S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis.

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

Genomic insights into metabolic flux in hummingbirds.

Hummingbirds are very well adapted to sustain efficient and rapid metabolic shifts. They oxidize ingested nectar to directly fuel flight when foraging but have to switch to oxidizing stored lipids derived from ingested sugars during the night or long-distance migratory flights. Understanding how this organism moderates energy turnover is hampered by a lack of information regarding how relevant enzymes differ in sequence, expression, and regulation. To explore these questions, we generated a chromosome-scale genome assembly of the ruby-throated hummingbird (A. colubris) using a combination of long- and short-read sequencing, scaffolding it using existing assemblies. We then used hybrid long- and short-read RNA sequencing of liver and muscle tissue in fasted and fed metabolic states for a comprehensive transcriptome assembly and annotation. Our genomic and transcriptomic data found positive selection of key metabolic genes in nectivorous avian species and deletion of critical genes (SLC2A4, GCK) involved in glucostasis in other vertebrates. We found expression of a fructose-specific version of SLC2A5 putatively in place of insulin-sensitive SLC2A5, with predicted protein models suggesting affinity for both fructose and glucose. Alternative isoforms may even act to sequester fructose to preclude limitations from transport in metabolism. Finally, we identified differentially expressed genes from fasted and fed hummingbirds, suggesting key pathways for the rapid metabolic switch hummingbirds undergo.

Highly specific σ2R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response.

The sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.

Static and Dynamic DNA Loops form AP-1-Bound Activation Hubs during Macrophage Development.

The three-dimensional arrangement of the human genome comprises a complex network of structural and regulatory chromatin loops important for coordinating changes in transcription during human development. To better understand the mechanisms underlying context-specific 3D chromatin structure and transcription during cellular differentiation, we generated comprehensive in situ Hi-C maps of DNA loops in human monocytes and differentiated macrophages. We demonstrate that dynamic looping events are regulatory rather than structural in nature and uncover widespread coordination of dynamic enhancer activity at preformed and acquired DNA loops. Enhancer-bound loop formation and enhancer activation of preformed loops together form multi-loop activation hubs at key macrophage genes. Activation hubs connect 3.4 enhancers per promoter and exhibit a strong enrichment for activator protein 1 (AP-1)-binding events, suggesting that multi-loop activation hubs involving cell-type-specific transcription factors represent an important class of regulatory chromatin structures for the spatiotemporal control of transcription.

The ABI4-RGL2 module serves as a double agent to mediate the antagonistic crosstalk between ABA and GA signals.

Abscisic acid (ABA) and gibberellins (GA) antagonistically mediate several biological processes, including seed germination, but the molecular mechanisms underlying ABA/GA antagonism need further investigation, particularly any role mediated by a transcription factors module. Here, we report that the DELLA protein RGL2, a repressor of GA signaling, specifically interacts with ABI4, an ABA signaling enhancer, to act as a transcription factor complex to mediate ABA/GA antagonism. The rgl2, abi3, abi4 and abi5 mutants rescue the non-germination phenotype of the ga1-t. Further, we demonstrate that RGL2 specifically interacts with ABI4 to form a heterodimer. RGL2 and ABI4 stabilize one another, and GA increases the ABI4-RGL2 module turnover, whereas ABA decreases it. At the transcriptional level, ABI4 enhances the RGL2 expression by directly binding to its promoter via the CCAC cis-element, and RGL2 significantly upregulates the transcriptional activation ability of ABI4 toward its target genes, including ABI5 and RGL2. Abscisic acid promotes whereas GA inhibits the ability of ABI4-RGL2 module to activate transcription, and ultimately ABA and GA antagonize each other. Genetic analysis demonstrated that both ABI4 and RGL2 are essential for the activity of this transcription factor module. These results suggest that the ABI4-RGL2 module mediates ABA/GA antagonism by functioning as a double agent.

Outcomes of octogenarians receiving aortic repair.

