Acetate dependence of tumors.

Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and the regulation of gene expression. Highly glycolytic or hypoxic tumors must produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions. Here, we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors.

PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies.

BACKGROUND: BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy. METHODS: Forty-five patients with stable coronary heart disease and 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants. RESULTS: BMS-986141 demonstrated highly selective inhibition of PAR4-AP (agonist peptide)-induced platelet aggregation, P-selectin expression, and platelet-monocyte aggregate expression (P≤0.001 for all), which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (-21%; P=0.001) and in patients receiving ticagrelor alone (-28%; P=0.001), aspirin alone (-23%; P=0.018), or both in combination (-24%; P≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP-induced platelet responses (P≤0.001 for all) and total thrombus area under high shear stress conditions (P≤0.01 for all). CONCLUSIONS: PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05093790.

The O-glycan is essential for the induction of protective antibodies against lethal infection by flagella A-bearing Pseudomonas aeruginosa.

To address the problem of increased antimicrobial resistance, we developed a glycoconjugate vaccine comprised of O-polysaccharides (OPS) of the four most prevalent serotypes of Klebsiella pneumoniae (KP) linked to recombinant flagellin types A and B (rFlaA and rFlaB) of Pseudomonas aeruginosa (PA). Flagellin is the major subunit of the flagellar filament. Flagella A and B, essential virulence factors for PA, are glycosylated with different glycans. We previously reported that while both rFlaA and rFlaB were highly immunogenic, only the rFlaB antisera reduced PA motility and protected mice from lethal PA infection in a mouse model of thermal injury. Since recombinant flagellin is not glycosylated, we examined the possibility that the glycan on native FlaA (nFlaA) might be critical to functional immune responses. We compared the ability of nFlaA to that of native, deglycosylated FlaA (dnFlaA) to induce functionally active antisera. O glycan was removed from nFlaA with trifluoromethanesulfonic acid. Despite the similar high-titered anti-FlaA antibody levels elicited by nFlaA, rFlaA, and dnFlaA, only the nFlaA antisera inhibited PA motility and protected mice following lethal intraperitoneal bacterial challenge. Both the protective efficacy and carrier protein function of nFlaA were retained when conjugated to KP O1 OPS. We conclude that unlike the case with FlaB O glycan, the FlaA glycan is an important epitope for the induction of functionally active anti-FlaA antibodies.

Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study.

The oxazaphosphorine cyclophosphamide (CP) is a DNA-alkylating agent commonly used in cancer chemotherapy. This anticancer agent is administered as a prodrug activated by a liver cytochrome P450-catalyzed 4-hydroxylation reaction that yields the active, cytotoxic metabolite. The primary metabolite, 4-hydroxycyclophosphamide, equilibrates with the ring-open aldophosphamide that undergoes ß-elimination to yield the therapeutically active DNA cross-linking phosphoramide mustard and the byproduct acrolein. The present paper presents a DFT investigation of the different metabolic phases and an insight into the mechanism by which CP exerts its cytotoxic action. A detailed computational analysis of the energy profiles describing all the involved transformations and the mechanism of DNA alkylation is given with the aim to contribute to an increase of knowledge that, after more than 60 years of unsuccessful attempts, can lead to the design and development of a new generation of oxazaphosphorines.

Latent Coronary Plaque Morphology From Computed Tomography Angiography, Molecular Disease Activity on Positron Emission Tomography, and Clinical Outcomes.

