Predictive Value of C-reactive Protein in the Spontaneous Passage of Lower Ureteric Stones: A Prospective Single-Centre Study.

INTRODUCTION: Ureteric stones, characterised by their presence in the ureter, present a common yet often painful urological condition requiring timely intervention. As C-reactive protein (CRP) emerges as a potential biomarker, its correlation with the spontaneous stone passage (SSP) offers valuable insights into patient management and treatment strategies. The present study aimed to assess if CRP levels can predict SSP in symptomatic lower ureteric calculi of size 5 mm-10 mm. MATERIALS AND METHODS: This prospective observational study, conducted at the Indira Gandhi Institute of Medical Sciences in Patna, India, from July 2022 to June 2023, focused on individuals aged 13 to 60 years presenting with ureteric colic and single distal ureteral stones (5 mm-10 mm). Patients underwent comprehensive initial assessment and monitoring, including diagnostic procedures such as a complete blood count, urinalysis, CRP levels, and renal function evaluations. Treatment consisted of hydration encouragement, tamsulosin (0.4 mg) daily administration, and diclofenac (50 mg) as needed. Follow-up assessments at one-month post-treatment involved clinical examination and imaging studies to evaluate treatment efficacy. RESULTS: This study analysed 157 patients with ureteric stones, finding that 76% experienced SSP. Lower CRP levels (≤6 mg/L), along with other laboratory parameters like low white blood cell counts, low neutrophil levels, absence of leukocyturia, absence of hematuria, and lower urine specific gravity, were associated with higher SSP rates. C-reactive protein levels ≤6 mg/L emerged as a strong predictor of SSP in multiple regression analysis. CONCLUSION: The findings underscore the potential utility of CRP as a predictive biomarker in guiding the management and treatment strategies for ureteric stones.

Assessing myBaits Target Capture Sequencing Methodology Using Short-Read Sequencing for Variant Detection in Oat Genomics and Breeding.

The integration of target capture systems with next-generation sequencing has emerged as an efficient tool for exploring specific genetic regions with a high resolution and facilitating the rapid discovery of novel alleles. Despite these advancements, the application of targeted sequencing methodologies, such as the myBaits technology, in polyploid oat species remains relatively unexplored. In this study, we utilized the myBaits target capture method offered by Daicel Arbor Biosciences to detect variants and assess their reliability for variant detection in oat genomics and breeding. Ten oat genotypes were carefully chosen for targeted sequencing, focusing on specific regions on chromosome 2A to detect variants. The selected region harbors 98 genes. Precisely designed baits targeting the genes within these regions were employed for the target capture sequencing. We employed various mappers and variant callers to identify variants. After the identification of variants, we focused on the variants identified via all variants callers to assess the applicability of the myBaits sequencing methodology in oat breeding. In our efforts to validate the identified variants, we focused on two SNPs, one deletion and one insertion identified via all variant callers in the genotypes KF-318 and NOS 819111-70 but absent in the remaining eight genotypes. The Sanger sequencing of targeted SNPs failed to reproduce target capture data obtained through the myBaits technology. Similarly, the validation of deletion and insertion variants via high-resolution melting (HRM) curve analysis also failed to reproduce target capture data, again suggesting limitations in the reliability of the myBaits target capture sequencing using short-read sequencing for variant detection in the oat genome. This study shed light on the importance of exercising caution when employing the myBaits target capture strategy for variant detection in oats. This study provides valuable insights for breeders seeking to advance oat breeding efforts and marker development using myBaits target capture sequencing, emphasizing the significance of methodological sequencing considerations in oat genomics research.

Systematic large-scale application of ClinGen InSiGHT APC -specific ACMG/AMP variant classification criteria substantially alleviates the burden of variants of uncertain significance in ClinVar and LOVD databases.