OBJECTIVE: Abdominal aortic aneurysm (AAA) repair is recommended for aneurysms greater than 5.5 cm in men and 5 cm in women. Because AAA is more common among the elderly, we sought to evaluate contemporary practices of elective AAA repair and 2-year postoperative outcomes in octogenarians. METHODS: We identified octogenarians undergoing elective AAA repair in the Vascular Quality Initiative from 2012 to 2019. We included patients undergoing endovascular (EVAR) and open (OAR) aortic repair. Demographics and comorbid conditions were compared between patient groups. Frailty was calculated using previously published methods. Patients with frailty scores above the 75th percentile of the operative cohort were considered high frailty. The primary outcome was 1- and 2-year mortality. Secondary outcomes included postoperative complications. Standard statistical methods were utilized. Cox proportional hazard models were used to identify factors that affect mortality. RESULTS: The frequency of AAA repair in octogenarians has remained stable. Of all aortic operations, 21.4% were performed on octogenarians; 9735 (23.3% of 41,712) EVAR and 755 (10.3% of 7325) OARs. Among octogenarian patients, 42.0% of EVARs were under size thresholds: 48.3% males ≤5.5 cm diameter and 21.5% females ≤5.0 cm diameter compared with 18.8% OARs: 23.4% males and 10.7% females. Additionally, 25.6% had high frailty scores. Among octogenarians, 1- and 2-year mortality was 9.3% ± 0.3% and 14.8% ± 0.4% for EVAR and 15.2% ± 1.3% and 18.9% ± 1.5% for OAR patients, respectively (P < .01). In-hospital mortality rate was higher after OAR (0.87% EVAR vs 7.55% OAR; P < .01) and differed with frailty (EVAR, low frailty 0.2% vs high frailty 1.7%; OAR, low frailty 2.3% vs high frailty 15.6%). For EVAR, patient factors associated with mortality included heart failure (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.06-1.25; P = .001) and dialysis (HR, 1.71; 95% CI, 1.13-2.59; P = .012). For OAR, coronary artery disease (HR, 1.55; 95% CI, 0.98-2.44; P = .062) was associated with mortality. Statin use was protective of mortality for all patients (EVAR: HR, 0.68; 95% CI, 0.60-0.78; P < .01): OAR: HR, 0.58; 95% CI, 0.37-0.92; P = .020). Among octogenarians, high frailty was independently associated with 2-year mortality (EVAR: HR, 3.36; 95% CI, 2.62-4.31; P < .01 and OAR: HR, 2.35; 95% CI, 1.09-5.10; P = .030). CONCLUSIONS: Nationally, a large portion of elective AAA repair in octogenarians is performed below recommended size thresholds, one-quarter of whom are frail with poor long-term 2-year mortality rates. High 2-year mortality following AAA repair in this age group exceeds the published risk of rupture for 5- to 5.5-cm AAA, suggesting that increase in the size threshold of elective repair among octogenarians should be explored.

ephrin-B2 promotes nociceptive plasticity and hyperalgesic priming through EphB2-MNK-eIF4E signaling in both mice and humans.

Ephrin-B-EphB signaling can promote pain through ligand-receptor interactions between peripheral cells, like immune cells expressing ephrin-Bs, and EphB receptors expressed by DRG neurons. Previous studies have shown increased ephrin-B2 expression in peripheral tissues like synovium of rheumatoid and osteoarthritis patients, indicating the clinical significance of this signaling. The primary goal of this study was to understand how ephrin-B2 acts on mouse and human DRG neurons, which express EphB receptors, to promote pain and nociceptor plasticity. We hypothesized that ephrin-B2 would promote nociceptor plasticity and hyperalgesic priming through MNK-eIF4E signaling, a critical mechanism for nociceptive plasticity induced by growth factors, cytokines and nerve injury. Both male and female mice developed dose-dependent mechanical hypersensitivity in response to ephrin-B2, and both sexes showed hyperalgesic priming when challenged with PGE2 injection either to the paw or the cranial dura. Acute nociceptive behaviors and hyperalgesic priming were blocked in mice lacking MNK1 (Mknk1 knockout mice) and by eFT508, a specific MNK inhibitor. Sensory neuron-specific knockout of EphB2 using Pirt-Cre demonstrated that ephrin-B2 actions require this receptor. In Ca2+-imaging experiments on cultured DRG neurons, ephrin-B2 treatment enhanced Ca2+ transients in response to PGE2 and these effects were absent in DRG neurons from MNK1-/- and EphB2-PirtCre mice. In experiments on human DRG neurons, ephrin-B2 increased eIF4E phosphorylation and enhanced Ca2+ responses to PGE2 treatment, both blocked by eFT508. We conclude that ephrin-B2 acts directly on mouse and human sensory neurons to induce nociceptor plasticity via MNK-eIF4E signaling, offering new insight into how ephrin-B signaling promotes pain.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

The Role of Integrated Air Transport System in Managing Patients with Abdominal Aortic Aneurysm Rupture.

