Large Anal Polyp Disguised as Rectal Prolapse.

Rectal prolapse is a relatively rare condition where the rectal mucosa protrudes out of the anal canal. The diagnosis is made through a physical exam and clinical evaluation, and surgical treatment options can vary. Anal polyps masquerading as rectal prolapse have rarely been described in the literature. A 79-year-old man presented with a four-year history of a bulging, protruding mass from his anus that is exacerbated with defecation and bowel movements. He was initially diagnosed with rectal prolapse and had a proctosigmoidectomy performed robotically. Shortly after the procedure, his symptoms recurred, and he was referred to a different surgeon for reevaluation. A large, prolapsed polyp was visible on the physical exam. A colonoscopy and an anoscopy were performed. The CT abdomen/pelvis revealed a mass within the rectum, and the biopsy showed an adenomatous polyp with high-grade dysplasia. The patient underwent a transanal excision of the rectal polyp, with symptoms permanently resolving. For an accurate diagnosis, it is crucial to conduct a comprehensive assessment of the patient's history, a physical exam, and an unusual clinical course of rectal prolapse. The rarity of large, prolapsed polyps, along with their similar presentation to that of other anorectal conditions, may have contributed to this patient's diagnosis of rectal prolapse and the subsequent proctosigmoidectomy in place of a transanal excision of a polyp. The palpation of a stalk on a physical exam should raise suspicion of a polyp, and further workup, such as a colonoscopy and/or anoscopy, should be conducted to confirm the diagnosis.

Chemical analogue based drug design for cancer treatment targeting PI3K: integrating machine learning and molecular modeling.

Cancer is a generic term for a group of disorders defined by uncontrolled cell growth and the potential to invade or spread to other parts of the body. Gene and epigenetic alterations disrupt normal cellular control, leading to abnormal cell proliferation, resistance to cell death, blood vessel development, and metastasis (spread to other organs). One of the several routes that play an important role in the development and progression of cancer is the phosphoinositide 3-kinase (PI3K) signaling pathway. Moreover, the gene PIK3CG encodes the catalytic subunit gamma (p110γ) of phosphoinositide 3-kinase (PI3Kγ), a member of the PI3K family. Therefore, in this study, PIK3CG was targeted to inhibit cancer by identifying a novel inhibitor through computational methods. The study screened 1015 chemical fragments against PIK3CG using machine learning-based binding estimation and docking to select the potential compounds. Later, the analogues were generated from the selected hits, and 414 analogues were selected, which were further screened, and as most potential candidates, three compounds were obtained: (a) 84,332, 190,213, and 885,387. The protein-ligand complex's stability and flexibility were then investigated by dynamic modeling. The 100 ns simulation revealed that 885,387 exhibited the steadiest deviation and constant creation of hydrogen bonds. Compared to the other compounds, 885,387 demonstrated a superior binding free energy (ΔG = -18.80 kcal/mol) with the protein when the MM/GBSA technique was used. The study determined that 885,387 showed significant therapeutic potential and justifies further experimental investigation as a possible inhibitor of the PIK3CG target implicated in cancer.

Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population.

Importance: The population prevalence of cardiac transthyretin amyloidosis (ATTR) caused by pathogenic variation in the TTR gene (vATTR) is unknown. Objective: To estimate the population prevalence of disease-causing TTR variants and evaluate associated phenotypes and outcomes. Design, Setting, and Participants: This population-based cohort study analyzed UK Biobank (UKB) participants with whole-exome sequencing, electrocardiogram, and cardiovascular magnetic resonance data. Participants were enrolled from 2006 to 2010, with a median follow-up of 12 (IQR, 11-13) years (cutoff date for the analysis, March 12, 2024). Sixty-two candidate TTR variants were extracted based on rarity (minor allele frequency ≤0.0001) and/or previously described associations with amyloidosis if more frequent. Exposure: Carrier status for TTR variants. Main Outcomes and Measures: Associations of TTR carrier status with vATTR prevalence and cardiovascular imaging and electrocardiogram traits were explored using descriptive statistics. Associations between TTR carrier status and atrial fibrillation, conduction disease, heart failure, and all-cause mortality were evaluated using adjusted Cox proportional hazards models. Genotypic and diagnostic concordance was examined using International Statistical Classification of Diseases, Tenth Revision codes from the hospital record. Results: The overall cohort included 469 789 UKB participants (mean [SD] age, 56.5 [8.1] years; 54.2% female and 45.8% male). A likely pathogenic/pathogenic (LP/P) TTR variant was detected in 473 (0.1%) participants, with Val142Ile being the most prevalent (367 [77.6%]); 91 individuals (0.02%) were carriers of a variant of unknown significance . The overall prevalence of LP/P variants was 0.02% (105 of 444 243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry. The LP/P variants were associated with higher left ventricular mass indexed to body surface area (ß = 4.66; 95% CI, 1.87-7.44), and Val142Ile was associated with a longer PR interval (ß = 18.34; 95% CI, 5.41-31.27). The LP/P carrier status was associated with a higher risk of heart failure (hazard ratio [HR], 2.68; 95% CI, 1.75-4.12) and conduction disease (HR, 1.88; 95% CI, 1.25-2.83). Higher all-cause mortality risk was observed for non-Val142Ile LP/P variants (HR, 1.98; 95% CI, 1.06-3.67). Thirteen participants (2.8%) with LP/P variants had diagnostic codes compatible with cardiac or neurologic amyloidosis. Variants of unknown significance were not associated with outcomes. Conclusions and Relevance: This study found that approximately 1 in 1000 UKB participants were LP/P TTR variant carriers, exceeding previously reported prevalence. The findings emphasize the need for clinical vigilance in identifying individuals at risk of developing vATTR and associated poor outcomes.

