Publications by authors named "Amy Yang"

148 Publications

Impact of an Interprofessional Surgical Skills Workshop on Undergraduate Medical and Nursing Student Interest in a Career in Surgery: A Thematic Analysis.

J Surg Educ 2020 Oct 5. Epub 2020 Oct 5.

Monash University, Clayton, Victoria, Australia.

Objective: Medical student interest in surgery is decreasing both internationally and in Australia. There is also a current shortage of perioperative nursing staff, and demand for both surgeons and perioperative nurses is only expected to rise. The aim of this qualitative thematic analysis is to explore: (1) medical and nursing student's influences on their perspectives on surgery, and (2) the impact of a novel, interprofessional, simulation-based workshop on medical and nursing student interest in surgery as a career.

Design: A paired, anonymous pre- and postworkshop written survey was completed by medical and nursing student participants before and immediately after the surgical skills workshop. Thematic analysis of the responses was performed by 2 researchers independently to identify themes and subthemes regarding the study aims.

Setting: The study was conducted at Monash Medical Centre, a tertiary care center in Melbourne, Australia.

Participants: One hundred and seventy-six undergraduate medical and nursing students attended the workshop, consisting of 144 fourth-year medical students (enrolled in a 5-year course) and 32 second-year nursing student volunteers (enrolled in a 3-year course).

Results: Analysis of how students' prior surgical experiences impacted their perspective on surgery revealed 5 themes: inclusive mentors and role models, learning through active participation, feeling unwelcome or intimidated, demands of the surgical lifestyle, and personal factors that influenced interest in surgery as a career.Most students reported that the workshop had a beneficial effect on their perception of surgery as a career. Analysis of student responses found 3 themes that affected the impact of the workshop on their interest in surgery: simulated practice of technical skills, exposure to nontechnical aspects of surgery, and simulation fidelity.

Conclusions: Interprofessional, simulated-based surgical skills workshops may improve medical and nursing students' perceptions of surgery as a career, and should be considered for inclusion in undergraduate medical and nursing curricula.
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http://dx.doi.org/10.1016/j.jsurg.2020.09.014DOI Listing
October 2020

Nonredundant functions of Mycobacterium tuberculosis chaperones promote survival under stress.

Mol Microbiol 2021 Feb 3;115(2):272-289. Epub 2020 Nov 3.

Department of Chemistry, New York University, New York, NY, USA.

Bacterial chaperones ClpB and DnaK, homologs of the respective eukaryotic heat shock proteins Hsp104 and Hsp70, are essential in the reactivation of toxic protein aggregates that occur during translation or periods of stress. In the pathogen Mycobacterium tuberculosis (Mtb), the protective effect of chaperones extends to survival in the presence of host stresses, such as protein-damaging oxidants. However, we lack a full understanding of the interplay of Hsps and other stress response genes in mycobacteria. Here, we employ genome-wide transposon mutagenesis to identify the genes that support clpB function in Mtb. In addition to validating the role of ClpB in Mtb's response to oxidants, we show that HtpG, a homolog of Hsp90, plays a distinct role from ClpB in the proteotoxic stress response. While loss of neither clpB nor htpG is lethal to the cell, loss of both through genetic depletion or small molecule inhibition impairs recovery after exposure to host-like stresses, especially reactive nitrogen species. Moreover, defects in cells lacking clpB can be complemented by overexpression of other chaperones, demonstrating that Mtb's stress response network depends upon finely tuned chaperone expression levels. These results suggest that inhibition of multiple chaperones could work in concert with host immunity to disable Mtb.
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http://dx.doi.org/10.1111/mmi.14615DOI Listing
February 2021

Translational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR.

Nat Commun 2020 09 16;11(1):4677. Epub 2020 Sep 16.

Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, 10016, USA.

The Integrated Stress Response (ISR) helps metazoan cells adapt to cellular stress by limiting the availability of initiator methionyl-tRNA for translation. Such limiting conditions paradoxically stimulate the translation of ATF4 mRNA through a regulatory 5' leader sequence with multiple upstream Open Reading Frames (uORFs), thereby activating stress-responsive gene expression. Here, we report the identification of two critical regulators of such ATF4 induction, the noncanonical initiation factors eIF2D and DENR. Loss of eIF2D and DENR in Drosophila results in increased vulnerability to amino acid deprivation, susceptibility to retinal degeneration caused by endoplasmic reticulum (ER) stress, and developmental defects similar to ATF4 mutants. eIF2D requires its RNA-binding motif for regulation of 5' leader-mediated ATF4 translation. Consistently, eIF2D and DENR deficient human cells show impaired ATF4 protein induction in response to ER stress. Altogether, our findings indicate that eIF2D and DENR are critical mediators of ATF4 translational induction and stress responses in vivo.
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http://dx.doi.org/10.1038/s41467-020-18453-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495428PMC
September 2020

Memory CD73+IgM+ B cells protect against Plasmodium yoelii infection and express Granzyme B.

PLoS One 2020 4;15(9):e0238493. Epub 2020 Sep 4.

United States Food and Drug Administration, Center for Biologics and Research, Division of Bacterial, Parasitic and Allergenic Diseases, Silver Spring, Maryland, United States of America.

To better understand anti-malaria protective immune responses, we examined the cellular mechanisms that govern protective immunity in a murine Plasmodium yoelii 17X NL (PyNL) re-infection model. Initially, we confirmed that immune B cells generated during a primary PyNL infection were largely responsible for protection from a second PyNL infection. Using the previously identified memory B cell markers CD80, PD-L2, and CD73, we found an increase in the frequency of CD80-PD-L2-CD73+ B cells up to 55 days after a primary PyNL infection and at 4-6 days following a second PyNL infection. Moreover, injection of enriched immune CD19+CD73+ B cells into nonimmune mice were significantly more protective against a PyNL infection than CD73- B cells. Interestingly, a substantial fraction of these CD73+ B cells also expressed IgM and granzyme B, a biomolecule that has been increasingly associated with protective responses against malaria.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238493PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473529PMC
October 2020

CXCL16 Stimulates Antigen-Induced MAIT Cell Accumulation but Trafficking During Lung Infection Is CXCR6-Independent.

