Recent Submissions

  • Defining Longer-Term Outcomes in an Ovine Model of Moderate Perinatal Hypoxia-Ischemia

    Mike, Jana Krystofova; Wu, Katherine Y.; White, Yasmine; Pathipati, Praneeti; Ndjamen, Blaise; Hutchings, Rachel S.; Losser, Courtney; Vento, Christian; Arellano, Kimberly; Vanhatalo, Oona; et al. (2022-01-01)
    Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide. Approximately 1 million infants born with HIE each year survive with cerebral palsy and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HIE exhibit variable outcomes that are highly unpredictable. Here, we describe an umbilical cord occlusion (UCO) model of moderate HIE with a 6-day follow-up. Near-term lambs (n = 27) were resuscitated after the induction of 5 min of asystole. Following recovery, lambs were assessed to define neurodevelopmental outcomes. At the end of this period, lambs were euthanized, and brains were harvested for histological analysis. Compared with prior models that typically follow lambs for 3 days, the observation of neurobehavioral outcomes for 6 days enabled identification of animals that recover significant neurological function. Approximately 35% of lambs exhibited severe motor deficits throughout the entirety of the 6-day course and, in the most severely affected lambs, developed spastic diparesis similar to that observed in infants who survive severe neonatal HIE (severe, UCOs). Importantly, and similar to outcomes in human neonates, while initially developing significant acidosis and encephalopathy, the remainder of the lambs in this model recovered normal motor activity and exhibited normal neurodevelopmental outcomes by 6 days of life (improved, UCOi). The UCOs group exhibited gliosis and inflammation in both white and gray matters, oligodendrocyte loss, neuronal loss, and cellular death in the hippocampus and cingulate cortex. While the UCOi group exhibited more cellular death and gliosis in the parasagittal cortex, they demonstrated more preserved white matter markers, along with reduced markers of inflammation and lower cellular death and neuronal loss in Ca3 of the hippocampus compared with UCOs lambs. Our large animal model of moderate HIE with prolonged follow-up will help further define pathophysiologic drivers of brain injury while enabling identification of predictive biomarkers that correlate with disease outcomes and ultimately help support development of therapeutic approaches to this challenging clinical scenario.
  • Pre-operative Machine Learning for Heart Transplant Patients Bridged with Temporary Mechanical Circulatory Support †

    Shou, Benjamin L.; Chatterjee, Devina; Russel, Joseph W.; Zhou, Alice L.; Florissi, Isabella S.; Lewis, Tabatha; Verma, Arjun; Benharash, Peyman; Choi, Chun Woo (2022-09-01)
    Background: Existing prediction models for post-transplant mortality in patients bridged to heart transplantation with temporary mechanical circulatory support (tMCS) perform poorly. A more reliable model would allow clinicians to provide better pre-operative risk assessment and develop more targeted therapies for high-risk patients. Methods: We identified adult patients in the United Network for Organ Sharing database undergoing isolated heart transplantation between 01/2009 and 12/2017 who were supported with tMCS at the time of transplant. We constructed a machine learning model using extreme gradient boosting (XGBoost) with a 70:30 train:test split to predict 1-year post-operative mortality. All pre-transplant variables available in the UNOS database were included to train the model. Shapley Additive Explanations was used to identify and interpret the most important features for XGBoost predictions. Results: A total of 1584 patients were included, with a median age of 56 (interquartile range: 46–62) and 74% male. Actual 1-year mortality was 12.1%. Out of 498 available variables, 43 were selected for the final model. The area under the receiver operator characteristics curve (AUC) for the XGBoost model was 0.71 (95% CI: 0.62–0.78). The most important variables predictive of 1-year mortality included recipient functional status, age, pulmonary capillary wedge pressure (PCWP), cardiac output, ECMO usage, and serum creatinine. Conclusions: An interpretable machine learning model trained on a large clinical database demonstrated good performance in predicting 1-year mortality for patients bridged to heart transplantation with tMCS. Machine learning may be used to enhance clinician judgement in the care of markedly high-risk transplant recipients.
  • Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-β blockade in HPV-unrelated head and neck cancer

