A survey of k-mer methods and applications in bioinformatics.

The rapid progression of genomics and proteomics has been driven by the advent of advanced sequencing technologies, large, diverse, and readily available omics datasets, and the evolution of computational data processing capabilities. The vast amount of data generated by these advancements necessitates efficient algorithms to extract meaningful information. K-mers serve as a valuable tool when working with large sequencing datasets, offering several advantages in computational speed and memory efficiency and carrying the potential for intrinsic biological functionality. This review provides an overview of the methods, applications, and significance of k-mers in genomic and proteomic data analyses, as well as the utility of absent sequences, including nullomers and nullpeptides, in disease detection, vaccine development, therapeutics, and forensic science. Therefore, the review highlights the pivotal role of k-mers in addressing current genomic and proteomic problems and underscores their potential for future breakthroughs in research.

Child Behavior Problems and Maltreatment Exposure.

OBJECTIVES: Establish the longitudinal cross-lagged associations between maltreatment exposure and child behavior problems to promote screening and the type and timing of interventions needed. METHODS: The Longitudinal Studies of Child Abuse and Neglect, a multiwave prospective cohort study of maltreatment exposure, enrolled children and caregivers (N = 1354) at approximately age 4 and followed them throughout childhood and adolescence. Families completed 7 waves of data collection with each wave occurring 2 years apart. Maltreatment was confirmed using official case records obtained from Child Protective Services. Six-month frequencies of behavior problems were assessed via caregiver-report. Two random-intercept, cross-lagged panel models tested the directional relations between maltreatment exposure and externalizing and internalizing behaviors. RESULTS: Maltreatment exposure predicted increases in externalizing behaviors at ages 8 (b = 1.06; 95% confidence interval [CI] 0.14-1.98), 12 (b = 1.09; 95% CI 0.08-2.09), and 16 (b = 1.67; 95% CI 0.30-3.05) as well as internalizing behaviors at ages 6 (b = 0.66; 95% CI 0.03-1.29), 12 (b = 1.25; 95% CI 0.33-2.17), and 14 (b = 1.92; 95% CI 0.76-2.91). Increases in externalizing behaviors predicted maltreatment exposure at age 12 (odds ratio 1.02; 95% CI 1.00-1.05). CONCLUSIONS: Maltreatment exposure is robustly associated with subsequent child behavior problems, strengthening inferences about the directionality of these relations. Early screening of externalizing behaviors in pediatric settings can identify children likely to benefit from intervention to reduce such behaviors as well as prevent maltreatment exposure at entry to adolescence.

Advances in computational and experimental approaches for deciphering transcriptional regulatory networks: Understanding the roles of cis-regulatory elements is essential, and recent research utilizing MPRAs, STARR-seq, CRISPR-Cas9, and machine learning has yielded valuable insights.

Understanding the influence of cis-regulatory elements on gene regulation poses numerous challenges given complexities stemming from variations in transcription factor (TF) binding, chromatin accessibility, structural constraints, and cell-type differences. This review discusses the role of gene regulatory networks in enhancing understanding of transcriptional regulation and covers construction methods ranging from expression-based approaches to supervised machine learning. Additionally, key experimental methods, including MPRAs and CRISPR-Cas9-based screening, which have significantly contributed to understanding TF binding preferences and cis-regulatory element functions, are explored. Lastly, the potential of machine learning and artificial intelligence to unravel cis-regulatory logic is analyzed. These computational advances have far-reaching implications for precision medicine, therapeutic target discovery, and the study of genetic variations in health and disease.

Incidence of tethered cord syndrome in neurofibromatosis types 1 and 2 pediatric patients: a population-level analysis.

