Duodenal gastrointestinal stromal tumor presenting with life-threatening upper GI bleeding in a young patient: A case report and literature review.

Key Clinical Message: Duodenal GISTs are rare and challenging tumors. Acute life-threatening upper GI bleeding is a possible presentation of duodenal GISTs. Surgery is the standard treatment for localized duodenal GISTs. Imatinib is an effective adjuvant therapy for duodenal GISTs. Abstract: GIST is the most common mesenchymal neoplasm of the gastrointestinal tract, accounting for 1%-2% of gastrointestinal tumors. They originate from the interstitial cells of Cajal and are rare in patients younger than 30 years. The stomach is the most common site, followed by the small intestine and colon. GISTs are caused by a gain-of-function mutation in the proto-oncogene receptor tyrosine kinase, with activating mutations in KIT being the most common. Most GISTs are asymptomatic. Even if gastrointestinal bleeding is the most common complication life-threatening hemorrhage is extremely uncommon. We present a case of a 31-year-old male patient presented with massive active hematemesis and melena with hemorrhagic shock. The patient presented with massive hematemesis and melena of 1 h duration. Endoscopy showed pulsating active bleeding from the third part of the duodenum which was difficult to manage via endoscopy. Histopathologic evaluation showed spindle cell type GIST. Intraoperatively, there was a nodular mass with active bleeding on the third part of the duodenum. Duodenectomy with end-to-end anastomosis was done. Discharged with no postoperative complication and was put on imatinib. There are considerable challenges that arise in the diagnosis and treatment of duodenal gastrointestinal stromal tumors (GISTs) when they present with life-threatening upper gastrointestinal hemorrhage. In order to achieve the best possible outcomes for patients, it is crucial to have a comprehensive understanding of the clinical presentation, diagnostic methods, and treatment approaches.

Bioactive compounds from Ocimum tenuiflorum and Poria cocos: A novel natural Compound for insomnia treatment based on A computational approach.

Insomnia, a widespread public health issue, is associated with substantial distress and daytime functionality impairments and can predispose to depression and cardiovascular disease. Cognitive Behavioral Anti-insomnia therapies including benzodiazepines often face limitations due to patient adherence or potential adverse effects. This study focused on identifying novel bioactive compounds from medicinal plants, aiming to discover and develop new therapeutic agents with low risk-to-benefit ratios using computational drug discovery methods. Through a systematic framework involving compound library preparation, evaluation of drug-likeness and pharmacokinetics, toxicity prediction, molecular docking, and molecular dynamic simulations, two natural compounds such as 2-(4-hydroxy-3-methoxyphenyl)-8-methoxy-6-prop-2-enyl-3,4-dihydro-2H-chromen-3-ol from Ocimum tenuiflorum and 7-(2-hydroxypropan-2-yl)-1,4a-dimethyl-9-oxo-3,4,10,10a-tetrahydro-2H-phenanthrene-1-carboxylic acid from Poria cocos exhibited high binding affinity with orexin receptor type 1 (OX1R) and type 2 (OX2R), surpassing commercial drugs used in insomnia treatment. Additionally, they showed interactions with critical amino acid residues within the receptors that play crucial roles in competitive inhibitor activity, like commercial drugs such as Suvorexant, Lemborexant, and Daridorexant. Further, molecular dynamics simulations of the protein-ligand complexes under conditions that mimic the in vivo environment revealed both compounds' sustained and robust interactions with the OX1R and OX2R, reinforcing their potential as effective therapeutic candidates. Furthermore, upon evaluating both compounds' drug-likeness, pharmacokinetics, and toxicity profiles, it was discerned that they displayed considerable drug-like properties and favorable pharmacokinetics, along with diminished toxicity. The research provides a solid foundation for further exploring and validating these compounds as potential anti-insomnia therapeutics.

The impact of advance organizers in virtual classrooms on the development of integrated science process skills.