Characterization and Cytotoxicity Assessment of Synthesized Palladium (II) Complex-Encapsulated Zinc Oxide Nanoparticles for Cancer Treatment.

The treatment of cancer often leads to a range of adverse effects. Encapsulating drugs can mitigate these effects and enhance drug efficacy by enabling a controlled release at the site of interest. This study details the successful synthesis of zinc oxide nanoparticles (ZnONPs) through the precipitation of Zn(NO3)2·6H2O with KOH. A Pd(II) complex drug was synthesized from a Schiff base ligand derived from 2-hydroxybenzohydrazide and (E)-1-(2-(p-tolyl)hydrazono)propan-2-one using potassium tetrachloropalladate(II). This complex was subsequently incorporated into ZnONPs. Characterization of the resulting compounds was performed using Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), Zeta Potential, Fourier Transform Infrared (FTIR) Spectroscopy, and UV-visible spectroscopy. TEM imaging revealed particle sizes of 160.69 ± 4.74 nm for ZnONPs and 185.28 ± 2.3 nm for the Pd(II) complex-encapsulated ZnONPs. The Zeta potential values were 6.53 mV for ZnONPs and 7.36 mV for Pd(II) complex-encapsulated ZnONPs. UV-visible spectroscopy showed an absorption peak at 360 nm for ZnONPs, while the Pd(II) complex-encapsulated ZnONPs exhibited a peak at 410 nm. FTIR analysis indicated the presence of the Pd(II) complex within the ZnONPs, as evidenced by a consistent Zn-O vibrational band at 832 cm-1 and a shift in another peak from 460 to 413 cm-1. Additionally, the detection of a C = N stretching vibration at 1548 cm-1 and a carbonyl stretch at 1626 cm-1 was observed. The Encapsulation Efficiency (E.E.) of the Pd(II) complex was 97.2%. A drug release experiment conducted at pH 7 showed a steady-state release pattern after 16 h, with a cumulative release of 44.3%. The cytotoxic effects of the Pd(II) complex and its encapsulated form in ZnONPs on the MCF-7 cell line were assessed via MTT test. The Pd(II) complex encapsulated within ZnONPs exhibited decreased toxicity relative to the unencapsulated drug, as evidenced by a higher IC50 value of 418.5 µg/ml. This suggests that the encapsulation facilitates a sustained release, which allows for targeted accumulation within cells. The elevated IC50 value indicates that the drug delivery system may be engineered to modulate the release of the drug in a more controlled manner, potentially resulting in a prolonged release profile rather than an immediate therapeutic impact.

Real-world effectiveness and safety of insulin glargine 100 U/mL plus lixisenatide in adults with type 2 diabetes: An international, multicentre, 12-month, prospective observational study.