BACKGROUND: Assessments of coronary disease activity with 18F-sodium fluoride positron emission tomography and radiomics-based precision coronary plaque phenotyping derived from coronary computed tomography angiography may enhance risk stratification in patients with coronary artery disease. We sought to investigate whether the prognostic information provided by these 2 approaches is complementary in the prediction of myocardial infarction. METHODS: Patients with known coronary artery disease underwent coronary 18F-sodium fluoride positron emission tomography and coronary computed tomography angiography on a hybrid positron emission tomography/computed tomography scanner. Coronary 18F-NaF uptake was determined by the coronary microcalcification activity. We performed quantitative plaque analysis of coronary computed tomography angiography datasets and extracted 1103 radiomic features for each plaque. Using weighted correlation network analysis, we derived latent morphological features of coronary lesions which were aggregated to patient-level radiomics nomograms to predict myocardial infarction. RESULTS: Among 260 patients with established coronary artery disease (age, 65±9 years; 83% men), 179 (69%) participants showed increased coronary 18F-NaF activity (coronary microcalcification activity>0). Over 53 (40-59) months of follow-up, 18 patients had a myocardial infarction. Using weighted correlation network analysis, we derived 15 distinct eigen radiomic features representing latent morphological coronary plaque patterns in an unsupervised fashion. Following adjustments for calcified, noncalcified, and low-density noncalcified plaque volumes and 18F-NaF coronary microcalcification activity, 4 radiomic features remained independent predictors of myocardial infarction (hazard ratio, 1.46 [95% CI, 1.03-2.08]; P=0.03; hazard ratio, 1.62 [95% CI, 1.04-2.54]; P=0.02; hazard ratio, 1.49 [95% CI, 1.07-2.06]; P=0.01; and hazard ratio, 1.50 (95% CI, 1.05-2.13); P=0.02). CONCLUSIONS: In patients with established coronary artery disease, latent coronary plaque morphological features, quantitative plaque volumes, and disease activity on 18F-sodium fluoride positron emission tomography are additive predictors of myocardial infarction.

A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance.

The majority of cancer cases are colorectal cancer, which is also the second largest cause of cancer-related deaths worldwide. Metastasis is the leading cause of death for patients with colorectal cancer. Metastatic colorectal cancer incidence are on the rise due to a tiny percentage of tumors developing resistant to medicines despite advances in treatment tactics. Cutting-edge targeted medications are now the go-to option for customized and all-encompassing CRC care. Specifically, multitarget kinase inhibitors, antivascular endothelial growth factors, and epidermal growth factor receptors are widely used in clinical practice for CRC-targeted treatments. Rare targets in metastatic colorectal cancer are becoming more well-known due to developments in precision diagnostics and the extensive use of second-generation sequencing technology. These targets include the KRAS mutation, the BRAF V600E mutation, the HER2 overexpression/amplification, and the MSI-H/dMMR. Incorporating certain medications into clinical trials has significantly increased patient survival rates, opening new avenues and bringing fresh viewpoints for treating metastatic colorectal cancer. These focused therapies change how cancer is treated, giving patients new hope and better results. These markers can significantly transform and individualize therapy regimens. They could open the door to precisely customized and more effective medicines, improving patient outcomes and quality of life. The fast-growing body of knowledge regarding the molecular biology of colorectal cancer and the latest developments in gene sequencing and molecular diagnostics are directly responsible for this advancement.

Preemptive airway management planning: A retrospective evaluation of the pediatric difficult airway consultation service.