Background: Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUS), APC-specific ACMG/AMP variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP). Methods: A streamlined algorithm using the APC -specific criteria was developed and applied to assess all APC variants in ClinVar and the InSiGHT international reference APC LOVD variant database. Results: A total of 10,228 unique APC variants were analysed. Among the ClinVar and LOVD variants with an initial classification of (Likely) Benign or (Likely) Pathogenic, 94% and 96% remained in their original categories, respectively. In contrast, 41% ClinVar and 61% LOVD VUS were reclassified into clinically actionable classes, the vast majority as (Likely) Benign. The total number of VUS was reduced by 37%. In 21 out of 36 (58%) promising APC variants that remained VUS despite evidence for pathogenicity, a data mining-driven work-up allowed their reclassification as (Likely) Pathogenic. Conclusions: The application of APC -specific criteria substantially reduced the number of VUS in ClinVar and LOVD. The study also demonstrated the feasibility of a systematic approach to variant classification in large datasets, which might serve as a generalisable model for other gene-/disease-specific variant interpretation initiatives. It also allowed for the prioritization of VUS that will benefit from in-depth evidence collection. This subset of APC variants was approved by the VCEP and made publicly available through ClinVar and LOVD for widespread clinical use.

Drug carrier wonders: Synthetic strategies of zeolitic imidazolates frameworks (ZIFs) and their applications in drug delivery and anti-cancer activity.

With the rapid advancement of nanotechnology, stimuli-responsive nanomaterials have emerged as a feasible choice for the designing of controlled drug delivery systems. Zeolitic imidazolates frameworks are a subclass of Metal-organic frameworks (MOFs) that are recognized by their excellent porosity, structural tunability and chemical modifications make them promising materials for loading targeted molecules and therapeutics agents. The biomedical industry uses these porous materials extensively as nano-carriers in drug delivery systems. These MOFs not only possess excellent targeted imaging ability but also cause the death of tumor cells drawing considerable attention in the current framework of anticancer drug delivery systems. In this review, the outline of stability, porosity, mechanism of encapsulation and release of anticancer drug have been reported extensively. In the end, we also discuss a brief outline of current challenges and future perspectives of ZIFs in the biomedical world.

Molecular characterization of human adenoviruses associated with pediatric respiratory infections in Karachi, Pakistan.

Human adenoviruses (HAdVs) are a diverse group of viruses associated with respiratory infections in humans worldwide. However, there is a lack of research on the genetic diversity and epidemiology of HAdVs in Pakistan. This study characterized HAdVs in pediatric patients with respiratory tract infections in Karachi, Pakistan, between 2022 and 2023. We analyzed 762 nasopharyngeal samples of children ≤ 5 years. DNA extraction, followed by PCR targeting E2B and hexon genes, was carried out. Data analysis was performed on SPSS 25.0, and phylogenetic analysis of hexon gene was performed on MEGA 11. HAdV was detected in 7.34% (56/762) of patients round the year, but at a significantly higher rate during the winter season. Age was insignificantly associated with HAdV incidence (p = 0.662), but more than 62.5% (35/56) of positive cases were younger than 10 months. The circulating HAdVs were identified as six different types from species B (78.57%) and C (21.42%), with the majority of isolates found to be like B3. HAdV was found to be co-infected with bocavirus (5.4%) and measles (7.14%). These findings revealed a high frequency and genetic diversity of respiratory HAdVs in Karachi, Pakistan. We conclude that periodic and continuous surveillance of adenoviruses and other respiratory pathogens is necessary to improve the prognosis and management of respiratory diseases, thereby reducing the child mortality rate in Pakistan.

Comprehensive Surgical Audit of Live-Related Donor Nephrectomy: Procedural Parameters, Demographics, Health Assessments, Complications, and Postoperative Outcomes.