Unlike virtual classrooms that have received extensive research attention in both academic and practical contexts because of their ability to improve students' outcomes, the use of advance organizers are still in need for more research to prove their efficacy in fulfilling expected learning outcomes in these virtual classrooms. Hence, the present study aims to identify the impact of using such organizers in virtual classrooms on the development of students' integrated science process skills. The present study was applied to 64 students who were studying for their Master's degree in the vocational education techniques in the "Research Project" course. Participants were randomly divided into two equal experimental groups with 32 students in each. An assessment card of five main domains was used to evaluate students' skills in research procedural definition, identification and control of the research variables, questions and/or hypotheses, procedures and experimentation besides research interpretation of the results. Data analysis showed that the use of advance organizers in virtual classes was of great effect on the development of participants' integrated science process skills because skills of students in the first experimental group were better mastered than the skills of their peers in the second experimental group in accordance with the subskills in the five domains.

Assessment of immune cells in the uterine fluid at the time of the embryo transfer.

PROBLEM: Although endometrial receptivity is a key factor in influencing implantation in both naturally conceived and assisted reproductive technology (ART) cycles, very little is known about the endometrium milieu around the time of implantation. Previous studies have demonstrated the presence of several cytokines in the endometrium that affect implantation. However, there is lacking data about the presence of immune cell subtypes within the endometrium and in the uterine cavity at the time of implantation. METHOD OF STUDY: This study was approved by the Institutional Review Board (# 225589). The study was designed as a prospective observational cohort study between May 2021 and December 2022 at a single academic-based fertility center. All patients underwent at least one In Vitro Fertilization (IVF) cycle and have frozen embryos. Twenty-four participants were recruited for this study which was conducted during the frozen embryo transfer (FET) cycle regardless of the outcome of previous cycles. Two samples were acquired from each subject, denoted as lower and upper. A trial transfer catheter was introduced under ultrasound guidance into the lower uterine segment. Upon removal, the tip was rinsed in IMDM medium containing 10% FBS (lower uterus). A transfer catheter was then loaded with the embryo that was placed in the upper uterus under ultrasound guidance. The tip of the transfer catheter was rinsed in separate aliquot of the above media (upper uterus). After centrifugation, pelleted cells were stained for the following surface markers: CD45, CD3, CD19, CD4, CD8, gamma delta TCR, CD25, CD127, CD66b, CD14, CD16, CD56 and acquired on Sony SP6800 Spectral Analyzer. RESULTS: Upon staining the pelleted cells, we were able to identify viable leukocytes from samples obtained from both, upper and lower uterus (0.125 × 106 cells ± SD 0.32), (0.123 × 106 cells ± SD 0.12), respectively. Among total viable cells, there was no significant difference in both percent and number of CD45+ cells between the upper and lower uterus (9.88% ± 6.98 SD, 13.67% ± 9.79 SD, p = .198) respectively. However, there was significantly higher expression of CD3+ (p = .006), CD19+ (p = .032) and CD14+ (p = .019) cells in samples collected from upper compared to lower uterus. Within all CD3+ cells, we found that gamma delta T cells (GDT) were the major population of T cells in both upper and lower uterus. In contrast, CD8+ T cells were significantly higher in the lower uterus when compared to the upper uterus (p = .009). There was no statistically significant difference in the expression of CD4+ T cells, T regulatory cells (CD4+CD25+CD127-), NK cells (CD56+), neutrophils (CD66b+) and FcγRIII+ cells (CD16+) between upper and lower uterus. CONCLUSIONS: We believe the immune milieu at the time of embryo transfer will affect implantation. Understanding the composition of immune cells will guide further research in identifying optimal immune milieus that favor implantation. Comprehensive analysis of endometrium is expected to lead to new diagnostic and therapeutic approaches to improve IVF outcomes.

Optimizing outcome reporting after robotic flexible ureteroscopy for management of renal calculi: Introducing the concept of tetrafecta.