    Redman, Jason M.; Friedman, Jay; Robbins, Yvette; Sievers, Cem; Yang, Xinping; Lassoued, Wiem; Sinkoe, Andrew; Papanicolau-Sengos, Antonios; Lee, Chyi Chia; Marte, Jennifer L.; et al. (2022-09-15)
    Background. Head and neck squamous cell carcinoma not associated with HPV (HPV-unrelated HNSCC) is associated with a high rate of recurrence and poor survival. Methods. We conducted a clinical trial in 14 patients with newly diagnosed HPV-unrelated HNSCC to evaluate the safety and efficacy of neoadjuvant bintrafusp alfa, a bifunctional fusion protein that blocks programmed death ligand 1 (PD-L1) and neutralizes TGF-β. Results. Bintrafusp alfa was well tolerated, and no treatment-associated surgical delays or complications occurred. Objective pathologic responses (PRs) were observed, and 12 of the 14 (86%) patients were alive and disease free at 1 year. Alterations in Treg infiltration and spatial distribution relative to proliferating CD8+ T cells indicated a reversal of Treg immunosuppression in the primary tumor. Detection of neoepitope-specific tumor T cell responses, but not virus-specific responses, correlated with the development of a PR. Detection of neoepitope-specific responses and PRs in tumors was not correlated with genomic features or tumor antigenicity but was associated with reduced pretreatment myeloid cell tumor infiltration. These results indicate that dual PD-L1 and TGF-β blockade can safely enhance tumor antigen-specific immunity and highlight the feasibility of multimechanism neoadjuvant immunotherapy for patients with HPV-unrelated HNSCC. Conclusion. Our studies provide insight into the ability of neoadjuvant immunotherapy to induce polyclonal neoadjuvant- specific T cell responses in tumors and suggest that features of the tumor microenvironment, such as myeloid cell infiltration, may be a major determinant of enhanced antitumor immunity following such treatment.
  • Use of Transcarotid Artery Revascularization, Transfemoral Carotid Artery Stenting, and Carotid Endarterectomy in the US from 2015 to 2019

    Stonko, David P.; Goldsborough, Earl; Kibrik, Pavel; Zhang, George; Holscher, Courtenay M.; Hicks, Caitlin W. (2022-09-16)
    Importance: A transcarotid artery revascularization (TCAR) device was approved by the US Food and Drug Administration in 2015 for carotid revascularization in patients at high risk for stroke, cranial nerve injury, or major cardiac event. It is unclear how the introduction of TCAR has changed the use of carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TFCAS). Objective: To quantify the temporal changes in the operative approach to carotid revascularization (CEA vs TFCAS vs TCAR), and to identify patient and disease characteristics commonly associated with each approach. Design, Setting, and Participants: This retrospective cohort study obtained data from the Vascular Quality Initiative database from January 1, 2015, to December 31, 2019. Patients with carotid artery stenosis who underwent CEA, TFCAS, or TCAR were included. Data were analyzed from January to April 2022. Exposures: Month and year of surgery as well as patient risk status. Main Outcomes and Measures: Number and proportion of carotid revascularization procedures by operative approach. Results: A total of 108676 patients (mean [SD] age 56.6 [12.5] years; 66 684 men [61.4%]) were included in the analysis. The most common operative approach overall was CEA (n = 81508 [75.0%]), followed by TFCAS (n = 15578 [14.3%]) and TCAR (n = 11590 [10.7%]). The number of procedures increased over the study period (16754 in 2015 vs 27269 in 2019; P <.001). In 2015, CEA was used in 84.9% of all cases, followed by TFCAS (14.4%) and TCAR (0.8%). In 2019, CEA was used in 64.8% of cases, followed by TCAR (21.9%) and TFCAS (13.3%). The proportional use of CEA decreased by 5.0% (95% CI, -7.4% to -2.6%) per year, and TCAR use increased by 5.3% (95% CI, 2.3%-8.3%) per year. Among patients at high risk, the change was greater: CEA use decreased by 7.8% (95% CI, -11.9% to -3.8%) per year, TFCAS decreased by 4.8% (95% CI, -9.5% to -0.14%) per year, and TCAR increased by 12.6% (95% CI, 7.1%-18.1%) per year. Multinomial logistic regression showed that patient risk status was the most important characteristic associated with TCAR compared with CEA (relative risk ratio, 36.10; 95% CI, 29.24-44.66; P <.001) and TFCAS (relative risk ratio, 14.10; 95% CI, 11.86-16.66; P <.001). Linear regression revealed no association between year of surgery and in-hospital myocardial infarction, stroke, or mortality. Conclusions and Relevance: Results of this study indicate that TCAR has become the dominant carotid revascularization approach, surpassing TFCAS and CEA in patients at high risk for stroke, cranial nerve injury, or cardiovascular events. Patient high-risk status was the main characteristic associated with a stenting approach, highlighting the perceived importance of carotid stenting therapies in this patient population.
  • Expanding the learning health system model to be health literate