AIM: To assess the impact of insulin glargine (100 U/mL) and lixisenatide (iGlarLixi) fixed-ratio combination therapy on the overall management of glycaemia in patients with type 2 diabetes (T2D), previously inadequately controlled with oral antidiabetic drugs ± basal insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). MATERIALS AND METHODS: This 12-month, international, multicentre, prospective, observational study included patients (age ≥ 18 years) with T2D who had initiated iGlarLixi within 1 month prior to study inclusion. Data were collected at study inclusion, month 3, month 6 and month 12 from patient diaries, self-measured plasma glucose, and questionnaires. The primary endpoint was change in HbA1c from baseline to month 6. RESULTS: Of the 737 eligible participants (mean age: 57.8 [standard deviation: 11.2] years; male: 49%), 685 had baseline and post-baseline HbA1c data available. The least squares mean change in HbA1c from baseline to month 6 was -1.4% (standard error [95% confidence interval (CI)]: 0.05 [-1.5, -1.3]). The absolute change from baseline at month 12 was -1.7% ± 1.9% (95% CI: -1.9, -1.5). There were 72 hypoglycaemia events reported during the study period, with a very low incidence of severe hypoglycaemia (two participants [rate: 0.003 events per patient-year]). CONCLUSIONS: This real-world observational study shows that initiation of iGlarLixi in people with T2D inadequately controlled on oral antidiabetic drugs ± basal insulin or GLP-1 RAs improves glycaemic control with a low incidence of hypoglycaemia.

Parenting Practices Are Associated With Out-of-School Physical Activity in US Adolescents in 2014.

INTRODUCTION: Lack of physical activity (PA) is associated with obesity, diabetes, hypertension, cardiovascular diseases, and cancer. Parenting practices influence PA in young children. However, there is little evidence available for adolescents. We examined whether parenting practices were associated with out-of-school PA (OSPA) in US adolescents. METHODS: This cross-sectional 2019 study analyzed data from the 2014 FLASHE study, a web-based, quota-sampled survey of parent-adolescent dyads. Inclusion required survey completion and parents to live with their teen (ages 12-17 y old). Physically limited adolescents were excluded. Dyads were stratified by teen age. Exposures included parental modeling, monitoring, facilitation, restriction, guided choice, and pressure. The outcomes of interest were OSPA Youth Activity Profile scores. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using adjusted logistic regressions. RESULTS: A total of 1109 dyads were included. Guided choice increased odds of OSPA for 15- to 17-year-olds (OR = 2.12; 95% CI, 1.17-3.84). Facilitation increased odds of OSPA for 12- to 14-year-olds (OR = 2.21; 95% CI, 1.13-4.33). Monitoring decreased odds of OSPA for 15- to 17-year-olds (OR = 0.34; 95% CI, 0.20-0.57) and 12- to 14-year-olds (OR = 0.45; 95% CI, 0.27-0.74). Friend support increased odds of OSPA in 15- to 17-year-olds (OR = 4.03; 95% CI, 2.29-7.08) and 12- to 14-year-olds (OR = 3.05; 95% CI 1.69-5.51). CONCLUSION: Future interventions should prioritize (1) shared decision making for older teens, (2) access to PA opportunities for younger adolescents, and (3) promoting peer PA and friend support for everyone.

Computational Approaches to Evaluate the Acetylcholinesterase Binding Interaction with Taxifolin for the Management of Alzheimer's Disease.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes that break down and reduce the level of the neurotransmitter acetylcholine (ACh). This can cause a variety of cognitive and neurological problems, including Alzheimer's disease. Taxifolin is a natural phytochemical generally found in yew tree bark and has significant pharmacological properties, such as being anti-cancer, anti-inflammatory, and antioxidant. The binding affinity and inhibitory potency of taxifolin to these enzymes were evaluated through molecular docking and molecular dynamics simulations followed by the MMPBSA approach, and the results were significant. Taxifolin's affinity for binding to the AChE-taxifolin complex was -8.85 kcal/mol, with an inhibition constant of 326.70 nM. It was observed to interact through hydrogen bonds. In contrast, the BChE-taxifolin complex binding energy was observed to be -7.42 kcal/mol, and it was significantly nearly equal to the standard inhibitor donepezil. The molecular dynamics and simulation signified the observed interactions of taxifolin with the studied enzymes. The MMPBSA total free energy of binding for AChE-taxifolin was -24.34 kcal/mol, while BChE-taxifolin was -16.14 kcal/mol. The present research suggests that taxifolin has a strong ability to bind and inhibit AChE and BChE and could be used to manage neuron-associated problems; however, further research is required to explore taxifolin's neurological therapeutic potential using animal models of Alzheimer's disease.

Ultrasonographic predictors of thyroid cancer in Bethesda III and IV thyroid nodules.

