Unfavorable Profile Research Articles

2740. Letermovir for the Prevention and Treatment of Cytomegalovirus Infection in Solid Organ Transplant Recipients

Abstract Background Cytomegalovirus (CMV) is a common infection that can lead to end-organ damage and graft rejection in solid organ transplant (SOT) recipients. Due to the increase in drug-resistant CMV and unfavorable side effect profile of available CMV-active agents, there is a need for additional prophylactic and treatment strategies in this patient population. The goal of this study is to evaluate SOT recipients prescribed letermovir for prophylaxis and/or treatment of CMV. Methods This study was a retrospective review of adult SOT recipients in the Cleveland Clinic Health System prescribed letermovir from 11/8/2017 to 8/1/2022. The primary objective was to describe the utilization of letermovir in SOT recipients. Secondary objectives included: proportion of SOT recipients that experienced CMV breakthrough on letermovir prophylaxis, proportion of SOT recipients that experienced refractory CMV infection on letermovir treatment, prevalence of letermovir resistance, and letermovir-induced adverse effects. Results A total of 45 patients were included in the study, with 52 letermovir courses. Lung was the most commonly transplanted organ (35%), followed by kidney (22%). 78% of patients were high-risk CMV and the most common immunosuppression regimen consisted of a calcineurin inhibitor in combination with a corticosteroid (82%). 11 patients received letermovir for primary CMV prophylaxis, with only one patient experiencing new/worsening viremia while on the agent. Of the 34 patients who received letermovir for secondary CMV prophylaxis, 11 experienced new/worsening viremia. 7 patients received letermovir for CMV treatment, at a median viral load of 991 IU/mL (IQR 603-2,738) on initiation and peak viral load of 3,892 IU/mL (IQR 1,407-10,209) while on therapy. No patients in the treatment group experienced refractory infection. 7/52 (13.5%) letermovir courses were discontinued due to new/worsening viremia, with no letermovir resistance identified. No letermovir-related adverse effects were documented. Conclusion Our study shows that letermovir appears to be effective in suppressing CMV viremia. Letermovir may be an alternative option for SOT recipients who are unable to tolerate or have resistance to traditional CMV therapeutics. Disclosures All Authors: No reported disclosures

A Pyrazine‐Pyridinamine Covalent Organic Framework as a Low Potential Anode for Highly Durable Aqueous Calcium‐Ion Batteries

AbstractRechargeable aqueous calcium‐ion batteries (CIBs) are promising for reliable large‐scale energy storage. However, they face significant challenges, primarily stemming from suboptimal anodes, resulting in unfavorable voltage profiles, limited capacity, and diminished durability, all of which hinder the development of CIBs. Here, a covalent organic framework (PTHAT‐COF) featuring repeated pyrazine and pyridinamine units, employed as the anode material for aqueous CIBs, is introduced. This innovative approach results in a remarkably flat ultralow potential plateau ranging from −0.6 to −1.05 V (vs Ag/AgCl), attributed to the high level of the lowest unoccupied molecular orbital. Furthermore, the PTHAT‐COF anode exhibits outstanding rate performance (152.3 mAh g−1 @ 1 A g−1), exceptional long‐term cycling stability, and remarkable capacity retention (10 000 cycles with 89.9% retention). Mechanistic studies, including experimental and theoretical calculations, reveal that C═N active sites reversibly trap Ca2+ ions via chemisorption during the discharging/charging process. The PTHAT‐COF demonstrates exceptional structural stability throughout cycling. Finally, by pairing PTHAT‐COF with a high‐voltage manganese‐based Prussian blue cathode, a complete aqueous CIB with a voltage interval of 2.2 V is achieved, exhibiting extraordinary durability (10 000 cycles with 83.6% retention). This research illuminates the potential of organic anode materials in aqueous batteries to achieve higher battery voltages.

Sudden cardiac death in people with schizophrenia: higher risk, poorer resuscitation profiles and differing pathologies

