Cognitive behavioral therapy for the treatment of insomnia in patients with cardiovascular diseases: a meta-analysis with GRADE analysis.

Insomnia, as a difficulty in initiating and maintaining sleep, coupled with cardiovascular diseases (CVDs) increase the risk of aggravate daytime symptoms, mortality, and morbidity. Cognitive behavioral therapy (CBT) is thought to have a significant impact on insomnia treatment, but in patients with CVDs, there is a paucity of data. To provide a comprehensive appraisal on the impact of CBT on the treatment of insomnia in patients with CVDs. We searched Ovid, Scopus, Web of science, and Cochrane central, to randomized controlled trials (RCTs) from inception till November 2022. Outcomes of interest were insomnia severity index (ISI), Pittsburgh Sleep Quality Index (PSQI), sleep efficiency (SE), Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS), and sleep disorders questionnaire (SDQ). Pooled data were analyzed using mean difference (MD) with its 95% confidence interval (CI) in a random effect model using STATA 17 for Mac. Nine RCTs comprising 365 patients were included in the analysis. CBT significantly reduced scores of ISI (MD = - 3.22, 95%  CI - 4.46 to - 1.98, p < 0.001), PSQI (MD = - 2.33, 95%  CI - 3.23 to - 1.44, p < 0.001), DBAS (MD = - 0.94, 95%  CI - 1.3 to - 0.58, p < 0.001), SDQ (MD = - 0.38, 95%  CI - 0.56 to - 0.2, p < 0.001). Also, it increased the score of SE (MD = 6.65, 95% CI 2.54 to 10.77, p < 0.001). However, there was no difference in terms of ESS. CBT is an easy and feasible intervention with clinically significant improvement in insomnia symptoms. Further large-volume studies are needed to assess sustained efficacy.

Efficacy and Safety of Intranasal Fentanyl in Pediatric Emergencies: A Systematic Review and Meta-analysis.

BACKGROUND: Intranasal fentanyl (INF) has gained popularity in pediatric emergency departments (EDs) as an effective alternative to intravenous morphine for treating acute moderate to severe pain. Intranasal fentanyl eliminates the need for invasive access, making it advantageous for patients with minor injuries. Our study aims to provide a comprehensive evaluation of the available evidence regarding the effectiveness and safety of INF administration in pediatric emergency wards, particularly compared with other treatment options described in the literature. METHODS: A thorough search strategy identified randomized controlled trials assessing INF in the pediatric emergency ward. Eligible studies were independently screened, and relevant data were extracted. The analysis used pooled risk ratio (RR) for dichotomous outcomes and the standardized mean difference (SMD) for continuous ones. Randomized controlled trials' quality was assessed using the Cochrane Risk of Bias Assessment Tool 2. RESULTS: In our study, 8 randomized controlled trials involving 806 patients, INF demonstrated superior effectiveness in reducing pain compared with other comparators at the 15- to 20-minute mark (SMD, -0.23; 95% confidence interval, -0.37 to -0.08; P = 0.002). However, no significant differences were found at the 30- and 60-minute time points (SMDs, -0.16; 95% CI, -0.50, 0.19; P = 0.37; and -0.16; 95% CI, -0.50 to 0.19; P = 0.78) except when excluding one study to resolve heterogeneity at the 30-minute mark (RR, -0.02; 95% CI, -0.24 to 0.20; P = 0.87). Intranasal fentanyl also exhibited a better adverse outcome profile, with a lower risk of total adverse events and nausea/vomiting (RR, 0.66; 95% CI, 0.48-0.91; P = 0.01; and RR, 0.43; 95% CI, 0.30-0.63; P > 0.001) compared with other analgesics. However, no significant differences were observed for dizziness and hallucination (RR, 0.43; 95% CI, 0.30-0.63; P = 0.68; and RR, 0.43; 95% CI, 0.30-0.63; P = 0.35). CONCLUSIONS: Our study assessed the effectiveness of INF compared with other analgesics in pain reduction. Intranasal fentanyl demonstrated superior pain reduction at the 15- to 20-minute point but showed no significant differences at 30 and 60 minutes. Intranasal fentanyl also had a more favorable adverse event profile, with a lower risk of nausea and vomiting than other analgesics. However, no significant differences were observed in dizziness and hallucination between the groups.

