Internal Medicine Commons^™

Transcriptomic And Proteomic Assessment Of Tocilizumab Response In A Randomized Controlled Trial Of Patients Hospitalized With Covid-19, Haridha Shivram, Jason A Hackney, Carrie M Rosenberger, Anastasia Teterina, Aditi Qamra, Olusegun Onabajo, Jacqueline Mcbride, Fang Cai, Min Bao, Larry Tsai, Aviv Regev, Ivan O Rosas, Rebecca N Bauer

Faculty, Staff and Students Publications

High interleukin (IL)-6 levels are associated with greater COVID-19 severity. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit remains unclear. We characterized the immune profile and identified cellular and molecular pathways modified by tocilizumab in peripheral blood samples from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial of the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19. We identified markers of inflammation, lymphopenia, myeloid dysregulation, and organ injury that predict disease severity and clinical outcomes. Proteomic …

Shp2 Promotes Sarcoidosis Severity By Inhibiting Skp2-Targeted Ubiquitination Of Tbet In Cd8+ T Cells, Sherly I Celada, Clarice X Lim, Alexandre F Carisey, Scott A Ochsner, Carlos F Arce Deza, Praveen Rexie, Fernando Poli De Frias, Rafael Cardenas-Castillo, Francesca Polverino, Markus Hengstschläger, Konstantin Tsoyi, Neil J Mckenna, Farrah Kheradmand, Thomas Weichhart, Ivan O Rosas, Luc Van Kaer, Lindsay J Celada

Faculty, Staff and Students Publications

Sarcoidosis is an interstitial lung disease (ILD) characterized by IFNγ and TBET dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular mechanisms underlying this process remain unclear. Here, we report that pharmacological inhibition of phosphorylated SH2 containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFNγ levels, decreases large granuloma formation and macrophage infiltration in the lungs of mice with sarcoidosis-like disease. Positive treatment outcomes were dependent on the effective enhancement of TBET ubiquitination within CD8+ T cells. Mechanistically, our findings identified a previously unknown post-translational modification (PTM) pathway in which the E3 F-box …

Global Impact Of Somatic Structural Variation On The Cancer Proteome, Fengju Chen, Yiqun Zhang, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Both proteome and transcriptome data can help assess the relevance of non-coding somatic mutations in cancer. Here, we combine mass spectrometry-based proteomics data with whole genome sequencing data across 1307 human tumors spanning various tissues to determine the extent somatic structural variant (SV) breakpoint patterns impact protein expression of nearby genes. We find that about 25% of the hundreds of genes with SV-associated cis-regulatory alterations at the mRNA level are similarly associated at the protein level. SVs associated with enhancer hijacking, retrotransposon translocation, altered DNA methylation, or fusion transcripts are implicated in protein over-expression. SVs combined with altered protein levels …

Hawks And Doves: Perceptions And Reality Of Faculty Evaluations, Jillian Zavodnick, Jonathan Doroshow, Sarah Rosenberg, Joshua Banks, Benjamin E. Leiby, Nina Mingioni

Department of Medicine Faculty Papers

OBJECTIVES: Internal medicine clerkship grades are important for residency selection, but inconsistencies between evaluator ratings threaten their ability to accurately represent student performance and perceived fairness. Clerkship grading committees are recommended as best practice, but the mechanisms by which they promote accuracy and fairness are not certain. The ability of a committee to reliably assess and account for grading stringency of individual evaluators has not been previously studied.