Front Immunol 2020 7;11:1773. Epub 2020 Aug 7.

Laboratory of Mucosal Pathogens and Cellular Immunology, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States.

Mucosa-associated invariant T (MAIT) cells are a unique T cell subset that contributes to protective immunity against microbial pathogens, but little is known about the role of chemokines in recruiting MAIT cells to the site of infection. Pulmonary infection with live vaccine strain (LVS) stimulates the accrual of large numbers of MAIT cells in the lungs of mice. Using this infection model, we find that MAIT cells are predominantly CXCR6 but do not require CXCR6 for accumulation in the lungs. However, CXCR6 does contribute to long-term retention of MAIT cells in the airway lumen after clearance of the infection. We also find that MAIT cells are not recruited from secondary lymphoid organs and largely proliferate in the lungs after infection. Nevertheless, the only known ligand for CXCR6, CXCL16, is sufficient to drive MAIT cell accumulation in the lungs in the absence of infection when administered in combination with the MAIT cell antigen 5-OP-RU. Overall, this new data advances the understanding of mechanisms that facilitate MAIT cell accumulation and retention in the lungs.
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http://dx.doi.org/10.3389/fimmu.2020.01773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426740PMC
August 2020

Artificially induced MAIT cells inhibit M. bovis BCG but not M. tuberculosis during in vivo pulmonary infection.

Sci Rep 2020 08 12;10(1):13579. Epub 2020 Aug 12.

Laboratory of Mucosal Pathogens and Cellular Immunology, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.

There is significant interest in targeting MAIT cells with immunostimulatory agents to enhance immune responses. Mycobacterium tuberculosis (M. tb.) is a pervasive respiratory disease that could benefit from treatments that augment immunity. Here we investigate the role of MAIT cells in M. tb. infection and the potential for MAIT cell-targeted immunotherapy to control bacterial burdens. We find that MAIT cells fail to substantially accumulate in the lungs during murine pulmonary M. bovis BCG and M. tb. infections but this defect is overcome by intranasal installation of a TLR2/6 agonist and a MAIT cell antigen. Although artificially induced MAIT cells produce important cytokines in both infections, they control BCG but not M. tb. growth in the lungs. Correspondingly, M. tb.-infected mouse macrophages are relatively resistant to MAIT cell antimicrobial activities in vitro. Thus, MAIT cell antigen-mediated immunotherapy for M. tb. presents a complex challenge.
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http://dx.doi.org/10.1038/s41598-020-70615-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423888PMC
August 2020

Video-Based Motion Analysis Use: A National Survey of Orthopedic Physical Therapists.

Phys Ther 2020 09;100(10):1759-1770

Department of Physical Therapy and Human Movement Sciences, Northwestern University Feinberg School of Medicine, 645 N Michigan Avenue, #1100, Chicago, IL 60611 (USA).

Objectives: Motion analysis is performed by physical therapists to assess and improve movement. Two-dimensional video-based motion analysis (VBMA) is available for smartphones/tablets and requires little to no equipment or cost. Research on VBMA use in clinical practice is limited. The purpose of this study was to examine the current use of VBMA in orthopedic physical therapist practice.

Methods: Members of the Academy of Orthopaedic Physical Therapy completed an online survey. Questions examined frequency of VBMA use, reasons for use, facilitators/barriers, device/apps used, practice patterns, other certificates/degrees, and demographic information.

Results: Among the final analysis sample of 477 respondents, 228 (47.8%) use VBMA. Of 228 VBMA users, 91.2% reported using it for ≤25% of their caseload, and 57.9% reported using their personal device to capture movement. Reasons for using VBMA included visual feedback for patient education (91.7%), analysis of movement (91.2%), and assessment of progress (51.8%). Barriers to use included lack of device/equipment (48.8%), lack of space (48.6%), and time restraint (32.1%). Those with ≤20 years of clinical experience (odds ratio [OR] = 1.83, 95% CI = 1.21-2.76), residency training (OR = 2.49, 95% CI = 1.14-5.43), and fellowship training (OR = 2.97, 95% CI = 1.32-6.66), and those from the West region of the United States (OR = 1.66, 95% CI = 1.07-2.56) were more likely to use VBMA.

Conclusions: More than 50% of surveyed orthopedic physical therapists do not use VBMA in clinical practice. Future research should be directed toward assessing reliability and validity of VBMA use by smartphones, tablets, and apps and examining whether VBMA use enhances treatment outcomes. Data security, patient confidentiality, and integration into the electronic medical record should be addressed.

Impact: This study is the first to our knowledge to describe the use of VBMA in orthopedic physical therapist practice in the United States. It is the first step in understanding how VBMA is used and might be used to enhance clinical assessment and treatment outcomes.
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http://dx.doi.org/10.1093/ptj/pzaa125DOI Listing
September 2020

Structure of the Human Respiratory Syncytial Virus M2-1 Protein in Complex with a Short Positive-Sense Gene-End RNA.

Structure 2020 09 21;28(9):979-990.e4. Epub 2020 Jul 21.

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322 USA. Electronic address:

The M2-1 protein of human respiratory syncytial virus (HRSV) is a transcription anti-terminator that regulates the processivity of the HRSV RNA-dependent RNA polymerase (RdRP). Here, we report a crystal structure of HRSV M2-1 bound to a short positive-sense gene-end RNA (SH7) at 2.7 Å resolution. We identified multiple critical residues of M2-1 involved in RNA interaction and examined their roles using mutagenesis and MicroScale Thermophoresis (MST) assay. We found that hydrophobic residue Phe23 is indispensable for M2-1 to recognize the base of RNA. We also captured spontaneous binding of RNA (SH7) to M2-1 in all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method. Both experiments and simulations revealed that the interactions of RNA with two separate domains of M2-1, the zinc-binding domain (ZBD) and the core domain (CD), are independent of each other. Collectively, our results provided a structural basis for RNA recognition by HRSV M2-1.
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http://dx.doi.org/10.1016/j.str.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484405PMC
September 2020

Intracerebroventricular Cerliponase Alfa for Neuronal Ceroid Lipofuscinosis Type 2 Disease: Clinical Practice Considerations From US Clinics.

