Human epicardial adipose tissue contains innate and adaptive lymphoid cells and a higher proportion of innate type 2 lymphoid cells compared to other adipose tissues.

IMPORTANCE: Epicardial adipose tissue (EAT) is a biologically active organ surrounding myocardium and coronary arteries that has been associated with coronary artery disease (CAD) and atrial fibrillation. Previous work has shown that EAT exhibits beige features. OBJECTIVE: Our objective was to determine whether the stromal vascular fraction of the human EAT contains innate or adaptive lymphoid cells compared to thoracic subcutaneous (thSAT), visceral abdominal (VAT) and subcutaneous abdominal (abSAT). PARTICIPANTS: New pangenomic microarray analysis was performed on previous transcriptomic dataset using significance analysis of microarray and ingenuity pathway analysis (n=41) to identify specific immune signature and its link with browning genes. EAT, thSAT, VAT and abSAT samples from explanted patients with severe cardiomyopathies and multi-organ donor patients (n=17) were used for flow cytometry (FC) immunophenotyping assay. Patients were on average 55±16 years-old; 47% had hypertension and 6% CAD. Phenotypic adaptive and innate immune profiles were performed using a TBNK panel and a specific ILC1-2-3 panel including CD127, CD117, CRTH2 (CD294) and activation markers such as CD25 and CD69. RESULTS: Transcriptomic analysis showed a significant positive correlation between the TH2 immune pathway (IL-4, IL-5, IL-13, IL-25, IL-33) and browning genes (UCP-1, PRDM16, TMEM26, CITED1, TBX1) in EAT versus thSAT (R=0.82, P<0.0001). Regarding adaptive immune cells, a preponderance of CD8T cells, a contingent of CD4T cells, and a few B cells were observed in all ATs (P<0.0001). In innate lymphoid cells (ILCs), an increase was observed in visceral ATs (i.e. EAT; VAT 35±8ILCs/g of tissue) compared to their subcutaneous counterpart (i.e. thSAT+abSAT: 8±3 ILCs/g of AT, P=0.002), with a difference in the proportion of the 3 subtypes of ILCs (ILC1>ILC3>ILC2). In addition, we observed an increase in EAT-ILC2 compared to other ATs and almost all these EAT-ILC2 expressed CD69 and/or CD25 activation markers (99.75±0.16%; P<0.0001). We also observed more NKs in EAT and VAT (1520±71 cells/g of AT) than in SATs (562±17 cells/g of AT); P=0.01. CONCLUSION: This is the first study to provide a comparison between innate and adaptive lymphoid cells in human epicardial versus abdominal or thoracic adipose tissues. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging. TRIAL REGISTRATION: CODECOH No. DC-2021-4518 The French agency of biomedicine PFS21-005.

Managing Delirium in the Emergency Department: An Updated Narrative Review.

Purpose of Review: Emergency departments (EDs) are facing an epidemic of overcrowding and ED boarding, particularly of older adults who often present with, or develop, delirium in the ED. Delirium is associated with increased complications, longer hospital length of stay, mortality, and costs to the healthcare system. However, we only have limited knowledge of how to successfully prevent and treat delirium in the ED in a pragmatic, sustainable, and cost-effective way. We present a narrative review of recent literature of delirium prevention and treatment programs in the ED. We aim to describe the components of successful delirium management strategies to be used by EDs in building delirium management programs. Recent Findings: We reviewed 10 studies (2005-2023) that report delirium interventions in the ED, and describe the different components of these interventions that have been studied. These interventions included: optimizing hemodynamics and oxygenation, treating pain, hydration and nutrition support, avoiding sedative hypnotics, antipsychotics and anticholinergics, promoting sleep, sensory stimulation, limiting the time spent in the ED, educating providers and staff, and developing multidisciplinary delirium protocols integrated into the electronic health record. Summary: Through our narrative review of the recent literature on delirium prevention and treatment programs in the ED, we have identified nine components of successful delirium prevention strategies in the ED. We also discuss three high priority areas for further research including identification of most effective components of delirium prevention strategies, conduct of additional high-quality trials in non-hip.