METHODS: This is a retrospective analysis of evaluations completed by faculty considered to be stringent, lenient, or neutral graders by members of a grading committee of a single medical college. Faculty evaluations …

Beyond The Symptom: The Biology Of Fatigue, David M Raizen, Janet Mullington, Christelle Anaclet, Gerard Clarke, Hugo Critchley, Robert Dantzer, Ronald Davis, Kelly L Drew, Josh Fessel, Patrick M Fuller, Erin M Gibson, Mary Harrington, W Ian Lipkin, Elizabeth B Klerman, Nancy Klimas, Anthony L Komaroff, Walter Koroshetz, Lauren Krupp, Anna Kuppuswamy, Julie Lasselin, Laura D Lewis, Pierre J Magistretti, Heidi Y Matos, Christine Miaskowski, Andrew H Miller, Avindra Nath, Maiken Nedergaard, Mark R Opp, Marylyn D Ritchie, Dragana Rogulja, Asya Rolls, John D Salamone, Clifford Saper, Vicky Whittemore, Glenn Wylie, Jarred Younger, Phyllis C Zee, H Craig Heller

Faculty, Staff and Student Publications

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a …

Strategies For Maintaining Brain Health: The Role Of Stroke Risk Factors Unique To Elderly Women, Melvin E Klegerman, Tao Peng, Shao-Ling Huang, Brion Frierson, Melanie R Moody, Hyunggun Kim, David D Mcpherson

Faculty, Staff and Student Publications

We have conducted a stability study of a complex liposomal pharmaceutical product, Atheroglitatide (AGT), stored at three temperatures, 4, 24, and 37 °C, for up to six months. The six parameters measured were functions of liposomal integrity (size and number), drug payload (loading efficiency), targeting peptide integrity (conjugation efficiency and specific avidity), and echogenicity (ultrasound-dependent controlled drug release), which were considered most relevant to the product's intended use. At 4 °C, liposome diameter trended upward, indicative of aggregation, while liposome number per mg lipid and echogenicity trended downward. At 24 °C, peptide conjugation efficiency (CE) and targeting efficiency (TE, specific …

A Two-Step Transcriptome Analysis Of The Human Heart Reveals Broad And Disease-Responsive Expression Of Ectopic Olfactory Receptors, Sadia Ashraf, O Howard Frazier, Sylvia Carranza, David D Mcpherson, Heinrich Taegtmeyer, Romain Harmancey

Faculty, Staff and Student Publications

G-protein-coupled receptors (GPCRs) are critical regulators of cardiac physiology and a key therapeutic target for the treatment of heart disease. Ectopic olfactory receptors (ORs) are GPCRs expressed in extra-nasal tissues which have recently emerged as new mediators in the metabolic control of cardiac function. The goals of this study were to profile OR gene expression in the human heart, to identify ORs dysregulated by heart failure caused by ischemic cardiomyopathy, and to provide evidence suggestive of a role for those altered ORs in the pathogenesis of heart failure. Left ventricular tissue from heart failure patients (

Trends And Associated Factors Of Hiv, Hcv And Syphilis Infection Among Different Drug Users In The China-Vietnam Border Area: An 11-Year Cross-Sectional Study (2010-2020), Tong Luo, Zhaosen Lin, Zhenxian Wu, Ping Cen, Aidan Nong, Rongye Huang, Jianhua Che, Fengfeng Liang, Yuan Yang, Jie Liu, Li Huang, Jie Cai, Yanyun Ou, Li Ye, Lijuan Bao, Bingyu Liang, Hao Liang

Faculty, Staff and Student Publications

BACKGROUND: Data on recent human immunodeficiency virus (HIV), hepatitis C virus (HCV) and syphilis prevalence among drug users in the Southwest China are sparse despite the high burden of drug use. This study aims at assessing the prevalence trends and related factors of HIV, HCV and syphilis infection among different drug users in the China-Vietnam border area.