Pediatr Neurol 2020 09 4;110:64-70. Epub 2020 May 4.

Department of Pediatrics, Irvine School of Medicine, University of California, Orange, California; Department of Metabolic Disorders, Children's Hospital of Orange County, CHOC Children's Specialists, Orange, California.

Background: Neuronal ceroid lipofuscinosis type 2 or CLN2 disease is a rare, autosomal recessive, neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 deficiency. Cerliponase alfa, a recombinant human tripeptidyl peptidase 1 enzyme, is the first and only approved treatment for CLN2 disease and the first approved enzyme replacement therapy administered via intracerebroventricular infusion.

Methods: A meeting of health care professionals from US institutions with experience in cerliponase alfa treatment of children with CLN2 disease was held in November 2018. Key common practices were identified, and later refined during the drafting of this article, that facilitate safe chronic administration of cerliponase alfa.

Results: Key practices include developing a multidisciplinary team of clinicians, pharmacists, and coordinators, and institution-specific processes. Infection risk may be reduced through strict aseptic techniques and minimizing connections and disconnections during infusion. The impact of intracerebroventricular device design on port needle stability during extended intracerebroventricular infusion is a critical consideration in device selection. Monitoring for central nervous system infection is performed at each patient contact, but with flexibility in the degree of monitoring. Although few institutions had experienced positive cerebrospinal fluid test results, the response to a positive cerebrospinal fluid culture should be determined on a case-by-case basis, and the intracerebroventricular device should be removed if cerebrospinal fluid infection is confirmed.

Conclusions: The key common practices and flexible practices used by institutions with cerliponase alfa experience may assist other institutions in process development. Continued sharing of experiences will be essential for developing standards and patient care guidelines.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.04.018DOI Listing
September 2020

The N370S/R496H genotype in type 1 Gaucher disease - Natural history and implications for pre symptomatic diagnosis and counseling.

Mol Genet Metab Rep 2020 Mar 30;22:100567. Epub 2020 Jan 30.

Lysosomal Storage Disease Program, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.

Type 1 Gaucher disease (GD1) patients with the N370S/R496H (N409S/R535H) genotype are increasingly identified through carrier and newborn screening panels. However, limited information is available on the phenotype associated with this genotype. Here, we report our experience with 14 patients with this genotype. Our data suggests that most patients with N370S/R496H present with mild manifestations and often do not require treatment. This information is important for counseling newly diagnosed patients and GD1 carrier couples.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000790PMC
March 2020

Clinical factors associated with acute exacerbations of chronic rhinosinusitis.

J Allergy Clin Immunol 2020 06 29;145(6):1598-1605. Epub 2020 Jan 29.

Department of Medicine, Division of Allergy and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Ill; Department of Otolaryngology-Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Ill. Electronic address:

Background: Chronic rhinosinusitis (CRS) is complicated by frequent acute exacerbations leading to significant health care burden and impaired quality of life.

Objective: The objective of this study was to identify clinical factors associated with frequent acute exacerbation of CRS (AECRS).

Methods: This is a retrospective cohort study of patients with CRS from January 1, 2014, to May 31, 2016. Frequent AECRS was defined as at least 4 episodes over a 12-month period in which an antibiotic was prescribed for worsening sinus symptoms, and infrequent AECRS was defined as 0 to 3 episodes. Clinical factors, including asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, and autoimmune disease, were evaluated for associations between the 2 groups.

Results: Of the 3109 patients with CRS who were identified, 600 (19.3%) were classified as having frequent exacerbation. Asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, and autoimmune disease were associated with frequent AECRS with statistically significant adjusted odds ratios (aORs) after controlling for age, race, and sex in multivariate analysis (asthma aOR = 2.61 [95% CI = 2.14-3.18]; allergic rhinitis aOR = 1.96 [95% CI = 1.58-2.42]; eosinophil count of at least 150 cells per microliter aOR = 1.54 [95% CI = 1.21-1.97]; and autoimmune disease aOR = 1.68 [95% CI = 1.36-2.07]). Antibody deficiency, antibiotic allergy, lower FEV, radiographic sinus disease severity, nasal polyposis, and systemic corticosteroid use were also associated with frequent AECRS.

Conclusion: Patients with frequent episodes of AECRS were characterized by a higher prevalence of asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, autoimmune disease, and other allergic and immunologic diseases. These findings identify a high-risk phenotype of patients with CRS for preventive interventions to reduce exacerbation frequency.
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http://dx.doi.org/10.1016/j.jaci.2020.01.023DOI Listing
June 2020

The landscape of chimeric RNAs in non-diseased tissues and cells.

Nucleic Acids Res 2020 02;48(4):1764-1778

Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.

Chimeric RNAs and their encoded proteins have been traditionally viewed as unique features of neoplasia, and have been used as biomarkers and therapeutic targets for multiple cancers. Recent studies have demonstrated that chimeric RNAs also exist in non-cancerous cells and tissues, although large-scale, genome-wide studies of chimeric RNAs in non-diseased tissues have been scarce. Here, we explored the landscape of chimeric RNAs in 9495 non-diseased human tissue samples of 53 different tissues from the GTEx project. Further, we established means for classifying chimeric RNAs, and observed enrichment for particular classifications as more stringent filters are applied. We experimentally validated a subset of chimeric RNAs from each classification and demonstrated functional relevance of two chimeric RNAs in non-cancerous cells. Importantly, our list of chimeric RNAs in non-diseased tissues overlaps with some entries in several cancer fusion databases, raising concerns for some annotations. The data from this study provides a large repository of chimeric RNAs present in non-diseased tissues, which can be used as a control dataset to facilitate the identification of true cancer-specific chimeras.
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http://dx.doi.org/10.1093/nar/gkz1223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038929PMC
February 2020

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

Genet Med 2020 03 14;22(3):538-546. Epub 2019 Nov 14.

Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
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http://dx.doi.org/10.1038/s41436-019-0693-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060121PMC
March 2020

Author Correction: Targeting CLDN18.2 by CD3 Bispecific and ADC Modalities for the Treatments of Gastric and Pancreatic Cancer.

Sci Rep 2019 Nov 8;9(1):16735. Epub 2019 Nov 8.

Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-53130-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838164PMC
November 2019

Introduction of an interprofessional gynaecology surgical skills workshop for undergraduate medical and nursing students.

Aust N Z J Obstet Gynaecol 2020 04 24;60(2):238-243. Epub 2019 Oct 24.

Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia.

Background: Medical and nursing students may feel under-prepared to perform basic surgical and gynaecology procedural skills. There also remains scope within undergraduate programs to integrate interprofessional education, and better prepare students for interprofessional collaboration to improve patient care.

Aims: A simulation-based gynaecology surgical skills workshop program was introduced for undergraduate medical and nursing students. The aim of this study was to explore students' perceptions of a simulation-based interprofessional gynaecological skills program, using students' pre- and post-workshop confidence in taught skills reported in a post-workshop questionnaire as an outcome measure.

Materials And Methods: One hundred and sixty undergraduate medical (n = 133) and nursing (n = 27) students attended the workshop program at a tertiary university in Melbourne, Australia. A survey was completed by all students immediately after the workshop, addressing students' perceptions of surgical education, the four skill-stations (gowning/gloving, suturing, intrauterine device insertion, and urethral catheterisation), and interprofessional education. A Wilcoxon signed-rank test was performed to compare students' pre- and post-workshop confidence scores.

Results: Most medical and nursing students (86%) agreed their course should provide more structured surgical education. There was a statistically significant increase in post-workshop self-reported confidence scores for medical and nursing students in all four taught skills. Confidence in interprofessional behaviours also improved in both cohorts, but the improvement in nursing students did not reach statistical significance.

Conclusions: Simulation-based, interprofessional, gynaecological surgery skills workshops are practical and valuable additions to undergraduate medical and nursing curricula. Further research should explore long-term retention of procedural skills and changes in interprofessional attitudes in clinical practice.
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http://dx.doi.org/10.1111/ajo.13086DOI Listing
April 2020

Rapid Generation of Somatic Mouse Mosaics with Locus-Specific, Stably Integrated Transgenic Elements.

Cell 2019 09;179(1):251-267.e24

Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Center for Neural Sciences in Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

In situ transgenesis methods such as viruses and electroporation can rapidly create somatic transgenic mice but lack control over copy number, zygosity, and locus specificity. Here we establish mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely defined chromosomal loci. We provide a toolkit of MADR elements for combination labeling, inducible and reversible transgene manipulation, VCre recombinase expression, and transgenesis of human cells. Further, we demonstrate the versatility of MADR by creating glioma models with mixed reporter-identified zygosity or with "personalized" driver mutations from pediatric glioma. MADR is extensible to thousands of existing mouse lines, providing a flexible platform to democratize the generation of somatic mosaic mice. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2019.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934691PMC
September 2019

Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes.

Nat Commun 2019 08 2;10(1):3495. Epub 2019 Aug 2.

Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA.

Immune tolerance to allografts has been pursued for decades as an important goal in transplantation. Administration of apoptotic donor splenocytes effectively induces antigen-specific tolerance to allografts in murine studies. Here we show that two peritransplant infusions of apoptotic donor leukocytes under short-term immunotherapy with antagonistic anti-CD40 antibody 2C10R4, rapamycin, soluble tumor necrosis factor receptor and anti-interleukin 6 receptor antibody induce long-term (≥1 year) tolerance to islet allografts in 5 of 5 nonsensitized, MHC class I-disparate, and one MHC class II DRB allele-matched rhesus macaques. Tolerance in our preclinical model is associated with a regulatory network, involving antigen-specific Tr1 cells exhibiting a distinct transcriptome and indirect specificity for matched MHC class II and mismatched class I peptides. Apoptotic donor leukocyte infusions warrant continued investigation as a cellular, nonchimeric and translatable method for inducing antigen-specific tolerance in transplantation.
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http://dx.doi.org/10.1038/s41467-019-11338-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677762PMC
August 2019

Ideal vs. real: a systematic review on handling covariates in randomized controlled trials.

BMC Med Res Methodol 2019 07 3;19(1):136. Epub 2019 Jul 3.

Department of Population Health, New York University Langone Health, New York, NY, USA.

Background: In theory, efficient design of randomized controlled trials (RCTs) involves randomization algorithms that control baseline variable imbalance efficiently, and corresponding analysis involves pre-specified adjustment for baseline covariates. This review sought to explore techniques for handling potentially influential baseline variables in both the design and analysis phase of RCTs.

Methods: We searched PubMed for articles indexed "randomized controlled trial", published in the NEJM, JAMA, BMJ, or Lancet for two time periods: 2009 and 2014 (before and after updated CONSORT guidelines). Upon screening (343), 298 articles underwent full review and data abstraction.

Results: Typical articles reported on superiority (86%), multicenter (92%), two-armed (79%) trials; 81% of trials involved covariates in the allocation and 84% presented adjusted analysis results. The majority reported a stratified block method (69%) of allocation, and of the trials reporting adjusted analyses, 91% were pre-specified. Trials published in 2014 were more likely to report adjusted analyses (87% vs. 79%, p = 0.0100) and more likely to pre-specify adjustment in analyses (95% vs. 85%, p = 0.0045). Studies initiated in later years (2010 or later) were less likely to use an adaptive method of randomization (p = 0.0066; 7% of those beginning in 2010 or later vs. 31% of those starting before 2000) but more likely to report a pre-specified adjusted analysis (p = 0.0029; 97% for those initiated in 2010 or later vs. 69% of those started before 2000).