    Rosen, Michael A.; Himmelfarb, Cheryl Dennison; Bauer, Thomas; Mullins, C. Daniel (2022-10-01)
    Nearly nine out of ten adults struggle to understand and use personal and public health information[1].Low health literacy is an economic burden for the USA, costing US$238 billion or more annually and representing between7% and 17% of all personal healthcare expenditures[2]. In 2012, the National Academy of Medicine identified ten attributes that exemplify a health-literate healthcare organization, meaning an environment that enables people to understand, access and benefit optimally from the range of healthcare services[3]. Almost 10 years later, few, if any, healthcare organizations embody these key attributes. We can no longer focus on individuals’ aptitudes but must recognize and address the “health literacy-related demands and complexities of our healthcare organizations”[3].More recently, Healthy People 2030, the nation’s 10-year plan to improve the health of all Americans, featured, for the first time, health literacy in its framework. Further, it expanded health literacy to include a new organizational component, recognizing the essential role healthcare organizations play in improving health literacy. If the demands of healthcare organizations can better align with an individual’s literacy skills and abilities, language and culture, we can address many of the persistent obstacles to achieving health equity.
  • Traumatic brain injury alters dendritic cell differentiation and distribution in lymphoid and non-lymphoid organs.

    Tsymbalyuk, Orest; Gerzanich, Volodymyr; Simard, J Marc; Rathinam, Chozha Vendan (2022-10-01)
    Background: Pathophysiological consequences of traumatic brain injury (TBI) mediated secondary injury remain incompletely understood. In particular, the impact of TBI on the differentiation and maintenance of dendritic cells (DCs), which are regarded as the most professional antigen presenting cells of the immune system, remains completely unknown. Here, we report that DC-differentiation, maintenance and functions are altered on day 3 and day 7 after TBI. Methods: Long bones, spleen, peripheral lymph nodes (pLNs), mesenteric lymph nodes (mLNs), liver, lungs, skin and blood were collected from mice with either moderate-level cortical impact (CCI) or sham on day 1, day 3 or day 7 after TBI. Bone marrow cells were isolated from the tibias and femurs of hind limb through flushing. Tissues were digested with Collagenase-D and DNase I. Skin biopsies were digested in the presence of liberase + DNase I. Single cell suspensions were made, red blood cells were lysed with Ammonium chloride (Stem Cell Technology) and subsequently filtered using a 70 μM nylon mesh. DC subsets of the tissues and DC progenitors of the BM were identified through 10-color flow cytometry-based immunophenotyping studies. Intracellular reactive oxygen species (ROS) were identified through H2DCFDA staining. Results: Our studies identify that; (1) frequencies and absolute numbers of DCs in the spleen and BM are altered on day 3 and day 7 after TBI; (2) surface expression of key molecules involved in antigen presentation of DCs were affected on day 3 and day 7 after TBI; (3) distribution and functions of tissue-specific DC subsets of both circulatory and lymphatic systems were imbalanced following TBI; (4) early differentiation program of DCs, especially the commitment of hematopoietic stem cells to common DC progenitors (CDPs), were deregulated after TBI; and (5) intracellular ROS levels were reduced in DC progenitors and differentiated DCs on day 3 and day 7 after TBI. Conclusions: Our data demonstrate, for the first time, that TBI affects the distribution pattern of DCs and induces an imbalance among DC subsets in both lymphoid and non-lymphoid organs. In addition, the current study demonstrates that TBI results in reduced levels of ROS in DCs on day 3 and day 7 after TBI, which may explain altered DC differentiation paradigm following TBI. A deeper understanding on the molecular mechanisms that contribute to DC defects following TBI would be essential and beneficial in treating infections in patients with acute central nervous system (CNS) injuries, such as TBI, stroke and spinal cord injury.
  • Subnormothermic Ex Vivo Porcine Kidney Perfusion Improves Energy Metabolism: Analysis Using P Magnetic Resonance Spectroscopic Imaging.

