The associations among co-morbidity, cardiac geometries and mechanics in hospitalized heart failure with or without preserved ejection fraction.

BACKGROUND: The associations among chronic health conditions, ventricular geometric alterations or cardiac contractile mechanics in different phenotypes heart failure (HF) remain largely unexplored. METHODS: We studied 438 consecutive hospitalized patients (mean age: 64.9 ± 16.6 years, 52.5% female) with or without clinical evidence of HF. We examined the associations among clinical co-morbidities, LV geometries and systolic mechanics in terms of global myocardial strains. RESULTS: Increasing clinical co-morbidities was associated with greater LV mass, worse longitudinal deformations and higher proportion of admission with HF diagnosis, which was more pronounced in HFpEF (from 6.4% to 40.7%, X2 < 0.001). The independent association between co-morbidity burden and longitudinal functional decay remained unchanged after adjusting for age and sex for all admissions and in HFpEF (Coef: 0.82 & 0.71, SE: 0.13 & 0.21, both p≤0.001). By using co-morbidity scores, the area under receiver operating characteristic curves (AUROC) in identifying HFpEF was 0.71 (95% CI: 0.65 to 0.77), 0.64 (95% CI: 0.58 to 0.71) for HFrEF and 0.72 for both (95% CI: 0.67 to 0.77). Co-morbidity burden superimposed on LV mass index and LV filling pressure (E/E') further expanded the AUROC significantly in diagnosing both types HF (c-statistics from 0.73 to 0.81, p for ΔAUROC: 0.0012). CONCLUSION: Chronic health conditions in the admission population were associated with unfavorable cardiac remodeling, impair cardiac contractile mechanics and further added significantly incremental value in HF diagnosis. Our data suggested the potentiality for better cardiac function by controlling baseline co-morbidities in hospitalized HF patients, especially HFpEF. ABBREVIATIONS: CAD: coronary artery disease; CKD: chronic kidney disease; DT: deceleration time; eGFR: Estimated glomerular filtration rate; HF: heart failure; IVRT: iso-volumic relaxation time; LV: left ventricular; LVEF: left ventricular ejection fraction; RWT: relative wall thickness; TDI: Tissue Doppler imaging.

Advances in Ketogenic Diet Therapies in Pediatric Epilepsy: A Systematic Review.

Objective: To review the effects of the ketogenic diet on epilepsy in children and adolescents.Data Sources: A literature search was conducted in PubMed with no publication date or language restrictions based on the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. Keywords used included children, adolescent, ketogenic diet, epilepsy, and seizure.Study Selection: After excluding articles that did not meet the inclusion criteria, such as missing variables of study, adult population, and nonrandomized clinical trials, a total of 12 studies were included in the final review.Data Extraction: Data on study design, duration, sample size, population, and type of intervention were collected using a standard template.Results: The ketogenic diet and its modified versions were noted to have beneficial effects in reduction of seizure frequency and severity, with manageable adverse effects such as gastrointestinal disturbances, dehydration, dyslipidemia, hyperuricemia, infection, and metabolic acidosis.Conclusions: Depending on patient compliance and comorbidities, all variations of the ketogenic diet were found to be helpful for seizure treatment, whether as an additive or an alternative treatment option, for children and adolescents with epilepsy.Prim Care Companion CNS Disord 2024;26(3):23r03661. Author affiliations are listed at the end of this article.

Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche.

Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here we use a chimeric mouse model of chronic myeloid leukaemia (CML) and human bone marrow (BM) derived macrophages to study the impact of the dysregulated BM microenvironment on bystander macrophages. Utilising single-cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages we reveal unique subpopulations of immature macrophages residing in the CML BM microenvironment. CML exposed macrophages separate from their normal counterparts by reduced expression of the surface marker CD36, which significantly reduces clearance of apoptotic cells. We uncover aberrant production of CML-secreted factors, including the immune modulatory protein lactotransferrin (LTF), that suppresses efferocytosis, phagocytosis, and CD36 surface expression in BM macrophages, indicating that the elevated secretion of LTF is, at least partially responsible for the supressed clearance function of Ph- macrophages.

Lc3 over-expression improves survival and attenuates lung injury through increasing autophagosomal clearance in septic mice.