Conclusion: While optimal reporting procedures and pre-specification of adjusted analyses for RCTs tend to be progressively more prevalent over time, we see the opposite effect on reported use of covariate-adaptive randomization methods.
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http://dx.doi.org/10.1186/s12874-019-0787-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610785PMC
July 2019

Targeting CLDN18.2 by CD3 Bispecific and ADC Modalities for the Treatments of Gastric and Pancreatic Cancer.

Sci Rep 2019 06 10;9(1):8420. Epub 2019 Jun 10.

Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.

Human CLDN18.2 is highly expressed in a significant proportion of gastric and pancreatic adenocarcinomas, while normal tissue expression is limited to the epithelium of the stomach. The restricted expression makes it a potential drug target for the treatment of gastric and pancreatic adenocarcinoma, as evidenced by efforts to target CLDN18.2 via naked antibody and CAR-T modalities. Herein we describe CLDN18.2-targeting via a CD3-bispecific and an antibody drug conjugate and the characterization of these potential therapeutic molecules in efficacy and preliminary toxicity studies. Anti-hCLDN18.2 ADC, CD3-bispecific and diabody, targeting a protein sequence conserved in rat, mouse and monkey, exhibited in vitro cytotoxicity in BxPC3/hCLDN18.2 (IC = 1.52, 2.03, and 0.86 nM) and KATO-III/hCLDN18.2 (IC = 1.60, 0.71, and 0.07 nM) respectively and inhibited tumor growth of pancreatic and gastric patient-derived xenograft tumors. In a rat exploratory toxicity study, the ADC was tolerated up to 10 mg/kg. In a preliminary assessment of tolerability, the anti-CLDN18.2 diabody (0.34 mg/kg) did not produce obvious signs of toxicity in the stomach of NSG mice 4 weeks after dosing. Taken together, our data indicate that targeting CLDN18.2 with an ADC or bispecific modality could be a valid therapeutic approach for the treatment of gastric and pancreatic cancer.
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http://dx.doi.org/10.1038/s41598-019-44874-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557842PMC
June 2019

Epidemiology and outcomes of hospitalized adults with respiratory syncytial virus: A 6-year retrospective study.

Influenza Other Respir Viruses 2019 07 11;13(4):331-338. Epub 2019 Apr 11.

Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Objectives: Respiratory syncytial virus (RSV) is an important cause of morbidity and mortality in adults. Existing studies are limited by the number of seasons studied and most have focused on the immunocompromised.

Methods: A retrospective cohort study was conducted on all adults (≥18 years) with a positive RSV molecular test admitted from 2009 to 2015 to one hospital in Chicago, IL. Epidemiologic and outcomes data were collected after IRB approval.

Results: Of the 489 eligible patients, 227 had RSV A and 262 had RSV B. Patients had a median age of 61 years and comorbidity (eg, chronic lung disease [40.6%], obesity [37.8%], and cardiac disease [34.3%]). On presentation, most had cough (86.5%), fever (42.4%), and shortness of breath (38.2%). Severe disease was present in 27.6% of patients. Antibiotic was used in 76.3% inpatients and 45.8% at discharged despite few patients (4.7%) having documented bacterial infections. Supplemental oxygen and mechanical ventilation were utilized in 44.6% and 12.3%, respectively, while ICU level care was required in 26.9%. Most patients were discharged home (82.7%). Most deaths (68.4%, 13/19) were attributed to pneumonia or hypoxemia likely from RSV. Most fatal cases were seen in those with recent cancer treatment and older adults.

Conclusions: Respiratory syncytial virus in hospitalized adults is associated with significant morbidity and mortality with 26.9% requiring ICU level care. Antibiotics are commonly prescribed to patients with documented RSV, and antibiotics are frequently continued after diagnosis. Novel antiviral therapies are needed for RSV to improve outcomes and potentially improve antibiotic stewardship in patients without a bacterial infection.
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http://dx.doi.org/10.1111/irv.12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586178PMC
July 2019

Primary Cortisol Deficiency and Growth Hormone Deficiency in a Neonate With Hypoglycemia: Coincidence or Consequence?

J Endocr Soc 2019 Apr 20;3(4):838-846. Epub 2019 Feb 20.

Division of Pediatric Endocrinology and Diabetes, Mount Sinai Kravis Children's Hospital, Icahn School of Medicine at Mount Sinai, New York, New York.

Cortisol and growth hormone (GH) deficiencies are causes of neonatal hypoglycemia. When they coexist, a pituitary disorder is suspected. We present an infant with hypoglycemia in whom an ACTH receptor defect was associated with transient GH deficiency. A full-term boy with consanguineous parents presented with hypoglycemia (serum glucose 18 mg/dL) at 4 hours of life with undetectable serum cortisol (<1 μg/dL). Examination showed diffuse hyperpigmentation with normal male genitalia. Patient developed hyperbilirubinemia and elevated transaminase levels. GH levels of 6.8 ng/mL and 7.48 ng/mL during episodes of hypoglycemia, peak of 9.2 ng/mL with glucagon stimulation, and undetectable IGF-1 suggested GH deficiency. Thyroid function, prolactin, and gonadotropins were normal. Baseline ACTH was elevated at 4868 pg/mL, whereas serum cortisol remained undetectable with ACTH stimulation. Hydrocortisone replacement resulted in normalization of blood glucose and cholestasis with decline in ACTH level. GH therapy was not initiated, given improvement in cholestasis and euglycemia. An ACTH receptor defect was confirmed with molecular genetic testing that revealed homozygosity for a known mutation of the melanocortin 2 receptor () gene. At 12 weeks, a random GH level was 10 ng/mL. IGF-1 was 75 ng/mL and 101 ng/mL at 7 and 9 months, respectively. This report describes glucocorticoid deficiency from an mutation associated with GH deficiency. With glucocorticoid replacement, GH secretion normalized. Our findings are consistent with a previously stated hypothesis that physiologic glucocorticoid levels may be required for optimal GH secretion [1].
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http://dx.doi.org/10.1210/js.2018-00386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447946PMC
April 2019

A Mindfulness-Based Intervention for Low-Income African American Women with Depressive Symptoms Delivered by an Experienced Instructor Versus a Novice Instructor.