METHODS: A continuous cross-sectional survey was conducted among drug users from 2010 to 2020 in the China-Vietnam border area. Chi-square trend tests were used to assess the trend of HIV, HCV and syphilis prevalence and the proportion for drug type used by drug …

Uptake Of Hiv Testing And Its Correlates Among Sexually Experienced College Students In Southwestern, China: A Web-Based Online Cross-Sectional Study, Jinfeng He, Ping Cen, Jiao Qin, Weiao Qin, Xiudong Xu, Yuanhong Yang, Jinglan Wu, Mu Li, Rongjing Zhang, Tong Luo, Zhifeng Lin, Xinju Huang, Chuanyi Ning, Hao Liang, Li Ye, Bin Xu, Bingyu Liang

Faculty, Staff and Student Publications

BACKGROUND: The prevalence of human immunodeficiency virus (HIV) is becoming more common among college students in China. However, latest data on the prevalence and correlates of HIV testing among sexually experienced college students is rarely.

METHODS: An online survey was conducted among college students aged 18 years or older using multistage stratified cluster sampling from 16 colleges. Data on socio-demographic, HIV testing, HIV-related awareness, attitudes, sexual education and behaviors were collected. Propensity score matching (PSM) and logistic regression model were used to identify factors associated with HIV testing.

RESULT: A total of 108,987 students participated the survey, of which 13,201 …

The Characterization And Evaluation Of The Soluble Triggering Receptor Expressed On Myeloid Cells-Like Transcript-1 In Stable Coronary Artery Disease, Zaida Bayrón-Marrero, Siobhan Branfield, Javier Menéndez-Pérez, Benjamín Nieves-López, Laura Ospina, Yadira Cantres-Rosario, Loyda M Melendez, Robert Hunter, Angelia Gibson, Gerónimo Maldonado-Martínez, A Valance Washington

Faculty, Staff and Student Publications

Platelets play crucial roles in the development and progression of coronary artery disease (CAD). The triggering receptor expressed in myeloid cells-like transcript-1 (TLT-1) is stored in platelet α granules, and activated platelets release a soluble fragment (sTLT-1). We set out to better characterize the constituent amino acids of sTLT-1 and to evaluate sTLT-1 for use as a biomarker in patients with stable CAD. We evaluated sTLT-1 release using immunoprecipitation and mass spectrometry and employed statistical methods to retrospectively correlate sTLT-1 concentrations, utilizing ELISA in plasma samples from 1510 patients with documented stable CAD. We identified TLT-1 residues to 133 in …

Biliary Dyskinesia In Stiff Person Syndrome: An Association Between Reduced Gaba Production And Gastroenteric Dysmotility, Scarlet Louis-Jean, Nirav Agrawal, Shire Chaudhry, Adrien Mazer

Journal of Community Hospital Internal Medicine Perspectives

Stiff person syndrome (SPS) and biliary dyskinesia are two rare but potentially debilitating conditions that can significantly impact quality of life. SPS is a rare neurological disorder characterized by muscle stiffness, rigidity, and muscle spasms that primarily affect the trunk and limbs and is associated with extra-axial manifestations involving the gastrointestinal tract. Biliary dyskinesia is a gastrointestinal disorder characterized by abnormal gallbladder emptying, leading to symptoms of intense abdominal pain, nausea, and vomiting. Despite their distinct clinical presentations, studies have suggested a possible connection between the two disorders. This link may be due to involvement of similar neurotransmitters and autoantibodies …

Real-World Use Of Mold-Active Triazole Prophylaxis In The Prevention Of Invasive Fungal Diseases: Results From A Subgroup Analysis Of A Multicenter National Registry, M Hong Nguyen, Luis Ostrosky-Zeichner, Peter G Pappas, Thomas J Walsh, Joseph Bubalo, Barbara D Alexander, Marisa H Miceli, Jeanette Jiang, Yi Song, George R Thompson

Faculty, Staff and Student Publications

BACKGROUND: Antifungal prophylaxis can prevent invasive fungal diseases (IFDs) in high-risk, immunocompromised patients. This study assessed the real-world use of mold-active triazoles (MATs) for the prevention of IFDs.