Abstract Background People with schizophrenia account for approximately 1.0% of the population and appear to experience increased rates of sudden cardiac death (SCD). This study determined characteristics of increased SCD in people with schizophrenia. Methods A prospective state-wide registry compared people aged 15-50 years with and without schizophrenia who experienced SCD within a two-year time-period and were referred for forensic evaluation. Results 579 individuals were identified, of whom 65 (11.2%) had schizophrenia. Patients with schizophrenia were more commonly smokers (46.2% vs 23.0%, p<0.0001), consumed excess alcohol (32.3% vs 21.4%, p=0.05), and used QTc-prolonging medications (69.2% vs 17.9%, p<0.0001). They were less likely to arrest while exercising (0.0% vs 6.4%, p=0.04). Unfavourable arrest-related factors included lower rates of witnessed arrest (6.2% vs 23.5%, p<0.0001), more likely to be found in asystole (92.3% vs 73.3%, p<0.0001), and being more likely to be found as part of a welfare check after a prolonged period of time (median 42 vs 12 hours, p=0.003). There was more frequent evidence of decomposition, and they more commonly underwent autopsy (41.2% vs 26.4%, p=0.04 and 93.8% vs 82.5%, p=0.05), with diagnosis of non-ischaemic cardiomyopathy being more common (29.2% vs 18.1%, p=0.04). Conclusion People with schizophrenia account for 11% of young SCD patients referred for forensic investigations, exceeding population rates eleven-fold. They have higher pre-existing cardiac risk factor burden, unfavourable resuscitation profiles and higher rates of non-ischaemic cardiomyopathy. Strategies targeting biopsychosocial support may deliver not only psychological benefits but also help reduce unwitnessed cardiac arrest.

Hypertensive disorders of pregnancy and cardiovascular disease risk: A Mendelian Randomisation study.

Observational studies show that hypertensive disorders of pregnancy (HDPs) are related to unfavourable maternal cardiovascular disease (CVD) risk profiles later in life. We investigated whether genetic liability to pre-eclampsia/eclampsia and gestational hypertension is associated with CVD risk factors and occurrence of CVD events. We obtained genetic associations with HDPs from a genome-wide association study and used individual-participant-data from the UK Biobank to obtain genetic associations with CVD risk factors and CVD events (defined as myocardial infarction or stroke). In our primary analysis, we applied Mendelian Randomisation using inverse-variance weighted regression analysis in ever pregnant women. In sensitivity analyses, we studied men and nulligravidae to investigate genetic liability to HDPs and CVD risk without the ability to experience the underlying phenotype. Our primary analysis included 221,155 ever pregnant women (mean age 56.8 [SD 7.9]) with available genetic data. Odds ratios for CVD were 1.20 (1.02-1.41) and 1.24 (1.12-1.38) per unit increase in the log odds of genetic liability to pre-eclampsia/eclampsia and gestational hypertension, respectively. Furthermore, genetic liability to HDPs was associated with higher levels of systolic and diastolic blood pressure and younger age at hypertension diagnosis. Sensitivity analyses revealed no statistically significant differences when comparing the findings to those of nulligravidae and men. Genetic liability to HDPs is associated with higher CVD risk, lower blood pressure levels, and earlier hypertension diagnosis. Our study suggests similar findings in ever pregnant women, nulligravidae and men, implying biological mechanisms relating to HDPs are causally related to CVD risk.

Abstract 15567: Associations Between Social Determinants of Health and Cardiovascular Health of Adult Cancer Survivors in the United States

Background: Relationships between social determinants of health (SDOH) and cardiovascular health (CVH) of cancer survivors are underexplored. Aims: To investigate associations between SDOH and CVH of adult cancer survivors in the United States (US). Methods: Data from the US National Health Interview Survey (2013-2017) were used. Participants reporting a history of cancer were included, excluding those with only non-melanoma skin cancer, or with missing data for any domain of SDOH or CVH. SDOH was quantified with a six-domain, 38-item score consistent with the Centers for Disease Control and Prevention recommendations (higher score indicated worse deprivation). CVH was quantified based on the American Heart Association’s Life’s Essential 8. As detailed dietary data were unavailable, a seven-item CVH score was used (higher score indicated worse CVH). Survey-specific multivariable Poisson regression was used to test associations between SDOH quartiles and CVH. Results: Altogether, 8254 participants were analyzed, representing a weighted population of 10,887,989 persons. Worse SDOH was associated with worse CVH (highest vs. lowest quartile: risk ratio 1.30 [95% confidence interval 1.25, 1.35], p<0.001), with a grossly linear relationship between SDOH and CVH scores ( Figure 1A) . Subgroup analysis found significantly stronger associations in younger participants (p interaction =0.026) and females (p interaction =0.001), but without statistically significant interactions with race (p interaction =0.051) ( Figure 1B) . Higher scores in all domains of SDOH were independently associated with worse CVH (all p<0.001). Higher SDOH scores were also independently associated with the presence of all items of the CVH score (all p<0.05 for highest SDOH quartile). Conclusions: An unfavorable SDOH profile was independently associated with worse CVH among adult cancer survivors, with notably stronger associations in females and younger individuals.