    Agius, Thomas; Songeon, Julien; Klauser, Antoine; Allagnat, Florent; Longchamp, Grégoire; Ruttimann, Raphael; Lyon, Arnaud; Ivaniesevic, Julijana; Meier, Raphael; Déglise, Sébastien; et al. (2022-09-26)
    The ideal preservation temperature for donation after circulatory death kidney grafts is unknown. We investigated whether subnormothermic (22 °C) ex vivo kidney machine perfusion could improve kidney metabolism and reduce ischemia-reperfusion injury. Methods: To mimic donation after circulatory death procurement, kidneys from 45-kg pigs underwent 60 min of warm ischemia. Kidneys were then perfused ex vivo for 4 h with Belzer machine perfusion solution UW at 22 °C or at 4 °C before transplantation. Magnetic resonance spectroscopic imaging coupled with LCModel fitting was used to assess energy metabolites. Kidney perfusion was evaluated with dynamic-contrast enhanced MRI. Renal biopsies were collected at various time points for histopathologic analysis. Results: Total adenosine triphosphate content was 4 times higher during ex vivo perfusion at 22 °C than at 4 °C perfusion. At 22 °C, adenosine triphosphate levels increased during the first hours of perfusion but declined afterward. Similarly, phosphomonoesters, containing adenosine monophosphate, were increased at 22 °C and then slowly consumed over time. Compared with 4 °C, ex vivo perfusion at 22 °C improved cortical and medullary perfusion. Finally, kidney perfusion at 22 °C reduced histological lesions after transplantation (injury score: 22 °C: 10.5 ± 3.5; 4 °C: 18 ± 2.25 over 30). Conclusions: Ex vivo kidney perfusion at 22°C improved graft metabolism and protected from ischemia-reperfusion injuries upon transplantation. Future clinical studies will need to define the benefits of subnormothermic perfusion in improving kidney graft function and patient's survival.
  • Design and Basic Characteristics of a National Patient-Powered Registry in ADPKD.

    Hoover, Elise; Perrone, Ronald D; Rusconi, Chris; Benson, Beverly; Dahl, Neera K; Gitomer, Berenice; Manelli, Amy; Mrug, Michal; Park, Meyeon; Seliger, Stephen L; et al. (2022-05-20)
    Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease worldwide. Over the past five years, the therapeutic pipeline for ADPKD has expanded, leading to a growing need for patient enrollment in clinical trials and improved understanding of patient-centered outcomes that can be used in trial design. To advance these goals, the Polycystic Kidney Disease Foundation (PKDF) established a national web-based ADPKD Registry. Methods: The ADPKD Registry is hosted on a secure, HIPAA-compliant, online platform (IQVIA, oc-meridian.com/pkdcure). Participants are consented through the online system and complete a series of modules. The Core Questionnaire includes patient-reported diagnosis, latest creatinine values, and comorbidities. Additional modules include surveys of family history, diet, quality of life, extrarenal manifestations, and attitudes surrounding research participation. Results: As of October 2021, 1563 ADPKD patients across the United States have registered and completed the Core Questionnaire. Participants have a median age of 44 years and are 72% women, 93% White, with 4% self-identifying as Hispanic/Latino and 2% as Black. All CKD stages are present, including post kidney transplant. To date, seven clinical studies have used the Registry as a recruitment tool. Additionally, quality-of-life burden scores revealed a correlation with disease stage as determined by kidney function. Conclusions: The Registry described here is the only one of its kind and is a valuable longitudinal research tool encompassing all stages of ADPKD. The registry will allow investigators to pursue a range of research questions related to the management of ADPKD, including definition of health-related quality of life (HRQoL) outcomes and recruitment for a variety of observational and therapeutic clinical protocols.
  • Lamotrigine-Induced Lupus With Aseptic Meningitis and Hemophagocytic Lymphohistiocytosis.