OBJECTIVE: Ruptured abdominal aortic aneurysms (rAAAs) are highly morbid emergencies. Not all hospitals are equipped to repair them, and an air ambulance network may aid in regionalising specialty care to quaternary referral centres. The association between travel distance by air ambulance and rAAA mortality in patients transferred as an emergency for repair was examined. METHODS: A retrospective review of institutional data. Adults with rAAA (2002 - 2019) transferred from an outside hospital (OSH) to a single quaternary referral centre for repair via air ambulance were identified. Patients who arrived via ground transport or post-repair at an OSH for continued critical care were excluded. Patients were divided into near and far groups based on the 75th percentile of the straight line travel distance (> 72 miles) between hospitals. The primary outcome was 30 day mortality. Multivariable logistic regression was used to assess the association between distance and mortality after adjusting for age, sex, race, cardiovascular comorbidities, and repair type. RESULTS: A total of 290 patients with rAAA were transported a median distance of 40.4 miles (interquartile range 25.5, 72.7) with 215 (74.1%) near and 75 (25.9%) far patients. Both the near and far groups had similar ages, sex, and race. There was no difference in pre-operative loss of consciousness, intubation, or cardiac arrest between groups. Endovascular aneurysm repair utilisation and intra-operative aortic occlusion balloon use were also similar. Neither the observed (26.8% vs. 23.9%, p = .61) nor the adjusted odds ratio (0.70, 95% confidence interval 0.36 - 1.39, p = .32) 30 day mortality rate differed significantly between the near and far groups. CONCLUSION: Increasing distance travelled during transfer by air ambulance was not associated with worse outcomes in patients with rAAA. The findings support the regionalisation of rAAA repair to large quaternary centres via an integrated and robust air ambulance network.

A digital score of peri-epithelial lymphocytic activity predicts malignant transformation in oral epithelial dysplasia.

Oral squamous cell carcinoma (OSCC) is amongst the most common cancers, with more than 377,000 new cases worldwide each year. OSCC prognosis remains poor, related to cancer presentation at a late stage, indicating the need for early detection to improve patient prognosis. OSCC is often preceded by a premalignant state known as oral epithelial dysplasia (OED), which is diagnosed and graded using subjective histological criteria leading to variability and prognostic unreliability. In this work, we propose a deep learning approach for the development of prognostic models for malignant transformation and their association with clinical outcomes in histology whole slide images (WSIs) of OED tissue sections. We train a weakly supervised method on OED cases (n = 137) with malignant transformation (n = 50) and mean malignant transformation time of 6.51 years (±5.35 SD). Stratified five-fold cross-validation achieved an average area under the receiver-operator characteristic curve (AUROC) of 0.78 for predicting malignant transformation in OED. Hotspot analysis revealed various features of nuclei in the epithelium and peri-epithelial tissue to be significant prognostic factors for malignant transformation, including the count of peri-epithelial lymphocytes (PELs) (p < 0.05), epithelial layer nuclei count (NC) (p < 0.05), and basal layer NC (p < 0.05). Progression-free survival (PFS) using the epithelial layer NC (p < 0.05, C-index = 0.73), basal layer NC (p < 0.05, C-index = 0.70), and PELs count (p < 0.05, C-index = 0.73) all showed association of these features with a high risk of malignant transformation in our univariate analysis. Our work shows the application of deep learning for the prognostication and prediction of PFS of OED for the first time and offers potential to aid patient management. Further evaluation and testing on multi-centre data is required for validation and translation to clinical practice. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Carotid Endarterectomy Should Not Be Recommended to End-Stage Kidney Disease Patients with Asymptomatic Carotid Artery Disease.