The Prevalence of Anxiety Among University Students in the United Arab Emirates Following the COVID-19 Lockdown.

INTRODUCTION: The COVID-19 pandemic, with its consequential lifestyle changes, is anticipated to contribute to increased anxiety levels, particularly among university students who already contend with significant academic stress. We aim to assess the prevalence of anxiety among university students in the United Arab Emirates (UAE) following the COVID-19 lockdown period. METHODS: We conducted a descriptive cross-sectional study among students enrolled in UAE universities. A self-administered questionnaire was utilized to gather demographic data, assess anxiety levels using the generalized anxiety disorder-7 scale, explore potential factors associated with heightened anxiety, investigate the impact of increased anxiety on academic performance, and identify coping mechanisms employed post-lockdown. RESULTS: Of the 369 participating students, anxiety levels were minimal in 87 (23.6%), mild in 163 (44.2%), and moderate to severe in 119 (32.2%) subjects. Moreover, increased anxiety levels were significantly correlated with poor/fair sleep quality (p=0.002). Importantly, students with moderate to severe anxiety levels exhibited poorer performance in exams and assignments (p=0.001) and encountered difficulties in maintaining focus on studies (p<0.001). The predominant coping mechanisms employed by students included self-distraction, prayer, and maintaining a positive attitude. CONCLUSION: The majority of students in our study experienced mild to severe levels of anxiety following the COVID-19 lockdown period. We hope that our findings will prompt university and government officials to implement effective screening and preventive strategies to adequately support university students in future public health crises.

Safety and efficacy of extended versus standard interval dosing of natalizumab in multiple sclerosis patients: a systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory, immune-mediated disease affecting the central nervous system. Natalizumab, an FDA-approved monoclonal antibody for MS, has been explored for its off-label extended interval dosing (EID), suggesting a potential reduction in the risk of progressive multifocal leukoencephalopathy (PML) compared to standard interval dosing (SID). Our objective was to assess the efficacy and safety of EID in comparison to SID for natalizumab treatment in patients with MS. METHODS: We searched PubMed, Embase, WOS, Scopus, Ovid, Science Direct, Clinical trials.gov, and Cochrane Library. Our assessed outcomes were clinical relapses, MRI activity, change in expanded disability status scale [EDSS], and the risk of PML. The EID group was defined as 5 to 8 weeks [EID (Q5-8W)]. The analysis was conducted using RevMan ver. 5.4. The effect estimates were presented as a risk ratio [RR] or mean difference with 95% confidence intervals [CI] using SID group as the reference for comparisons. RESULTS: Fourteen studies met our inclusion criteria: 2 RCTs, 1 switched single-arm trial, and 12 observational studies. No significant differences were found in all efficacy outcomes of interest. Risk of clinical relapses [RR = 0.90, (95%CI 0.80, 1.02)], risk of new or newly enlarging T2 hyperintense MRI lesions [RR = 0.78, (95%CI 0.59, 1.04)], risk gadolinium enhancing lesions [RR = 1.30, (95%CI 0.98, 1.72)], change in EDSS [MD = 0.09 (95%CI - 0.57, 0.76)], risk of PML [RR = 1.09, 95%CI (0.24, 4.94)]. CONCLUSION: In summary, our meta-analysis indicates that natalizumab maintains its effectiveness under extended interval dosing [up to 8 weeks], presenting comparable risks for clinical relapses, MRI lesions, EDSS, and PML. Caution is advised given study limitations and heterogeneity. Robust conclusions necessitate well-designed high-quality prospective studies.

Safety and feasibility of rotational atherectomy (RA) versus conventional stenting in patients with chronic total occlusion (CTO) lesions: a systematic review and meta-analysis.