OBJECTIVE: To clarify the role of autophagy in sepsis-induced lung injury. BACKGROUND: The role of autophagy as a protective or maladaptive response in lung cells during sepsis has not yet been determined. The lack of specificity of the autophagic process has driven the development of new approaches that assess autophagosomes from formation to fusion with lysosomes. METHODS: Sepsis was induced by cecal ligation and puncture (CLP). The autophagic process was manipulated using the pharmacological inhibitors of the autophagy pathway. Green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) transgenic mice were further used to determine the role of autophagy. RESULTS: The formation of autophagosomal protein LC3-II progressively accumulated in the lungs over 24 hours after CLP, with the Lc3 gene expression returning to baseline levels at 24 hours. Autophagosome-lysosome fusion, however, gradually decreased from 8 to 24 hours after CLP, suggesting impaired clearance of autophagosomes rather than upregulation of autophagy in the septic lung. In contrast, transgenic mice overexpressing the Lc3 gene exhibited increased clearance of autophagosomes and improved survival after CLP. This protective effect was also seen in decreased cell death, inflammatory responses, neutrophil accumulation, albumin leakage, and edema formation. However, blockade of autophagosome-lysosome fusion with bafilomycin A1 abolished the protective effects in transgenic mice. This indicates that Lc3 transgene attenuates lung injury/inflammation in sepsis, possibly through increasing the clearance of autophagosomes. CONCLUSIONS: Autophagy in the septic lung represents a protective response. However, autophagy, by virtue of excessive autophagosome accumulation, may play a maladaptive role in the late stage of sepsis, leading to acute lung injury.

High pericardial and peri-aortic adipose tissue burden in pre-diabetic and diabetic subjects.

BACKGROUND: Central obesity in relation to insulin resistance is strongly linked to the development of type 2 diabetes. However, data regarding the association between pericardial and peri-aortic adiposity, a potential estimate of visceral adipose tissue burden, and pre-diabetes status remains unclear.The aim of this study was to examine whether the degree of pericardial and thoracic peri-aortic adipose tissue, when quantified by multi-detector computed tomography (MDCT), differs significantly in a normal, pre-diabetic, and overtly diabetic population. METHODS: We studied 562 consecutive subjects including 357 healthy, 155 pre-diabetic, and 50 diabetic patients selected from participants who underwent annual health surveys in Taiwan. Pre-diabetes status was defined by impaired fasting glucose or impaired glucose intolerance according to American Diabetes Association guidelines. Pericardial (PCF) and thoracic peri-aortic (TAT) adipose tissue burden was assessed using a non-contrast 16-slice multi-detector computed tomography (MDCT) dataset with off-line measurement (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). Body fat composition, serum high-sensitivity C-reactive protein (hs-CRP) level and insulin resistance (HOMA-IR) were also assessed. RESULTS: Patients with diabetes and pre-diabetes had greater volume of PCF (89 ± 24.6, 85.3 ± 28.7 & 67.6 ± 26.7 ml, p < 0.001) as well as larger TAT (9.6 ± 3.1 ml vs 8.8 ± 4.2 & 6.6 ± 3.5 ml, respectively, p < 0.001) when compared to the normal group, although there were no significant differences in adiposity between the diabetic and pre-diabetic groups. For those without established diabetes in our study, increasing TAT burden, but not PCF, appear to correlate with insulin resistance (HOMA-IR) and hs-CRP in the multivariable models. CONCLUSIONS: Pre-diabetic and diabetic subjects, compared to normoglycemia, were associated with significantly higher pericardial and peri-aortic adipose tissue burden. In addition, visceral fat accumulation adjacent to the thoracic aorta seemed to exert a significant impact on insulin resistance and systemic inflammation.

Epidemiology, Trends, Utilization Disparities, and Outcomes of Catheter Ablation and Its Association With Coronary Vasospasm Amongst Patients With Non-valvular Atrial Fibrillation: A Nationwide Burden of Last Decade.