Treatment-Free Remission after Ponatinib Cessation in Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients. the Ponastop Observational Study

Introduction: Ponatinib has proven its efficacy as salvage therapy for patients intolerant, or resistant (and ABL1T315I+ mutation) to at least 2 tyrosine kinase inhibitors (TKI) in CP-CML. Despite the unfavourable profile of such patients, some durable deep molecular response (DMR, i. e. MR 4 and MR4.5) might be observed, and it is arguable to propose a treatment-free remission (TFR) strategy to these patients, despite the fact that this is not currently recommended. The aim of this study is to analyse the results of TFR in CP-CML patients that have received ponatinib as last line of therapy for any reason. Methods: This a retrospective multicentric European analysis of CP-CML patients undergoing ponatinib at any dose for prior TKI-intolerance or -resistance and obtaining at least 2 years of MR4.5, assessed on at least 4 successive samples, and undergoing a treatment-free remission (TFR) procedure and follow-up. All BCR::ABL1 assessments have been performed in ELN reference laboratories and expressed in % on the international scale (IS). Loss of major molecular response (MMR i. e. BCR::ABL1 transcript ≥0.1% IS) on one datapoint was sufficient to consider relapse. Clinical information were extracted from individual patients' files. All patients have given their written agreement in participating to this observational study. Results: Fifteen cases could be collected and analysed with 27% males, 73% females of a median age of 43 (24-79) years at CML diagnosis and of 56 (30-83) at ponatinib cessation. All patients were in CP at diagnosis and at ponatinib cessation. None of these patients were harbouring additional chromosomal abnormalities at diagnosis or beyond. Sokal scores were low in 50%, intermediate in 25% and high in 25% of patients, ELTS scores were low in 64% and intermediate in 36% of patients. None of these patients has undergone allogeneic stem cell transplant. Three patients were ABL1T315I mutated. The median time between CP-CML diagnosis and ponatinib initiation was 52 (1.5-145) months, the median initial dose of ponatinib was 45 mg QD for 12 patients, 30 mg QD for 2 patients and 15 mg QD for 1 patient. One patient had 4 previous lines of TKI prior to ponatinib, 4 patients 3 prior lines, 5 patients 2 prior lines, 4 patients 1 prior line and 1 patient was in ponatinib first-line (EPIC trial). Thirteen arterial events occurred on ponatinib in these 15 patients, all prior to ponatinib cessation. At cessation, the median dose of ponatinib was 30 mg QD for 1 patient, 15 mg QD for 7 patients, 7.5 mg QD for 2 patients, and ≤ 6.4 mg QD for 4 patients. Ten (67%) patients were resistant to prior TKI before ponatinib, 3 were intolerant, 1 intolerant and resistant and 1 was in first-line ponatinib. The median ponatinib treatment duration prior to cessation was 71 (21- 124) months and the time from ponatinib initiation to sustained DMR was 14 (2-112) months. The median follow-up after cessation was 11 (2-55) months. One patient died in TFR of severe SARS-CoV2 lung infection 23 months after cessation. The median survival without MMR loss after ponatinib cessation was 69.26% at 12-months, 24-months and 54-months. Time to MMR-loss KM curve is presented in Figure 1. The four patients loosing MMR after ponatinib cessation resumed low dose ponatinib (≤ 15 mg QD) for 2 and asciminib (80 mg BID) for 2, three patients regained MMR (one non evaluable with too short follow-up). Conclusions: TFR attempt represents a strategy that can be applied to ponatinib patients in the setting of heavily pretreated CP-CML in a similar way as of less advanced CP-CML patients, with high success rates and no disease progression. If those data are confirmed by further studies and longer follow-up, TFR strategies might have to be considered also in previously heavily pre-treated patients.

Associations Between Social Determinants of Health and Cardiovascular Health of U.S. Adult Cancer Survivors

BackgroundRelationships between the social determinants of health (SDOH) and cardiovascular health (CVH) of cancer survivors are underexplored. ObjectivesThis study sought to investigate associations between the SDOH and CVH of adult cancer survivors. MethodsData from the U.S. National Health Interview Survey (2013-2017) were used. Participants reporting a history of cancer were included, excluding those with only nonmelanotic skin cancer, or with missing data for any domain of SDOH or CVH. SDOH was quantified with a 6-domain, 38-item score, consistent with the Centers for Disease Control and Prevention recommendations (higher score indicated worse deprivation). CVH was quantified based on the American Heart Association’s Life’s Essential 8, but due to unavailable detailed dietary data, a 7-item CVH score was used, with a higher score indicating worse CVH. Survey-specific multivariable Poisson regression was used to test associations between SDOH quartiles and CVH. ResultsAltogether, 8,254 subjects were analyzed, representing a population of 10,887,989 persons. Worse SDOH was associated with worse CVH (highest vs lowest quartile: risk ratio 1.30; 95% CI: 1.25-1.35; P < 0.001), with a grossly linear relationship between SDOH and CVH scores. Subgroup analysis found significantly stronger associations in younger participants (Pinteraction = 0.026) or women (Pinteraction = 0.001) but without significant interactions with race (Pinteraction = 0.051). Higher scores in all domains of SDOH were independently associated with worse CVH (all P < 0.001). Higher SDOH scores were also independently associated with each component of the CVH score (all P < 0.05 for highest SDOH quartile). ConclusionsAn unfavorable SDOH profile was independently associated with worse CVH among adult cancer survivors in the United States.