METHODS: This subgroup analysis of a multicenter, observational, prospective registry in the United States from March 2017 to April 2020 included patients who received MATs for prophylaxis (isavuconazole, posaconazole, and voriconazole) at study index/enrollment. The primary objective was to describe patient characteristics and patterns of MAT use. Exploratory assessments included the frequency of breakthrough IFDs and MAT-related adverse drug reactions (ADRs).

RESULTS: A total of 1177 patients (256 isavuconazole, 397 posaconazole, 272 …

Outpatient Management Of Urinary Tract Infections By Medical Officers In Nairobi, Kenya: Lack Of Benefit From Audit And Feedback On Adherence To Treatment Guidelines, Florence Mbatia, James Orwa, Mary B. Adam, Gulnaz Mohamoud, Rodney Adam

Family Medicine, East Africa

Introduction: Acute uncomplicated urinary tract infections are common in outpatient settings but are not treated optimally. Few studies of the outpatient use of antibiotics for specifc diagnoses have been done in sub-Saharan Africa, so little is known about the prescribing patterns of medical ofcers in the region.

Methods: Aga Khan University has 16 outpatient clinics throughout the Nairobi metro area with a medical ofcer specifcally assigned to that clinic. A baseline assessment of evaluation and treatment of suspected UTI was performed from medical records in these clinics. Then the medical ofcer from each of the 16 clinics was recruited from …

An Electronic Health Record System Implementation In A Resource Limited Country—Lessons Learned, Sayed Karar, Muhammad Haroon Khan, Jasmit Shah, Nadeem Ahmed

Internal Medicine, East Africa

Electronic health records have revolutionized the medical world by improving medical care, refining provider documentation, standardizing care, and minimizing sentinel events. Successful implementation of electronic health records remains a daunting task and requires careful strategic planning and buy-in from key stakeholders. Much has been published in resource-rich settings and high-income countries about implementations of electronic health records. However, little is known about the experience in resource-limited settings where challenges remain unique and distinct from other parts of the world. Our intention is to share lessons learned during implementation of a web-based electronic health record at a tertiary care center in …

Inferior Vena Cava Collapsibility Index Versus Passive Leg Raise To Assess Fluid Responsiveness In Non-Intubated Septic Patients A Prospective Observational Study, Anne Githaiga, Wangari Siika, Jeilan Mohamed, Vitalis Mung’Ayi, Idris Chikophe

Anaesthesiology, East Africa

Background: Rapid fluid loading at diagnosis of sepsis is part of standard treatment. Predictive tools of fluid responsiveness are required to guide fluid resuscitation. The Passive Leg Raise [PLR] manoeuvre can predict fluid responsiveness in non-intubated patients with sepsis. The Inferior Vena Cava Collapsibility Index [IVCCI] can also be utilised but is not routinely performed.

Aim: To investigate the correlation between Inferior Vena Cava Collapsibility Index [IVCCI] and a Passive Leg Raise [PLR] manoeuvre for the assessment of fluid responsiveness in non-intubated septic patients in a tertiary referral hospital in Sub-Saharan Africa.

Methodology: A prospective observational study which recruited non-intubated …

Stress-Dose Steroids: A Potential Therapeutic Option For Refractory Hyperkalemia., Pooya Zardoost, Zeryab Khan, Rachel Kim, Kelsey Scott, Henry L Wehrum

Ambulatory and Primary Care Articles

Hyperkalemia refractory to standard temporization measures can be life-threatening, and urgent hemodialysis is often utilized as a final resort. Our patient presented with hyperkalemia that was multifactorial in etiology, with acute kidney injury complicated by adrenal insufficiency. Her hyperkalemia was refractory to temporization and excretion agents, and hemodialysis was being considered. Given a recent infection, surgery, and borderline hypotension with low adrenocorticotropic hormone, there was a concern for adrenal insufficiency. However, a full investigation for secondary adrenal insufficiency via magnetic resonance imaging could not be conducted as the patient suffered from claustrophobia. Continued concern for adrenal insufficiency prompted the initiation …