BACKGROUND: Catheter ablation (CA) is an important curative treatment for non-valvular atrial fibrillation (NVAF), however, nationwide data on its utilization and disparities is limited. Coronary vasospasm is a rare, life-threatening, peri-operative complication of CA with limited literature in Caucasians. METHODS: We performed a retrospective study on adult hospitalizations in the USA from 2007 to 2017 by obtaining the data from National Inpatient Sample. The primary endpoints of our study were to identify the utilization rate of CA, disparities in utilization, and study the outcomes associated with CA. The secondary endpoints of the study were to identify the incidence of coronary vasospasm amongst patients who underwent CA, evaluate their association, and identify the predictors of coronary vasospasm. RESULTS: From 35,906,946 patients with NVAF, 343641 (0.96%) underwent CA. Its utilization decreased from 1% in 2007 to 0.71% in 2017. Patients who underwent CA, compared to those without CA, fared better in terms of hospital length of stay, mortality rate, disability rate, and discharge to the non-home facility. Patients in the 50-75 years age group, Native Americans, those with private insurance, and median household income of 76-100th percentile were associated with higher odds of CA utilization. Urban teaching hospitals and large-bedded hospitals performed more ablations, while the Mid-West region fared lower than the South, the West, and the Northeast. The prevalence of coronary vasospasm was higher amongst CA in comparison without CA, however, in regression analysis, no significant association was demonstrated between CA and coronary vasospasm. CONCLUSION: CA is an important treatment modality that is associated with improved clinical outcomes. Identification of factors associated with lower utilization of CA and its disparities will help to mitigate the burden associated with NVAF.

Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients.

Myelofibrosis is a myeloproliferative neoplasm (MPN) which typically results in reduced length and quality of life due to systemic symptoms and blood count changes arising from fibrotic changes in the bone marrow. While the JAK2 inhibitor ruxolitinib provides some clinical benefit, there remains a substantial unmet need for novel targeted therapies to better modify the disease process or eradicate the cells at the heart of myelofibrosis pathology. Repurposing drugs bypasses many of the hurdles present in drug development, such as toxicity and pharmacodynamic profiling. To this end we undertook a re-analysis of our pre-existing proteomic data sets to identify perturbed biochemical pathways and their associated drugs/inhibitors to potentially target the cells driving myelofibrosis. This approach identified CBL0137 as a candidate for targeting Jak2 mutation-driven malignancies. CBL0137 is a drug derived from curaxin targeting the Facilitates Chromatin Transcription (FACT) complex. It is reported to trap the FACT complex on chromatin thereby activating p53 and inhibiting NF-kB activity. We therefore assessed the activity of CBL0137 in primary patient samples and murine models of Jak2-mutated MPN and found it preferentially targets CD34+ stem and progenitor cells from myelofibrosis patients by comparison with healthy control cells. Further we investigate its mechanism of action in primary haemopoietic progenitor cells and demonstrate its ability to reduce splenomegaly and reticulocyte number in a transgenic murine model of myeloproliferative neoplasms.

Effectiveness of Repetitive Transcranial Magnetic Stimulation in Depression, Schizophrenia, and Obsessive-Compulsive Disorder: An Umbrella Meta-Analysis.

Objective: To analyze the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder, schizophrenia, and obsessive-compulsive disorder (OCD) via umbrella meta-analysis.Data Sources: Meta-analysis studies were searched in PubMed from inception to May 2021 using the keywords anxiety, depression, ADHD, schizophrenia, mood disorder, OCD, psychiatric disorders, GAD, bipolar disorders, ASD, PTSD, transcranial magnetic stimulation, transcranial, magnetic, stimulation. PRISMA guidelines were followed.Study Selection: Abstracts and full-length articles were reviewed for meta-analysis studies with data on the safety and efficacy of rTMS and sham and were collected for quantitative analysis. The full texts of all identified studies were independently screened and assessed to determine eligibility. Any disagreement was resolved through consensus.Data Extraction: The descriptive variables extracted included the author names, study year, sample size, studies included in the meta-analysis, study period, and type of intervention.Results: 28 meta-analyses were included; 13 were on treatment-resistant depression, 9 on schizophrenia, and 6 on OCD. In treatment-resistant depression, the rTMS group had higher odds of response compared to sham (odds ratio [OR] = 3.27; 95% CI, 2.76-3.87; P < .00001) and higher odds of remission (secondary outcome) (OR = 2.83; 95% CI, 2.33-3.45; P < .00001). rTMS was superior to sham in the reduction of negative symptoms of schizophrenia (mean difference [MD]: 0.47; 95% CI, 0.23-0.7; P < .0001). However, no significant difference was found between the effects of rTMS and sham on auditory hallucinations (MD: 0.24; 95% CI, 0.26-0.74; P = .35), which resulted in 94% heterogeneity. TMS was better than sham in reducing the severity of OCD symptoms (MD: 0.81; 95% CI, 0.53-1.10; P < .00001).Conclusions: The effectiveness of rTMS for symptom reduction in various psychiatric disorders is associated with differences in neuropathology, disease-specific target site, and frequency of rTMS.Prim Care Companion CNS Disord 2023;25(5):22r03423. Author affiliations are listed at the end of this article.