Antibiotic therapy for nonfermenting Gram-negative bacilli infections: future perspectives.

Serious infections caused by nonfermenting Gram-negative bacteria (NF-GNB) pose a significant challenge for clinicians due to the limited treatment options available, which are frequently associated with issues of toxicity and unfavourable pharmacokinetic profiles. The aim of this review is to provide a brief overview of the existing data concerning the ongoing development of antiinfective agents targeting NF-GNB. Several agents exhibiting efficacy against NF-GNB are under clinical investigation. Durlobactam-sulbactam and cefepime-taniborbactam emerge as promising therapeutic avenues against carbapenem-resistant Acinetobacter baumanii. Cefepime-zidebactam may serve as a suitable treatment option for urinary tract infections caused by a wide range of NF-GNB. Cefepime-enmetazobactam demonstrates potent in vitro activity against various NF-GNB strains; however, its role as an anti-Pseudomonal agent is inadequately substantiated by available data. Xeruborbactam is a wide β-lactamase inhibitor that can be associated with a range of agents, enhancing in-vitro activity of these against many NF-GNB, including those resistant to newer, broader spectrum options. Lastly, murepavadin appears to be a potential pathogen-specific solution for severe Pseudomonas infections; however, additional investigation is necessary to establish the safety profile of this compound. Each of the novel molecules reviewed possesses an interesting range of in-vitro activity against NF-GNB. In addition, some of them have already been proved effective in vivo, underscoring their potential as future treatment options.

Local application of engineered insulin-like growth factor I mRNA demonstrates regenerative therapeutic potential in vivo

Insulin-like growth factor I (IGF-I) is a growth-promoting anabolic hormone that fosters cell growth and tissue homeostasis. IGF-I deficiency is associated with several diseases, including growth disorders and neurological and musculoskeletal diseases due to impaired regeneration. Despite the vast regenerative potential of IGF-I, its unfavorable pharmacokinetic profile has prevented it from being used therapeutically. In this study, we resolved these challenges by the local administration of IGF-I mRNA, which ensures desirable homeostatic kinetics and non-systemic, local dose-dependent expression of IGF-I protein. Furthermore, IGF-I mRNA constructs were sequence engineered with heterologous signal peptides, which improved invitro protein secretion (2- to 6-fold) and accelerated invivo functional regeneration (16-fold) over endogenous IGF-I mRNA. The regenerative potential of engineered IGF-I mRNA was validated in a mouse myotoxic muscle injury and rabbit spinal disc herniation models. Engineered IGF-I mRNA had a half-life of 17-25h in muscle tissue and showed dose-dependent expression of IGF-I over 2-3days. Animal models confirm that locally administered IGF-I mRNA remained at the site of injection, contributing to the safety profile of mRNA-based treatment in regenerative medicine. In summary, we demonstrate that engineered IGF-I mRNA holds therapeutic potential with high clinical translatability in different diseases.

THU341 Associations Of Longitudinal Nighttime Sleep Characteristics With Nighttime/Daytime Glucose Values As Assessed By Continuous Glucose Monitoring In Type 2 Diabetes