    Tran, Dena H; Jaggon, Kory S; Mikdashi, Jamal; Chow, Robert D; Verceles, Avelino C; Sood, Aseem (2022-09-26)
    Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by disordered immune activation resulting in cytokine storm and inflammation. We present a 27-year-old woman who had a fever and diffuse rash after recently starting lamotrigine. She developed meningismus and polyarthralgia. Laboratory results revealed cytopenia, elevated serum aminotransferases, hypofibrinogenemia and elevated ferritin. Cerebrospinal fluid analysis suggested aseptic meningitis. Antinuclear antibody and rheumatoid factor serologies were positive, complement levels of C3 were decreased, and antihistone antibody was negative. A bone marrow biopsy demonstrated hemophagocytic macrophages and the diagnosis of HLH was made. The patient was empirically started on high-dose intravenous dexamethasone following which both her mental status and laboratory indices markedly improved. Lamotrigine has been shown to induce lupus-like syndrome, aseptic meningitis, and HLH, but not concomitantly. Our patient was recently started on lamotrigine, likely inducing her underlying undiagnosed lupus, in addition to, resulting in aseptic meningitis and a cytokine storm leading to HLH.
  • Mining on Alzheimer's diseases related knowledge graph to identity potential AD-related semantic triples for drug repurposing.

    Nian, Yi; Hu, Xinyue; Zhang, Rui; Feng, Jingna; Du, Jingcheng; Li, Fang; Bu, Larry; Zhang, Yuji; Chen, Yong; Tao, Cui (2022-09-30)
    Background: To date, there are no effective treatments for most neurodegenerative diseases. Knowledge graphs can provide comprehensive and semantic representation for heterogeneous data, and have been successfully leveraged in many biomedical applications including drug repurposing. Our objective is to construct a knowledge graph from literature to study the relations between Alzheimer's disease (AD) and chemicals, drugs and dietary supplements in order to identify opportunities to prevent or delay neurodegenerative progression. We collected biomedical annotations and extracted their relations using SemRep via SemMedDB. We used both a BERT-based classifier and rule-based methods during data preprocessing to exclude noise while preserving most AD-related semantic triples. The 1,672,110 filtered triples were used to train with knowledge graph completion algorithms (i.e., TransE, DistMult, and ComplEx) to predict candidates that might be helpful for AD treatment or prevention. Results: Among three knowledge graph completion models, TransE outperformed the other two (MR = 10.53, Hits@1 = 0.28). We leveraged the time-slicing technique to further evaluate the prediction results. We found supporting evidence for most highly ranked candidates predicted by our model which indicates that our approach can inform reliable new knowledge. Conclusion: This paper shows that our graph mining model can predict reliable new relationships between AD and other entities (i.e., dietary supplements, chemicals, and drugs). The knowledge graph constructed can facilitate data-driven knowledge discoveries and the generation of novel hypotheses.
  • Role of RGC-32 in multiple sclerosis and neuroinflammation - few answers and many questions.