Mental health disparities amongst sexual-minority adolescents of the US - A national survey study of YRBSS-CDC.

OBJECTIVE: We aimed to evaluate the prevalence and trend of identifying as a sexual minority among the American adolescent population. Additionally, we aimed to evaluate the prevalence and odds of substance abuse, hopelessness, and suicidality among the sexual minority adolescents compared to their heterosexual peers. METHODS: We performed a retrospective cross-sectional study using Youth Risk Behavior Surveillance System (YRBSS) data from 2015 to 2019. YRBSS divides "Sexual identity" into three groups: heterosexuals, sexual minorities (gay or lesbian or bisexual), and unsure. We identified "hopelessness and suicidality" using the survey questions exploring if participants felt sad or hopeless for >2 weeks, considered suicide, made a suicide plan, and attempted suicide requiring medical care. Univariate and multivariable survey logistic regression analyses were performed to establish an association between hopelessness, suicidality, substance abuse, and identifying as a sexual minority. RESULTS: Out of 41,377 adolescents, 4055 (9.8%) identified as a sexual minority. An increasing percentage of adolescents identified themselves as a sexual minority between 2015 to 2019 (8% to 11.2%) (pTrend<0.0001). The sexual minority had a higher prevalence of feeling sad and hopeless (63.4 vs. 28.6%), considering suicide (46 vs. 14.2%), planning suicide (38.9 vs. 11.5%), attempting suicide, and having injurious suicide attempts compared to heterosexuals. (p<0.0001) Amongst sexual minorities, the prevalence of substance abuse was higher compared to their heterosexual peers, which includes cigarettes (15 vs 7.8%), e-cigarette (27.2 vs 23.2%), inhalants (14.1 vs 5.3%), cocaine (8.4 vs 3.9%), marijuana (31.2 vs 20.2%), alcohol (36.9 vs 30.3%), steroids (6.4 vs 2.2%), heroin (4.4 vs 1.2%), and injectable drugs (4.0 vs 1.1%) (p<0.0001). In regression analysis, the sexual minority had higher odds of substance abuse, feeling sad and hopeless (aOR:4.6; 95%CI:4.0-5.2; p<0.0001), considering suicide (3.2; 2.8-3.7; p<0.0001), planning suicide (2.0; 1.7-2.3; p<0.0001) compared to heterosexual. CONCLUSION: Sexual minorities not only have higher prevalence and odds of hopelessness and suicidality but also have higher prevalence and odds of substance abuse like cigarettes, marijuana, cocaine, heroin, inhalants, and steroids. Hence, early identification, risk stratification, and interventions to reduce mental health disparities are needed.

Prevalence, Trends, and Outcomes of Pulmonary Embolism Treated with Mechanical and Surgical Thrombectomy from a Nationwide Inpatient Sample.