BACKGROUND/AIMS: The pediatric Difficult Airway Consultation Service (pDACS) was created in 2017 to identify patients with potentially difficult airways and create airway management plans prior to airway management. METHODS: Consults were either nurse-initiated, physician-initiated, or both nurse-and-physician-initiated and were examined for demographic and clinical factors. If a child had difficult airway risk factors, a consult note with airway management recommendations was completed. RESULTS: We included 419 consults from the 4-year study period for analysis. Sixty-one patients had chronic tracheostomies in place and thus, were analyzed separately. Of the remaining 358 consults, 50% (n = 179) were nurse-initiated, 30.2% (n = 108) physician-initiated, and 19.8% (n = 71) nurse-and-physician-initiated consults. Differences in observed frequency of airway edema (difference, 6.3%; 95%CI 0.1%-12.5%; p = .04), cleft lip/palate (difference, 8.1%; 95%CI 0.07%-16.3%, p = .04), craniofacial abnormalities (difference, 12.3%; 95%CI 1.9%-22.7%, p = .02), and trauma/burn (difference, 6.5%; 95%CI 0.09%-12.8%, p = .04) were calculated. Observed frequencies were higher in physician-initiated compared to nurse-initiated consults. Airway edema was also more prevalent in dual nurse-and-physician-initiated consults (difference, 8.7%; 95%CI 1.6%-15.8%; p = .01). Physician-initiated consults were associated with a greater proportion of high-risk difficult airways than nurse-initiated consults (difference, 26.7%; 95%CI 14.0%-39.4%, p < .001). Approximately 41.9% of patients at high-risk for having a difficult airway were identified by nurse-screening only. Using bag-valve-mask was often the primary ventilation recommendation (89.3%, n = 108) and supraglottic airway placement was the most common tertiary plan (74.2%, n = 83). Direct laryngoscopy (47.1%, n = 65) and videolaryngoscopy (40.6%, n = 56) were the most recommended modes of intubation. Three patients with airway emergencies had previously documented airway management plans and were successfully intubated without complications following the primary intubation technique recommended in their consult note. CONCLUSIONS: In our study, nurse-screening identified patients at high-risk for a difficult airway that would likely not have been identified prior to initiation of a screening protocol. Furthermore, airway management plans outlined prior to an emergent difficult airway event may increase first-attempt success at securing the difficult airway, reducing morbidity and mortality.

Phytochemical-mediated modulation of autophagy and endoplasmic reticulum stress as a cancer therapeutic approach.

Autophagy and endoplasmic reticulum (ER) stress are conserved processes that generally promote survival, but can induce cell death when physiological thresholds are crossed. The pro-survival aspects of these processes are exploited by cancer cells for tumor development and progression. Therefore, anticancer drugs targeting autophagy or ER stress to induce cell death and/or block the pro-survival aspects are being investigated extensively. Consistently, several phytochemicals have been reported to exert their anticancer effects by modulating autophagy and/or ER stress. Various phytochemicals (e.g., celastrol, curcumin, emodin, resveratrol, among others) activate the unfolded protein response to induce ER stress-mediated apoptosis through different pathways. Similarly, various phytochemicals induce autophagy through different mechanisms (namely mechanistic target of Rapamycin [mTOR] inhibition). However, phytochemical-induced autophagy can function either as a cytoprotective mechanism or as programmed cell death type II. Interestingly, at times, the same phytochemical (e.g., 6-gingerol, emodin, shikonin, among others) can induce cytoprotective autophagy or programmed cell death type II depending on cellular contexts, such as cancer type. Although there is well-documented mechanistic interplay between autophagy and ER stress, only a one-way modulation was noted with some phytochemicals (carnosol, capsaicin, cryptotanshinone, guangsangon E, kaempferol, and δ-tocotrienol): ER stress-dependent autophagy. Plant extracts are sources of potent phytochemicals and while numerous phytochemicals have been investigated in preclinical and clinical studies, the search for novel phytochemicals with anticancer effects is ongoing from plant extracts used in traditional medicine (e.g., Origanum majorana). Nonetheless, the clinical translation of phytochemicals, a promising avenue for cancer therapeutics, is hindered by several limitations that need to be addressed in future studies.

New prospective insecticidal agents based on N-(arylcarbamothioyl)arylmide derivatives against Spodoptera frugiperda: Design, Synthesis, Toxicological, Biological, Biomedical Studies and Antibacterial Activity.

In this work, a novel series of N-(arylcarbamothioyl)arylmide) 2-11 were synthesized by treating One-Pot three-multicomponent of Aroyl chloride ammonium isothiocyanate and amine compounds under refluxing conditions. Using spectroscopic methods, the chemical structure of the novelty developed compounds were investigated. After five days, the proposed derivatives' insecticidal bioassay was assessed using the median lethal concentration (LC50) against the second & fourth larvae of Spodoptera frugiperda as toxicity agents. The findings showed that, to varying degrees, every tested substance exerted insecticidal effects on S. frugiperda larvae in both of their instars. Compound 9 was the most poisonous of them all, having an LC50 against larvae in their second and fourth instars of 60.45 and 123.21 mg/L, respectively. Additionally, a few biological and biochemical characteristics of the substances that were generated in a lab setting were also looked at. Furthermore, this work discusses how to discover novel compounds that may one day be employed as insecticidal agents. Finally, all the designed components were monitored for their antibacterial effectiveness toward both Gram-positive & Gram-negative bacteria.