Robotic flexible ureteroscopy (RFURS) has shown encouraging results in terms of stone free rate (SFR) and better ergonomics compared to conventional FURS. However, few studies have reported its outcomes. The goal of this study was to report our initial results of RFURS, furthermore we proposed a novel metrics for composite outcome reporting named tetrafecta. A retrospective analysis of electronic records of 100 patients treated with RFURS for renal stones between 2019 till 2023 was performed. Tetrafecta criteria included, complete stone removal after a single treatment session, without auxiliary procedures, absence of high-grade complications (GIII-V) and same-day hospital discharge. Mean patient age and stone size were 40.7 ± 9.2 and 11.7 ± 5.8 mm, respectively. Median stone volume was 916 (421-12,235) mm3. Twenty-eight patients had multiple renal stones. Staghorn stones were seen in 12 patients. Preoperative DJ stent was fixed in 58 patients. Median operative time and stone treatment time were 116 min (97-148) and 37 (22-69) min. The median stone treatment efficiency (STE) was 21.6 (8.9-41.6). A strong positive correlation between stone volume and STE (R = 0.8, p < 0.0001). Overall, 73 patients were stone free after the initial treatment session while tetrafecta was achieved in 70 patients. Univariate analysis showed that the stone size (p = 0.008), acute infundibulopelvic angle (p = 0.023) and preoperative stenting (p = 0.017) had significant influence on achieving tetrafecta. Multivariate analysis identified preoperative stenting (OR 0.3, 95% CI 0.1-0.8, p = 0.019) as the only independent predictor of tetrafecta achievement. A comprehensive reporting methodology for reporting outcomes of RFURS is indicated for patient counseling and comparing different techniques. Tetrafecta was achieved in 70% of cases. Presence of significant residual stones ≥ 3mm was the leading cause of missing tetrafecta. Absence of preoperative stent was the only predictor of missing tetrafecta.

Does Pre-Emptive Availability of PREDICT 2.1 Results Change Ordering Practices for Oncotype DX? A Multi-Center Prospective Cohort Study.

For early-stage hormone receptor (HR)-positive and HER2-negative breast cancer, tools to estimate treatment benefit include free and publicly available algorithms (e.g., PREDICT 2.1) and expensive molecular assays (e.g., Oncotype DX). There remains a need to identify patients who de-rive the most benefit from molecular assays and where this test may be of poor value. In this multicenter prospective cohort study, we evaluated whether use of PREDICT 2.1 would impact physician decision making. For the first 6 months of the study, data on physician use of both PREDICT 2.1 and Oncotype DX ordering were collected on all newly diagnosed patients eligible for molecular testing. After 6 months, an educational intervention was undertaken to see if providing physicians with PREDICT 2.1 results affects the frequency of Oncotype DX requests. A total of 602 patients across six cancer centers in Ontario, Canada were recruited between March 2020 and November 2021. Providing PREDICT 2.1 results and an educational intervention did not alter the ordering of an Oncotype DX. For patients with low clinical risk, either by clinico-pathologic features or by PREDICT 2.1, the probability of obtaining a high Oncotype DX recurrence score was substantially lower compared to patients with high-clinical-risk disease. The introduction of an educational intervention had no impact on molecular assay requests. However, routine ordering of molecular assays for patients with low-clinical-risk disease is of poor value.

Three-dimensional choroidal contour mapping in healthy population.

Purpose was to study 3-dimensional choroidal contour at choroidal inner boundary (CIB) and choroidal outer boundary (COB) in healthy eyes. Healthy eyes imaged on wide field swept-source optical coherence tomography were included. Delineation of CIB and COB was done based on our previously reported methods. Quantitative analysis of the surfaces of CIB and COB was based on analyzing best fit spherical radius (R) (overall and sectoral). One hundred and seven eyes of 74 subjects with a mean age of 46.4 ± 19.3 years were evaluated. Overall, R COB (mean ± SD: 22.5 ± 4.8 mm) < R CIB (32.4 ± 9.4 mm). Central sector had the least R at COB (7.2 ± 5.9 mm) as well as CIB (25.1 ± 14.3 mm) across all age groups. Regression analysis between R (CIB) and age (r = -0.31, r2 = 0.09) showed negative correlation (P < 0.001) and that between R (COB) and age was positive (r = 0.26, r2 = 0.07) (P = 0.01). To conclude, central sector is the steepest sector in comparison to all the other sectors. This is indicative of a prolate shape of choroidal contour at CIB and COB. Outer boundary of choroid is steeper than inner boundary across all age groups. However, with ageing, outer boundary becomes flatter and inner boundary becomes steeper.

Indigofera cryptantha-induced pigmenturia in cattle in South Africa.