BACKGROUND AND AIM: Interventional cardiologists face challenges in managing chronic total occlusion (CTO) lesions, with conflicting results when comparing rotational atherectomy (RA) to conventional PCI. This meta-analysis aims to provide a critical evaluation of the safety and feasibility of RA in CTO lesions. METHODS: PubMed, Scopus, Web of Science, Ovid, and Cochrane central library until April 2023 were searched for relevant studies. MACE was our primary outcomes, other outcomes were all cause of death, cardiac death, MI, and TVR. Also, we reported angiographic outcomes as technical success, procedural success, and procedural complications in a random effect model. The pooled data was analyzed using odds ratio (OR) with its 95% CI using STATA 17 MP. RESULTS: Seven studies comprising 5494 patients with a mean follow-up of 43.1 months were included in this meta-analysis. Our pooled analysis showed that RA was comparable to PCI to decrease the incidence of MACE (OR = 0.98, 95% CI [0.74 to 1.3], p = 0.9). Moreover, there was no significant difference between RA and conventional PCI in terms of other clinical or angiographic outcomes. CONCLUSION: Our study showed that RA had comparable clinical and angiographic outcomes as conventional PCI in CTO lesions, which offer interventional cardiologists an expanded perspective when addressing calcified lesions. PROSPERO REGISTRATION: CRD42023417362.

Vesical ectopic pregnancy due to vesicouterine fistula: A case report with literature review.

This case report describes the presentation, diagnosis, and surgical management of a rare vesical ectopic pregnancy in a 36-year-old woman with a history of multiple cesarean sections. The patient presented with symptoms of suprapubic pain, fever, and amenorrhea. An initial ultrasound indicated retained products of conception, leading to a preliminary diagnosis of septic miscarriage. However, subsequent rescanning revealed an empty uterus and a non-viable fetus within the bladder, connected to the uterine cavity. Cystoscopy confirmed the presence of fetal parts inside the bladder. Finally, a laparotomy was performed and the fetus was removed from the bladder with repair of the underlying uterovesical fistula. An uneventful postoperative period ensued. The literature review revealed only four previously reported cases with similar overall presentations. This case highlights the importance of considering vesical ectopic pregnancies in patients with a history of cesarean sections and unusual symptoms, as prompt surgical intervention is crucial for ensuring successful management of the condition.

Bismuth Oxide Composite-Based Agricultural Waste for Wound Dressing Applications.

The purpose of this study was to enhance the antimicrobial activity of bagasse paper by coating the paper with bismuth oxide (Bi2O3) and using it to accelerate the process of wound healing. Paper sheets were prepared from sugarcane waste (bagasse). First, the paper sheets were coated with different Bi2O3 concentrations to improve the antimicrobial activity of the paper. After that, the paper sheets were allowed to dry in an oven at 50 °C for 3 h. Then, in vitro antimicrobial activity was evaluated against different microbial species, including Gram-negative bacteria (i.e., Klebsiella pneumonia, Escherichia coli) and Gram-positive bacteria (i.e., Staphylococcus aureus, Streptococcus pyogenes). The obtained results showed that the paper coated with 25% and 100% Bi2O3 had activity against all models of bacteria; however, the paper coated with 100% Bi2O3 composite had the strongest inhibitory effect. Then, bagasse paper was coated with 100% Bi2O3 and different antibiotics, to investigate their wound-healing potency in a wounded rat model for 14 days. Moreover, the paper coated with 100% Bi2O3 inhibited the cellular migration in vitro. Conclusively, coating paper with Bi2O3 enhances the wound-healing potential when applied to wounds. This impact could be ascribed to Bi2O3's broad antibacterial activity, which reduced infection and accelerated the healing process.

Wastewater-based epidemiology for tracking bacterial diversity and antibiotic resistance in COVID-19 isolation hospitals in Qatar.

BACKGROUND: Hospitals are hotspots for antimicrobial resistance genes (ARGs), and play a significant role in their emergence and spread. Large numbers of ARGs will be ejected from hospitals via wastewater systems. Wastewater-based epidemiology has been consolidated as a tool to provide real-time information, and represents a promising approach to understanding the prevalence of bacteria and ARGs at community level. AIMS: To determine bacterial diversity and identify ARG profiles in hospital wastewater pathogens obtained from coronavirus disease 2019 (COVID-19) isolation hospitals compared with non-COVID-19 facilities during the pandemic. METHODS: Wastewater samples were obtained from four hospitals: three assigned to patients with COVID-19 patients and one assigned to non-COVID-19 patients. A microbial DNA quantitative polymerase chain reaction was used to determine bacterial diversity and ARGs. FINDINGS: The assay recorded 27 different bacterial species in the samples, belonging to the following phyla: Firmicutes (44.4%), Proteobacteria (33.3%), Actinobacteria (11%), Bacteroidetes (7.4%) and Verrucomicrobiota (3.7%). In addition, 61 ARGs were detected in total. The highest number of ARGs was observed for the Hazem Mebaireek General Hospital (HMGH) COVID-19 patient site (88.5%), and the lowest number of ARGs was found for the HMGH non-patient site (24.1%). CONCLUSION: The emergence of contaminants in sewage water, such as ARGs and high pathogen levels, poses a potential risk to public health and the aquatic ecosystem.