BACKGROUND: Carotid endarterectomy (CEA) for asymptomatic carotid artery disease is advised for patients with low perioperative stroke risk and life expectancy of 3-5 years. We sought to explore the role of risk stratification and postoperative medical management in identifying appropriate asymptomatic candidates for CEA in the end-stage kidney disease (ESKD) population. METHODS: We identified ESKD patients on dialysis from the United States Renal Data System that underwent CEA (2008-2014) for asymptomatic carotid artery disease. We used the Liu comorbidity index as well as a novel risk prediction model based on Cox proportional hazards model to stratify patients. The primary outcome evaluated was 3-year survival, and Kaplan-Meier methods were used to generate survival estimates. We further conducted a subanalysis of patients with Medicare part D data to determine postoperative usage of the following medications: statins, antiplatelets, and antihypertensives. We evaluated the association of medication utilization and 3-year survival using Kaplan-Meier methods and Cox proportional hazards modeling. RESULTS: We analyzed 1,813 patients meeting inclusion criteria. The population was predominantly older (mean age 70.2 ± 9.1), White (84.8%), and had a high prevalence of cardiovascular comorbidities, such as hypertension (90.7%), diabetes (62.5%), and congestive heart failure (35.4%). Among the entire cohort, 23.0% had a Liu comorbidity index ≤8, 35.0% had index 9-12, and 42.0% had index >12. Increasing Liu comorbidity index was associated with worse survival (P < 0.01); however, even the group with Liu index ≤8 had poor 3-year survival of 58.8% (53.9-63.4). The Cox proportional hazards model identified variables for inclusion in the risk model such as age >80 (adjusted hazard ratio [aHR] = 2.49, 95% confidence interval [CI] [1.87-3.33], P < 0.001), congestive heart failure (aHR = 1.31, 95% CI [1.14-1.51], P < 0.001), and Liu comorbidity index >12(aHR = 1.89, 95% CI [1.56-2.28], P < 0.001). The risk score generated ranged from 0 to 6.5, and patients were divided into 3 groups: score ≤2 (43.4%), 2-4 (41.2%), and >4 (15.4%). Increasing risk score was associated with worse survival (P < 0.01) but even the "low-risk" group had 3-year survival of 58.5% (54.9-61.9). Subanalysis of the 1,249 (68.8% of total) patients with part D data found that statins and calcium channel blocker use was associated with improved survival, although observed rates for patients on drug were still low. CONCLUSIONS: The overall long-term survival of ESKD patients undergoing CEA for asymptomatic carotid artery disease is low. Risk stratification and analysis of postoperative medical management did not identify a subgroup of patients with adequate 3-year survival. Hence, the preventive benefits of CEA are not realized in these patients.

Knowledge, attitude, and practices of parents regarding the red flags of developmental milestones in children aged 0-5 years in Karachi, Pakistan: a cross-sectional study.

BACKGROUND: Developmental delays in children are assessed in four basic domains: gross motor, fine motor, social, and language. Early years of life are crucial in a child's development, so it is imperative that parents be aware of developmental milestones to facilitate early diagnosis and treatment in case of a developmental delay. This study assessed parental knowledge, attitude, and practices regarding children's developmental milestones and associated "red flags". METHODS: A cross-sectional study was conducted at the Department of Pediatrics at Liaquat National Hospital, Karachi. 390 parents, who had at least one child under 5 years of age, with no diagnosed developmental delay, were interviewed during outpatient clinic visits. The questionnaire consisted of three components to assess parental knowledge, attitude, and practices. RESULTS: 59% and 54% of parents had poor knowledge of gross and fine motor milestones respectively; In the social domain, 56% of the respondents had inadequate knowledge. 42% had inadequate knowledge of language milestones; 29% of parents strongly agreed that their pediatricians provide satisfactory information regarding red flags of developmental milestones. 60% of parents strongly agreed that their child's developmental delay would be a cause of concern for them. In the case of developmental delay, 55% of parents said they would consult a general pediatrician, 11% preferred a pediatric neurologist, 21% opted for a developmental pediatrician and 13% opted for a family physician. Residence and family systems were found to be associated with language-related milestones with significantly higher odds of knowledge among urban residents than rural ones and a significantly lower likelihood of language milestones knowledge among joint families than nuclear families. Female gender was found to be significantly associated with positive attitude. CONCLUSION: The majority of our respondents showed considerably poor knowledge regarding developmental milestones. This highlights the need to devise ways to educate parents on this subject to enable them to vigilantly monitor their child's developmental status and any associated abnormalities and ultimately facilitate the right course of action.

Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain.

Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States experience chronic pain. This economic burden is greater than annual costs associated with heart disease, cancer, and diabetes combined. Treatment options for chronic pain are inadequately efficacious and riddled with adverse side effects. There is thus an urgent unmet need for novel approaches to treating chronic pain. Sensitization of neurons along the nociceptive pathway causes chronic pain states driving symptoms that include spontaneous pain and mechanical and thermal hypersensitivity. More than a decade of preclinical research demonstrates that translational mechanisms regulate the changes in gene expression that are required for ongoing sensitization of nociceptive sensory neurons. This review will describe how key translation regulation signaling pathways, including the integrated stress response, mammalian target of rapamycin, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase-interacting kinases, impact the translation of different subsets of mRNAs. We then place these mechanisms of translation regulation in the context of chronic pain states, evaluate currently available therapies, and examine the potential for developing novel drugs. Considering the large body of evidence now published in this area, we propose that pharmacologically manipulating specific aspects of the translational machinery may reverse key neuronal phenotypic changes causing different chronic pain conditions. Therapeutics targeting these pathways could eventually be first-line drugs used to treat chronic pain disorders. SIGNIFICANCE STATEMENT: Translational mechanisms regulating protein synthesis underlie phenotypic changes in the sensory nervous system that drive chronic pain states. This review highlights regulatory mechanisms that control translation initiation and how to exploit them in treating persistent pain conditions. We explore the role of mammalian/mechanistic target of rapamycin and mitogen-activated protein kinase-interacting kinase inhibitors and AMPK activators in alleviating pain hypersensitivity. Modulation of eukaryotic initiation factor 2α phosphorylation is also discussed as a potential therapy. Targeting specific translation regulation mechanisms may reverse changes in neuronal hyperexcitability associated with painful conditions.

PIF4 interacts with ABI4 to serve as a transcriptional activator complex to promote seed dormancy by enhancing ABA biosynthesis and signaling.

Transcriptional regulation plays a key role in the control of seed dormancy, and many transcription factors (TFs) have been documented. However, the mechanisms underlying the interactions between different TFs within a transcriptional complex regulating seed dormancy remain largely unknown. Here, we showed that TF PHYTOCHROME-INTERACTING FACTOR4 (PIF4) physically interacted with the abscisic acid (ABA) signaling responsive TF ABSCISIC ACID INSENSITIVE4 (ABI4) to act as a transcriptional complex to promote ABA biosynthesis and signaling, finally deepening primary seed dormancy. Both pif4 and abi4 single mutants exhibited a decreased primary seed dormancy phenotype, with a synergistic effect in the pif4/abi4 double mutant. PIF4 binds to ABI4 to form a heterodimer, and ABI4 stabilizes PIF4 at the protein level, whereas PIF4 does not affect the protein stabilization of ABI4. Subsequently, both TFs independently and synergistically promoted the expression of ABI4 and NCED6, a key gene for ABA anabolism. The genetic evidence is also consistent with the phenotypic, physiological and biochemical analysis results. Altogether, this study revealed a transcriptional regulatory cascade in which the PIF4-ABI4 transcriptional activator complex synergistically enhanced seed dormancy by facilitating ABA biosynthesis and signaling.

Heart Failure and Echocardiography Derived Myocardial Wall Stress Link in Diabetic Cases with Acute Myocardial Infarction Managed by Revascularization.

Background: Diabetes is associated with left ventricular remodeling. Myocardial wall stress is a measurable factor connected to the ventricular breadth and force and is related to myocardial thickness; it can be measured by echocardiography. The present study aimed to assess the link between heart failure (HF) and echocardiography-derived myocardial wall stress in diabetic patients with ST elevation myocardial infarction (STEMI) who were managed with revascularization. Methods: This study was a comparative prospective study that took place between February 2022 and February 2023. It included 100 diabetic patients presented with STEMI and managed by percutaneous coronary intervention (PCI). Patients were selected from the cardiology departments at Al-Azhar University Hospital, Damietta, Egypt. During the hospital stay, patients were checked for HF symptoms and signs. They were also observed for 3 months after discharge for detection of HF. Those who did not develop HF were assigned to group I, and those with HF were assigned to group II. Results: The mean value of end-systolic wall stress (ESWS) was 77.09 ± 12.22 and 97 ± 13.44, and the mean value of end-diastolic wall stress (EDWS) was 12.61 ± 2.76 and 15.87 ± 2.86 in groups I and II respectively, with significant differences between the 2 groups. The cutoff point to detect HF was 88 KPa for ESWS and 13.5 KPa for EDWS, with a sensitivity of 70% and 79% and a specificity of 80% and 61% for ESWS and EDWS, respectively. Conclusion: Elevated left ventricle (LV) myocardial stress is related to increased HF in diabetic patients whose HF was managed by PCI after STEMI. LV wall stress is a potentially helpful risk stratification tool using routine echocardiography to determine the treatment plane according to the risk status.