Human epicardial fat has a beige profile and contains higher type 2 innate lymphoid cells than subcutaneous fat.

OBJECTIVE: Epicardial adipose tissue (EAT) is a visceral fat that has been associated with coronary artery disease and atrial fibrillation. Previous work has revealed that EAT exhibits beige features. METHODS: First, a new pan-genomic microarray analysis was performed on previously collected paired human EAT and thoracic subcutaneous AT (thSAT) from the EPICAR study (n = 31) to decipher a specific immune signature and its link with browning genes. Then, adaptive (T and B cells) and innate lymphoid cell (ILC1, ILC2, and ILC3) immunophenotyping assay panels, including CD127, CD117, and prostaglandin D2 receptor 2, were performed on prospectively collected paired human multiorgan donors (n = 18; INTERFACE study). RESULTS: In the EPICAR study, a positive correlation between the T helper cell subtype Th2 immune pathway and browning genes was found in EAT versus thSAT (r = 0.82; p < 0.0001). In the INTERFACE study, this correlation was also observed (r = 0.31; p = 0.017), and a preponderance of CD4+T cells, CD8+T cells, and a few B cells was observed in all ATs (p < 0.0001). An increase in ILCs was observed in visceral AT (VAT) (i.e., EAT + VAT; 30 ± 5 ILCs per gram of AT) compared with subcutaneous counterparts (i.e., thSAT + abdominal SAT; 8 ± 2 ILCs per gram of AT; p = 0.001), with ILC1 being the most frequent (ILC1 > ILC3 > ILC2). Numbers of ILCs per gram of AT correlated with several Th2 or browning genes (IL-13, TNF receptor superfamily member 9 [TNFRSF9], and alkaline phosphatase, biomineralization associated [ALPL]). Interestingly, a specific increase in EAT-ILC2 compared with other ATs was observed, including a significant proportion expressing CD69 and/or CD25 activation markers (97.9% ± 1.2%; p < 0.0001). Finally, more natural killer cells were observed in EAT + VAT than in thSAT + abdominal SAT (p = 0.01). Exclusion of patients with coronary artery disease in the EPICAR and INTERFACE studies did not modify the main findings. Gene expression phenotyping confirmed specific upregulation of Th2 pathway and browning genes (IL-33 and uncoupling protein 1 [UCP-1]) in EAT. CONCLUSIONS: This is the first study, to our knowledge, to provide a comparison between innate and adaptive lymphoid cells in human EAT. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging.

The prevalence of multidrug resistance in uropathogens of patients admitted in the intensive care unit of a tertiary care hospital.

Urinary tract infections (UTIs) are among the most common bacterial infections, posing significant public health challenges due to increasing antimicrobial resistance (AMR). This study aims to assess the prevalence, demographic characteristics, microbial profile, and antimicrobial resistance patterns in Indian patients with UTIs admitted to intensive care unit. A total of 154 patients with positive UTIs were included in this cross-sectional study. The prevalence data including demographics, microbial isolates, and antimicrobial susceptibility patterns were collected. Additionally, risk factors for multidrug resistance uropathogens were assessed using multivariate analyses. The patient cohort had diverse demographic, with a slight male predominance of 52.6% (n = 81). The most common comorbidities were hypertension 59.1% (n = 91) and diabetes mellitus 54.5% (n = 84). The microbial profile was dominated by gram-negative bacteria, particularly Escherichia coli 26.62% (n = 41) and Klebsiella pneumoniae 17.53% (n = 27). The predominant gram-positive and fungal isolate was Enterococcus faecium 7.14% (n = 11) and Candida spp. 18.83% (n = 29), respectively. Substantial resistance was noted against common antimicrobials, with variations across different pathogens. Gram-negative bacteria, particularly Escherichia coli and Klebsiella pneumoniae, exhibited high MDR rates, emphasizing the challenge of antimicrobial resistance. Multivariate logistic regression identified age groups 50-65 and over 65, and prolonged catheterization as significant risk factors for MDR infections. A significantly high resistance rate among pathogens emphasizes the need for judicious antimicrobial use. Our findings emphasize the necessity of ongoing surveillance and tailored interventions based on local pathogen prevalence and antibiogram data to effectively address the threat of AMR threat for better management of UTI management in ICU settings.

