mcknight, Nathanael D Heckmann, Xiao T Chen, Kevork Hindoyan, J Ryan Hill, Graham Goldbeck, Reza Omid, George F Rick Hatch Iii, Timothy P Charlton

Open Access Publications

Background: Ulnar collateral ligament (UCL) reconstruction is frequently performed on Major League Baseball (MLB) pitchers. Previous studies have investigated the effects of UCL reconstruction on fastball and curveball velocity, but no study to date has evaluated its effect on fastball accuracy or curveball movement among MLB pitchers.

Purpose/Hypothesis: The primary purpose of this study was to determine the effects of UCL reconstruction on fastball accuracy, fastball velocity, and curveball movement in MLB pitchers. Our hypothesis was that MLB pitchers who underwent UCL reconstruction would return to their presurgery fastball velocity, fastball accuracy, and curveball movement. The secondary purpose of this …

The Intriguing Interaction Of Escherichia Coli With The Host Environment And Innovative Strategies To Interfere With Colonization: A Summary Of The 2019 E. Coli And The Mucosal Immune System Meeting, Eric Cox, Meryem Aloulou, James M Fleckenstein, Christina Schäffer, Åsa Sjöling, Stephanie Schüller, Kurt Hanevik, Bert Devriendt, Weiping Zhang, Ann-Mari Svennerholm, Edward G Dudley

Open Access Publications

The third