Pulmonary embolism (PE) is the third most common vascular disease in the US, a frequently underdiagnosed and potentially fatal condition where embolic material blocks one or more pulmonary arteries impairing blood flow. In this study, we aim to describe the prevalence, outcomes, and predictors of mortality of PE patients treated with mechanical (MT) and surgical thrombectomy (ST). This is a retrospective study using the Agency for Healthcare Research and Quality's HCUP NIS data from 2010−2018. We used the ninth and tenth revisions of the International Classification of Diseases clinical modification codes (ICD-9-CM and ICD-10-CM) to identify patients admitted with a primary diagnosis of PE (ICD-10-CM codes I26.02, I26.09, I26.92, I26.93, I26.94, and I26.99; ICD-9-CM codes 415.11, 415.13, and 415.19). We extracted demographics, hospital-level, and patient-level characteristics, and defined the severity of comorbid conditions using Deyo modification of the Elixhauser Comorbidity Index. The primary outcomes of interest were the utilization trends of PE (treated with MT and ST); the secondary outcomes were mortality, discharge to facility, peri-procedural complications, and length of hospital (LOS) stay; the tertiary outcome was to identify the predictors of in-hospital mortality. From 2010−2018, there were 1,627,718 hospitalizations for PE, of which 6531 (0.39%) underwent MT and 3465 (0.21%) underwent ST. The utilization trend of MT increased from 336 (0.20%) in 2010 to 1655 (0.87%) in 2018; the utilization trend of ST was 260 (0.15%) in 2010 and 430 (0.23%) in 2018. The unadjusted in-hospital mortality for MT was 9.1% with the mean LOS being 7(±0.3) days; for ST, mortality was 13.9% with a mean LOS of 13(±0.4) days. The occurrences of periprocedural complications for MT and ST were as follows: invasive mechanical ventilation was 13.8% and 32%; cardiopulmonary bypass was 3.3% and 68.3%; pulmonary embolectomy surgery was 1.7%; and bleeding complications were 1.4% and 3.4%. Predictors associated with in-hospital mortality for MT were: increasing age (OR 1.2, 95% CI 1.0−1.3, p < 0.026), female sex (OR 1.9, 95% CI 1.2−2.8, p < 0.004), large hospitals (OR 2.2, 95% 1.4−3.5, p < 0.001), and teaching hospitals (OR 1.8, 95% CI 1.1−3.1, p < 0.023). The predictor of in-hospital mortality for ST was increasing age (OR 1.2, 95% CI 1.0−1.4, p < 0.046). The number of MT procedures performed has rapidly increased over the past decade. Further studies are warranted to determine their rise and therapeutic use.

ADSCs stimulated by resistin promote breast cancer cell malignancy via CXCL5 in a breast cancer coculture model.

The tumor microenvironment represents one of the main obstacles in breast cancer treatment owing to the presence of heterogeneous stromal cells, such as adipose-derived stem cells (ADSCs), that may interact with breast cancer cells and promote cancer development. Resistin is an adipocytokine associated with adverse breast cancer progression; however, its underlying mechanisms in the context of the breast tumor microenvironment remain largely unidentified. Here, we utilized a transwell co-culture model containing patient-derived ADSCs and breast cancer cell lines to investigate their potential interaction, and observed that breast cancer cells co-cultured with resistin-treated ADSCs (R-ADSCs) showed enhanced cancer cell growth and metastatic ability. Screening by proteome arrays revealed that C-X-C motif chemokine ligand 5 (CXCL5) was released in the conditioned medium of the co-culture system, and phosphorylated ERK was increased in breast cancer cells after co-culture with R-ADSCs. Breast cancer cells treated with the recombinant proteins of CXCL5 showed similarly enhanced cell migration and invasion ability as occurred in the co-culture model, whereas application of neutralizing antibodies against CXCL5 reversed these phenomena. The orthotopic xenograft in mice by breast cancer cells after co-culture with R-ADSCs had a larger tumor growth and more CXCL5 expression than control. In addition, clinical analysis revealed a positive correlation between the expression of resistin and CXCL5 in both tumor tissues and serum specimens of breast cancer patients. The current study suggests that resistin-stimulated ADSCs may interact with breast cancer cells in the tumor microenvironment via CXCL5 secretion, leading to breast cancer cell malignancy.

Depression in Childhood Asthma vs. Adult-Onset Asthma: A Cross-Sectional Study from the National Health and Nutrition Examination Survey (NHANES).