The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21-ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

Long-term outcome and troponin I concentrations in Great Danes screened for dilated cardiomyopathy: an observational retrospective epidemiological study.

INTRODUCTION: Dilated cardiomyopathy (DCM) is common in Great Danes (GDs) but screening for this condition can be challenging. We hypothesised that cardiac troponin-I (cTnI) concentration is elevated in GDs with DCM and/or ventricular arrhythmias (VAs), and is associated with reduced survival time in GDs. ANIMALS: One hundred and twenty-four client-owned GDs assigned echocardiographically as normal (n = 53), equivocal (n = 37), preclinical DCM (n = 21), or clinical DCM (n = 13). MATERIALS AND METHODS: A retrospective epidemiological study. Echocardiographic diagnosis, VAs, and contemporaneous cTnI concentrations were recorded. Diagnostic accuracy and cTnI cut-offs were determined with receiver operating characteristic analyses. Effects of the cTnI concentration and disease status on survival and cause of death were explored. RESULTS: Median cTnI was greater in clinical DCM (0.6 ng/mL [25th-75th percentiles: 0.41-1.71 ng/mL]) and GDs with VAs (0.5 ng/mL [0.27-0.80 ng/mL], P<0.001). Elevated cTnI detected these dogs with good accuracy (area under the curve: 0.78-0.85; cut-offs 0.199-0.34 ng/mL). Thirty-eight GDs (30.6%) suffered a cardiac death (CD); GDs suffering CD (0.25 ng/mL [0.21-0.53 ng/mL]) and specifically sudden cardiac death (SCD) (0.51 ng/mL [0.23-0.72 ng/mL]) had higher cTnI than GDs dying of other causes (0.20 ng/mL [0.14-0.35 ng/mL]; P<0.001). Elevated cTnI (>0.199 ng/mL) was associated with shorter long-term survival (1.25 years) and increased risk of SCD. Great Danes with VAs had shorter survival times (0.97 years). CONCLUSIONS: A cardiac troponin-I concentration is a useful adjunctive screening tool. Elevated cTnI is a negative prognostic indicator.

Statistical Methods Inspired by Challenges in Pediatric Cancer Multi-omics.

Pediatric cancer multi-omics is a uniquely rewarding and challenging domain of biomedical research. Public generosity bestows an abundance of resources for the study of extremely rare diseases; this unique dynamic creates a research environment in which problems with high-dimension and low sample size are commonplace. Here, we present a few statistical methods that we have developed for our research setting and believe will prove valuable in other biomedical research settings as well. The genomic random interval (GRIN) method evaluates the loci and frequency of genomic abnormalities in the DNA of tumors to identify genes that may drive the development of malignancies. The association of lesions with expression (ALEX) method evaluates the impact of genomic abnormalities on the RNA transcription of nearby genes to inform the formulation of biological hypotheses on molecular mechanisms. The projection onto the most interesting statistical evidence (PROMISE) method identifies omic features that consistently associate with better prognosis or consistently associate with worse prognosis across multiple measures of clinical outcome. We have shown that these methods are statistically robust and powerful in the statistical bioinformatic literature and successfully used these methods to make fundamental biological discoveries that have formed the scientific rationale for ongoing clinical trials. We describe these methods and illustrate their application on a publicly available T-cell acute lymphoblastic leukemia (T-ALL) data set. A companion github site ( https://github.com/stjude/TALL-example ) provides the R code and data necessary to recapitulate the example data analyses of this chapter.

Polygenic Pharmacogenomic Markers as Predictors of Toxicity Phenotypes in the Treatment of Acute Lymphoblastic Leukemia: A Single-Center Study.