New optimization strategies for SWMM modeling of stormwater quality applications in urban area.

Build-up/wash-off models were originally developed for small-scale laboratory facilities with uniform properties. The effective translation of these models to catchment scale necessitates the meticulous calibration of model parameters. The present study combines the Mat-SWMM tool with a genetic algorithm (GA) to improve the calibration of build-up and wash-off parameters. For this purpose, Mat-SWMM was modified to equip it with the capacity to provide comprehensive water quality analysis outcomes. Additionally, this research also conducts a comparative examination of two distinct types of objective functions in the optimization. Rather than depending on previous literature, this study undertook a numerical campaign to ascertain an appropriate range for the relevant parameters within the case study, thereby ensuring the optimization algorithm's efficient functionality. This research also implements an integrated event calibration approach, i.e., a novel method that calibrates all rainfall events collectively, thus improving systemic interaction representation and model robustness. The findings indicate that employing this methodology significantly enhances the reliability of the outcomes, thereby establishing a more robust procedure. The first objective function (TSS instantaneous less squared difference function, OF 1), which is widely employed in the literature, was designed to minimize the difference between observed and predicted instantaneous Total Suspended Solids (TSS) concentrations. In contrast, the second function (mass and mass peak consistency function, OF 2) considers integral model outputs, i.e., the overall mass balance, the time of the peak mass flow rate, and its intensity. The analysis of the outputs revealed that both objective functions demonstrated sufficient performance. OF 1 provided slightly better performance in predicting the TSS concentrations, whereas OF 2 demonstrated superior ability in capturing global event characteristics. Notably, the optimal parameter set identified through OF 2 aligned with the physically plausible ranges traditionally recommended in technical manuals for urban catchments. In contrast, OF 1's optimal set necessitated an expansion in the acceptable parameter ranges. Finally, from a computational burden viewpoint, OF 1 demanded a significantly higher number of function evaluations, thus implying an escalating computational cost as the range expands. Conversely, OF 2 necessitated fewer evaluations to converge toward the optimal solution.

FACTORS AFFECTING MOTHERS' AWARENESS REGARDING CHILD WEANING PRACTICE.

Weaning is an organized process of introduction of appropriate food at the accurate time in addition to the mother's milk to deliver essential nourishment to the baby and the infants should be breastfed completely through the early six months of life. Aim of the study - Assessment of the Mothers' awareness (knowledge, attitude, and practice) and to determine possible factors affecting it. A total sample of 112 mothers enrolled in the present study, from which data was collected including demographic characteristics of the child and mother with feeding history. Knowledge and practice assessment regarding the weaning process. Appropriate time of introduction of complementary feeds was started in 41.1% of the children. 69.6% weaned their children suddenly cessed. Factors influencing complementary and weaning knowledge were the mother's education and occupation and source of information and practice was poorly achieved, and the factors were the mother's age and type of family. The approval for WHO recommendations on complementary and weaning practices was not optimum. It is consequently a significant point to change the interventions at joining the hole between these practices in urban locations and WHO endorsements.

Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study.