J Altern Complement Med 2019 Jul 26;25(7):699-708. Epub 2019 Mar 26.

2Department of Medical Social Sciences, and Feinberg School of Medicine, Northwestern University, Chicago, IL.

In the present study, the authors pilot a streamlined mindfulness teacher training protocol for Federally Qualified Health Center (FQHC) staff and examine the distribution and variability of psychologic outcomes for participants in groups led by an experienced instructor compared to a FQHC staff instructor who received the streamlined training. Seventy-four adult women aged 18-65 with depressive symptoms enrolled to participate in the 8-week group mindfulness intervention led by an experienced instructor ( = 33) or a novice instructor ( = 41). The effect of instructor on the outcomes depression, stress, mindfulness, functioning, well-being, and depression stigma was assessed at baseline, 8, and 16 weeks. Depressive symptoms and stress significantly decreased, and mindfulness significantly increased in the experienced and novice instructor groups. In the novice instructor group, there was also a significant increase in well-being and functioning. The change in depressive symptoms, stress, functioning, and well-being was significantly greater in the novice instructor group than the experienced instructor groups. Preliminary data suggest that health care staff who receive streamlined training to deliver mindfulness-based interventions have comparable outcomes as experienced instructors.
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http://dx.doi.org/10.1089/acm.2018.0393DOI Listing
July 2019

Value and Barriers to Use of the SIMPL Tool for Resident Feedback.

J Surg Educ 2019 May - Jun;76(3):620-627. Epub 2019 Feb 13.

University of Kentucky, Department of Surgery, Lexington, Kentucky. Electronic address:

Objective: The System for Improving and Measuring Procedural Learning (SIMPL) is a smart-phone application used to provide residents with an evaluation of operative autonomy and feedback. This study investigated the perceived benefits and barriers to app use.

Design: A database of previously performed SIMPL evaluations was analyzed to identify high, low, and never users. Potential predisposing factors to use were explored. A survey investigating key areas of value and barriers to use for the SIMPL application was sent to resident and faculty users. Respondents were asked to self-identify how often they used the app. The perceived benefits and barriers were correlated with the level of usage. Qualitative analysis of free text responses was used to determine strategies to increase usage.

Setting: General surgery training programs who are members of the Procedural Learning and Safety Collaborative.

Participants: Surgical residents and faculty.

Results: At least 1 SIMPL evaluation was created for 411 residents and 524 faculty. Thirty percent of both faculty and residents were high-frequency users. Thirty percent of faculty were never users. One hundred eighty-eight residents and 207 faculty (response rate 46%) completed the survey. High-frequency resident users were more likely to perceive a benefit for both numerical evaluations (76% vs 30%) and dictated feedback (92% vs 30%). Faculty and residents commonly blamed each other for not creating and completing evaluations regularly (87% of residents, 81% of faculty). Suggested strategies to increase usage included reminders and integration with existing data systems.

Contributions: Frequent users perceive value from the application, particularly from dictated feedback and see a positive impact on feedback in their programs. Faculty engagement represents a major barrier to adoption. Mechanisms which automatically remind residents to initiate an evaluation will help improve utilization but programs must work to enhance faculty willingness to respond and dictate feedback.
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http://dx.doi.org/10.1016/j.jsurg.2019.01.012DOI Listing
August 2020

Four maternal characteristics determine the 12-month course of chronic severe postpartum depressive symptoms.

Depress Anxiety 2019 04 15;36(4):375-383. Epub 2019 Jan 15.

Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Postpartum depression is a heterogeneous disorder in phenotype and etiology. Characterizing the longitudinal course of depressive symptoms over the first year after birth and identifying variables that predict distinct symptom trajectories will expedite efficient mental health treatment planning. The purpose was to determine 12-month trajectories of postpartum depressive symptoms, identify characteristics that predict the trajectories, and provide a computational algorithm that predicts trajectory membership.

Methods: A prospective cohort of women delivering at an academic medical center (2006-2011) was recruited from an urban women's hospital in Pittsburgh, PA. Women with a postpartum depressive disorder (n = 507) participated and completed symptom severity assessments at 4-8 weeks (intake), 3 months, 6 months, and 12 months. Women were predominantly Caucasian (71.8%), married (53.3%), and college educated (38.7%). Clinician interviews of depressive symptom severity, medical and psychiatric history, assessment of function, obstetric experience, and infant status were conducted.

Results: Analyses resulted in identification of three distinct trajectories of depressive symptoms: (1) gradual remission (50.4%), (2) partial improvement (41.8%), and (3) chronic severe (7.8%). Key predictive characteristics of the chronic severe versus gradual remission and partial improvement trajectories included parity, education, and baseline global functioning and depression severity. We were able to predict trajectory membership with 72.8% accuracy from these characteristics.

Conclusions: Four maternal characteristics predicted membership in the chronic severe versus gradual remission and partial improvement trajectories with 72.8% accuracy. The trajectory groups comprise clinically relevant subgroups with the potential for tailored treatments to reduce the disease burden of postpartum depression.
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http://dx.doi.org/10.1002/da.22879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494079PMC
April 2019

Personal growth Initiative: A robust and malleable predictor of treatment outcome for depressed partial hospital patients.

J Affect Disord 2019 03 25;246:548-555. Epub 2018 Dec 25.

Department of Psychological Sciences, Texas Tech University, Lubbock, TX, USA.

Background: Current methods for treating depressive disorders ineffectively treat large portions of patients. We need to identify malleable factors that predict treatment outcome and can be modified prior to or concurrently with treatment to enhance outcomes. We examined personal growth initiative (PGI) as a malleable predictor of treatment outcome for depressed patients in partial hospital treatment.