PURPOSE: Tethered spinal cord syndrome (TCS) is characterized by cutaneous attachments on the filum terminale that stretch the spinal cord, leading to musculoskeletal and urogenital sequelae. While the neurocutaneous associations with TCS remain undefined, a recent study reports a high incidence of TCS among a pediatric neurofibromatosis (NF) cohort. This present study utilizes a population-level database to estimate TCS incidence among pediatric patients with neurofibromatosis types 1 and 2 (NF1, NF2). METHODS: The TriNetX Research Network was queried to identify patients diagnosed with NF and/or TCS before the age of 21. Symptomatic TCS requiring surgical intervention was identified using corresponding procedural codes within 12 months following TCS diagnosis. Odds ratios (OR) were calculated to measure the associations of NF1/NF2 with TCS. RESULTS: 19,426 pediatric NF patients were evaluated (NF1: 18,383, NF2: 1042). The average ages of TCS diagnosis among NF1, NF2, and non-NF patients were 12, 16, and 9 years, respectively. The incidence of TCS was 1.2% in NF1 patients and 7.3% in NF2 patients, compared to 0.074% in the general population. The associations of NF incidence with TCS were significantly increased in both NF1 (OR 16.42; 14.38-18.76) and NF2 (OR 105.58; 83.56-133.40) patients compared to the general population. Symptomatic TCS requiring surgical intervention was not significantly associated with NF1/NF2 patients compared to the general TCS population. CONCLUSION: This analysis demonstrates a high incidence of TCS but delayed intervention in pediatric NF patients. Considering TCS counseling, spinal MRI, and earlier intervention may be warranted for NF patients experiencing musculoskeletal symptomatology.

Frequentmers - a novel way to look at metagenomic next generation sequencing data and an application in detecting liver cirrhosis.

Early detection of human disease is associated with improved clinical outcomes. However, many diseases are often detected at an advanced, symptomatic stage where patients are past efficacious treatment periods and can result in less favorable outcomes. Therefore, methods that can accurately detect human disease at a presymptomatic stage are urgently needed. Here, we introduce "frequentmers"; short sequences that are specific and recurrently observed in either patient or healthy control samples, but not in both. We showcase the utility of frequentmers for the detection of liver cirrhosis using metagenomic Next Generation Sequencing data from stool samples of patients and controls. We develop classification models for the detection of liver cirrhosis and achieve an AUC score of 0.91 using ten-fold cross-validation. A small subset of 200 frequentmers can achieve comparable results in detecting liver cirrhosis. Finally, we identify the microbial organisms in liver cirrhosis samples, which are associated with the most predictive frequentmer biomarkers.

Simultaneous versus staged bilateral carpal tunnel release via open and endoscopic surgeries: a retrospective propensity score-matched patient comorbidity analysis.

OBJECTIVE: Carpal tunnel syndrome (CTS) presents bilaterally in nearly 60%-70% of affected patients. Bilateral carpal tunnel release (CTR) can be performed in a staged or simultaneous fashion. There remains a limited understanding of the optimal preoperative factors to use for patient selection when determining simultaneous versus staged bilateral CTR. Moreover, it is unclear how these factors influence postoperative outcomes. In this study, the authors aimed to identify and compare preoperative comorbidities and postoperative outcomes in patients who had undergone simultaneous versus staged open and endoscopic bilateral CTR. METHODS: The authors performed a retrospective analysis of data collected from the TriNetX database. Patients with bilateral CTS who had been treated from February 1, 2002, to February 1, 2022, were dichotomized by their bilateral release approach: simultaneous or staged within 3 months. The resulting groups were analyzed separately by open versus endoscopic techniques. Next, cohorts were analyzed for preoperative comorbidities to identify possible factors for surgical determination. Then, they were propensity score matched on demographics and comorbidities. Postoperative outcomes within 6 months of surgery were measured with and without matching. RESULTS: After matching, 9286 and 3709 patients remained in the open and endoscopic groups, respectively. Those who had undergone staged surgeries via an open or endoscopic approach had more preoperative comorbidities. After matching, staged open release was associated with significantly higher rates of postprocedural care, hand/joint pain, limb pain, trigger finger, and upper respiratory tract infections. Simultaneous open release was associated with higher rates of emergency room visits. Staged endoscopic release was associated with significantly higher rates of postprocedural care, limb pain, and trigger finger. No significant outcomes were favored in the simultaneous endoscopic group. CONCLUSIONS: Before matching, patients who had undergone staged CTR had significantly higher rates of preoperative medical comorbidities compared with patients in the simultaneous CTR group. Moreover, staged CTR was significantly associated with higher rates of postoperative complications. After matching on demographics and comorbidities, staged CTR was still associated with higher rates of postoperative complications, suggesting that preoperative comorbidities do not influence postoperative outcome. Further prospective studies could be used to validate these results and provide new findings for the management and treatment of these groups.