Two field cases of reddish-black pigmenturia occurred where cattle grazed on an established Cenchrus ciliaris (blue buffalo grass) pasture in South Africa. The pasture was noticeably invaded by Indigofera cryptantha, which was heavily grazed. Apart from the discolored urine, no other clinical abnormalities were detected. Urinalysis revealed hemoglobinuria, proteinuria and an alkaline pH. When the animals were immediately removed from the infested pasture, they made an uneventful recovery. However, a bull died when one of the herds could not be removed from the I. cryptantha-infested pasture. Macroscopically, the kidneys were dark red in color and the urinary bladder contained the dark pigmented urine. Microscopically, the renal tubules contained eosinophilic, granular pigment casts in the lumen. In addition, many renal tubular epithelial cells were attenuated with granular cytoplasm and were detached from the basement membranes. Chemical analysis was performed on dried, milled plant material and two urine samples collected during the field investigations. Qualitative UPLC-UV-qTOF/MS analysis revealed the presence of indican (indoxyl-ß-glucoside) in the stems, leaves and pods of I. cryptantha and indoxyl sulfate was identified, and confirmed with an analytical standard, in the urine samples. It is proposed that following ingestion of I. cryptantha, indican will be hydrolysed in the liver to indoxyl and conjugated with sulfate. Indoxyl sulfate will then be excreted in relatively high concentrations in the urine. In the alkaline urine, two indoxyl molecules might dimerize to form leucoindigo with subsequent oxidation to indigo, thus, contributing to the dark pigmentation of the urine. It is also possible that indoxyl sulfate contributed to the renal failure and death of the bull. Although I. suffruticosa-induced hemoglobinuria has been described in Brazil, this is the first report of I. cryptantha-induced pigmenturia in cattle in South Africa.

A multi-country comparative study of two treponemal tests for the serodiagnosis of syphilis amongst men who have sex with men (MSM): Chemo-luminescent assay vs Treponema pallidum particle agglutination assay.

INTRODUCTION: International guidelines recommend routine screening for syphilis (aetiological agent: Treponema pallidum subspecies pallidum) amongst key populations and vulnerable populations using tests detecting treponemal and non-treponemal antibodies. Whilst treponemal tests have high sensitivities and specificities, they differ regarding subjective or objective interpretation, throughput and workload. Chemiluminescence immunoassays (CLIAs) are cost- and time-effective automated methods for detecting treponemal antibodies. The Treponema pallidum particle agglutination assay (TPPA) has been considered the "gold standard" treponemal assay, however, this includes a highly manual procedure, low throughput and subjective interpretation. The present multi-country study evaluated the ADVIA Centaur® Syphilis CLIA (Siemens Healthcare) assay compared to the reference SERODIA-TP·PA® (Fujirebio Diagnostics) for the serodiagnosis of syphilis amongst men who have sex with men (MSM). METHOD: 1,485 MSM were enrolled in Brighton (UK), Malta, and Verona (Italy) as part of a larger WHO multi-country and multi-site ProSPeRo study. Ethical approval was obtained. Serum was tested with the ADVIA Centaur® Syphilis CLIA assay and SERODIA-TP·PA®, in accordance with the manufacturers' instructions, for a first round of validation. A second round of validation was carried out for discrepant results that were additionally tested with both Western Blot (Westernblot EUROIMMUN®) and an Immunoblot (INNO-LIA, Fujirebio Diagnostics). Sensitivity, specificity, positive and negative predictive value (PPV and NPV), likelihood ratios (positive/negative), and the Diagnostic Odds Ratio (DOR)/pre-post-test probability (Fagan's nomogram) were calculated. RESULTS: Out of 1,485 eligible samples analysed in the first phase, the SERODIA-TP·PA® identified 360 positive and 1,125 negative cases. The ADVIA Centaur® Syphilis CLIA assay (Siemens) identified 366 positives, missclassifying one TPPA-positive sample. In the second phase, the ADVIA Centaur® Syphilis CLIA resulted in 1 false negative and 4 false positive results. Considering the syphilis study prevalence of 24% (95% CI: 22-26.7), The sensitivity of the ADVIA Centaur® Syphilis CLIA assay was 99.7% (95% CI: 98.5-100), and the specificity was 99.4% (95% CI: 98.7-99.7). The ROC area values were 0.996 (95% CI: 0.992-0.999), and both the PPV and NPV values were above 98% (PPV 98.1%, 95% CI: 96.1-99.2; NPV 99.9%, 95% CI: 99.5-100). CONCLUSIONS: The ADVIA Centaur® Syphilis CLIA assay showed similar performance compared to the SERODIA-TP·PA®. Considering the study is based on QUADAS principles and with a homogeneous population, results are also likely to be generalisable to MSM population but potentially not applicable to lower prevalence populations routinely screened for syphilis. The automated CLIA treponemal assay confirmed to be accurate and appropriate for routine initial syphilis screening, i.e. when the reverse testing algorithm is applied.