    Tatomir, Alexandru; Cuevas, Jacob; Badea, Tudor C; Muresanu, Dafin F; Rus, Violeta; Rus, Horea (2022-09-12)
    Recent advances in understanding the pathogenesis of multiple sclerosis (MS) have brought into the spotlight the major role played by reactive astrocytes in this condition. Response Gene to Complement (RGC)-32 is a gene induced by complement activation, growth factors, and cytokines, notably transforming growth factor β, that is involved in the modulation of processes such as angiogenesis, fibrosis, cell migration, and cell differentiation. Studies have uncovered the crucial role that RGC-32 plays in promoting the differentiation of Th17 cells, a subtype of CD4+ T lymphocytes with an important role in MS and its murine model, experimental autoimmune encephalomyelitis. The latest data have also shown that RGC-32 is involved in regulating major transcriptomic changes in astrocytes and in favoring the synthesis and secretion of extracellular matrix components, growth factors, axonal growth molecules, and pro-astrogliogenic molecules. These results suggest that RGC-32 plays a major role in driving reactive astrocytosis and the generation of astrocytes from radial glia precursors. In this review, we summarize recent advances in understanding how RGC-32 regulates the behavior of Th17 cells and astrocytes in neuroinflammation, providing insight into its role as a potential new biomarker and therapeutic target.
  • Editorial: Harnessing placebo mechanisms.

    Seneviratne, Chamindi; Noel, Jason; Franklin, Patricia D; Colloca, Luana (2022-09-12)
    The placebo phenomenon is receiving increasing attention because of the high translational value of basic research that can effectively translates into better study designs and symptoms management (1). This Theme Issue collection represents current trends in placebo research by focusing on two main strategies: (1) characterizing temporal effects, and (2) identify neuropsychobiological factors that can be used to subgroup individuals in clinical research for personalized treatments or interventions. The present collection predominantly focuses on placebo and nocebo effects associated with pain-related outcomes that were presented at the 3rd International conference of the Society for Placebo Studies (SIPS) in 2021. The first major section comprises of six studies that examined placebo and nocebo effects, with a focus on contextual features and individual predictors to be considered in designing rigorous research in these areas. The second major section is comprised of another six studies that investigated the potential for use of techniques that elicit nocebo and or placebo responses in clinical practice, with a focus on treating acute and chronic pain.
  • Comparability of Patients in Trials of eHealth and Face-to-Face Psychotherapeutic Interventions for Depression: Meta-synthesis

    Aemissegger, Vera; Lopez-Alcalde, Jesus; Witt, Claudia M.; Barth, Jürgen (2022-09-14)
  • To Drive or Not to Drive?: Commentary on an article by Ariel E. Badger, MS, et al.: "Patients Who Undergo Rotator Cuff Repair Can Safely Return to Driving at 2 Weeks Postoperatively"

    Henn, R. Frank; Hasan, S. Ashfaq; Gilotra, Mohit N.; Weir, Tristan B. (2022-09-21)
    “When can I drive?” This common question from patients involves multiple patient, surgeon, societal, and medicolegal considerations1. Limited evidence on the safety of driving after shoulder surgery and a lack of formal guidelines further complicate the surgeon’s role in advising patients. We commend Badger et al. on their efforts to study driving fitness after rotator cuff repair. Using thorough subjective and objective serial assessments of real-world driving, they provide empirical evidence that routine driving performance in a sling is adequate as soon as 2 weeks after rotator cuff repair. Not only was driving performance noninferior to baseline on all parameters at all time points, but the patients also exhibited less aggressive braking and more stable steering by 2 weeks after the surgical procedure. The findings strongly suggest that patients are more cautious while driving after rotator cuff repair and can effectively compensate for the limitations of the operatively treated extremity for routine driving. Patients were more self-critical of their ability to parallel park than the on-board safety monitor.
  • Isoniazid preventive therapy-related adverse events among Malawian adults on antiretroviral therapy: A cohort study.