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most prevalent cause of childhood cancer and requires a long course of therapy consisting of three primary phases with interval intensification blocks. Although these phases are necessary to achieve remission, the primary chemotherapeutic agents have potentially serious toxicities, which may lead to delays or discontinuations of therapy. The purpose of this study was to perform a comprehensive pharmacogenomic evaluation of common antileukemic agents and develop a polygenic toxicity risk score predictive of the most common toxicities observed during ALL treatment. METHODS: This cross-sectional study included 75 patients with pediatric ALL treated between 2012 and 2020 at the University of Florida. Toxicity data were collected within 100 days of initiation of therapy using CTCAE v4.0 for toxicity grading. For pharmacogenomic evaluation, single-nucleotide polymorphisms (SNPs) and genes were selected from previous reports or PharmGKB database. 116 unique SNPs were evaluated for incidence of various toxicities. A multivariable multi-SNP modeling for up to 3-SNP combination was performed to develop a polygenic toxicity risk score of prognostic value. RESULTS: We identified several SNPs predictive of toxicity phenotypes in univariate analysis. Further multivariable SNP-SNP combination analysis suggest that susceptibility to chemotherapy-induced toxicities is likely multigenic in nature. For 3-SNPscore models, patients with high scores experienced increased risk of GI (P = 2.07E-05, 3 SNPs: TYMS-rs151264360/FPGS-rs1544105/GSTM1-GSTM5-rs3754446), neurologic (P = .0005, 3 SNPs: DCTD-rs6829021/SLC28A3-rs17343066/CTPS1-rs12067645), endocrine (P = 4.77E-08, 3 SNPs: AKR1C3-rs1937840/TYMS-rs2853539/CTH-rs648743), and heme toxicities (P = .053, 3 SNPs: CYP3A5-rs776746/ABCB1-rs4148737/CTPS1-rs12067645). CONCLUSION: Our results imply that instead of a single-SNP approach, SNP-SNP combinations in multiple genes in drug pathways increases the robustness of prediction of toxicity. These results further provide promising SNP models that can help establish clinically relevant biomarkers allowing for greater individualization of cancer therapy to maximize efficacy and minimize toxicity for each patient.

Posterior pericardiotomy for the prevention of atrial fibrillation after cardiac surgery: a systematic review and meta-analysis of 25 randomised controlled trials.

BACKGROUND: Atrial fibrillation (AF) associated with postoperative pericardial effusion is the most commonly reported adverse event after cardiac surgery. AIMS: We aimed to determine the role of posterior pericardiotomy in preventing postoperative AF (POAF). METHODS: We searched PubMed, Scopus, Web of Science, Ovid, and EBSCO from inception until 30 June 2022. We included randomised clinical trials (RCTs) that compared posterior pericardiotomy (PP) versus control (no PP) in patients undergoing cardiac surgery. The primary endpoint was the incidence of POAF after cardiac surgery. The secondary endpoints were supraventricular arrhythmias, early/late pericardial effusion, pericardial tamponade, pleural effusion, length of hospital/intensive care unit stay, intra-aortic balloon pump use, revision surgery for bleeding, and mortality. RESULTS: Twenty-five RCTs comprising 4,467 patients were included in this systematic review and meta-analysis. The overall incidence rate of POAF was 11.7% in the PP group compared with 23.67% in the no PP or control group, with a significant decrease in the risk of POAF following PP (odds ratio [OR] 0.49, 95% confidence interval [CI]: 0.38-0.61). Compared with the control group, the risk of supraventricular tachycardia (OR 0.66, 95% CI: 0.43-0.89), early pericardial effusion (OR 0.32, 95% CI: 0.22-0.46), late pericardial effusion (OR 0.15, 95% CI: 0.09-0.25), and pericardiac tamponade (OR 0.18, 95% CI: 0.10-0.33) were lower in the PP group. CONCLUSIONS: PP is an effective intervention for reducing the risk of POAF after cardiac surgery. Also, PP is economically efficient in terms of decreasing the length of hospital stay.

Oncoplastic versus conventional breast-conserving surgery in breast cancer: a pooled analysis of 6941 female patients.