Background: asthma, a chronic respiratory disease caused by inflammation and narrowing of the small airways in the lungs, is the most common chronic childhood disease. Prevalence of childhood asthma in the United States is 5.8%. In boys, prevalence is 5.7% and it is 6% in girls. Asthma is associated with other comorbidities such as major depressive disorder and anxiety disorder. This study explores the association between asthma and depression. Methods: we conducted a retrospective cross-sectional study using NHANES data from 2013 to 2018. Asthma and childhood onset asthma were assessed using questionnaires MCQ010 and MCQ025, respectively. Sociodemographic variables were summarized, and univariate analysis was performed to determine the association between asthma and major depressive disorder and its individual symptoms. Results: there were 402,167 participants from 2013−2018 in our study: no asthma in 84.70%; asthma in 15.30%. Childhood onset asthma (COA) included 10.51% and adult-onset asthma (AOA) included 4.79%. Median age of COA is 5 years and AOA is 41 years. Among the asthma groups, most AOA were females (67.77%, p < 0.0001), most COA were males (52.16%, p < 0.0001), and ethnicity was predominantly White in AOA (42.39%, p < 0001) and in COA (35.24%, p < 0.0001). AOA mostly had annual household income from $0−24,999 (35.91%, p < 0.0001), while COA mostly had annual household income from $25,000−64,999 (36.66%, p < 0.0001). There was a significantly higher prevalence of MDD in COA (38.90%) and AOA (47.30%) compared to NOA (31.91%). Frequency of symptoms related to MDD were found to have a significantly higher prevalence and severity in the asthma groups compared to no asthma, and slightly greater and more severe in AOA than in COA. Symptoms include having little interest in doing things (COA 18.38% vs. AOA 22.50% vs. NOA 15.44%), feeling down, depressed, or hopeless (COA 20.05% vs. AOA 22.77% vs. NOA 15.85%), having trouble sleeping or sleeping too much (COA 27.38% vs. AOA 23.15% vs. NOA 22.24%), feeling tired or having little energy (COA 39.17% vs. AOA 34.24% vs. NOA 33.97%), having poor appetite or overeating (COA 19.88% vs. AOA 20.02% vs. NOA 15.11%), feeling bad about yourself (COA 13.90% vs. AOA 13.79% vs. NOA 10.78%), having trouble concentrating on things (COA 12.34% vs. AOA 14.41% vs. NOA 10.06%), moving or speaking slowly or too fast (COA 8.59% vs. AOA 9.72% vs. NOA 6.09%), thinking you would be better off dead (COA 3.12% vs. AOA 4.38% vs. NOA 1.95%) and having the difficulties these problems have caused (COA 21.66% vs. AOA 26.73% vs. NOA 19.34%, p < 0.0001). Conclusion: MDD and related symptoms were significantly higher and more severe in participants with asthma compared to no asthma. Between adult-onset asthma compared to childhood onset asthma, adult-onset asthma had slightly greater and more severe MDD and related symptoms compared to childhood onset asthma.

Complete induction of autophagy is essential for cardioprotection in sepsis.

OBJECTIVE: To investigate the entire process of autophagy in the left ventricle of septic mice, and the functional significance of autophagy by using pharmacological agents. BACKGROUND: Myocardial dysfunction is a common feature in sepsis and contributes to an increased risk of developing multiple organ failure. Autophagy functions predominantly as a prosurvival pathway in the heart during cellular stress. A dynamic process of autophagy that involves the complete activation of autophagy from autophagosome formation to fusion with lysosomes has driven the development of new approaches to detecting autophagy. METHODS: Male mice were subjected to cecal ligation and puncture (CLP) or sham operation. At 1 hour after CLP operation, mice received either rapamycin (induction of autophagy), bafilomycin A1 (inhibition of autophagosomal degradation), or vehicle. RESULTS: The formation of autophagosomes was increased whereas the degradation of autophagosomes was decreased in the left ventricle at 24 hours after CLP. This was consistent with the morphologic finding that septic hearts revealed an increase in autophagosomes but few autolysosomes, indicating incompletion of the autophagic process. Rapamycin, which induced complete activation of autophagy, restored CLP-induced depressed cardiac performances. This cardioprotective effect was also seen in increased ATP levels, and decreased inflammatory responses. Bafiomycin A1, which resulted in incompletion of the autophagic process, did not show any above beneficial effects in CLP mice. CONCLUSIONS: Incompletion of the autophagic process may contribute to sepsis-induced cardiac dysfunction. Treatment with rapamycin may serve a cardioprotective role in sepsis, possibly through the effect of complete induction of autophagy.

Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape.