Abnormal Motion Capture In Acute Stroke (Bionics): A Low-Cost Tele-Evaluation Tool For Automated Assessment Of Upper Extremity Function In Stroke Patients, Syed A Zamin, Kaichen Tang, Emily A Stevens, Melissa Howard, Dorothea M Parker, Allyson Seals, Xiaoqian Jiang, Sean Savitz, Shayan Shams

Faculty, Staff and Student Publications

BACKGROUND: The incidence of stroke and stroke-related hemiparesis has been steadily increasing and is projected to become a serious social, financial, and physical burden on the aging population. Limited access to outpatient rehabilitation for these stroke survivors further deepens the healthcare issue and estranges the stroke patient demographic in rural areas. However, new advances in motion detection deep learning enable the use of handheld smartphone cameras for body tracking, offering unparalleled levels of accessibility.

METHODS: In this study we want to develop an automated method for evaluation of a shortened variant of the Fugl-Meyer assessment, the standard stroke rehabilitation scale …

Stop-Bang Questionnaire For Screening Obstructive Sleep Apnea Syndrome Among Hypertensive Patients In Kenya, Salim Abdallah, Jasmit Shah, Jumaa Bwika, Sayed Karar

Internal Medicine, East Africa

Introduction: Obstructive sleep apnea (OSA) is a type of breathing problem during sleep caused by the blockage of the upper airway, which can cause cessation of airflow. There is limited research on the prevalence of OSA in hypertensive patients in sub-Saharan Africa (SSA). The study aimed to describe the prevalence and clinical characteristics of OSA among hypertensive patients at a tertiary hospital in Nairobi, Kenya.

Methods: This cross-sectional study was conducted at the Aga Khan University Hospital in Nairobi, Kenya. Two hundred and fifty-one hypertensive patients were screened for OSA risk using the STOP-Bang questionnaire (SBQ). Patients with a SBQ …

Kenyan Palliative Care Providers’ And Leaders’ Perceptions Of Palliative Care Research Needs And Support To Facilitate Rigorous Research, K. Cartmell, E. Doherty, Nancy Gikaara, Z. Ali, S. Qanungo, E. S. Melikam, R. A. Powell

Internal Medicine, East Africa

Background: Palliative care (PC) can reduce symptom distress and improve quality of life for patients and their families experiencing life-threatening illness. While the need for PC in Kenya is high, PC service delivery and research is limited. Qualitative research is needed to explore potential areas for PC research and support needed to enable that research. This insight is critical for informing a national PC research agenda and mobilizing limited resources for conducting rigorous PC research in Kenya.

Objectives: To explore perceptions of priority areas for PC research and support needed to facilitate rigorous research from the perspective of Kenyan PC …

Reduced Digestion Of Circulating Genomic Dna In Systemic Sclerosis Patients With The Dnase1l3 R206c Variant\, Brian Skaug, Xinjian Guo, Yuanteng Jeff Li, Julio Charles, Kay T Pham, Jacob Couturier, Dorothy E Lewis, Claudia Bracaglia, Ivan Caiello, Maureen D Mayes, Shervin Assassi

Faculty, Staff and Student Publications

Objectives: Polymorphism in a coding region of deoxyribonuclease I-like III (DNASE1L3), causing amino acid substitution of Arg-206 to Cys (R206C), is a robustly replicated heritable risk factor for SSc and other autoimmune diseases. DNASE1L3 is secreted into the circulation, where it can digest genomic DNA (gDNA) in apoptosis-derived membrane vesicles (AdMVs). We sought to determine the impact of DNASE1L3 R206C on digestion of circulating gDNA in SSc patients and healthy controls (HCs).

Methods: The ability of DNASE1L3 to digest AdMV-associated gDNA was tested in vitro. The effect of R206C substitution on extracellular secretion of DNASE1L3 was determined using a transfected …