Methods: Archival data were extracted from medical records of 521 adult patients with depression diagnoses (67.2% women) in a partial hospital program (2008 - 2010). Demographic data and admission and discharge scores for depression and PGI were extracted. ANCOVA assessed the extent to which reliable or clinically significant change in PGI predicted level of depression at discharge, controlling for admission depression levels.

Results: PGI and depression were significantly correlated at admission. PGI scores increased significantly from admission to discharge. Reliable and clinically significant improvement in PGI each significantly, uniquely, and negatively predicted depression at discharge, adjusting for admission depression.

Limitations: The correlational nature of the longitudinal design precludes definitive statements regarding causality. A large portion of the initial sample was dropped due to substantial missing data, yielding the final N = 521. Dropped patients had higher levels of depression at discharge and increased likelihood of leaving treatment against medical advice, raising concerns about potential other, unmeasured differences.

Conclusions: Our findings confirm the utility of PGI as a malleable predictor of treatment outcome for depressed patients in partial hospital treatment and may have implications for using PGI-based interventions to enhance treatment outcomes.
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http://dx.doi.org/10.1016/j.jad.2018.12.121DOI Listing
March 2019

Validity of the WHIPLASHED as a tool to identify bipolar disorder in women.

J Affect Disord 2019 03 17;246:69-73. Epub 2018 Dec 17.

Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Obstetrics and Gynecology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.

Background: The aim of this study was to investigate the validity of the WHIPLASHED clinician-administered interview, a mnemonic of questions on clinical factors and illness course used to screen for bipolar disorder, as a self-report questionnaire.

Methods: Participants (n = 82) were females recruited from an outpatient academic women's mental health clinic. Relevant symptom data were extracted from a self-report questionnaire designed to parallel the WHIPLASHED interview questions. A score of ≥5 on WHIPLASHED was defined as a positive screen for bipolar spectrum disorder by its developer. We examined the capacity of self-reported WHIPLASHED scores ≥5 to differentiate bipolar from unipolar depression in women. Diagnostic assessments were conducted with the Mini International Neuropsychiatric Interview.

Results: Women were diagnosed with unipolar (n = 54) and bipolar (n = 28) depression. The majority of subjects were white (67%), employed (68%) and married (57%) with a mean age of 36.8 years. The receiver operating characteristic curve demonstrated that WHIPLASHED had strong predictive ability (AUC = 0.877) in differentiating bipolar from unipolar depression. A cutoff score of ≥5 generated 96% sensitivity and 52% specificity, while raising the threshold to 6 generated 89% sensitivity and 76% specificity for a bipolar disorder diagnosis.

Limitations: Our sample was small and composed of female patients at a single treatment center.

Conclusions: In this sample, WHIPLASHED was a valid screening tool to differentiate bipolar from unipolar depression. While existing instruments focus on primary symptoms of bipolar disorder, the WHIPLASHED is useful in exploring subtypes of bipolar disorder in which depression dominates the clinical course.
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http://dx.doi.org/10.1016/j.jad.2018.12.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563604PMC
March 2019

Plasma and cerebrospinal fluid inflammatory cytokines in perinatal depression.

Am J Obstet Gynecol 2019 03 14;220(3):271.e1-271.e10. Epub 2018 Dec 14.

Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL.

Background: While perinatal depression is one of the most common complications of pregnancy, there is an insufficient understanding of the mechanistic underpinnings of disease. While an association between peripheral inflammatory cytokines and major depressive disorder has been demonstrated, cytokines cannot freely cross the blood-brain barrier, and thus, they give little insight into alternations in brain function. Because the brain is in direct communication with the cerebrospinal fluid, assessment of inflammation in the cerebrospinal fluid may be more directly related to the biologic markers of affective change.

Objective: Our objectives were to examine the association between perinatal depression and inflammatory cytokines in plasma, the association between perinatal depression and inflammatory cytokines in cerebrospinal fluid, and the correlations between plasma and cerebrospinal fluid inflammatory cytokines.

Study Design: This was a prospective, observational study of women with a singleton gestation at term undergoing a scheduled cesarean delivery. Women were screened for depression and those with depressive symptomatology preferentially enrolled. The Mini-International Neuropsychiatric Interview was administered to confirm the clinical diagnosis of depression. Maternal plasma and cerebrospinal fluid were collected preoperatively and cytokines measured via flow cytometry. Bivariable and multivariable analyses were used to determine the association between each cytokine and perinatal depression. Correlations were measured between the cytokines in plasma and cerebrospinal fluid.

Results: Of the 117 women who met inclusion criteria, 76 (65%) screened positive for depression, 15 (20%) of whom met the clinical diagnostic criteria for depression. There were no significant associations between any of the plasma cytokines and perinatal depression in our sample. Conversely, in multivariable analyses, higher cerebrospinal fluid interleukin-1β (adjusted odds ratio, 232.7, 95% confidence interval, 5.9-9148.5), interleukin-23 (adjusted odds ratio, 22.1, 95% confidence interval, 1.7-294.5), and interleukin-33 (adjusted odds ratio, 1.7, 95% confidence interval, 1.1-2.6) concentrations were significantly associated with increased odds of perinatal depression. The plasma and cerebrospinal fluid cytokine concentrations were not strongly correlated.

Conclusion: Higher concentrations of cerebrospinal fluid cytokines were associated with perinatal depression. These cerebrospinal fluid cytokines were not strongly correlated with plasma cytokines, and accordingly, plasma cytokines were not significantly associated with perinatal depression. Central neuroinflammation, as opposed to peripheral inflammation, may represent a mechanistic pathway that contributes to perinatal depression.
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http://dx.doi.org/10.1016/j.ajog.2018.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020951PMC
March 2019

Atrial fibrillation is highly prevalent yet undertreated in patients with biopsy-proven nonalcoholic steatohepatitis.