The quest for treatment-free remission (TFR) and deep molecular response (DMR) in chronic myeloid leukemia (CML) has been profoundly impacted by tyrosine kinase inhibitors (TKIs). Immunologic surveillance of residual leukemic cells is hypothesized to be one of the critical factors in successful TFR, with self-renewing leukemic stem cells implicated in relapse. Immunological characterization in CML may help to develop novel immunotherapies that specifically target residual leukemic cells upon TKI discontinuation to improve TFR rates. This review focuses on immune dysfunction in newly diagnosed CML patients, and the role that TKIs and other therapies have in restoring immune surveillance. Immune dysfunction and immunosurveillance in CML points towards several emerging areas in the key goals of DMR and TFR, including: (1) Aspects of innate immune system, in particular natural killer cells and the newly emerging target plasmacytoid dendritic cells. (2) The adaptive immune system, with promise shown in regard to leukemia-associated antigen vaccine-induced CD8 cytotoxic T-cells (CTL) responses, increased CTL expansion, and immune checkpoint inhibitors. (3) Immune suppressive myeloid-derived suppressor cells and T regulatory cells that are reduced in DMR and TFR. (4) Immunomodulator mesenchymal stromal cells that critically contribute to leukomogenesis through immunosuppressive properties and TKI- resistance. Therapeutic strategies that leverage existing immunological approaches include donor lymphocyte infusions, that continue to be used, often in combination with TKIs, in patients relapsing following allogeneic stem cell transplant. Furthermore, previous standards-of-care, including interferon-α, hold promise in attaining TFR in the post-TKI era. A deeper understanding of the immunological landscape in CML is therefore vital for both the development of novel and the repurposing of older therapies to improve TFR outcomes.

Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML.

Over the last 50 years, there has been a steady improvement in the treatment outcome of acute myeloid leukemia (AML). However, median survival in the elderly is still poor due to intolerance to intensive chemotherapy and higher numbers of patients with adverse cytogenetics. Fadraciclib (CYC065), a novel cyclin-dependent kinase (CDK) 2/9 inhibitor, has preclinical efficacy in AML. In AML cell lines, myeloid cell leukemia 1 (MCL-1) was downregulated following treatment with fadraciclib, resulting in a rapid induction of apoptosis. In addition, RNA polymerase II (RNAPII)-driven transcription was suppressed, rendering a global gene suppression. Rapid induction of apoptosis was observed in primary AML cells after treatment with fadraciclib for 6-8 h. Twenty-four hours continuous treatment further increased efficacy of fadraciclib. Although preliminary results showed that AML cell lines harboring KMT2A rearrangement (KMT2A-r) are more sensitive to fadraciclib, we found that the drug can induce apoptosis and decrease MCL-1 expression in primary AML cells, regardless of KMT2A status. Importantly, the diversity of genetic mutations observed in primary AML patient samples was associated with variable response to fadraciclib, confirming the need for patient stratification to enable a more effective and personalized treatment approach. Synergistic activity was demonstrated when fadraciclib was combined with the BCL-2 inhibitor venetoclax, or the conventional chemotherapy agents, cytarabine, or azacitidine, with the combination of fadraciclib and azacitidine having the most favorable therapeutic window. In summary, these results highlight the potential of fadraciclib as a novel therapeutic approach for AML.

MRE11 as a molecular signature and therapeutic target for cancer treatment with radiotherapy.

MRE11, the core of the MRE11/RAD50/NBS1 complex, is one of key DNA damage response proteins. Increasing evidence suggests that its expression in cancer cells is critical to developing radioresistance; as such, MRE11 is an emerging marker for targeted radiosensitization strategies. Elevated MRE11 in tumor tissues has been associated with poor survival in patients undergoing radiotherapy, although in some cancer types, the opposite has been noted. The recent discovery of ionizing radiation-induced truncation of MRE11, which decreases its efficacy, may explain some of these paradoxical findings. The progress of research on the biological modulation of MRE11 expression is also discussed, with the potential application of small molecule or large molecule inhibitors of MRE11 for enhancing radiosensitivity. Current research has further highlighted both nuclease and non-nuclease activities of MRE11 in cancer cells treated with ionizing radiation, and differentiation between these is essential to verify the targeting effects of radiosensitizing agents. These updates clarify our understanding of how MRE11 expression may be utilized in future stratification of cancer patients for radiotherapy, and how it may be leveraged in shaping novel radiosensitization strategies.