Abstract Disclosure: Y. Li: None. K.K. Danielson: None. J.C. Park: None. J. McAnany: None. F.Y. Chau: None. B. Prasad: None. E.C. Hanlon: None. S. Reutrakul: None. Background: Sleep disturbances have been shown to be associated with incident diabetes and poor glycemic control. Recently, evidence emerged that nightly sleep may affect glucose levels both during that night and the following day. In this study, we explored the association of serial measures of nightly sleep parameters with night/day glucose levels in patients with type 2 diabetes (T2D). Methods: Baseline data of 28 T2D patients participating in an ongoing study exploring the relationship between diabetes retinopathy (DR) and sleep (NCT 04547439) were included. Sleep was objectively recorded using 14-days actigraphy. Sleep parameters nightly included sleep duration, sleep efficiency, wake time after sleep onset (WASO), and mid-sleep time (MST, time between sleep time and waketime). Glucose was recorded using blinded continuous glucose monitors (CGM). CGM data were divided into nighttime and daytime glucose values, utilizing the sleep time from actigraphy. CGM parameters included mean glucose, percent time spent in range (TIR%; glucose values 70-180 mg/dL), percent time above range (&amp;gt;180 mg/dL), and percent time below range (&amp;lt;70 mg/dL). Glucose variability indices included percent coefficient of variation (%CV) and Continuous Overall Net Glycemic Action (CONGA). Longitudinal mixed linear regression models, adjusting for age, sex, insulin use and DR status, were used to determine the associations between sleep parameters and nighttime/subsequent daytime CGM values. Associations were considered statistically significant at p&amp;lt;0.01 due to the multiple comparisons. Results: Mean (SD) age was 55.0 (6.5) years, A1C was 7.8 (1.5)%, 57% of the participants were female and 60.1% had DR. Average sleep duration was 6.1 (1.0) hours, sleep efficiency was 79.8 (9.6)%, WASO was 49.0 (27.1) minutes and MST was 3:25 (1:23) AM. There were a total of 281 nights and 254 days of CGM recordings. For nighttime CGM analyses, sleep duration (mins) was significantly longer in %TIR of ≥70% vs. &amp;lt;70% (β=57, SE=13, p=0.0005), but there were no associations of duration with other CGM parameters. WASO (log) was positively associated with CONGA (β=2.3, SE=0.9, p=0.008). Earlier MST was associated with greater glucose variability including higher CONGA (β=−1.6, SE=0.4, p&amp;lt;0.0001), and %CV (β=−1.6, SE=0.4, p&amp;lt;0.0001). For the following day CGM analyses, only the association between earlier MST and greater time spent below range (β=−0.7, SE=0.2, p=0.006) was significant. Conclusion: Longer nightly sleep duration was associated with higher nighttime %TIR, while poor sleep continuity was associated with higher nighttime glucose variability. In contrast to previous findings, earlier sleep timing was associated with unfavorable glucose profiles both during nighttime and daytime. These pilot data highlighted the associations between nighttime sleep and metabolic control, and should be explored in a larger cohort. Presentation: Thursday, June 15, 2023

Unfavorable transcriptome profiles and social disadvantage in hematopoietic cell transplantation: a CIBMTR analysis

AbstractPatient-reported outcomes (PROs) capture subjective social determinants of health (SDOHs), which can affect health outcomes through the stress response pathway. The conserved transcriptional response to adversity (CTRA) is a stress-mediated proinflammatory transcriptomic pattern that has been linked to adverse hematopoietic cell transplant (HCT) outcomes. This study examined the association of pretransplant CTRA with patient-reported SDOHs in allogeneic HCT recipients. In this cross-sectional study, pre-HCT SDOH-related PROs included the 36-Item Short Form Health Survey and the Functional Assessment of Cancer Therapy–Bone Marrow Transplant (FACT-BMT). CTRA was assessed by RNA sequencing of whole blood specimens, with mixed effects linear regression models relating CTRA expression to PRO scores while controlling for age, sex, race, disease, and performance status. Among 121 patients, the median age was 54 years, 42% were female, and 91% were White. CTRA was elevated in participants reporting lower scores on the FACT-BMT (P = .003), including the general (P = .003) and BMT-specific (P = .014) components. Effects were driven by the social well-being domain (P = .0001). This corresponded to an 8% to 15% difference in CTRA RNA expression across a 4 standard deviation range in patient-reported SDOHs. Ancillary bioinformatics analyses confirmed the association of well-being with reduced proinflammatory transcription pathway activity [cyclic AMP response element-binding protein, (CREB), NF-κB, and activating protein-1 (AP-1)]. In conclusion, HCT-treated patients who experience unfavorable social conditions show elevated CTRA expression in pretransplant blood samples. These data highlight the biologic sequelae of social well-being and community context and suggest a potential molecular mechanism for the impact of social gradients in HCT outcomes. Targeting this pathway could optimize outcomes in this high-risk population.

Molecular characteristics of isthmus papillary thyroid cancers: Supporting evidence for unfavorable clinical behavior

BackgroundPrevious studies demonstrate isthmus thyroid nodules are more likely to be malignant than lobar nodules. Additional data suggest that isthmus papillary thyroid cancers (PTCs) are more aggressive than lobar PTCs. We hypothesize that isthmus PTCs have a more unfavorable molecular profile. MethodsThe Cancer Genome Atlas (TCGA) database was queried to analyze clinical, mutation and gene expression data of isthmus PTCs compared to non-isthmus PTCs. ResultsWe analyzed characteristics of 472 ​PTCs, including 19 isthmus PTCs. There were no significant differences between isthmus and non-isthmus PTC demographic and clinical variables or the frequency of RAS family, fusion driver, TERT, and tumor suppressor gene mutations. There was a trend towards increased BRAF mutations (68% vs 55%, p ​= ​0.28). A more aggressive gene expression profile was observed in isthmus PTC compared to lobar/multifocal PTC with differences in ERK score (19.4 vs 7.71, p ​< ​0.05) and TDS score (−0.58 vs 0.02, p ​< ​0.05). ConclusionsThese results provide a possible molecular explanation for the more aggressive behavior reported in isthmus PTCs.