Mechanical Properties of Rubberised Geopolymer Concrete.

The environmental impact of non-biodegradable rubber waste can be severe if they are buried in moist landfill soils or remain unused forever. This study deals with a sustainable approach for reusing discarded tires in construction materials. Replacing ordinary Portland cement (OPC) with an environmentally friendly geopolymer binder and integrating crumb rubber into pre-treated or non-treated geopolymer concrete as a partial replacement of natural aggregate is a great alternative to utilise tire waste and reduce CO2 emissions. Considering this, two sets of geopolymer concrete (GPC) mixes were manufactured, referred to as core mixes. Fine aggregates of the core geopolymer mixes were partially replaced with pre-treated and non-treated rubber crumbs to produce crumb rubber geopolymer concrete (CRGPC). The mechanical properties, such as compressive strength, stress-strain relationship, and elastic modulus of a rubberised geopolymer concrete of the reference GPC mix and the CRGPC were examined thoroughly to determine the performance of the products. Also, the mechanical properties of the CRGPC were compared with the existing material models. The result shows that the compressive strength and modulus of elasticity of CRGPC decrease with the increase of rubber content; for instance, a 33% reduction of the compressive strength is observed when 25% natural fine aggregate is replaced with crumb rubber. However, the strength and elasticity reduction can be minimised using pre-treated rubber particles. Based on the experimental results, stress-strain models for GPC and CRGPC are developed and proposed. The proposed models can accurately predict the properties of GPC and CRGPC.

Role of the IL8 rs4073 polymorphism in central nervous system toxicity in patients receiving multidrug-resistant tuberculosis treatment.

OBJECTIVE: To determine the role of the IL8 rs4073 polymorphism in predicting the risk of central nervous system (CNS) toxicity in patients receiving standard pharmacological treatment for multidrug-resistant tuberculosis (MDR-TB). METHODS: A cohort of 85 consenting MDR-TB patients receiving treatment with second-line antituberculosis drugs had their blood samples amplified for the IL8 (rs4073) gene and genotyped. All patients were clinically screened for evidence of treatment toxicity and categorized accordingly. Crude and adjusted associations were assessed. RESULTS: The chief complaints fell into the following categories: CNS toxicity; gastrointestinal toxicity; skin toxicity; and eye and ear toxicities. Symptoms of gastrointestinal toxicity were reported by 59% of the patients, and symptoms of CNS toxicity were reported by 42.7%. With regard to the genotypes of IL8 (rs4073), the following were identified: AA, in 64 of the study participants; AT, in 7; and TT, in 11. A significant association was found between the dominant model of inheritance and CNS toxicity for the crude model (p = 0.024; OR = 3.57; 95% CI, 1.18-10.76) and the adjusted model (p = 0.031; OR = 3.92; 95% CI, 1.13-13.58). The AT+TT genotype of IL8 (rs4073) showed a 3.92 times increased risk of CNS toxicity when compared with the AA genotype. CONCLUSIONS: The AT+TT genotype has a tendency to be associated with an increased risk of adverse clinical features during MDR-TB treatment.

Independent clinic-based evaluation of dual POCTs for screening for HIV and syphilis in men who have sex with men in Italy, Malta, Peru, and the United Kingdom.