Emerging Needs and Viability of Telepsychiatry During and Post COVID-19 Era: A Literature Review.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in nationwide stay-at-home orders in an effort to slow the spread severely impacting the healthcare sector. Telepsychiatry provides a platform bridging the gap through advanced technologies connecting mental health providers and patients who need their services, overcoming previous barriers of great distances, lack of transportation, and even time constraints. The most obvious benefit is increased accessibility to mental healthcare, especially in underserved and remote areas where there is no easy access for in-person care. It is important to note that benefits are not limited to patients, but also allow clinicians greater flexibility in scheduling and reduced practice overhead costs, both of which aid with physician burnout and burden. Telepsychiatry during COVID-19 provides its own unique advantages over in-person visits. The risk of exposure to healthcare workers and patients receiving care is reduced, allowing immunocompromised patients to receive much-needed psychiatric care. Without the need to meet in person, self-isolating psychiatrists can still provide care, decreasing strain on their co-workers. Although telepsychiatry is relatively new, it has already exhibited considerable success in its effectiveness at treating psychiatric conditions and widespread corollary benefits. Telepsychiatric consults may be carried out synchronously and asynchronously, each having benefits and setbacks. Different mobile application interventions have been explored, which are available for the purpose of both monitoring/assessing patients and/or providing treatment. The scope of conditions these applications address is broad, from anxiety disorders to schizophrenia to depression. As promising and beneficial telepsychiatry may seem, it is necessary to recognize that building the program can be challenging. It involves adapting to new methods in medicine. We highlighted barriers to general telepsychiatry, the most prominent being technological literacy of both physician and patient, and possible negative effects of eliminating the in-person patient-doctor interaction.

Differential Changes in Inflammatory Mononuclear Phagocyte and T-Cell Profiles within Psoriatic Skin during Treatment with Guselkumab vs. Secukinumab.

Cellular sources of IL-23 and IL-17A driving skin inflammation in psoriasis remain unclear. Using high-dimensional unsupervised flow cytometry analysis, mononuclear phagocytes and T cells were examined in the same lesions of patients before and during guselkumab (IL-23p19 blocker) or secukinumab (IL-17A blocker) treatment. Among CD11c+HLA-DR+ mononuclear phagocytes, CD64brightCD163-CD14brightCD1c-CD1a‒ inflammatory monocyte‒like cells were the predominant IL-23-producing cells and, together with CD64-CD163-CD14-IL-23p19-TNF-α+ inflammatory dendritic cell‒like cells, were increased in lesional compared with those in nonlesional skin taken from the same patient. Within T cells, CD8+CD49a+ and/or CD103+ tissue-resident memory T cells, CD4+CD25+FoxP3+ regulatory T cells, and CD4+CD49a-CD103- T cells were increased. Moreover, CD4+CD49a-CD103- T cells and the relatively rare CD8+ memory T cells equally contributed to IL-17A production. Both treatments decreased the frequencies of inflammatory monocyte‒like, inflammatory dendritic cell‒like, and CD4+CD49a-CD103- T cells. In contrast, guselkumab reduced memory T cells while maintaining regulatory T cells and vice versa for secukinumab. Neither drug modified the frequencies of IL-17A+IL‒17F+/- CD4+ or CD8+ T cells. This study reveals the identity of the major IL-23+ mononuclear phagocyte and IL-17+ T-cell subsets in psoriatic skin lesions and paves the way for a better understanding of the mode of action of drugs targeting the IL-23/IL-17A pathway in psoriasis.

MRE11 promotes oral cancer progression through RUNX2/CXCR4/AKT/FOXA2 signaling in a nuclease-independent manner.

MRE11, the nuclease component of RAD50/MRE11/NBS1 DNA repair complex which is essential for repair of DNA double-strand-breaks in normal cells, has recently garnered attention as a critical factor in solid tumor development. Herein we report the crucial role of MRE11 in oral cancer progression in a nuclease-independent manner and delineate its key downstream effectors including CXCR4. MRE11 expression in oral cancer samples was positively associated with tumor size, cancer stage and lymph node metastasis, and was predictive of poorer patient survival and radiotherapy resistance. MRE11 promoted cell proliferation/migration/invasion in a nuclease-independent manner but enhanced radioresistance via a nuclease-dependent pathway. The nuclease independent promotion of EMT and metastasis was mediated by RUNX2, CXCR4, AKT, and FOXA2, while CXCR4 neutralizing antibody mitigated these effects in vitro and in vivo. Collectively, MRE11 may serve as a crucial prognostic factor and therapeutic target in oral cancer, displaying dual nuclease dependent and independent roles that permit separate targeting of tumor vulnerabilities in oral cancer treatment.