Improved outpatient medical visit compliance with sociodemographic discrepancies in vascular telehealth evaluations.

OBJECTIVE: The COVID-19 (coronavirus disease 2019) pandemic has led to a rapid expansion in the use of telemedicine across all medical fields but has also exposed telehealth care disparities with differing access to technology across racial and ethnic groups. The objective of our study was to investigate the effects of telehealth on vascular visit compliance and to explore the effects of sociodemographic factors on vascular surgery outpatient telehealth usage during the COVID-19 pandemic. METHODS: Consecutive patients who had undergone an outpatient vascular surgery evaluation between February 24, 2020 (the launch of our telemedicine program) and December 31, 2020, were reviewed. The baseline demographic and outcomes were obtained from the electronic medical records. Telehealth and in-person evaluations were defined according to the patient's index visit during the study period. Medical visit compliance was established on completion of the telehealth or in-person encounter. We used χ2 tests and logistic regression analyses. RESULTS: A total of 23,553 outpatient visits had been scheduled for 10,587 patients during the study period. Of the outpatient visits, 1559 had been scheduled telehealth encounters compared with 21,994 scheduled in-person encounters. Of the scheduled outpatient encounters, 13,900 medical visits (59.0%) had been completed: 1183 telehealth visits and 12,717 in-person visits. The mean travel distance saved for the telehealth visits was 22.1 ± 27.1 miles, and the mean travel time saved was 46.3 ± 41.47 minutes. We noted no sociodemographic differences between the patients scheduled for telehealth vs in-person visits. We found a trend toward a lower proportion of African-American patients in the telehealth group vs the in-person group (7.8% vs 10.6%; P = .116), without statistical significance. A significantly higher rate of medical visit completion was found for the telehealth group compared with the in-person group (79.5% vs 59.4%; P < .001). Among the patients scheduled for an outpatient medical visit, a scheduled telemedicine evaluation (vs in-person) was associated with 2.3 times the odds of completing the medical visit (odds ratio, 2.31; 95% confidence interval, 2.05-2.61), adjusting for age, sex, race, ethnicity, language, and the distance between the patient's home zip code and the outpatient vascular center's zip code. Selecting for scheduled telemedicine visits, African-American race was associated with a decreased odds of telemedicine usage (odds ratio, 0.73; 95% confidence interval, 0.59-0.90) after adjusting for age, sex, ethnicity, language, and visit type. CONCLUSIONS: Use of the vascular surgery outpatient telehealth evaluation appeared to improve medical visit completion in our region with apparent sociodemographic disparities. Further studies are needed to confirm whether telemedicine expansion has improved access to care in other geographic areas.

Trends in mortality and postoperative complications among octogenarian patients undergoing carotid endarterectomy.