Case report: a unique presentation of memantine overdose causing echolalia and hypertension.

BACKGROUND: Since 2003 when memantine was first approved for use in the management of moderate-severe Alzheimer's dementia, its use has become more widespread and is being explored in other diseases like neuropathic pain, epilepsy, and mood disorders. Our case uniquely highlights two important adverse effects in a patient who overdosed on memantine. One is hypertension, which is easy to overlook as a medication side effect. The other is echolalia which is the repetition of words and phrases spoken by another person. It is commonly seen in children with autism spectrum disorder and has been reported in older adults with head injuries, delirium, and neurocognitive disorders. The aim of this patient story is to highlight the importance of medication reconciliation with caregivers and knowledge of adverse drug reactions in patient management. This case report has been presented previously in the form of an abstract at the American Geriatrics Society Presidential poster session in May 2023. CASE PRESENTATION: Our patient is an 86-year-old man with mild dementia and hypertension, who was brought to the emergency department (ED) due to abrupt onset of altered mental status and auditory hallucinations. Investigations including blood work, CT head and an electroencephalogram (EEG) did not reveal an etiology for this change in his condition. Due to elevated blood pressure on presentation, a nicardipine drip was started, and he was given IV midazolam to assist with obtaining imaging. While reviewing medications with his daughter, it was noted that sixty memantine pills were missing from the bottle. Poison control was contacted and they confirmed association of these features with memantine. With supportive care, his symptoms resolved in less than 100 h, consistent with the half-life of memantine. Notably, our patient was started on Memantine one month prior to this presentation. CONCLUSIONS: Hypertensive urgency and echolalia were the most striking symptoms of our patient's presentation. Though hypertension is a known sign of memantine overdose, it can easily be contributed to medication non-compliance in patients with dementia, being treated for hypertension. According to our literature review, this the first case of memantine overdose presenting with echolalia, a sign that is not commonly associated with adverse reactions to medications. This highlights the importance of an early medication review, especially with caregivers of people with dementia.

Mucormycosis: A hidden mystery of fungal infection, possible diagnosis, treatment and development of new therapeutic agents.

Mucormycosis is a fungal infection which got worsens with time if not diagnosed and treated. The current COVID-19 pandemic has association with fungal infection specifically with mucormycosis. Already immunocompromised patients are easy target for COVID-19 and mucormycosis as well. COVID-19 infection imparts in weak immune system so chances of infection is comparatively high in COVID-19 patients. Furthermore, diabetes, corticosteroid medicines, and a weakened immune system are the most prevalent risk factors for this infection as we discussed in case studies here. The steroid therapy for COVID-19 patients sometimes have negative impact on the patient health and this state encounters many infections including mucormycosis. There are treatments available but less promising and less effective. So, researchers are focusing on the promising agents against mucormycosis. It is reported that early treatment with liposomal amphotericin B (AmB), manogepix, echinocandins isavuconazole, posacanazole and other promising therapeutic agents have overcome the burden of mucormycosis. Lipid formulations of AmB have become the standard treatment for mucormycosis due to their greater safety and efficacy. In this review article, we have discussed case studies with the infection of mucormycosis in COVID-19 patients. Furthermore, we focused on anti-mucormycosis agents with mechanism of action of various therapeutics, including coverage of new antifungal agents being investigated as part of the urgent global response to control and combat this lethal infection, especially those with established risk factors.

Browning Epicardial Adipose Tissue: Friend or Foe?