Preclinical characterization of tunlametinib, a novel, potent, and selective MEK inhibitor.

Background: Aberrant activation of RAS-RAF-MEK-ERK signaling pathway has been implicated in more than one-third of all malignancies. MEK inhibitors are promising therapeutic approaches to target this signaling pathway. Though four MEK inhibitors have been approved by FDA, these compounds possess either limited efficacy or unfavorable PK profiles with toxicity issues, hindering their broadly application in clinic. Our efforts were focused on the design and development of a novel MEK inhibitor, which subsequently led to the discovery of tunlametinib. Methods: This study verified the superiority of tunlametinib over the current MEK inhibitors in preclinical studies. The protein kinase selectivity activity of tunlametinib was evaluated against 77 kinases. Anti-proliferation activity was analyzed using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) or (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay. ERK and phospho-ERK levels were evaluated by Western blot analysis. Flow cytometry analysis was employed to investigate cell cycle and arrest. Cell-derived xenograft (CDX) and Patient-derived xenograft (PDX) models were used to evaluate the tumor growth inhibition. The efficacy of tunlametinib as monotherapy treatment was evaluated in KRAS/BRAF mutant or wild type xenograft model. Furthermore, the combination studies of tunlametinib with BRAF/KRASG12C/SHP2 inhibitors or chemotherapeutic agent were conducted by using the cell proliferation assay in vitro and xenograft models in vivo. Results: In vitro, tunlametinib demonstrated high selectivity with approximately 19-fold greater potency against MEK kinase than MEK162, and nearly 10-100-fold greater potency against RAS/RAF mutant cell lines than AZD6244. In vivo, tunlametinib resulted in dramatic tumor suppression and profound inhibition of ERK phosphorylation in tumor tissue. Mechanistic study revealed that tunlametinib induced cell cycle arrest at G0/G1 phase and apoptosis of cells in a dose-proportional manner. In addition, tunlametinib demonstrated a favorable pharmacokinetic profile with dose-proportionality and good oral bioavailability, with minimal drug exposure accumulation. Furthermore, tunlametinib combined with BRAF/KRASG12C/SHP2 inhibitors or docetaxel showed synergistically enhanced response and marked tumor inhibition. Conclusion: Tunlametinib exhibited a promising approach for treating RAS/RAF mutant cancers alone or as combination therapies, supporting the evaluation in clinical trials. Currently, the first-in-human phase 1 study and pivotal clinical trial of tunlametinib as monotherapy have been completed and pivotal trials as combination therapy are ongoing.

Antibiotic resistance of microorganisms isolated from patients with communityacquired pneumonia associated with the new coronavirus infection (COVID-19) in a polyclinic hospital in the city of Tomsk

Aim. To study the structure and antibiotic resistance of microorganisms isolated from the lower respiratory tract of patients with community-acquired pneumonia associated with COVID-19 in the period from 2020 to 2022.Materials and methods. In total, 1714 medical records of patients admitted to the Alperovich City Clinical Hospital No. 3. The study included cases with the documented diagnosis of community-acquired pneumonia associated with COVID-19. Respiratory samples were collected from patients within the first 24 hours of admission to the hospital.Results. Enterobacterales predominated in the overall structure of microorganisms (46%). Among this group, K. pneumoniae and K. oxytoca were the most common strains. K. pneumoniae was distinguished by a high frequency of resistance to carbapenems. Pseudomonadaceae ranked second in the overall structure of microorganisms (21%). The proportion of P. aeruginosa isolates insensitive to imipenem, meropenem, and ertapenem was 30%, 23%, and 25%, respectively. The study showed high resistance of S. pneumoniae to levofloxacin (30%), erythromycin (60%), and ampicillin (60%). Staphylococcus ranked fourth in the overall structure, represented by S. aureus. All strains were susceptible to vancomycin, linezolid, and tigecycline.Conclusions. The identification frequency of bacterial pathogens in patients with community-acquired pneumonia associated with COVID-19 did not exceed 8%. Gram-negative bacteria, mainly representatives of the Enterobacterales family, prevailed in the structure of microorganisms. Among gram-positive bacteria, Streptococcaceae were the leading pathogens. The obtained isolates were quite diverse in structure and exhibited an unfavorable profile of resistance to antimicrobial therapy.