Eligibility for screening with low-dose CT in a real-world cohort of patients with lung cancer in Greece: A brief report.

INTRODUCTION: NELSON and NLST prompted the implementation of lung cancer screening programs in the United States followed by several European countries. This study aimed to assess the sensitivity of different screening criteria among patients with lung cancer in Greece and investigate reasons for ineligibility. METHODS: We performed a retrospective analysis on patients with lung cancer referred to the largest referral center in Athens, Greece, between June 2014 and May 2023. The proportion of patients who would meet the updated USPSTF and NLST criteria was compared to the corresponding proportion of the Greek population over 15 years of age. RESULTS: Out of 2434 patients with lung cancer, 77.4 % (N = 1883) would meet the updated USPSTF criteria, and 58.9 % (N = 1439) would meet the NLST criteria at diagnosis; the corresponding proportions for the Greek population over 15 years would be 13.8 % and 8.2 %, respectively. Ineligible patients were more likely to be female, former or never-smokers, have adenocarcinoma histology, and have driver mutations (p < 0.001). CONCLUSIONS: Although the updated USPSTF criteria demonstrated good sensitivity, a substantial proportion of patients with lung cancer would still not be eligible for screening. Future studies to shape a comprehensive screening strategy should focus on the incorporation of additional risk factors for lung cancer, including air pollution and individual genetic susceptibility.

The association of epigenetic age acceleration and depressive and anxiety symptom severity among children recently exposed to substantiated maltreatment.

Child maltreatment is a major risk factor for both depressive and anxiety disorders. However, many children exposed to maltreatment never meet diagnostic threshold for either disorder while experiencing only transitory symptoms post-exposure. Recent research suggests DNA methylation adds predictive value in explaining variation in the onset and course of multiple psychiatric disorders following exposure to child maltreatment. Epigenetic age acceleration (EAA), the biological aging of cells not attributable to chronological aging, is a stress-sensitive biomarker capturing genome-wide variation in DNA methylation with the potential to identify children who have been maltreated at greatest risk for depressive and anxiety disorders. The current study examined two EAA clocks appropriate for the pediatric population, the Horvath and Pediatric Buccal Epigenetic (PedBE) clocks, and their associations with depressive and anxiety symptom severity following child maltreatment. Children (N = 71) 8-15 years of age, all of whom were exposed to substantiated child maltreatment in the 12 months prior to study entry, were enrolled. Risk modeling adjusting for several confounders revealed that EAA estimated via the Horvath clock was significantly associated with more severe depressive and anxiety symptoms. The PedBE clock was not associated with either depressive or anxiety symptom severity. Sensitivity analyses demonstrated that EAA via the Horvath clock robustly predicted depressive and anxiety symptom severity across multiple modeling scenarios. Our findings advance existing research suggesting EAA, as estimated with the Horvath clock, may be a promising biomarker for identifying children at greatest risk for more severe depressive and anxiety symptoms following maltreatment.

The Efficacy of Tumor Mutation Burden as a Biomarker of Response to Immune Checkpoint Inhibitors.

Cancer is one of the leading causes of death in the world; therefore, extensive research has been dedicated to exploring potential therapeutics, including immune checkpoint inhibitors (ICIs). Initially, programmed-death ligand-1 was the biomarker utilized to predict the efficacy of ICIs. However, its heterogeneous expression in the tumor microenvironment, which is critical to cancer progression, promoted the exploration of the tumor mutation burden (TMB). Research in various cancers, such as melanoma and lung cancer, has shown an association between high TMB and response to ICIs, increasing its predictive value. However, the TMB has failed to predict ICI response in numerous other cancers. Therefore, future research is needed to analyze the variations between cancer types and establish TMB cutoffs in order to create a more standardized methodology for using the TMB clinically. In this review, we aim to explore current research on the efficacy of the TMB as a biomarker, discuss current approaches to overcoming immunoresistance to ICIs, and highlight new trends in the field such as liquid biopsies, next generation sequencing, chimeric antigen receptor T-cell therapy, and personalized tumor vaccines.

Strand asymmetries across genomic processes.