BACKGROUND: Breast cancer is the most prevalent cancer in women. In the past few years, surgical interventions for breast cancer have experienced massive changes from radical excision to conserving approaches. In this study, we aim to compare the two breast surgery interventions, including conventional breast-conserving surgery (CBCS) versus oncoplastic breast-conserving surgery (OPBCS). METHODS: We searched on PubMed, Web of Science (WOS), Scopus, Embase, and Cochrane till 2 October 2021. All relevant randomized controlled trials (RCTs) and observational studies were included. The data were extracted and pooled using Review Manager software (RevMan 5.4). RESULTS: The pooled meta-analysis of the included studies showed that OPBCS was significantly superior to CBCS in most of the outcomes. Re-excision significantly favoured CBCS (RR = 0.49, 95% CI [0.37, 0.63], P < 0.00001). However, local recurrence (RR = 0.55, 95% CI [0.27, 1.09], P = 0.09), close surgical margins (RR = 0.37, 95% CI [0.14, 1.00], P = 0.05) and end up to the risk of mastectomy (RR = 0.73, 95% CI [0.54, 97], P = 0.06) showed no significant difference between both techniques. Notably, while performing a sensitivity analysis, other outcomes as local recurrence, significantly showed favourable results towards OPBCS. In terms of safety outcomes, there was no significant difference between OPBCS and CBCS. CONCLUSION: We recommend the oncoplastic approach rather than the conventional one in females with breast cancer. Re-excision rates showed better results following OPBCS.

SAMHD1 single nucleotide polymorphisms impact outcome in children with newly diagnosed acute myeloid leukemia.

Cytarabine arabinoside (Ara-C) has been the cornerstone of acute myeloid leukemia (AML) chemotherapy for decades. After cellular uptake, it is phosphorylated into its active triphosphate form (Ara-CTP), which primarily exerts its cytotoxic effects by inhibiting DNA synthesis in proliferating cells. Interpatient variation in the enzymes involved in the Ara-C metabolic pathway has been shown to affect intracellular abundance of Ara-CTP and, thus, its therapeutic benefit. Recently, SAMHD1 (SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1) has emerged to play a role in Ara-CTP inactivation, development of drug resistance, and, consequently, clinical response in AML. Despite this, the impact of genetic variations in SAMHD1 on outcome in AML has not been investigated in depth. In this study, we evaluated 25 single nucleotide polymorphisms (SNPs) within the SAMHD1 gene for association with clinical outcome in 400 pediatric patients with newly diagnosed AML from 2 clinical trials, AML02 and AML08. Three SNPs, rs1291128, rs1291141, and rs7265241 located in the 3' region of SAMHD1 were significantly associated with at least 1 clinical outcome: minimal residual disease after induction I, event-free survival (EFS), or overall survival (OS) in the 2 cohorts. In an independent cohort of patients from the COG-AAML1031 trial (n = 854), rs7265241 A>G remained significantly associated with EFS and OS. In multivariable analysis, all the SNPs remained independent predictors of clinical outcome. These results highlight the relevance of the SAMHD1 pharmacogenomics in context of response to Ara-C in AML and warrants the need for further validation in expanded patient cohorts.

Demographic and treatment risk factors of cancer-specific mortality among children and adolescent leukemia patients: a population-based study.

Leukemia is the 15th most commonly diagnosed cancer and the 11th leading cause of cancer mortality. The high mortality rate of leukemia could be attributed to numerous factors. Therefore, we aimed to identify the demographic and treatment risk factors influencing mortality among patients diagnosed with leukemia. Patients' data from 1975 to 2016 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. We used the Person's chi-square test to examine the associations among the categorical variables. Kaplan-Meier and Cox regression were applied for univariate and multivariate analyses. Standardized mortality ratios were utilized to compare the mortality rates of leukemia patients and the general US population. We carried out the statistical analysis using SPSS software. A total of 18,880 patients with leukemia were studied. The leukemia incidence was increased in children than in adolescents. Acute lymphoid leukemia (ALL) was the most common type diagnosed among children and adolescents: 10,331 and 4112 patients, respectively. All mortality ratios were significantly higher in leukemia patients compared to the US population. The risk of mortality among leukemia patients was higher among adolescents, females, Black, urban areas with a 20,000 population, and patients not receiving chemotherapy. In contrast, the mortality risk was decreased in patients with higher family incomes, those not treated with radiation, and diagnosed from 2000 to 2016. In conclusion, Leukemia's incidence increases with time. Adolescents, males, Black, in some urban areas, and patients who have not received chemotherapy had the highest mortality risk among leukemia patients.

Genome-wide CRISPR/Cas9 screen identifies etoposide response modulators associated with clinical outcomes in pediatric AML.