BACKGROUND AND OBJECTIVES: End-stage renal disease (ESRD) rates are on the rise globally, including in India. However, the affordability of dialysis treatment remains a significant challenge for many, with costs varying across different regions. Although cost-effective, kidney transplantation faces challenges like a surgeon shortage, lack of infrastructure, and lack of logistic support. The study examines Indian laparoscopic nephrectomy outcomes and their benefits for donor recovery. It covers kidney donor procedural details, demographics, preoperative health evaluations, complications, and one-month follow-up. METHODS: Ethical approval was obtained, and the study involved 102 cases at the Indira Gandhi Institute of Medical Science, Patna, Bihar, India, from 2019 to 2023. Detailed preoperative assessments, postoperative complications, and one-month follow-up analyses were conducted. Statistical analysis employed SPSS version 17 (IBM Corp., Armonk, NY). RESULTS: The results revealed an average surgery time of 152.3 min, blood loss of 205 ± 42 ml, and a hospital stay of 4.6 ± 2.2 days. The study found a female predominance (80.39%), with a mean donor age of 35.9 ± 5.2 years. Preoperative assessments showed robust patient health, with glomerular filtration rate (GFR) exceeding the expected threshold and normal urea levels, creatinine, electrolytes, liver enzymes, bilirubin, albumin, and total protein. Post-nephrectomy complications were reported, with females experiencing more difficulties than males. CONCLUSION: This study underscores the efficiency and safety of laparoscopic nephrectomy in the Indian context, providing valuable insights into donor demographics, preoperative health assessments, complications, and postoperative outcomes. The findings contribute to understanding laparoscopic nephrectomy outcomes and associated risk factors despite certain limitations.

Cognitive behaviour therapy as an evidence-based intervention for opioid use disorder: A systematic review.

Objective: To explore the effectiveness of cognitive behaviour therapy as an evidence-based intervention for patients with opioid use disorder and to estimate the effect of cognitive behaviour therapy in mental health care settings. METHODS: The systematic review was conducted from January to April 2023, and comprised search on Web of Science, PsycINFO, Medline, Embase, Google Scholar, Science Direct, PubMed, ClinicalTrials and OvidSP databases for experimental studies and randomised controlled trials related to opioid use disorders published in peer-reviewed English-language journals between December 2022 and April 2023. The studies' quality was assessed using the Modified Cochrane Collaboration risk of the bias assessment criteria. RESULTS: Of the 314 studies initially identified, 42(13%) were subjected to full-text assessment, and 10(23.8%) were analysed. There were 5(50%) studies done in the United States, 2(20%) in Iran, and 1(10%) each in Germany, China and England. All 10(100%) studies were randomised controlled trials with intervention-based cognitive behaviour therapy, and reported significant results in patients diagnosed with opioid use disorders. Conclusion: All the studies analysed were heterogeneous. Cognitive behaviour therapy had a short-term impact and remained influential in the long term as well in handling cognitive and behaviour setbacks among patients with opioid use disorders.

A Systematic Review on the Mental Health Status of Patients Infected With Monkeypox Virus.

Objectives: This study aims to extract and summarize the literature on the mental health status of patients with monkeypox. Methods: This review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using different databases and publishers such as Scopus, Sage, ScienceDirect, PubMed, BMJ, Wiley Online Library, Wolters Kluwer OVID-SP, and Google Scholar. The literature review was based on monkeypox and mental health. The year of publication was 2021-2023, during the monkeypox disease period. Data were extracted from opinions, editorials, empirical studies, and surveys. Results: Based on the literature related to the mental status of patients with monkeypox, the following themes and subthemes were identified: anxiety and depression, self-harm and suicidal tendencies, neuropsychiatric symptoms, mental health, social stigma, sex workers, vaccination, and stress-related diseases. Conclusion: A review of monkeypox virus infection studies reveals that 25%-50% of patients experience anxiety and depression due to isolation, boredom, and loneliness. Factors such as infected people, a lack of competence among healthcare professionals, and shame over physical symptoms exacerbate mental insults. The implications of society include increased self-harm, suicide, low productivity, fear of stigmatization, and transmission of infection.

Towards classification and comprehensive analysis of AI-based COVID-19 diagnostic techniques: A survey.