Across biological systems, a number of genomic processes, including transcription, replication, DNA repair, and transcription factor binding, display intrinsic directionalities. These directionalities are reflected in the asymmetric distribution of nucleotides, motifs, genes, transposon integration sites, and other functional elements across the two complementary strands. Strand asymmetries, including GC skews and mutational biases, have shaped the nucleotide composition of diverse organisms. The investigation of strand asymmetries often serves as a method to understand underlying biological mechanisms, including protein binding preferences, transcription factor interactions, retrotransposition, DNA damage and repair preferences, transcription-replication collisions, and mutagenesis mechanisms. Research into this subject also enables the identification of functional genomic sites, such as replication origins and transcription start sites. Improvements in our ability to detect and quantify DNA strand asymmetries will provide insights into diverse functionalities of the genome, the contribution of different mutational mechanisms in germline and somatic mutagenesis, and our knowledge of genome instability and evolution, which all have significant clinical implications in human disease, including cancer. In this review, we describe key developments that have been made across the field of genomic strand asymmetries, as well as the discovery of associated mechanisms.

Expedited Surgical Care of Appendicitis is Associated With Improved Resource Utilization.

INTRODUCTION: Appendectomy for acute appendicitis is the most common pediatric intra-abdominal operation. Current literature supports the notion that modest in-hospital, preoperative delays are not associated with greater patient morbidity. However, there is less certainty regarding the role that hour-of-presentation plays in determining the timing of surgery. Thus, we aimed to evaluate how after-hours presentation may relate to the timing of surgery and to assess the outcomes and resource utilization associated with expedited appendectomy compared to nonexpedited. METHODS: Patient records for children who underwent an appendectomy at a freestanding pediatric hospital from 2015 to 2019 were reviewed. Business hour presentations were defined as arrival at the emergency department from 7 AM to 6 PM. Primary outcomes were hospital length of stay (LOS), cost derived from the Pediatric Health Information System database, perforation, surgical complications, and 30-day readmissions. RESULTS: Nine hundred forty-two patients underwent appendectomy over the study period. The median time to OR was 2.0 h in the expedited cohort and 9.8 h in the nonexpedited group. Presentation during business hours was associated with 4.4 higher odds (P < 0.001) of expedited workflow. Expedited appendectomies were associated with shorter hospital LOS (11.5 h, P < 0.001), less costly admissions ($1,155, P < 0.001); LOS measured in midnights, perforation and readmission rates were similar between groups. CONCLUSIONS: We found reduced resource utilization associated with expedited appendectomy. Additionally, the demonstrated association between the time of presentation to the emergency department (ED) and the timing of surgery may be utilized to inform staffing and resource deployment decisions. Further research regarding the generalizability and sustainability of an expedited presurgical workflow in pediatric appendectomy is certainly indicated.

To wrap or not to wrap: A retrospective review of circumcision dressing and post-procedural bleeding.

INTRODUCTION: Bleeding is an infrequent, but important, complication after circumcision. Our aim was to examine postoperative bleeding events after circumcision comparing patients managed with a circumferential wrap to ointment alone. METHODS: Boys ≤18 years of age who underwent circumcision at a tertiary children's hospital were retrospectively reviewed between 2017 and 2018. Postoperative bleeding was defined by phone calls, clinic or Emergency Department visits, or return to the operating room. Outcomes were examined by univariate association and multivariable modeling. RESULTS: Of 681 boys undergoing circumcision, 503 (74%) patients received a wrap dressing and 178 (26%) only ointment. There were 28 (4%) patients who had a postoperative bleeding event: 14/503 (2.7%) among wrap dressings and 14/178 (7.8%) among ointment alone (p < 0.01). The majority of events were phone calls related to bleeding (75%). Univariate analysis demonstrated no association between postoperative bleeding and surgeon specialty (p = 0.72), age at circumcision (p = 0.44) or technique type (p = 0.09). After controlling for age, technique type, and surgeon specialty, dressing type remained significantly associated with postoperative bleeding (OR = 2.81, p < 0.01). CONCLUSION: This single-center, retrospective review found circumferential wrap dressings are associated with a decrease in bleeding events after circumcision. LEVEL OF EVIDENCE: III - retrospective case-control study.