Effects of cardiorespiratory fitness and body mass index on cardiometabolic risk factors in schoolchildren

IntroductionHigh levels of physical fitness established during childhood and adolescence have been associated with positive effects on cardiometabolic risk factors (CMRF), which persist into adulthood. Conversely, a sedentary lifestyle, overweight, and obesity during this period are considered public health problems. These conditions tend to worsen in adulthood, increasing the incidence of chronic diseases, deteriorating CMRF, and consequently leading to higher comorbidity and mortality rates.ObjectiveTo investigate the effect of cardiorespiratory fitness (CRF) and body mass index (BMI) on CMRF in children and adolescents.MethodsThe sample consisted of 49 schoolchildren of both sexes aged 10–17 years. Anthropometric assessments, CRF test, muscle strength test, and blood pressure (BP) measurement were conducted. Participants were allocated into groups based on BMI (eutrophic, overweight, obese), and CRF levels (low-fit, normal-fit, and high-fit).ResultsObese individuals had lower CRF values compared to the eutrophic and overweight groups. The cardiometabolic risk profile (CMRP) was significantly higher in the obese group compared to the eutrophic group but showed no significant difference compared to the overweight group. The hight-fit group had lower CMRP values compared to the low-fit group.ConclusionsHigher BMI and CRF values had negative and positive effects on CMRF and CMRP in schoolchildren, respectively. Overweight or obese schoolchildren with low levels of CRF constitute an unfavourable cardiometabolic risk profile.

Pharmacoepidemiological analysis of the consumption of antibacterial drugs for the treatment of patients with nosocomial infections associated with previous hospitalization in multidisciplinary hospitals in the Tomsk region

BACKGROUND: Healthcare-associated infections (HAIs) are one of the common complications associated with patients stay in a medical organization. An urgent practical problem is the choice of antibiotic therapy for the treatment of patients with nosocomial infections because these infections are caused by antibiotic-resistant strains. HAIs associated with previous hospitalization (HAPH) manifest in patients after discharge from the hospital, and their risk of isolating resistant strains often remains unrecognized by specialists. Thus, more studies are required to examine the structure of HAPH pathogens and patterns of consumption of antibacterial drugs for the treatment of HAPH to further determine antibiotic therapy in these patients.&#x0D; AIMS: To analyze the use of antibiotic therapy for the treatment of HAPH with known etiological agents and the level of antibiotic resistance.&#x0D; MATERIALS AND METHODS: The study analyzed the results of a multicenter descriptive retrospective study based on the Clinics Siberian State Medical University and the State Clinical Hospital No. B.I. Alperovich (Tomsk). A total of 108 HAPH cases were examined according to the medical records of inpatients (Form 003/y). For pharmacoepidemiological analysis, the anatomical therapeutic chemical/defined daily dose (DDD) methodology was used, and antibiotic intake was assessed using the number of established daily doses. The etiological structure of HSV microorganisms was evaluated using the AMRcloud online platform. Quantitative and qualitative indicators were presented as shares (%) and absolute numbers.&#x0D; RESULTS: In total, 116 isolates from patients with HAPH were assessed. Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli were the dominant pathogens causing HAPH in the overall distribution of pathogens. For the treatment of these patients, a wide range of drugs was used, including 13 groups of antibiotics. In most cases, the parenteral route of drug administration was used: intravenous route, 56.0%; intramuscular, 28.0%; and oral, 16.0%. The DDD analysis showed that antibiotic intake for the treatment of patients with HAPH was 137.8 NDDD/100 bed-days; surgical infection, 48.2 NDDD/100 bed-days (35.0%); and pneumonia, 89.6 NDDD/100 bed-days (65.0%). Cephalosporins were the most commonly used group of antibiotics for both surgical infection and pneumonia, mainly third-generation cephalosporins.&#x0D; CONCLUSION: Etiological agents of HAPH are phenotypically similar to nosocomial strains. Among antibacterial drugs, cephalosporins and fluoroquinolones were mainly consumed, and HAPH isolates had unfavorable resistance profiles to these drugs.

Prospective Characterization of Circulating Tumor Cell Kinetics in Patients With Oligometastatic Disease Receiving Definitive Intent Radiation Therapy.