The unpredictable pandemic came to light at the end of December 2019, known as the novel coronavirus, also termed COVID-19, identified by the World Health Organization (WHO). The virus first originated in Wuhan (China) and rapidly affected most of the world's population. This outbreak's impact is experienced worldwide because it causes high mortality risk, many cases, and economic falls. Around the globe, the total number of cases and deaths reported till November 12, 2022, were >600 million and 6.6 million, respectively. During the period of COVID-19, several diverse diagnostic techniques have been proposed. This work presents a systematic review of COVID-19 diagnostic techniques in response to such acts. Initially, these techniques are classified into different categories based on their working principle and detection modalities, i.e. chest X-ray imaging, cough sound or respiratory patterns, RT-PCR, antigen testing, and antibody testing. After that, a comparative analysis is performed to evaluate these techniques' efficacy which may help to determine an optimum solution for a particular scenario. The findings of the proposed work show that Artificial Intelligence plays a vital role in developing COVID-19 diagnostic techniques which support the healthcare system. The related work can be a footprint for all the researchers, available under a single umbrella. Additionally, all the techniques are long-lasting and can be used for future pandemics.

Scald resistance in hybrid rye (Secale cereale): genomic prediction and GWAS.

Rye (Secale cereale L.) is an important cereal crop used for food, beverages, and feed, especially in North-Eastern Europe. While rye is generally more tolerant to biotic and abiotic stresses than other cereals, it still can be infected by several diseases, including scald caused by Rhynchosporium secalis. The aims of this study were to investigate the genetic architecture of scald resistance, to identify genetic markers associated with scald resistance, which could be used in breeding of hybrid rye and to develop a model for genomic prediction for scald resistance. Four datasets with records of scald resistance on a population of 251 hybrid winter rye lines grown in 2 years and at 3 locations were used for this study. Four genomic models were used to obtain variance components and heritabilities of scald resistance. All genomic models included additive genetic effects of the parental components of the hybrids and three of the models included additive-by-additive epistasis and/or dominance effects. All models showed moderate to high broad sense heritabilities in the range of 0.31 (SE 0.05) to 0.76 (0.02). The model without non-additive genetic effects and the model with dominance effects had moderate narrow sense heritabilities ranging from 0.24 (0.06) to 0.55 (0.08). None of the models detected significant non-additive genomic variances, likely due to a limited data size. A genome wide association study was conducted to identify markers associated with scald resistance in hybrid winter rye. In three datasets, the study identified a total of twelve markers as being significantly associated with scald resistance. Only one marker was associated with a major quantitative trait locus (QTL) influencing scald resistance. This marker explained 11-12% of the phenotypic variance in two locations. Evidence of genotype-by-environment interactions was found for scald resistance between one location and the other two locations, which suggested that scald resistance was influenced by different QTLs in different environments. Based on the results of the genomic prediction models and GWAS, scald resistance seems to be a quantitative trait controlled by many minor QTL and one major QTL, and to be influenced by genotype-by-environment interactions.

Urinary Tract Infections in Patients Undergoing Invasive Urodynamic Study: A Prospective Observational Study at a Tertiary Care Centre in Eastern India.

OBJECTIVE: The aim of the study was to find the estimate of the prevalence of urinary tract infections following invasive urodynamic studies (UDS) in a hospital setup and to identify the risk factors related to it. METHOD: A total of 100 patients were enrolled in this prospective observational study after standard preoperative work, which included both urine analysis and culture procedure. The study was carried out from April 2022 to April 2023 at the Department of Urology, Indira Gandhi Institute of Medical Sciences, India. Three days following the UDS test, all the patients underwent repeat urine analysis and culture, besides screening for any lower urinary tract symptoms, abdominal pain, and fever. RESULT: Among all, 14 patients (i.e., 6.1% of 85 individuals) had significant bacteriuria, and six patients (4.7%) developed symptoms of UTI. However, a strong association was observed between the maximal detrusor pressure during voiding (Pdet at Q max) and post-void residue (PVR), which were >20 mL before UDS, along with positive urine cultures after UDS, which was significant at <0.05. CONCLUSION: The study demonstrated that the risk of UTIs with this diagnostic technique is minimal and that prophylactic antibiotic medication is not necessary prior to UDS in all patients.