BACKGROUND: Type 2 myocardial infarction is caused by myocardial oxygen supply-demand imbalance, and its diagnosis is increasingly common with the advent of high-sensitivity cardiac troponin assays. Although this diagnosis is associated with poor outcomes, widespread uncertainty and confusion remain among clinicians as to how to investigate and manage this heterogeneous group of patients with type 2 myocardial infarction. METHODS: In a prospective cohort study, 8064 consecutive patients with increased cardiac troponin concentrations were screened to identify patients with type 2 myocardial infarction. We excluded patients with frailty or renal or hepatic failure. All study participants underwent coronary (invasive or computed tomography angiography) and cardiac (magnetic resonance or echocardiography) imaging, and the underlying causes of infarction were independently adjudicated. The primary outcome was the prevalence of coronary artery disease. RESULTS: In 100 patients with a provisional diagnosis of type 2 myocardial infarction (median age, 65 years [interquartile range, 55-74 years]; 43% women), coronary and cardiac imaging reclassified the diagnosis in 7 patients: type 1 or 4b myocardial infarction in 5 and acute myocardial injury in 2 patients. In those with type 2 myocardial infarction, median cardiac troponin I concentrations were 195 ng/L (interquartile range, 62-760 ng/L) at presentation and 1165 ng/L (interquartile range, 277-3782 ng/L) on repeat testing. The prevalence of coronary artery disease was 68% (63 of 93), which was obstructive in 30% (28 of 93). Infarct-pattern late gadolinium enhancement or regional wall motion abnormalities were observed in 42% (39 of 93), and left ventricular systolic dysfunction was seen in 34% (32 of 93). Only 10 patients had both normal coronary and normal cardiac imaging. Coronary artery disease and left ventricular systolic dysfunction were previously unrecognized in 60% (38 of 63) and 84% (27 of 32), respectively, with only 33% (21 of 63) and 19% (6 of 32) on evidence-based treatments. CONCLUSIONS: Systematic coronary and cardiac imaging of patients with type 2 myocardial infarction identified coronary artery disease in two-thirds and left ventricular systolic dysfunction in one-third of patients. Unrecognized and untreated coronary or cardiac disease is seen in most patients with type 2 myocardial infarction, presenting opportunities for initiation of evidence-based treatments with major potential to improve clinical outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03338504.

Early computed tomography coronary angiography and preventative treatment in patients with suspected acute coronary syndrome: A secondary analysis of the RAPID-CTCA trial.

BACKGROUND: Computed tomography coronary angiography (CTCA) offers detailed assessment of the presence of coronary atherosclerosis and helps guide patient management. We investigated influences of early CTCA on the subsequent use of preventative treatment in patients with suspected acute coronary syndrome. METHODS: In this secondary analysis of a multicenter randomized controlled trial of early CTCA in intermediate-risk patients with suspected acute coronary syndrome, prescription of aspirin, P2Y12 receptor antagonist, statin, renin-angiotensin system blocker, and beta-blocker therapies from randomization to discharge were compared within then between those randomized to early CTCA or to standard of care only. Effects of CTCA findings on adjustment of these therapies were further examined. RESULTS: In 1,743 patients (874 randomized to early CTCA and 869 to standard of care only), prescription of P2Y12 receptor antagonist, dual antiplatelet, and statin therapies increased more in the early CTCA group (between-group difference: 4.6% [95% confidence interval, 0.3-8.9], 4.5% [95% confidence interval, 0.2-8.7], and 4.3% [95% confidence interval, 0.2-8.5], respectively), whereas prescription of other preventative therapies increased by similar extent in both study groups. Among patients randomized to early CTCA, there were additional increments of preventative treatment in those with obstructive coronary artery disease and higher rates of reductions in antiplatelet and beta-blocker therapies in those with normal coronary arteries. CONCLUSIONS: Prescription patterns of preventative treatment varied during index hospitalization in patients with suspected acute coronary syndrome. Early CTCA facilitated targeted individualization of these therapies based on the extent of coronary artery disease.

Safety and Feasibility of Robot-Assisted Minimally Invasive Esophagectomy (RAMIE) with Three-Field Lymphadenectomy and Neoadjuvant Chemoradiotherapy in Patients with Resectable Esophageal Cancer and Cervical Lymph Node Metastasis.