The epicardial adipose tissue (EAT) is the visceral fat depot of the heart which is highly plastic and in direct contact with myocardium and coronary arteries. Because of its singular proximity with the myocardium, the adipokines and pro-inflammatory molecules secreted by this tissue may directly affect the metabolism of the heart and coronary arteries. Its accumulation, measured by recent new non-invasive imaging modalities, has been prospectively associated with the onset and progression of coronary artery disease (CAD) and atrial fibrillation in humans. Recent studies have shown that EAT exhibits beige fat-like features, and express uncoupling protein 1 (UCP-1) at both mRNA and protein levels. However, this thermogenic potential could be lost with age, obesity and CAD. Here we provide an overview of the physiological and pathophysiological relevance of EAT and further discuss whether its thermogenic properties may serve as a target for obesity therapeutic management with a specific focus on the role of immune cells in this beiging phenomenon.

Extracellular Vesicle-Based Therapy for COVID-19: Promises, Challenges and Future Prospects.

The COVID-19 pandemic has become a serious concern and has negatively impacted public health and the economy. It primarily targets the lungs, causing acute respiratory distress syndrome (ARDS); however, it may also lead to multiple organ failure (MOF) and enhanced mortality rates. Hence, there is an urgent need to develop potential effective therapeutic strategies for COVID-19 patients. Extracellular vesicles (EVs) are released from various types of cells that participate in intercellular communication to maintain physiological and pathological processes. EVs derived from various cellular origins have revealed suppressive effects on the cytokine storm during systemic hyper-inflammatory states of severe COVID-19, leading to enhanced alveolar fluid clearance, promoted epithelial and endothelial recovery, and cell proliferation. Being the smallest subclass of EVs, exosomes offer striking characteristics such as cell targeting, being nano-carriers for drug delivery, high biocompatibility, safety, and low-immunogenicity, thus rendering them a potential cell-free therapeutic candidate against the pathogeneses of various diseases. Due to these properties, numerous studies and clinical trials have been performed to assess their safety and therapeutic efficacy against COVID-19. Hence, in this review, we have comprehensively described current updates on progress and challenges for EVs as a potential therapeutic agent for the management of COVID-19.

A Novel Curriculum on Using Life Expectancy to Inform Cancer Screening in Older Adults.

BACKGROUND: Many older adults with limited life expectancy still receive cancer screening. One potential contributor is that primary care providers (PCP) are not trained to incorporate life expectancy in cancer screening recommendations. We describe the development and evaluation of a novel curriculum to address this need. METHODS: We developed and implemented a web-based learning module within a large Maryland group practice with PCPs for older adults. We assessed attitude, knowledge, self-efficacy, and self-reported behavior outcomes before the module, immediately after completing the module, and 6 months afterwards. RESULTS: Of 172 PCPs who were invited, 86 (50%) completed the module and of these, 50 (58.1%) completed the 6-months follow up survey. Immediately after the module, there was a significant increase in perceived importance of life expectancy (increase of 0.50 point on 10-point scale, 95% confidence intervals (CI) = 0.27-0.73), confidence in predicting life expectancy (increase of 2.32 points on 10-point scale, 95% CI = 1.95-2.70) and confidence in discussion screening cessation (increase of 1.69 points on 10-point scale, 95% CI = 1.37-2.02). Knowledge in patient-preferred communication strategies improved from 55% correct response to 97% (P < .001). However, most of these improvements dissipated by 6 months and there was no change in self-reported behavior at 6 months compared to baseline (P = .34). CONCLUSION: Although the module resulted in significant short-term improvement in attitude, knowledge, and self-efficacy, the changes were not sustained over time. Educational interventions such as this can be coupled with ongoing reinforcing strategies and/or decision support interventions to improve cancer-screening practices in older adults.

A quality improvement initiative to improve management of procedural pain in preterm neonates.