INTRODUCTION: Globally, the incidence of HIV and syphilis can be reduced by the use of validated point of care tests (POCTs). As part of the WHO PRoSPeRo Network, we aimed to evaluate the performance, acceptability, and operational characteristics of two dual HIV/syphilis POCTs (Bioline HIV/Syphilis Duo (Abbott) and DPP® HIV-Syphilis assay (Chembio) for the screening of HIV and syphilis amongst men who have sex with men (MSM). METHOD AND ANALYSES: A cross sectional study of 2,577 MSM in Italy, Malta, Peru, and the United Kingdom (UK) presenting to seven clinic sites, were enrolled. Finger prick blood was collected to perform POCTs and results compared with standard laboratory investigations on venepuncture blood. Acceptability and operational characteristics were assessed using questionnaires. Diagnostic meta-analysis was used to combine data from the evaluation sites. RESULTS: Based on laboratory tests, 23.46% (n = 598/2549) of participants were confirmed HIV positive, and 35.88% of participants (n = 901/2511) were positive on treponemal reference testing. Of all participants showing evidence of antibodies to Treponema pallidum, 50.56% (n = 455/900) were Rapid Plasma Reagin (RPR) test reactive. Of HIV positive individuals, 60.62% (n = 354/584) had evidence of antibodies to T. pallidum, and of these 60.45% (n = 214/354) exhibited reactive RPR tests indicating probable (co)infection. For Bioline POCT, pooled sensitivities and specificities for HIV were 98.95% and 99.89% respectively, and for syphilis were 73.79% and 99.57%. For Chembio pooled sensitivities and specificities for HIV were 98.66% and 99.55%, and for syphilis were 78.60% and 99.48%. Both tests can detect greater than 90% of probable active syphilis cases, as defined by reactive RPR and treponemal test results. These dual POCTs were preferred by 74.77% (n = 1,926) of participants, due to their convenience, and the operational characteristics made them acceptable to health care providers (HCPs). CONCLUSIONS: Both the Bioline and the Chembio dual POCT for syphilis and HIV had acceptable performance, acceptability and operational characteristics amongst MSM in the PRoSPeRo network. These dual POCTs could serve as a strategic, more cost effective, patient and healthcare provider (HCP) friendly alternative to conventional testing; in clinical and other field settings, especially those in resource-limited settings.

The role of physiotherapy interventions in the management of temporomandibular joint ankylosis: a systematic review and meta-analysis : Running title: Physiotherapy in TMJ ankylosis.

BACKGROUND: The main aim of this systematic review and meta-analysis was to identify peer-reviewed scholarly journal articles reporting the significance of physiotherapy interventions in managing TMJ ankylosis. In addition, this study aimed to critically appraise the existing evidence on the prevalence and clinical presentation, physiotherapy intervention approaches, efficacy of physiotherapy interventions, adverse effects, and safety of physiotherapy interventions in TMJ ankylosis management. METHODS: An all-inclusive literature search was conducted using the PubMed, Google Scholar, and Scopus electronic databases. The researchers screened the potential articles and assessed for eligibility based on the reported inclusion and exclusion criteria. The quality evaluation tool for observational cohort and cross-sectional studies developed by the National Institutes of Health (NIH) and the Cochrane Collaboration's Risk of Bias Tool were used to assess the quality of the included studies. Researchers also comprehensively analyzed the data, reported the results, and discussed them according to the predominant themes. RESULTS: The primary electronic database search yielded 409 articles, of which 25 were included in this review. A secondary search was conducted from citations of the included studies, yielding 74 articles, of which six were included in the study. A significantly higher prevalence of bony ankylosis than fibrous ankylosis, with an overall effect size of p < 0.00001. In addition, there were significantly more unilateral than bilateral presentations with an overall effect size of p < 0.00001. Moreover, there were 78 reported complications out of 245 subjects according to five included studies demonstrating a significant effect size with p = 0.001 following the treatment protocols. CONCLUSION: This study highlighted the prevalence of bony ankylosis in temporomandibular joint ankylosis, emphasizing its impact on patients' well-being. On the other hand, the results show that physiotherapy is essential to optimize postoperative outcomes and minimize adverse events such as re-ankylosis. Practitioners and healthcare professionals must monitor postoperative recovery and ensure strict adherence to physiotherapy protocols for optimal outcomes.