Background: Bethesda III and IV thyroid nodules continue to be difficult to manage. Although molecular testing may assist in decision-making, it is expensive, not widely available, and not without pitfalls. The objective of this study is to assess whether certain thyroid ultrasonographic features may predict the risk of thyroid cancer in patients with Bethesda III and IV thyroid nodules and be used as additional decision-making tools to complement cytopathological results in deciding on diagnostic thyroidectomy. Methods: We retrospectively evaluated the ultrasonographic features of Bethesda categories III and IV thyroid nodules in patients who underwent subsequent thyroidectomy. We used the final histopathological examination of the surgical specimens as the gold-standard test and analyzed individual preoperative ultrasonographic features as predictors of malignancy. Results: Of the 278 patients who were diagnosed with Bethesda III and IV thyroid nodules on fine needle aspiration cytology (FNAC), 111 (39.9%) had thyroid cancer, and 167 (59.9%) exhibited benign nodules. The malignancy rate was higher in patients with Bethesda IV nodules (28/50, 56%) than those with Bethesda III nodules (83/228, 36.4%; p=0.016). In univariate analysis, hypoechogenicity (55.6% in malignant vs. 35.3% in benign, p=0.006) and calcifications (54.5 in malignant vs. 35.4% in benign, p=0.008) were significantly different between the benign and malignant pathology groups, whereas the size of the dominant nodule, number of nodules, irregular borders, taller-than-wide shape, and the presence of lymph nodes were comparable between the two groups. These two ultrasonographic features (hypoechogenicity and calcifications) remained significantly associated with the risk of malignancy in multivariate logistic regression analysis (for hypoechogenicity, p=0.014, odds ratio: 2.1, 95% CI:1.0-3.7 and for calcifications, p=0.019, odds ratio: 1.98, 95% CI:1.12-3.50). The sensitivity, specificity, positive and negative predictive values, and accuracy were 31.5%, 83%, 55.6%,64.7%, and 62.6%, for hypoechogenicity, respectively and 32.4%, 82%, 54.5%, 67.8%, and 62%, for calcification, respectively. Conclusions: Hypoechogenicity and calcifications in Bethesda III and IV thyroid nodules are strong predictors of thyroid cancer and associated with a two-fold increased risk of malignancy.

Multimodal Imaging Findings Associated With Cardiac Oxalosis Cardiomyopathy.

We report the case of a 50-year-old woman with secondary oxalosis following bowel resection resulting in restrictive cardiomyopathy and a diagnosis of cardiac amyloidosis based on the initial workup. The case documented findings by cardiac magnetic resonance imaging and technetium Tc 99m-labeled pyrophosphate scan in patients with cardiac oxalosis, which can mimic findings in cardiac amyloidosis, expanding the differential diagnosis.

Role of T cells in cervical cancer.

Cervical cancer is an important health problem and it is considered the fourth most lethal women's cancer worldwide. The intertumoral T cell pool is exposed in a number of immunosuppressive pathways. Therefore, it is of interest to document the effect of cervical cancer on immune system, the role of T cells in the development and pathogenesis of cervical cancer. HPV is considered the most important risk factors for developing cervical cancer, HPV 16 and 18, the two most common oncogenic types which are high risk HPV cause 70% of cervical cancer cases. In the cervical mucosa, the proportion of CD4+ and CD8+ T cells is related to the severity of the lesions. Cervical cancer can be treated by immunotherapeutic vaccine which involves T cells. T cells play an important part in cervical cancer pathogenesis because HPV exploits several methods to avoid host T-cell immune surveillance. T-cell-based immunotherapy is important because it is selective and has therapeutic potential.

Study of novel bidentate heterocyclic amine-based metal complexes and their biological activities: cytotoxicity and antimicrobial activity evaluation.