BACKGROUND: Neonates managed in neonatal intensive care units undergo several invasive procedures. However, neonatal procedural pain is not well recognized and managed in most neonatal units. AIMS: To decrease the severity of procedural pain in preterm neonates (<37 weeks gestational age at birth), as measured by Premature Infant Pain Profile , by 50% by April 2020. METHODS: A quality improvement initiative was conducted in a level 3 neonatal intensive care unit in South India. The pain was assessed independently by 2 interns not involved in clinical care using Premature Infant Pain Profile. After a baseline data recording and questionnaire assessing knowledge of healthcare personnel regarding neonatal pain, the interventions were planned. These were conducted as plan-do-study-act cycles-(i) Educational sessions, (ii) Introduction of bedside visual aids, (iii) Simulation sessions demonstrating the use of nonpharmacological measures and introduction of procedure surveillance chart in daily rounds, and (iv) Video feedback-based sessions. In the maintenance phase, the observations were continued. RESULTS: The healthcare personnel under recognized pain related to heel pricks and endotracheal intubation. They also had poor awareness of signs and symptoms of neonatal pain. A total of 202 procedures were observed during the study period. The mean pain score decreased significantly from 12.8 ± 4.5 in baseline period to 6.2 ± 1.8 in the maintenance phase. The use of analgesic measures increased from 13% in the baseline period to 73% in the maintenance phase. The use of automated lancet for heel prick increased from 0% to 94% in maintenance phase. More and more procedures were done with appropriate environment and baby state. The mean number of procedures per day decreased from 6.5 ± 1.8 in baseline period to 2.7 ± 0.9 in the maintenance phase. CONCLUSIONS: Targeted interventions can improve neonatal procedural pain management by improving use of analgesic measures, decreasing the number of procedures, and educating and training healthcare personnel.

A Single Center Evaluation of the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging against Transperineal Prostate Mapping Biopsy: An Analysis of Men with Benign Histology and Insignificant Cancer following Transrectal Ultrasound Biopsy.

PURPOSE: In this study we evaluated the diagnostic performance of transrectal ultrasound guided biopsy and multiparametric magnetic resonance imaging to detect prostate cancer against transperineal prostate mapping biopsy as the reference test. MATERIALS AND METHODS: Transrectal ultrasound guided biopsy, multiparametric magnetic resonance imaging and transperineal prostate mapping biopsy were performed in 426 patients between April 2012 and January 2016. Patients initially underwent systematic 12 core transrectal ultrasound guided biopsy followed 3 months later by 1.5 Tesla, high resolution T2, diffusion-weighted, dynamic contrast enhanced multiparametric magnetic resonance imaging. Two specialist uroradiologists blinded to the results of transperineal prostate mapping biopsy allocated a PI-RADS™ (Prostate Imaging-Reporting and Data System) score to each multiparametric magnetic resonance imaging study. Transperineal prostate mapping biopsy with 5 mm interval sampling, which was performed within 6 months of multiparametric magnetic resonance imaging, served as the reference test. RESULTS: Transrectal ultrasound guided biopsy identified 247 of 426 patients with prostate cancer and 179 of 426 with benign histology. Transperineal prostate mapping biopsy detected prostate cancer in 321 of 426 patients. On transperineal prostate mapping biopsy 94 of 179 patients with benign transrectal ultrasound guided biopsy had prostate cancer and 95 of 247 with prostate cancer on transrectal ultrasound guided biopsy were identified with cancer of higher grade. Using a multiparametric magnetic resonance imaging PI-RADS score of 3 or greater to detect significant prostate cancer, defined as any core containing Gleason 4 + 3 or greater prostate cancer on transperineal prostate mapping biopsy, the ROC AUC was 0.754 (95% CI 0.677-0.819) with 87.0% sensitivity (95% CI 77.3-97.0), 55.3% specificity (95% CI 50.2-60.4) and 97.1% negative predictive value (95% CI 94.8-99.4). CONCLUSIONS: Multiparametric magnetic resonance imaging is a more accurate diagnostic test than transrectal ultrasound guided biopsy. However, a significant proportion of ISUP (International Society of Urological Pathology) Grade Group 2 prostate cancer remained undetected following multiparametric magnetic resonance imaging. Although multiparametric magnetic resonance imaging could avoid unnecessary biopsy in many patients with ISUP Grade Group 3 or greater prostate cancer, at less stringent definitions of significant cancer a substantial proportion of prostate cancer would remain undetected after multiparametric magnetic resonance imaging.