BACKGROUND: In the West, patients with cervical lymph node metastasis of resectable esophageal cancer at diagnosis are generally precluded from curative treatment. This study prospectively explored the safety and feasibility of neoadjuvant chemoradiotherapy followed by robot-assisted minimally invasive esophagectomy (RAMIE) with three-field lymphadenectomy for these patients. METHODS: Between 2015 and 2021, patients with resectable thoracic esophageal cancer and cervical lymph node metastasis were recruited nationwide in the Netherlands. Patients without interval metastasis following neoadjuvant chemoradiotherapy and good physical condition underwent RAMIE with bilateral three-field lymphadenectomy. Safety was predefined as ≤50% Clavien-Dindo grade ≥3b postoperative complications. RESULTS: Neoadjuvant chemoradiotherapy was administered to 29 patients (19 (66%) adenocarcinoma and 10 (34%) squamous cell carcinoma). After restaging, nine (31%) patients were excluded (interval metastasis, clinical deterioration, or withdrawn consent). RAMIE was performed in 20 patients (R0-rate 95%). A median of 42 [range 21-71] lymph nodes were resected of which 13 [range 2-35] were cervical. Only 1 (5%) patient had an unexpected contralateral cervical lymph node metastasis. Complications grade ≥3b occurred in 50%. Most frequent complications of any grade were recurrent laryngeal nerve palsy (45%) and pneumonia (40%). Overall survival at 1 year was 85% and quality of life at 6 months was comparable to esophageal cancer patients treated with curative intent. CONCLUSIONS: RAMIE with three-field lymphadenectomy following neoadjuvant chemoradiotherapy for patients with resectable esophageal cancer presenting with cervical lymph node metastasis is feasible in a Western population. Because contralateral cervical metastasis is rare, a unilateral neck dissection would suffice in the majority of cases. CLINICAL TRIAL: gov Identifier: NCT02426879. Dutch trial register Identifier: NTR 4552.

Primary mucosal melanomas of the head and neck are characterised by overexpression of the DNA mutating enzyme APOBEC3B.

AIMS: Primary head/neck mucosal melanomas (MMs) are rare and exhibit aggressive biologic behaviour and elevated mutational loads. The molecular mechanisms responsible for high genomic instability observed in head/neck MMs remain elusive. The DNA cytosine deaminase APOBEC3B (A3B) constitutes a major endogenous source of mutation in human cancer. A3B-related mutations are identified through C-to-T/-G base substitutions in 5'-TCA/T motifs. Herein, we present immunohistochemical and genomic data supportive of a role for A3B in head/neck MMs. METHODS AND RESULTS: A3B protein levels were assessed in oral (n = 13) and sinonasal (n = 13) melanomas, and oral melanocytic nevi (n = 13) by immunohistochemistry using a custom rabbit α-A3B mAb (5210-87-13). Heterogeneous, selective-to-diffuse, nuclear only, A3B immunopositivity was observed in 12 of 13 (92.3%) oral melanomas (H-score range = 9-72, median = 40) and 8 of 13 (62%) sinonasal melanomas (H-score range = 1-110, median = 24). Two cases negative for A3B showed prominent cytoplasmic staining consistent with A3G. A3B protein levels were significantly higher in oral and sinonasal MMs than intraoral melanocytic nevi (P < 0.0001 and P = 0.0022, respectively), which were A3B-negative (H-score range = 1-8, median = 4). A3B levels, however, did not differ significantly between oral and sinonasal tumours (P > 0.99). NGS performed in 10 sinonasal MMs revealed missense NRAS mutations in 50% of the studied cases and one each KIT and HRAS mutations. Publicly available whole-genome sequencing (WGS) data disclosed that the number of C-to-T mutations and APOBEC3 enrichment score were markedly elevated in head/neck MMs (n = 2). CONCLUSION: The above data strongly indicate a possible role for the mutagenic enzyme A3B in head/neck melanomagenesis, but not benign melanocytic neoplasms.

The Impact of Cancer Relapse and Poor Patient Outcomes on Health Care Providers Practicing in the Oncology Field.