BACKGROUND: Elderly patients represent a large portion of patients undergoing vascular surgery. This study aims to assess the contemporary frequency of octogenarians undergoing carotid endarterectomy (CEA) and to evaluate their postoperative complications and survival rates. METHODS: The Vascular Quality Initiative (VQI) dataset was queried for patients who underwent elective CEA between 2012 and 2021. Patients aged >90 years were excluded, as well as emergent and combined cases. The population was divided into two age groups: <80 years and ≥80 years. Frailty scores were generated using Vascular Quality Initiative variables grouped into 11 domains historically associated with frailty. Patients with scores within the first 25th percentile, between the 25th and 50th percentile, and above the 75th percentile were categorized into low, medium, and high frailty classes, respectively. Procedural indications were defined as hard (stenosis ≥80% or ipsilateral neurologic symptoms) or soft. Primary outcomes of interest were 2-year stroke-free and 2-year overall survival comparing (i) octogenarians with nonoctogenarians and (ii) octogenarians by frailty class. Standard statistical methods were used. RESULTS: Overall, 83,745 cases were included in this analysis. Between 2012 and 2021, a consistent proportion averaging 17% of CEA patients were octogenarians. Among this age group, the proportion of patients undergoing CEA for hard indications increased over time from 43.7% to 63.8% (P < .001). This increase was accompanied by a statistically significant increase in the combined 30-day perioperative stroke and mortality rate from 1.56% in 2012 to 2.96% in 2021 (P = .019). A Kaplan-Meier analysis showed a significantly lower 2-year stroke-free survival among octogenarians compared with the younger group (78.1% vs 87.6%; P < .001). Similarly, there was a significantly lower 2-year overall survival among octogenarians compared with the younger group (90.5% vs 95.1%; P < .001). Multivariate Cox proportional hazard analyses showed that high frailty class was associated with increased 2-year stroke risk (hazard ratio, 2.26; 95% confidence interval, 1.61-3.17; P < .001) and 2-year mortality (hazard ratio, 2.43; 95% confidence interval, 1.71-3.47; P < .001). Repeat Kaplan-Meier analysis stratifying octogenarians by frailty class revealed that octogenarians with low frailty can have stroke-free and overall survival rates comparable with nonoctogenarians (88.2% vs 87.6% [P = .158] and 96.0% vs 95.1% [P = .151], respectively). CONCLUSIONS: Chronological age should not be regarded as a contraindication for CEA. Frailty score calculation is a better predictor for postoperative outcomes and is an appropriate tool to risk stratify octogenarians, aiding in the decision between best medical treatment or intervention. The risk benefit assessment for high frailty class octogenarians is paramount because the postoperative risks may outweigh the long-term survival benefits of the prophylactic CEA.

Characterization of multiple organ failure after ruptured abdominal aortic aneurysm repair.

BACKGROUND: Multiple organ failure (MOF) is associated with poor outcomes and increased mortality in sepsis and trauma. There are limited data regarding MOF in patients after ruptured abdominal aortic aneurysm (rAAA) repair. We aimed to identify the contemporary prevalence and characteristics of patients with rAAA with MOF. METHODS: We retrospectively reviewed patients with rAAA who underwent repair (2010-2020) at our multihospital institution. Patients who died within the first 2 days after repair were excluded. MOF was quantified by modified (excluding hepatic system) Denver, Sequential Organ Failure Assessment (SOFA) score, and Multiple Organ Dysfunction Score (MODS) for postoperative days 3 to 5 to determine the prevalence of MOF. MOF was defined as a Denver score of >3, dysfunction in two or more organ systems by SOFA score, or a MODS score of >8. Kaplan-Meier curves and log-rank testing were used to evaluate differences in 30-day mortality between multiple organ failure and patients without MOF. Logistic regression was used to assess predictors of MOF. RESULTS: Of 370 patients with rAAA, 288 survived past two days (mean age, 73±10.1 years; 76.7% male; 44.1% open repair), and 143 had data for MOF calculation recorded. From postoperative days 3 to 5, 41 (14.24%) had MOF by Denver, 26 (9.03%) by SOFA, and 39 (13.54%) by MODS criteria. Among these scoring systems, pulmonary and neurological systems were impacted most commonly. Among patients with MOF, pulmonary derangement occurred in 65.9% (Denver), 57.7% (SOFA), and 56.4% (MODS). Similarly, neurological derangement occurred in 92.3% (SOFA) and 89.7% (MODS), but renal derangement occurred in 26.8% (Denver), 23.1% (SOFA), and 10.3% (MODS). MOF by all three scoring systems was associated with increased 30-day mortality (Denver: 11.3% vs 41.5% [P < .01]; DOFA: 12.6% vs 46.2% [P < .01]; MODS: 12.5% vs 35.9% [P < .01]), as was MOF by any criteria (10.8% vs 35.7 %; P < .01). Patients with MOF were more likely to have a higher body mass index (55.9±26.6 vs 49.0±15.0; P = .011) and to have had a preoperative stroke (17.9% vs 6.0%; P = .016). Patients with MOF were less likely to have undergone endovascular repair (30.4% vs 62.1%; P < .001). Endovascular repair was protective against MOF (any criteria) on multivariate analysis (odds ratio, 0.23; 95% confidence interval, 0.08-0.64; P = .019) after adjusting for age, gender, and presenting systolic blood pressure. CONCLUSIONS: MOF occurred in only 9% to 14% of patients after rAAA repair, but was associated with a three-fold increase in mortality. Endovascular repair was associated with a reduced MOF incidence.