Stanford type B aortic dissection in a patient with aberrant right subclavian artery.

An aberrant right subclavian artery is a rare aortic arch anomaly where the right subclavian artery arises from the proximal part of the descending thoracic aorta and distal to origin of left subclavian artery. It usually courses behind the esophagus. Type B aortic dissection along with aberrant right subclavian artery is not common. A middle-aged man presented with complaints of epigastric pain and on evaluation was found to have aberrant right subclavian artery with type B aortic dissection. A total arch replacement with frozen elephant trunk surgery and an extra-anatomic bypass of right subclavian artery were performed. Type B aortic dissection is more often an incidental finding and its association with aberrant right subclavian artery is unusual. Such association should be identified and treated accordingly to avert clinical complications.

Histone Deacetylase Inhibitors Directly Modulate T Cell Gene Expression and Signaling and Promote Development of Effector-Exhausted T Cells in Murine Tumors.

Epigenetic regulation plays a crucial role in the development and progression of cancer, including the regulation of antitumor immunity. The reversible nature of epigenetic modifications offers potential therapeutic avenues for cancer treatment. In particular, histone deacetylase (HDAC) inhibitors (HDACis) have been shown to promote antitumor T cell immunity by regulating myeloid cell types, enhancing tumor Ag presentation, and increasing expression of chemokines. HDACis are currently being evaluated to determine whether they can increase the response rate of immune checkpoint inhibitors in cancer patients. Although the potential direct effect of HDACis on T cells likely impacts antitumor immunity, little is known about how HDAC inhibition alters the transcriptomic profile of T cells. In this article, we show that two clinical-stage HDACis profoundly impact gene expression and signaling networks in CD8+ and CD4+ T cells. Specifically, HDACis promoted T cell effector function by enhancing expression of TNF-α and IFN-γ and increasing CD8+ T cell cytotoxicity. Consistently, in a murine tumor model, HDACis led to enrichment of CD8+ T cell subsets with high expression of effector molecules (Prf1, Ifng, Gzmk, and Grmb) but also molecules associated with T cell exhaustion (Tox, Pdcd1, Lag3, and Havcr2). HDACis further generated a tumor microenvironment dominated by myeloid cells with immune suppressive signatures. These results indicate that HDACis directly and favorably augment T cell effector function but also increase their exhaustion signal in the tumor microenvironment, which may add a layer of complexity for achieving clinical benefit in combination with immune checkpoint inhibitors.

Percutaneous nephrolithotomy in supine position with less than 24-hour hospital stay; a single-center experience.

Objectives: To report our initial experience of day care percutaneous nephrolithotomy (PCNL) with early hospital discharge within less than 24 hours of the procedure. Patients and Methods: The files of patients treated with PCNL between 1st January 2020 till 31st December 2022 were retrospectively reviewed. Day care PCNL was defined as the discharge of patients either on the same day or within 24 hours after surgery. Patient age, ASA score, body mass index, stone diameter, laterality, stone burden, Hounsfield unit, and Guy's score were analyzed. Operative time, size of the access tract, method of lithotripsy, estimated blood loss, and length of hospital stay were also recorded. Postoperative complications were stratified according to the Dindo-Clavien classification. The primary outcome was to evaluate the feasibility and safety of early discharge within 24 hours after PCNL compared to the in-patients who were kept in hospital for at least 2 days after surgery. Results: A total of 85 patients underwent PCNL at our center of whom 36 patients were discharged within 24 hours (day care PCNL) of the procedure and 49 patients were kept for at least 2 days (in-patient PCNL). In the day care group, median stone burden was 465 mm2 (360-980) and 18 patients (50%) had Guy's stone score ≥ III. The median tract size was 24 (13-30) and endoscopic combined intrarenal surgery (ECIRS) was performed in 7 cases in the day care group. Tubeless PCNL was carried out in 88.8% of the day care surgery group compared to 37.5% in the in-patient group (p < 0.0001). The postoperative complication rate was comparable between both groups (13.8% vs 22.4% for day care vs in-patient group, respectively, p = 0.08). Conclusions: Day care PCNL is feasible and safe for selected patients including those having large stone burden without increasing the risk of complications or readmission rate.