INTRODUCTION: Devastating cancer-related events are not uncommon, and these events have weakened communication performance and induced stress among health care providers (HCPs), particularly physicians. This study aimed to investigate the perspective of HCPs emotionally affected by poor clinical outcomes due to the failure of cancer therapy. METHODS: A cross-sectional, online survey was conducted over 3 months among HCPs practicing in the field of oncology in Saudi Arabia, comprising physicians, pharmacists, and nurses. Data were analyzed using Statistical Package for Social Sciences version 26.0. A P-value <.05 was considered statistically significant. RESULTS: This study demonstrated a positive correlation between HCPs' length of experience and emotional impact of treatment failure, albeit this was not statistically significant (P = .071). Analysis of their perspective toward failure of cancer therapies revealed a significant impact of occupation and sex (P = .014 and P = .047, respectively). Moreover, occupation played a significant role in shaping the viewpoint of HCPs toward the need for conducing further research to test the appropriateness of treatment protocols on local patients (P = .022). Despite the emotional responses of HCPs to suboptimal clinical outcomes, factors such as work burnout, lack of concentration and patience, work or personal problems, and under appreciation were frequently identified as triggers of such outcomes. CONCLUSION: Our results revealed that poor clinical outcomes observed among cancer patients are emotional triggers for HCPs practicing in the oncology field. The emotional response is often perceived negatively, and can potentially lead to a decline in the quality of care provided to these patients.

Outcomes of complex colorectal polyps managed by multi-disciplinary team strategies-a multi-centre observational study.

PURPOSE: Team management strategies for complex colorectal polyps are recommended by professional guidelines. Multi-disciplinary meetings are used across the UK with limited information regarding their impact. The aim of this multi-centre observational study was to assess procedures and outcomes of patients managed using these approaches. METHOD: This was a retrospective, observational study of patients managed by six UK sites. Information was collected regarding procedures and outcomes including length of stay, adverse events, readmissions and cancers. RESULTS: Two thousand one hundred ninety-two complex polyps in 2109 patients were analysed with increasing referrals annually. Most presented symptomatically and the mean polyp size was 32.1 mm. Primary interventions included endoscopic therapy (75.6%), conservative management (8.3%), colonic resection (8.1%), trans-anal surgery (6.8%) or combined procedures (1.1%). The number of primary colonic resections decreased over the study period without a reciprocal increase in secondary procedures or recurrence. Secondary procedures were required in 7.8%. The median length of stay for endoscopic procedures was 0 days with 77.5% completed as day cases. Median length of stay was 5 days for colonic resections. Overall adverse event and 30-day readmission rates were 9.0% and 3.3% respectively. Malignancy was identified in 8.8%. Benign polyp recurrence occurred in 13.1% with a median follow up of 30.4 months. Screening detected lesions were more likely to undergo bowel resection. Colonic resection was associated with longer stays, higher adverse events and more cancers on final histology. CONCLUSION: Multi-disciplinary team management of complex polyps is safe and effective. Standardisation of organisation and quality monitoring is needed to continue positive effects on outcomes and services.

N-substituted tetrahydro-beta-carboline as mu-opioid receptors ligands: in silico study; molecular docking, ADMET and molecular dynamics approach.

Manipulating intracellular signals by interaction with transmembranal G-protein-coupled receptors (GPCRs) is the way of action of more than 30% of available medicines. Designing molecules against GPCRs is most challenging due to their flexible binding orthosteric and allosteric pockets, a property that lead to different mode and extent of activation of intracellular mediators. Here, in the current study we aimed to design N-substituted tetrahydro-beta-carbolines (THßC's) targeting Mu Opioid Receptors (MORs). We performed ligand docking study for reference and designed compounds against active and inactive states of MOR, as well as the active state bound to intracellular mediator of Gi. The reference compounds include 40 known agonists and antagonists, while the designed compounds include 25,227 N-substituted THßC analogues. Out of the designed compounds, 15 compounds were comparatively having better extra precision (XP) Gscore and were analyzed for absorption, distribution, metabolism, and excretion-toxicity (ADMET) properties, drug-likness, and molecular dynamic (MD) simulation. The results showed that N-substituted tetrahydro-beta-carbolines with and without C6-methoxy group substitutions (THBC/6MTHBC) analogues of A1/B1 and A9/B9 have relatively acceptable affinity and within pocket-stability toward MOR compared to the reference compounds of morphine (agonist) and naloxone (antagonist). Moreover, the designed analogues interact with key residue within the binding pocket of Asp 147 that is reported to be involved in receptor activation. In conclusion, the designed THBC analogues represent a good starting point for designing opioid receptor ligands other than morphinan scaffold, that have good synthetic accessibility which promotes feasible structural manipulation to tailor pharmacological effects with minimal side effects. Workflow rational in the discovery of potential Mu Opioid Receptor ligands.