Cardioprotective effect of tetra(aniline) containing terpolymers through miR-15a-5p and MFN-2 regulation against hypertrophic responses.

OBJECTIVE: Cardiac hypertrophy is a condition of abnormal cardiomyocyte enlargement accompanied by ventricular wall thickening. The study aims to investigate the role of miR-15a-5p in the regulation of mitofusin-2 (MFN-2) and to explore the cardioprotective effect of terpolymers ES-37 and L-37. METHODS: In this study, the Sprague Dawley rats' cardiac hypertrophic model was established by administering 5 mg/kg Isoproterenol subcutaneously every other day for 14 days. As treatment rats received NAC (50 mg/kg), NAC treatment (50 mg/kg NAC + 5 mg/kg ISO), ES-37 (1 mg/kg) and ES-37 treatment (1 mg/kg ES-37+5 mg/kg ISO), L-37 (1 mg/kg) and L-37 treatment (1 mg/kg L-37+5 mg/kg ISO). subcutaneously every other day for 14 days. NAC, ES 37 and L-37 were given after 1 h of Isoproterenol administration in treatment groups. Cardiac hypertrophy was confirmed through morphological and histological analysis. For estimation of oxidative stress profiling, ROS and TBARS and antioxidative profiling superoxide dismutase (SOD), Catalase, and Glutathione (GSH) levels were checked. Triglyceride, cholesterol, alanine transaminase (ALT), and aspartate transaminase (AST) were performed to evaluate levels of lipid profiling and liver profiling. Molecular expression analysis was checked through real-time PCR, and western blotting both at the transcriptional and translational levels. Molecular docking studies were performed to study the interactions and modes of binding between the synthetic polymers with three proteins (Mitofusin-2, DRP-1 and PUMA). All the studies were carried out using the AutoDock Vina software and the protein-ligand complexes were visualized in Biovia Discovery Studio. Cardiac hypertrophy was confirmed by the relative changes in the cellular structure of the heart by histopathological examination and physiological changes by estimating organ weights. Biochemical profiling results depict elevated oxidative and lipid profiles signify myocardial damage. N-acetyl cysteine (NAC), ES-37, and L-37 overcome the cardiac hypertrophic responses through attenuating oxidative stress and enhancing the antioxidative signaling mechanism. miR-15a-5p was identified as hypertrophic microRNA directly regulating the expression of Mitofusin-2 (MFN-2). Significantly increased expression of miR-15a-5p, Dynamin related protein 1 (Drp1), and P53 upregulated modulator of apoptosis (PUMA), was observed in the disease group, whereas MFN-2 expression was observed downregulated. N-acetyl cysteine (NAC), ES-37, and L-37 showed increased expression of antiapoptotic maker MFN-2 and decreased expression of miR-15a-5p, Drp1, and PUMA in treatment groups suggesting their cardioprotective role in attenuation of cardiac hypertrophy. An analysis of the docking results shows that ES-37 has greater binding affinity with the target proteins compared to L-37, with the highest binding values reported for MFN-2. CONCLUSION: The physiochemical properties of ES-37 and L-37 predicted it as a good drug-like molecule and its mechanism of action is predictably through inhibition of ROS. Molecular docking results shows that the polymer ES-37 has greater binding affinity with the target proteins compared to L-37, with the highest binding values reported for MFN-2. Thus, the study validates the role and targeting of miR-15a-5p and MFN-2 in cardiac hypertrophy as well as the therapeutic potential of NAC, ES-37, and L-37 in overcoming oxidative stress and myocardial damage.

NCCN Guidelines® Insights: B-Cell Lymphomas, Version 6.2023.

Novel targeted therapies (small molecule inhibitors, antibody-drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton's tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.