Etoposide is used to treat a wide range of malignant cancers, including acute myeloid leukemia (AML) in children. Despite the use of intensive chemotherapeutic regimens containing etoposide, a significant proportion of pediatric patients with AML become resistant to treatment and relapse, leading to poor survival. This poses a pressing clinical challenge to identify mechanisms underlying drug resistance to enable effective pharmacologic targeting. We performed a genome-wide CRISPR/Cas9 synthetic-lethal screening to identify functional modulators of etoposide response in leukemic cell line and integrated results from CRISPR-screen with gene expression and clinical outcomes in pediatric patients with AML treated with etoposide-containing regimen. Our results confirmed the involvement of well-characterized genes, including TOP2A and ABCC1, as well as identified novel genes such as RAD54L2, PRKDC, and ZNF451 that have potential to be novel drug targets. This study demonstrates the ability for leveraging CRISPR/Cas9 screening in conjunction with clinically relevant endpoints to make meaningful discoveries for the identification of prognostic biomarkers and novel therapeutic targets to overcome treatment resistance.

The genomic landscape of pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.

Novel multi epitope-based vaccine against monkeypox virus: vaccinomic approach.

While mankind is still dealing with the COVID-19 pandemic, a case of monkeypox virus (MPXV) has been reported to the WHO on May 7, 2022. Monkeypox is a viral zoonotic disease that has been a public health threat, particularly in Africa. However, it has recently expanded to other parts of the world, so it may soon become a global issue. Thus, the current work was planned and then designed a multi-epitope vaccine against MPXV utilizing the cell surface-binding protein as a target in order to develop a novel and safe vaccine that can evoke the desirable immunological response. The proposed MHC-I, MHC-II, and B-cell epitopes were selected to design multi-epitope vaccine constructs linked with suitable linkers in combination with different adjuvants to enhance the immune responses for the vaccine constructs. The proposed vaccine was composed of 275 amino acids and was shown to be antigenic in Vaxijen server (0.5311) and non-allergenic in AllerTop server. The 3D structure of the designed vaccine was predicted, refined and validated by various in silico tools to assess the stability of the vaccine. Moreover, the solubility of the vaccine construct was found greater than the average solubility provided by protein-Sol server which indicating the solubility of the vaccine construct. Additionally, the most promising epitopes bound to MHC I and MHC II alleles were found having good binding affinities with low energies ranging between - 7.0 and - 8.6 kcal/mol. According to the immunological simulation research, the vaccine was found to elicit a particular immune reaction against the monkeypox virus. Finally, the molecular dynamic study shows that the designed vaccine is stable with minimum RMSF against MHC I allele. We conclude from our research that the cell surface-binding protein is one of the primary proteins involved in MPXV pathogenesis. As a result, our study will aid in the development of appropriate therapeutics and prompt the development of future vaccines against MPXV.

A ten-gene DNA-damage response pathway gene expression signature predicts gemtuzumab ozogamicin response in pediatric AML patients treated on COGAAML0531 and AAML03P1 trials.

Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody linked to calicheamicin, a DNA damaging agent, and is a well-established therapeutic for treating acute myeloid leukemia (AML). In this study, we used LASSO regression modeling to develop a 10-gene DNA damage response gene expression score (CalDDR-GEx10) predictive of clinical outcome in pediatric AML patients treated with treatment regimen containing GO from the AAML03P1 and AAML0531 trials (ADE + GO arm, N = 301). When treated with ADE + GO, patients with a high CalDDR-GEx10 score had lower complete remission rates (62.8% vs. 85.5%, P = 1.7 7 * 10-5) and worse event-free survival (28.7% vs. 56.5% P = 4.08 * 10-8) compared to those with a low CalDDR-GEx10 score. However, the CalDDR-GEx10 score was not associated with clinical outcome in patients treated with standard chemotherapy alone (ADE, N = 242), implying the specificity of the CalDDR-GEx10 score to calicheamicin-induced DNA damage response. In multivariable models adjusted for risk group, FLT3-status, white blood cell count, and age, the CalDDR-GEx10 score remained a significant predictor of outcome in patients treated with ADE + GO. Our findings present a potential tool that can specifically assess response to calicheamicin-induced DNA damage preemptively via assessing diagnostic leukemic cell gene expression and guide clinical decisions related to treatment using GO.