Metallic antitumor drugs with heterocyclic ligands, such as novel AMI (amino methyl imidazole) complexes [Pd(AMI)Cl2](1), [Cu(AMI)L1](2), and [Cu(AMI)L2·2H2O](3) where L1 = oxalate and L2 = malonate, were synthesized and characterized. Assessments included elemental analyses, mass spectrometry, Fourier transform-infrared spectroscopy, ultraviolet-visible spectroscopy, and thermal analysis. The cytotoxicity of AMI complexes compared to cisplatin was assessed using MTT (3-[4,5-dimethylthiazol-2-yl] 2,5diphenyl tetrazolium bromide) assay with breast (MCF-7) and cervical (HeLa) cancer cell lines. After treating these cells with the AMI complexes' IC50 values for 48 h, malondialdehyde levels and catalase activity were used to assess oxidative stress, antioxidant activity was evaluated with DPPH radical scavenging method, comet assays assessed DNA damage, and DNA fragmentation was evaluated using the gel electrophoresis. In vitro, antimicrobial activity was assessed using a disc diffusion method. The anticancer activity results showed that IC50 (half-maximal inhibitory concentration) values of complex one, two, and three against MCF-7 and HeLa cancer cells are 0.156 ± 0.0006, 0.125 ± 0.001, 0.277 ± 0.002 µM respectively for MCF-7 cells and 0.222 ± 0.0005, 0.126 ± 0.0009, 0.152 ± 0.001 µM respectively for HeLa cells. Complex two demonstrated strong anticancer activity against MCF-7 and Hela cells. The study of oxidative stress parameters revealed that Malondialdehyde levels increased in cancer cell lines treated with complexes compared to untreated cells. Catalase activity decreased in cells treated with palladium chelate. The DPPH radical scavenging assay results identified that complex one was a more potent antioxidant in MCF-7 and Hela cells than other complexes with SC50 values of 227.5 ± 0.28 and 361 ± 1.2 µL/mL, respectively. The comet assay results showed that complex two caused significant DNA damage in MCF-7 and HeLa cancer cells treated. Antimicrobial assays identified complex three as the most effective. Copper complexes give better antifungal activity against A. flavus than the palladium complex. We conclude that complex two is the most active in both cell types and might be assessed as a clinically useful drug for breast cancer treatment. The significance of the current study is the synthesis of antitumor drugs containing heterocyclic ligands, such as novel AMI complexes, and the study of their biological activities.

Sex-specific associations between daytime sleepiness, chronic diseases and mortality in obstructive sleep apnea.

Objective: Excessive daytime sleepiness (EDS) is common in obstructive sleep apnea (OSA) and has been linked to adverse outcomes, albeit inconsistently. Furthermore, whether the prognostic impact of EDS differs as a function of sex is unclear. We aimed to assess the associations between EDS and chronic diseases and mortality in men and women with OSA. Methods: Newly-diagnosed adult OSA patients who underwent sleep evaluation at Mayo Clinic between November 2009 and April 2017 and completed the Epworth Sleepiness Scale (ESS) for assessment of perceived sleepiness (N = 14,823) were included. Multivariable-adjusted regression models were used to investigate the relationships between sleepiness, with ESS modeled as a binary (ESS > 10) and as a continuous variable, and chronic diseases and all-cause mortality. Results: In cross-sectional analysis, ESS > 10 was independently associated with lower risk of hypertension in male OSA patients (odds ratio [OR], 95% confidence interval [CI]: 0.76, 0.69-0.83) and with higher risk of diabetes mellitus in both OSA men (OR, 1.17, 95% CI 1.05-1.31) and women (OR 1.26, 95% CI 1.10-1.45). Sex-specific curvilinear relations between ESS score and depression and cancer were noted. After a median 6.2 (4.5-8.1) years of follow-up, the hazard ratio for all-cause death in OSA women with ESS > 10 compared to those with ESS ≤ 10 was 1.24 (95% CI 1.05-1.47), after adjusting for demographics, sleep characteristics and comorbidities at baseline. In men, sleepiness was not associated with mortality. Conclusion: The implications of EDS for morbidity and mortality risk in OSA are sex-dependent, with hypersomnolence being independently associated with greater vulnerability to premature death only in female patients. Efforts to mitigate mortality risk and restore daytime vigilance in women with OSA should be prioritized.

Novel palladium(II) and Zinc(II) Schiff base complexes: Synthesis, biophysical studies, and anticancer activity investigation.