There are currently no predictive molecular biomarkers to identify patients with oligometastatic disease (OMD) who will benefit from definitive-intent radiation therapy (RT). We prospectively characterized circulating tumor cell (CTC) kinetics in patients with OMD undergoing definitive-intent RT. This prospective correlative biomarker study included patients with any solid malignancy ≤5 metastatic sites in ≤3 anatomic organ systems undergoing definitive-intent RT to all disease sites. Circulating tumor cells (CTCs) were captured and enumerated using a biomimetic cell rolling and nanotechnology-based assay functionalized with antibodies against epithelial cell adhesion molecule, against human epidermal growth factor receptor 2, and against epidermal growth factor receptor before and during RT and at follow-up visits up to 2 years post-RT. We enrolled 43 patients with a median follow-up of 14.3 months. The pretreatment CTC level (cells captured/mL) was not associated with the number of disease sites (median one metastatic site/patient, range 1-5) or metastasis location (bone, brain, visceral) on Wilcoxon signed-rank test, P > .05. Post-RT, 56% of patients received systemic therapy, and 72% of patients experienced subsequent local or systemic progression. For 90% of patients, a CTC level <15 within 130 days post-RT corresponded to a durable control of irradiated lesions. Patients with a favorable versus an unfavorable clearance profile experienced significantly longer progression-free survival after RT (median 13 v 4 months, log-rank test, P = .0011). On logistic regression, CTC level >15 at a given time point was associated with clinical disease progression within the subsequent 6 months (odds ratio 3.31, P = .007). In 26% of patients with disease progression, a CTC level >15 preceded radiographic or clinical progression. CTCs may serve as a biomarker for disease control in OMD and may predict disease progression before standard assessments for patients receiving diverse cancer-directed therapies.

Cognitive effect of antiseizure medications in medial temporal lobe epilepsy.

The specific effects of antiseizure medications (ASMs) on cognition are a rich field of study, with many ongoing questions. The aim of this study was to evaluate these effects in a homogeneous group of patients with epilepsy to guide clinicians to choose the most appropriate medications. We retrospectively identified 287 refractory patients with medial temporal lobe epilepsy associated with hippocampal sclerosis. Scores measuring general cognition (global, verbal and performance IQ), working memory, episodic memory, executive functions, and language abilities were correlated with ASM type, number, dosage and generation (old vs. new). We also assessed non-modifiable factors affecting cognition, such as demographics and epilepsy-related factors. Key parameters were total number of ASMs and specific medications, especially topiramate (TPM) and sodium valproate (VPA). Four cognitive profiles of the ASMs were identified: (i) drugs with an overall detrimental effect on cognition (TPM, VPA); (ii) drugs with negative effects on specific areas: verbal memory and language skills (carbamazepine), and language functions (zonisamide); (iii) drugs affecting a single function in a specific and limited area: visual denomination (oxcarbazepine, lacosamide); and (iv) drugs without documented cognitive side effects. Non-modifiable factors such as age at testing, age at seizure onset, and history of febrile seizures also influenced cognition and were notably influenced by total number of ASMs. We conclude that ASMs significantly impact cognition. Key parameters were total number of ASMs and specific medications, especially TPM and VPA. These results should lead to a reduction in the number of drugs received and the avoidance of medications with unfavorable cognitive profiles.

Dexmedetomidine in the Treatment of Depression: An Up-to-date Narrative Review.

Depressive disorders (DD) are common, and their prevalence is expected to rise over the next decade. Depressive disorders are linked to significant morbidity and mortality. The clinical conundrum of depressive disorders lies in the heterogeneity of their phenomenology and etiology. Further, the currently available antidepressants have several limitations, including a delayed onset of action, limited efficacy, and an unfavorable side effect profile. In this review, Dexmedetomidine (DEX), a highly selective and potent α2-adrenergic receptor (α2-AR) agonist, is proposed as a potentially novel antidepressant with multiple mechanisms of action targeting various depression pathophysiological processes. These mechanisms include modulation of the noradrenergic system, regulation of neuroinflammation and oxidative stress, influence on the Brain-Derived Neurotrophic Factor (BDNF) levels, and modulation of neurotransmitter systems, such as glutamate. The review begins with an introduction before moving on to a discussion of DEX's pharmacological features. The pathophysiological and phenomenological targets of DD are also explored, along with the review of the existing preclinical and clinical evidence for DEX's putative anti-depressant effects. Finally, the review ends by presenting the pertinent conclusions and future directions.

Therapy-related Myeloid Neoplasms: Considerations for Patients' Clinical Evaluation.

Therapy-related myeloid neoplasms (t-MNs) encompass a specific sub-group of myeloid malignancies arising after exposure to radio/cytotoxic agents for the treatment of unrelated diseases. Such malignancies present unique features, including advanced age, high comorbidities burden, and unfavorable genetic profiles. All these features justify the need for a specific diagnostic work-up and dedicated treatment algorithms. However, as new classification systems recognize the unique clinical characteristics exhibited by t-MN patients, how to assess fitness status in this clinical setting is largely unexplored. Optimizing fitness assessment would be crucial in the management of t-MN patients, considering that factors usually contributing to a worse or better outcome (like age, comorbidities, and treatment history) are patient-specific. In the absence of specific tools for fitness assessment in this peculiar category of AML, the aim of this review is to describe all those factors related to patient, treatment, and disease that allow planning treatments with an optimal risk/benefit ratio.