One pot application of a green chemistry-based finish for cotton fabric, providing hydrophobic, flame retardant, and antimicrobial properties.

Fluorinated and formaldehyde-based compounds impart excellent hydrophobicity and flame-retardant properties to cotton fabrics. However, they come with various health and environmental risks. A novel hydrophobic, flame retardant, and antimicrobial finishing agent free from fluorine and formaldehyde was synthesized. The diammonium phosphate octadecyl citrate (DAPOC) was synthesized by using stearic acid (octadecanoic acid), citric acid (propane-1,2,3-tricarboxylic acid), and diammonium hydrogen phosphate. It was grafted onto the cotton fabrics by employing the conventional pad-dry-cure method. The results indicated that this newly developed finish could be chemically bonded to cotton fabrics through C-O-C covalent bonds. The contact angle of the cotton fabric finished with a 12% concentration of the finishing agent reached 151.9°. Additionally, the finished cotton fabrics displayed evident flame-retardant properties. After undergoing 20 laundering cycles, DAPOC maintained strong hydrophobic and flame-retardant characteristics, demonstrating its durability. The chemical structure of DAPOC was verified by nuclear magnetic resonance spectroscopy (1H-NMR). The thermogravimetric analysis confirmed the flame-retardant nature of the treated cotton fabric samples. Scanning electron microscopy (SEM), Energy dispersive X-ray analysis (EDX), and Fourier-transform infrared spectroscopy (FTIR) results demonstrated the successful grafting of the newly created finish onto the cotton fiber. X-ray diffraction (XRD) spectra depicted that the crystalline structure of finished cotton fabric remained mostly unaltered. Furthermore, the finished cotton fabric exhibited commendable antimicrobial properties due to the inclusion of citric acid.

Factors affecting the efficiency of equine embryo transfer (EET) in polo mares under subtropical conditions of Pakistan.

Equine embryo transfer (EET) is a prominent technology in the equine breeding industry, and its efficacy is affected by a number of factors. The current study aimed to determine the effects of the breed of donor/recipient mares, estrus/ovulation induction treatment, cooled transportation of embryos, and synchrony between donor and recipient mares on the efficiency of the EET under subtropical conditions of Pakistan. A total of eighty-four (n = 84) Polo-playing donor mares (Argentino-polo = 41 and Anglo-Arab = 43) and seventy (n = 70) recipient mares (light breed = 26 and heavy breed = 44) were used for EET. The donor mares exhibiting natural estrus (n = 28) were detected by teaser a stallion, and corpus luteum (CL) having mares (n = 56) were treated with prostaglandin (150 µg of Cloprostenol) for estrus induction. The mares' follicular growth was monitored through ultrasonography until the dominant follicle's size reached 35 mm or more with a moderate to obvious uterine edema score. Afterward, the mares were treated either with GnRH, i.e., 50 µg of Lecirelin acetate (n = 41) or Ovusyn, i.e., 1500 IU hCG (n = 43). Insemination with chilled semen was performed 24 hours later. The embryos were collected non-surgically, 7 or 8 days after ovulation, from the donor mares. The collected embryos were transferred into the well-synchronized recipient mares as fresh (n = 44) or chilled (n = 26) embryos. The pregnancy after ET was checked through ultrasonography. Statistical analysis revealed that the embryo recovery rate (ERR) remained significantly higher (P<0.05) for the Prostaglandin (PG) treated group of donors as compared to the natural heat group of donors. The breed of donor mares, type of ovulatory treatment given, and day of embryo collection did not significantly (P>0.05) affect the ERR. There was no significant effect of the type (fresh vs chilled), classification, and stage of development of embryo on pregnancy outcomes (P>0.05). ET pregnancy rate was significantly affected by the breed of recipient mares and ovulation synchrony between donor and recipient mares (P<0.05). In conclusion, under the subtropical conditions of Pakistan, PG-based estrus induction of donor mares, breed of recipient mares, and ovulation synchrony between the donor and recipient mares had a substantial effect on the efficiency of EET.