Pediatric community acquired urinary tract infections due to extended-spectrum beta-lactamase versus non-extended-spectrum beta-lactamase producing bacteria.

BACKGROUND: This study aimed to evaluate the demographics, clinical characteristics, risk factors, and antibiotic resistance of pediatric community-acquired urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing and non-ESBL-producing uropathogens. METHODS: This retrospective study was conducted at a tertiary care hospital in Saudi Arabia, among children aged between 0 and 14 years, with a culture-proven diagnosis of community-acquired UTI between February 2019 and September 2021. Patients were divided into two groups based on whether or not their UTI was caused by ESBL-producing bacteria. RESULTS: A total of 383 patients with community-acquired UTI were evaluated. Escherichia coli was detected in 72.6% of cultures. Extended-spectrum beta-lactamase-producing organisms were responsible for 35.7% of UTI episodes. Of these 69% and 31% were caused by E. coli and Klebsiella pneumoniae, respectively. There were no significant differences between the two groups with regard to clinical presentation or urine analysis. The resistance rates in the ESBL-producing group were 39.4% for amoxicillin/clavulanic acid, 65.7% for ciprofloxacin, 72.3% for co-trimoxazole, 32.8% for nitrofurantoin, 21.2% for gentamicin, and 0.7% for amikacin and carbapenems. In the non-ESBL-producing group, it was 22.4% for amoxicillin/clavulanic acid, 22.4% for ciprofloxacin, 38.2% for co-trimoxazole, 23.6% for nitrofurantoin, 6.1% for gentamicin, and zero for amikacin and carbapenems. The presence of renal abnormalities (p = 0.014) and male gender (p = 0.026) were determined to be independent risk factors for ESBL UTIs. CONCLUSIONS: Recognizing risk factors and antibiotic resistance for ESBL-producing bacteria may aid in tailoring an antibiotic regimen for pediatric patients at high risk of ESBL-UTIs.

Cross-cultural adaptation, validity and reliability of the Arabic version of the Forgotten Joint Score for knee arthroplasty.

PURPOSE: To evaluate the validity and reliability of the Arabic version of this questionnaire in Arabic patients who underwent total knee arthroplasty (TKA). METHODS: The Arabic version of the English FJS (Ar-FJS) was modified according to cross-cultural adaptation best practices. The study included 111 patients who underwent TKA 1-5 years ago and completed the Ar-FJS. The reduced Western Ontario and McMaster Universities Osteoarthritis Index (rWOMAC) and 36-Item Short Form (SF-36) were used to assess the construct validity of the study. Fifty-two individuals took the Ar-FJS test twice to evaluate the test-retest reliability. RESULTS: The reliability of the Ar-FJS demonstrated a Cronbach's α value of 0.940 and an intraclass correlation coefficient of 0.951. The ceiling effect of the Ar-FJS was 5.4% (n = 6), whereas the floor effect was 1.8% (n = 2). Additionally, the Ar-FJS showed correlation coefficients of 0.753 and 0.992 for the rWOMAC and SF-36, respectively. CONCLUSION: The Ar-FJS-12 demonstrated excellent internal consistency, repeatability, construct validity, and content validity and can be recommended for patients in Arabic-speaking communities who have undergone knee arthroplasty.