    Tsirizani-Galileya, Lufina; Milanzi, Elasma; Mungwira, Randy; Divala, Titus; Mallewa, Jane; Mategula, Donnie; Nampota, Nginache; Mwapasa, Victor; Buchwald, Andrea; Laurens, Matthew B; et al. (2022-09-30)
    Adverse events may be a cause of observed poor completion of isoniazid preventive therapy (IPT) among people living with HIV in high tuberculosis burden areas. Data on IPT-related adverse events (AE) from sub-Saharan Africa are scarce. We report IPT-related AEs, associated clinical characteristics, and IPT discontinuations in adults who were stable on antiretroviral therapy (ART) when they initiated IPT. Cohort study nested within a randomized, controlled, clinical trial of cotrimoxazole and chloroquine prophylaxis in Malawians aged ≥ 18 years and virologically suppressed on ART. Eight hundred sixty-nine patients were followed for a median of 6 months after IPT initiation. IPT relatedness of AEs was determined retrospectively with the World Health Organization case-causality tool. Frailty survival regression modeling identified factors associated with time to first probably IPT-related AE. The overall IPT-related AE incidence rate was 1.1/person year of observation. IPT relatedness was mostly uncertain and few AEs were severe. Most common were liver and hematological toxicities. Higher age increased risk of a probably IPT-related AE (aHR = 1.02; 95% CI 1.00-1.06; P = .06) and higher weight reduced this risk (aHR = 0.98; 95% CI 0.96-1.00; P = .03). Of 869 patients, 114 (13%) discontinued IPT and 94/114 (82%) discontinuations occurred at the time of a possibly or probably IPT-related AE. We observed a high incidence of mostly mild IPT-related AEs among individuals who were stable on ART. More than 1 in 8 persons discontinued IPT. These findings inform strategies to improve implementation of IPT in adults on ART, including close monitoring of groups at higher risk of IPT-related AEs.
  • SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis.

    Zhu, Jun-Yi; Wang, Guanglei; Huang, Xiaohu; Lee, Hangnoh; Lee, Jin-Gu; Yang, Penghua; van de Leemput, Joyce; Huang, Weiliang; Kane, Maureen A; Yang, Peixin; et al. (2022-09-30)
    SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection. Here, by expressing individual SARS-CoV-2 proteins in the Drosophila heart, we demonstrate interaction of virus Nsp6 with host proteins of the MGA/MAX complex (MGA, PCGF6 and TFDP1). Complementing transcriptomic data from the fly heart reveal that this interaction blocks the antagonistic MGA/MAX complex, which shifts the balance towards MYC/MAX and activates glycolysis-with similar findings in mouse cardiomyocytes. Further, the Nsp6-induced glycolysis disrupts cardiac mitochondrial function, known to increase reactive oxygen species (ROS) in heart failure; this could explain COVID-19-associated cardiac pathology. Inhibiting the glycolysis pathway by 2-deoxy-D-glucose (2DG) treatment attenuates the Nsp6-induced cardiac phenotype in flies and mice. These findings point to glycolysis as a potential pharmacological target for treating COVID-19-associated heart failure.
  • Recommendations for Medical and Mental Health Care in Assisted Living Based on an Expert Delphi Consensus Panel: A Consensus Statement.

    Zimmerman, Sheryl; Sloane, Philip D; Wretman, Christopher J; Cao, Kevin; Silbersack, Johanna; Carder, Paula; Thomas, Kali S; Allen, Josh; Butrum, Kim; Chicotel, Tony; et al. (2022-09-01)
    Importance: Assisted living (AL) is the largest provider of residential long-term care in the US, and the morbidity of AL residents has been rising. However, AL is not a health care setting, and concern has been growing about residents' medical and mental health needs. No guidance exists to inform this care. Objective: To identify consensus recommendations for medical and mental health care in AL and determine whether they are pragmatic. Evidence review: A Delphi consensus statement study was conducted in 2021; as a separate effort, the extent to which the recommendations are reflected in practice was examined in data obtained from 2016 to 2021 (prepandemic). In the separate effort, data were from a 7-state study (Arkansas, Louisiana, New Jersey, New York, Oklahoma, Pennsylvania, Texas). The 19 Delphi panelists constituted nationally recognized experts in medical, nursing, and mental health needs of and care for older adults; dementia care; and AL and long-term care management, advocacy, regulation, and education. One invitee was unavailable and nominated an alternate. The primary outcome was identification of recommended practices based on consensus ratings of importance. Panelists rated 183 items regarding importance to care quality and feasibility. Findings: Consensus identified 43 recommendations in the areas of staff and staff training, nursing and related services, resident assessment and care planning, policies and practices, and medical and mental health clinicians and care. To determine the pragmatism of the recommendations, their prevalence was examined in the 7-state study and found that most were in practice. The items reflected the tenets of AL, the role of AL in providing dementia care, the need for pragmatism due to the diversity of AL, and workforce needs. Conclusions and relevance: In this consensus statement, 43 recommendations important to medical and mental health care in AL were delineated that are highly pragmatic as a guide for practice and policy.
  • Vγ2Vδ2 T-cell co-stimulation increases natural killer cell killing of monocyte-derived dendritic cells