Intratumoral presence of the genotoxic gut bacteria pks+ E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer.

BACKGROUND: This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks+ Escherichia coli (pks+E.coli+), pks+E.coli- (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum). METHODS: We screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR. RESULTS: Pks+E.coli+ was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks+E.coli+ and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks+E.coli- (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01). CONCLUSION: Intratumoral pks+E.coli+ but not pks+E.coli- are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause.

Context-dependent accuracy of the cobas plasma separation card for HCV RNA viral load measurement.

Collection and preservation of plasma are challenging in remote or under-resourced settings. The cobas® Plasma Separation Card (PSC) is an alternative specimen type for blood-borne pathogen nucleic acid quantitation. We assessed PSC as a specimen type for HCV RNA quantitation in Pakistan. Plasma from venous blood and PSC from finger prick blood were prepared at two sites: Site 1 (in Lahore, n = 199) consisted of laboratory-based outpatient clinics. Specimens were prepared in the same facility and stored frozen. Site 2 was a catchment area within a resource-limited, semi-urban locality of Islamabad with limited access to healthcare services (n = 151). Community public health outreach staff collected blood and prepared the PSC in the participants' homes. Specimens were transported to the central hepatitis laboratory in Lahore to be stored frozen until tested. HCV RNA testing was performed using the cobas HCV RNA test in a central laboratory. Concordance with respect to RNA detectability was high at Site 1 (97.4%), but lower at Site 2 (82.4%). At Site 1, HCV viral load in plasma and PSC were well correlated across the linear range with a 0.21 log10 IU/mL mean bias toward higher concentrations in PSC. At Site 2, HCV viral load in plasma and PSC were poorly correlated. There was a 0.11 log10 IU/mL mean bias toward higher concentrations in PSC. PSC performance can be excellent in underserved settings where refrigerated transport of traditional specimens is difficult. In very challenging field settings, extra support must be provided to ensure correct specimen collection and handling.

Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival.

Background and Aims: The microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain of Escherichia coli harboring the pks island that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown. Methods: SBS88-positive CRCs were identified from targeted sequencing data from 5,292 CRCs from 17 studies and tested for their association with clinico-pathological features, oncogenic pathways, genomic characteristics and survival. Results: In total, 7.5% (398/5,292) of the CRCs were SBS88-positive, of which 98.7% (392/398) were microsatellite stable/microsatellite instability low (MSS/MSI-L), compared with 80% (3916/4894) of SBS88 negative tumors (p=1.5x10-28). Analysis of MSS/MSI-L CRCs demonstrated that SBS88 positive CRCs were associated with the distal colon (OR=1.84, 95% CI=1.40-2.42, p=1x10-5) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6x10-6) tumor sites compared with the proximal colon. The top seven recurrent somatic mutations associated with SBS88-positive CRCs demonstrated mutational contexts associated with colibactin-induced DNA damage, the strongest of which was the APC:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3x10-80). Large copy number alterations (CNAs) including CNA loss on 14q and gains on 13q, 16q and 20p were significantly enriched in SBS88-positive CRCs. SBS88-positive CRCs were associated with better CRC-specific survival (p=0.007; hazard ratio of 0.69, 95% CI=0.52-0.90) when stratified by age, sex, study, and by stage. Conclusion: SBS88-positivity, a biomarker of colibactin-induced DNA damage, can identify a novel subtype of CRC characterized by recurrent somatic mutations, copy number alterations and better survival. These findings provide new insights for treatment and prevention strategies for this subtype of CRC.

Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family.

Genetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1, a gene associated with breast and ovarian cancer and RNF43, a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998-2008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variant BRCA1:c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant RNF43:c.988 C > T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of the RNF43 variant met the 2019 World Health Organization (WHO2019) criteria for SPS, developing a BRAF p.V600 wildtype CRC. Loss of the wildtype allele for both BRCA1 and RNF43 variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our findings show digenic inheritance of pathogenic variants in BRCA1 and RNF43 segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.

Gene-specific ACMG/AMP classification criteria for germline APC variants: Recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel.

PURPOSE: The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and the Clinical Genome Resource, who set out to develop recommendations for the interpretation of germline APC variants underlying Familial Adenomatous Polyposis, the most frequent hereditary polyposis syndrome. METHODS: Through a rigorous process of database analysis, literature review, and expert elicitation, the APC VCEP derived gene-specific modifications to the ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) variant classification guidelines and validated such criteria through the pilot classification of 58 variants. RESULTS: The APC-specific criteria represented gene- and disease-informed specifications, including a quantitative approach to allele frequency thresholds, a stepwise decision tool for truncating variants, and semiquantitative evaluations of experimental and clinical data. Using the APC-specific criteria, 47% (27/58) of pilot variants were reclassified including 14 previous variants of uncertain significance (VUS). CONCLUSION: The APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25). Moving forward, the APC VCEP will continue to interpret prioritized lists of VUS, the results of which will represent the most authoritative variant classification for widespread clinical use.

Synthesis, characterization, computational assay and anti-inflammatory activity of thiosemicarbazone derivatives: Highly potent and efficacious for COX inhibitors.

Multiple studies in the literature have demonstrated that synthetic compounds containing heterocyclic rings possess a reparative potential against acute and chronic inflammation. In the present study, two novel thiosemicarbazone derivatives based on l-ethyl-6-(thiophen-2-yl)indoline-2,3-dione with different phenyl substituted thiosemicarbazides were synthesized by condensation reaction and the structures of proposed target compounds (KP-2 and KP-5) were confirmed by UV-VIS, FTIR, 1H-NMR and 13C-NMR. In-vitro anti-inflammatory behavior of KP-2 and KP-5 was confirmed by bovine serum albumin (BSA) and ovine serum albumin (OSA) analysis. Acute and chronic anti-inflammatory potential of synthesized compounds were evaluated by using carrageenan and complete Freund's adjuvant (CFA) as inflammation-inducing agents, respectively. Inhibition of pro-inflammatory mediators and prevention of protein denaturation owing to synchronization of more electronegative flouro-groups substituted on phenyl rings along with heterocyclic indoline ring provides anti-inflammatory effects and are corroborated by radiological, histopathological analysis. Additional support was provided through density functional theory (DFT) and molecular docking. KP-5 exhibited excellent lead-likeness based on its physicochemical parameters, making it a viable drug candidate. The synthesized compounds also showed promising ADMET properties, enhancing their potential as therapeutic agents. These findings emphasize the pivotal role of new compounds for drug design and development.

A cost effective communication model for requirements elicitation in global software development.

Requirement elicitation stands as a pivotal activity within requirement engineering, gaining even greater significance in the context of global software development. Effective communication among stakeholders assumes paramount importance in this arena. Factors such as time zone disparities, cultural variations, and language differences exert a formidable impact on communication within the sphere of global software development. These dynamics inevitably impinge upon timely coordination, potentially compromising the software's quality. In response, researchers have proffered communication models tailored for requirement elicitation within the ambit of global software development. The purpose of this study is to conduct an in-depth critical review of existing communication models for demand elicitation in global software development. Through this comprehensive review, we aim to discern prevailing publication trends, provide an introductory overview, and illuminate the strengths and limitations inherent in the existing communication models. By identifying these limitations, we seek to advance a novel, low-cost communication approach designed primarily for demand elicitation in global software development. To culminate our endeavor, we will undertake a case study-based experiment, meticulously designed to assess the efficacy and practical utility of the proposed techniques.