Liver Int 2019 05 21;39(5):933-940. Epub 2018 Dec 21.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background & Aims: Nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular disease. Atrial fibrillation is a prominent risk marker for underlying cardiovascular disease with a prevalence of 2% in patients <65 years old. Atrial fibrillation prevalence in NASH is unknown. We sought to assess the prevalence and impact of atrial fibrillation on healthcare utilization in NASH.

Methods: Patients were identified from a tertiary care centre Electronic Database from 2002 to 2015. International Classification of Diseases 9 (ICD9) codes identified comorbidities and atrial fibrillation. Descriptive statistics were used to compare characteristics between patients with NASH with and without atrial fibrillation.

Results: Of 9108 patients with ICD9 diagnosis of NASH, 215 (2.3%, mean age 57 years, 32% male) had biopsy-proven NASH. Atrial fibrillation prevalence was 4.6%. Patients with NASH and atrial fibrillation had a higher prevalence of heart failure (54.5% vs 8.8%, P < 0.001) and cerebrovascular (27.3% vs 2.0%, P < 0.001) or vascular disease (54.5% vs 13.2%, P = 0.002), compared to NASH without atrial fibrillation. All patients with NASH and atrial fibrillation had a CHA2DS2VASc score ≥2 indicating high stroke risk and need for anticoagulation. Eight of 10 patients were eligible for anticoagulation and 5 of 8 (62.5%) received appropriate therapy.

Conclusion: Atrial fibrillation prevalence is two-fold higher in patients with NASH compared to the general population. Patients with NASH have a high risk of stroke; however, many do not receive appropriate guideline-directed therapy. Future studies are needed to identify whether guideline-based management of atrial fibrillation in NASH reduces cardiovascular morbidity and mortality.
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http://dx.doi.org/10.1111/liv.14018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483865PMC
May 2019

Development of a Predictive Model for Hyperglycemia in Nondiabetic Recipients After Liver Transplantation.

Transplant Direct 2018 Oct 20;4(10):e393. Epub 2018 Sep 20.

Division of Endocrinology Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.

Background: Posttransplant hyperglycemia has been associated with increased risks of transplant rejection, infections, length of stay, and mortality.

Methods: To establish a predictive model to identify nondiabetic recipients at risk for developing postliver transplant (LT) hyperglycemia, we performed this secondary, retrospective data analysis of a single-center, prospective, randomized, controlled trial of glycemic control among 107 adult LT recipients in the inpatient period. Hyperglycemia was defined as a posttransplant glucose level greater than 200 mg/dL after initial discharge up to 1 month following surgery. Candidate variables with less than 0.10 in univariate analyses were used to build a multivariable logistic regression model using forward stepwise selection. The final model chosen was based on statistical significance and additive contribution to the model based on the Bayesian Information Criteria.

Results: Forty-three (40.2%) patients had at least 1 episode of hyperglycemia after transplant after the resolution of the initial postoperative hyperglycemia. Variables selected for inclusion in the model (using model optimization strategies) included length of hospital stay (odds ratio [OR], 0.83; < 0.001), use of glucose-lowering medications at discharge (OR, 3.76; = 0.03), donor female sex (OR, 3.18; = 0.02) and donor white race (OR, 3.62; = 0.01). The model had good calibration (Hosmer-Lemeshow goodness-of-fit test statistic = 9.74, = 0.28) and discrimination (C-statistic = 0.78; 95% confidence interval, 0.65-0.81, bias-corrected C-statistic = 0.78).

Conclusions: Shorter hospital stay, use of glucose-lowering medications at discharge, donor female sex and donor white race are important determinants in predicting hyperglycemia in nondiabetic recipients after hospital discharge up to 1 month after liver transplantation.
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http://dx.doi.org/10.1097/TXD.0000000000000830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233666PMC
October 2018

Fetal cord blood and tissue immune responses to chronic placental inflammation and chorioamnionitis.

Allergy Asthma Clin Immunol 2018 19;14:66. Epub 2018 Nov 19.

1Division of Allergy and Immunology, Department of Pediatrics, Northwestern Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, 255 E Chicago Ave, Box #60, Chicago, IL 60611 USA.

Background: Chorioamnionitis is a risk factor for future asthma development. Animal models of chorioamnionitis demonstrate increased T17-to-T ratios associated with proinflammatory cytokine elevations. The association of chorioamnionitis on human neonatal immune cells systemically and within tissues is not known.

Methods: We enrolled two cohorts to evaluate T17 and regulatory T cell (T) phenotypic markers in chorioamnionitis. From a cohort of 19 live birth infants, we collected cord blood and placenta samples to evaluate for signs of acute and chronic histologic inflammation and cell phenotype characterization. We analyzed a second cohort of stillborn infants with and without chorioamnionitis to classify and enumerate cell infiltrate phenotypes in the spleen, thymus, and lung. We used linear regression analysis determine the association of retinoic acid-related orphan receptor gamma t positive (RORγt) and T cell frequency with different types of inflammation seen in the live cohort subjects. Using linear mixed models, we evaluated for any associations between chorioamnionitis and T- and B-cell with a logarithmic scale for level of expression of cellular markers. We then performed Wilcoxon rank sum tests to assess the associations between cell count and chorioamnionitis.

Results: In the live birth subjects with chronic placental inflammation we observed an increased proportion of RORγt cells in Foxp3 cells, regardless of the presence of acute inflammation, compared to subjects with neither acute nor chronic inflammation. We also found an increased proportion of RORγt cells within Foxp3 cells in subjects with acute high stage fetal and maternal inflammation compared to those without acute or chronic inflammation. In the stillborn subjects with chorioamnionitis, we observed a decrease in splenic Foxp3 cells and an increase in lung CD3 cells compared with subjects that did not have chorioamnionitis.

Conclusion: Exposure to chorioamnionitis in utero may affect immune activation in neonates with an increased frequency of RORγt cells systemically as well as lymphocytic infiltrate in the lung. Our findings suggest an increase in RORγt cells during chorioamnionitis and thus may support the known associations between chorioamnionitis with asthma.
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http://dx.doi.org/10.1186/s13223-018-0297-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240933PMC
November 2018