Utility of early transperineal template-guided prostate biopsy for risk stratification in men undergoing active surveillance for prostate cancer.

OBJECTIVE: To assess the accuracy and utility of routine multiparametric magnetic resonance imaging (mpMRI) and transperineal template-guided prostate biopsy (TPB) after enrolment in active surveillance (AS). PATIENTS AND METHODS: From April 2012 to December 2016 consecutive men from our single institution, diagnosed with low- or intermediate-risk prostate cancer on transrectal ultrasonography-guided biopsy, were offered further staging with early mpMRI and TPB within 12 months of diagnosis. Data were collected prospectively. Eligibility criteria comprised: age ≤77 years; Gleason score ≤3 + 4; clinical stage T1-T2; PSA ≤15 ng/mL; and <50% positive biopsy cores. RESULTS: A total of 208 men were enrolled, including 196 with Gleason score 3 + 3 and 12 with Gleason score 3 + 4 disease. The median (range) number of TPB cores was 50 (17-161), with a mean TPB core density of 1.2 cores/cm3 prostate volume. A total of 83 men (39.9%) underwent histopathological upgrading after TPB, including 76 men (38.8%) with Gleason score 3 + 3 disease and seven men (58.3%) with Gleason score 3 + 4 disease. Of these, 26 (31.3%) were found to harbour primary pattern Gleason grade ≥4 disease. In all, 24 (28.9%) upgraded cases had Prostate Imaging Reporting and Data System (PI-RADS) score 1 or 2 lesions on mpMRI, including five men with Gleason score ≥4 + 3 disease. Of these, 14 (58.3%) had a prostate-specific antigen (PSA) density of ≥0.15, including four out of the five men with Gleason ≥4 + 3 disease. Overall there was a change in prostate cancer management in 77 men (37.0%) after TPB. CONCLUSIONS: Early TPB during AS is associated with significant upgrading and a change in treatment plan in over a third of men. If TPB was omitted in men with a PI-RADS score <3 and a PSA density <0.15, 12% of those harbouring more significant disease would have been misclassified.

Hyperactivation of mammalian target of rapamycin complex 1 by HIV-1 is necessary for virion production and latent viral reactivation.

Generation of new HIV-1 virions requires the constant supply of proteins, nucleotides, and energy; however, it is not known which cellular pathways are perturbed and what molecular mechanisms are employed. We hypothesized that HIV-1 may regulate pathways that control synthesis of biomolecules in the cell. In this study, we provide evidence that HIV-1 hyperactivates mammalian target of rapamycin complex 1 (mTORC1), the central regulator of biosynthesis. Mechanistically, we identify the viral regulatory gene tat (transactivator) as being responsible for increasing mTORC1 activity in a PI3K-dependent manner. Furthermore, we show that hyperactivation of mTORC1 leads to activation of the enzyme, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase, and repression of initiation factor 4E-binding protein 1 activity. These are regulators of nucleotide biogenesis and protein translation, respectively. Moreover, we are able to replicate these results in HIV-1 latent cell line models. Finally, we show that inhibition of mTORC1 or PI3K inhibits viral replication and viral reactivation as a result of a decrease in biosynthesis. Overall, our study identifies a new avenue in HIV-1 biology that can lead to development of novel therapeutic targets.-Kumar, B., Arora, S., Ahmed, S., Banerjea, A. C. Hyperactivation of mammalian target of rapamycin complex 1 by HIV-1 is necessary for virion production and latent viral reactivation.