    Cairo, Cristiana; Surendran, Naveen; Harris, Kristina M.; Mazan-Mamczarz, Krystyna; Sakoda, Yukimi; Diaz-Mendez, Felisa; Tamada, Koji; Gartenhaus, Ronald B.; Mann, Dean L.; Pauza, C. David (2015-03-01)
    Interactions between natural killer (NK) cells and dendritic cells (DC) affect maturation and function of both cell populations, including NK cell killing of DC (editing), which is important for controlling the quality of immune responses. We also know that antigen-stimulated Vγ2Vδ2 T cells co-stimulate NK cells via 4-1BB to enhance the killing of tumour cell lines but we do not know what regulates 4-1BB expression or whether other NK effector functions including DC killing, might also be influenced by NK–γδ T-cell cross-talk. Here we show that antigen-stimulated γδ T cells co-stimulate NK cells through inducible T-cell co-stimulator (ICOS)– ICOS ligand (ICOSL) and this signal increases NK cell killing of autologous DC. Effects of NK–γδ T-cell co-culture, which could be repro-duced with soluble ICOS-Fc fusion protein, included increased CD69 and 4-1BB expression, interferon-γ, tumour necrosis factor-α, macrophage inflammatory protein-1β, I-309, RANTES and sFas ligand production, as well as elevated mRNA levels for co-stimulatory receptors OX40 (TNFRSF4) and GITR (TNFRSF18). Hence, ICOS–ICOSL co-stimulation of NK by Vγ2Vδ2 T cells had broad effects on NK phenotype and effector functions. The NK–γδ T-cell cross-talk links innate and antigen-specific lymphocyte responses in the control of cytotoxic effector function and DC killing. © 2014 John Wiley & Sons Ltd, Immunology.
  • An 18-Year-old Prisoner with Abdominal Pain

    Windsor, T. Andrew; Darby, Anna (2018-01-01)
    CASE PRESENTATION (Anna Darby, MD, MPH) An 18-year-old male presented to the emergency department (ED) with a complaint of severe abdominal pain for three days along with painful urination, vomiting, diarrhea and subjective fever and chills. The patient reported brief, severe, colicky episodes of mid and left upper quadrant (LUQ) abdominal pain that radiated to his testicles. He vomited several times because of the pain, which he stated began suddenly while he was lying down. Notably, the patient had recently got over a diarrheal illness a few days prior, followed by constipation, and had recurrence of one loose stool on the day of presentation. He denied any flank pain or back pain, and had never experienced anything like this current illness before.
  • 65-year-old Female with Cardiac Arrest and Return of Spontaneous Circulation

    Kirk, Megan; Ablaihed, Leen; Dezman, Zachary D.W.; Bontempo, Laura J. (2018-08-01)
    CASE PRESENTATION A 65-year-old female was transported to the emergency department (ED) at approximately 2:00 AM following a witnessed cardiac arrest. According to the patient’s husband, she had been asleep in bed when she awoke suddenly, sat upright, and reached for her albuterol inhaler before “collapsing.” He found her to be pulseless and initiated cardiopulmonary resuscitation (CPR) while placing a call to emergency medical services (EMS). On EMS arrival, the patient was unresponsive and continued to receive CPR. She was intubated in the field using a size 7.0 endotracheal tube. Her initial rhythm was pulseless electrical activity (PEA), but she converted to normal sinus rhythm after receiving 1mg of epinephrine intravenously and 15 total minutes of CPR. No further history was available.

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