A community based seroprevalence of SARS-CoV-2 antibodies in Somali Region, Eastern Ethiopia.

BACKGROUND: Coronavirus disease 19 (COVID-19) is life-threatening infectious disease caused by SARS-CoV-2 virus that caused a global pandemic. SARS-CoV-2 has been widely transmitted throughout Ethiopia, with over 501,060 cases confirmed and 7574 deaths until November 2023. This study assessed for the first time the seroprevalence SARS-CoV-2 in the general population of the Somali Region during the COVID-19 pandemic. METHODS: A cross-sectional study design was conducted from May to June 2021 in 14 districts of Somali Region. Blood samples were collected in 820 participants in addition to administering a questionnaire that included sociodemographic characteristics and history of clinical symptoms of COVID-19. Blood samples were tested for the presence or absence of anti-SARS-CoV-2 using a commercial Enzyme-Linked Immunosorbent Assay (ELISA) kit (Euroimmun). RESULTS: Overall, 477 (58.2%) were male and 343 (41.8%) were female. The majority of the participants (N = 581; 70.9%) were between 18 and 34 years old and not vaccinated against COVID-19 (N = 793; 96.7%). The overall seroprevalence of SARS-CoV-2 antibodies was 41.7% (95% CI: 33.3%-47.6%). The highest prevalence was found in Goljano district (70%) and the lowest in Gunagado district (22.5%). Only age was found to be associated with COVID-19 seropositivity. CONCLUSION: Prevalence of SARS-CoV-2 antibodies was the highest ever reported in Ethiopia, indicating that a large proportion of the population had been infected 14 months after the start of the outbreak in the country. Such studies are important to swiftly reassess and improve specific COVID-19 preventive and control measures to reduce transmissions within the community in a given setting.

Toll-like receptor 7 and tumor necrosis factor alpha polymorphisms in Egyptian patients with autoimmune thyroid diseases.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) susceptibility depends on a complex interaction between environmental and genetic factors. Genes for tumor necrosis factor alpha (TNF-α) and toll-like receptors (TLRs) have been incorporated into the pathophysiology of autoimmune disorders. Our aim is to assess the association between TLR7 (rs179009) and TNF-α (rs1800629) polymorphisms and susceptibility to autoimmune thyroid disorders. One-hundred ninety-nine individuals, divided into 68 HT patients in group I, 57 GD patients in group II, and 74 age- and gender-matched healthy subjects in group III, underwent laboratory investigations, including the detection of TLR7 and TNF-α polymorphisms using real-time PCR technique. TLR7 (rs179009) genotypes, A/G and G/G, were significantly more prevalent in HT patients (group I) compared to normal controls. Meanwhile, TNF-α (rs1800629) genotypes in GD patients (group II) showed a six fold increase in the risk of the disease in the G/A and A/A genotypes. Our findings propose the fact that the polymorphisms of TLR7 (rs179009) play a role in the susceptibility and the development of Hashimoto's thyroiditis, whereas TNF-α (rs1800629) polymorphisms play a role in the susceptibility and development of Graves' disease.

Comprehensive review of melatonin as a promising nutritional and nutraceutical supplement.

Background: Melatonin is an indoleamine hormone secreted by the pineal gland at night and has an essential role in regulating human circadian rhythms (the internal 24-h clock) and sleep-wake patterns. However, it has recently gained considerable attention for its demonstrated ability in disease management. This review discusses the major biological activities of melatonin, its metabolites as nutritional supplements, and its bioavailability in food sources. Methods: The information acquisition process involved conducting a comprehensive search across academic databases including PubMed, Scopus, Wiley, Embase, and Springer using relevant keywords. Only the most recent, peer-reviewed articles published in the English language were considered for inclusion. Results: The molecular mechanisms by which melatonin induces its therapeutic effects have been the subject of various studies. Conclusion: While melatonin was initially understood to only regulate circadian rhythms, recent studies indicate that it has a far-reaching effect on various organs and physiological systems, such as immunity, cardiovascular function, antioxidant defense, and lipid hemostasis. As a potent antioxidant, anti-cancer, anti-inflammatory, and immunoregulatory agent, multiple therapeutic applications have been proposed for melatonin.