BACKGROUND: Schiff base metal complexes are considered promising chemotherapeutic agents due to their potential application in cancer therapy. METHODS: The current work sought to synthesize a brand-new Schiff base ligand obtained from 2-hydroxybenzohydrazide and (E)- 1-(2-(p-tolyl)hydrazono)propan-2-one with metal ions which included Pd(II) and Zn(II) ions. Elemental analyses, FT-IR, mass spectra, 1H NMR, UV-Vis spectrometer, and computational analysis characterized the compound's structure. In vitro, the breast cancer cell line (MCF-7) was tested for its sensitivity to Schiff base (HL) and its Pd(II) and Zn(II) complexes. The half-maximal inhibitory concentration IC50 of the compounds was determined and used to perform the comet assay, which was carried out to reveal the photo-induced DNA damaging ability of the compounds of individual cells. Moreover, the compounds' effects on antioxidant defense systems of enzymes in cells: superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and oxidant Malondialdehyde (MDA) were examined in MCF-7 cells. RESULTS: The Pd(II) complex displayed approximately the same IC50 as Cisplatin, while Zn(II) complex had better activity than Cisplatin with very low IC50, 1.40 µg/ml. Significant alterations in SOD, CAT, GPx, and MDA production were discovered, inducing oxidative stress, enlarging ROS production, and reducing the antioxidant amount. This change was approximately similar in most compounds. Consequently, it promoted apoptosis, particularly the Zn(II) complex, which demonstrated an improved impact because of its ability to influence the antioxidant defense systems of enzymes, mostly SOD and GPx, besides increasing MDA levels. CONCLUSION: It can be concluded that Zn(II) complex is the most effective anticancer drug since it induced a very similar genotoxic effect as Cisplatin and has a very low IC50 value.

Patient on Hemodialysis with Elevated International Normalized Ratio Presents for Removal of Residual Roots in the Mandible.

Dentists should consult the patient's nephrologist to obtain the most recent medical records for patients with chronic kidney disease (CKD) including the stage and level of control. Patients on hemodialysis are ideally seen the day after dialysis with consideration to arteriovenous shunt placement for blood pressure measurement and avoiding or changing the dose of certain drugs based on the patient's glomerular filtration rate. Drugs cleared during hemodialysis may require a supplemental dose. Patients taking oral anticoagulants and requiring oral surgery should have the international normalized ratio (INR) measured the day of the procedure.

Patient with End-Stage Liver Disease and Prolonged Prothrombin Time Presents for Placement of a New Dental Implant.

Dentists should consult with the patient's hepatologist to obtain the most recent medical records with liver function tests and a coagulation panel. In the absence of severe liver dysfunction and with good medical management, dentists may proceed with treatment. Isolated prolongation of prothrombin time does not reflect a risk of bleeding and other coagulation parameters should be assessed. Amide local anesthesia can be safely administered and bleeding is controlled by local hemostatic measures and minimizing trauma. Other aspects of dental treatment that may require modification include the adjustment of doses of certain drugs metabolized by the liver.

Case of Bilateral Atrial Myxomas in Carney Syndrome.

Carney complex is rare neoplastic disorder. Intracardiac myxoma presenting the most common non-cutaneous lesions in this complex. We are reporting a 31-year-old Saudi female known case of Carney complex presented with asymptomatic biatrial myxoma that was identified on routine transthoracic echocardiogram, and was successfully excised. However, these patients need a careful surveillance in order to detect any new masses and prevent their complications.

The role of CD8+ T-cell clones in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multidimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterized patients with ITP and compared them with age-matched controls using immunophenotyping, next-generation sequencing of T-cell receptor (TCR) genes, single-cell RNA sequencing, and functional T-cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L-) expressing intracellular interferon gamma, tumor necrosis factor α, and granzyme B, defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the TCR showed expanded T-cell clones in patients with ITP. T-cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP.

Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations.

Telomerase is an outstanding biological target for cancer treatment. BIBR1532 is a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising telomerase inhibitors. Therefore, two novel series of pyridazine-linked to cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized to investigate the telomerase inhibitory activity of candidates. Notably, 8e and 9e exhibited the best inhibition profiles. Moreover, 8e showed strong antitumor effects against both MCF-7 and A549 cancer cell lines. The effects of 8e on the cell cycle and apoptosis were measured. Besides, 8e was evaluated for its in vivo antitumor activity using solid Ehrlich carcinoma. The reduction in both the tumor weight and volume was greater than doxorubicin. Also, molecular docking and ADME studies were performed. Finally, a SAR study was conducted to gain further insights into the different telomerase inhibition potentials upon variable structural modifications.

Role of liver biopsy in management of liver diseases without hepatic nodules following end of the interferon era: experience of a tertiary referral center.

Liver biopsy (LB) is the cornerstone in the management of patients with liver diseases. However, a lot of queries had emerged about its role following the end of the interferon era. The aim of this study was to re-evaluate the current role of LB in the diagnosis of liver diseases. All patients who had underwent LB at the Department of Hepatology, National Liver Institute, from January 2015 through December 2018 were recruited. Indications for LB, pathology reports and medical records of all cases were retrieved, reviewed and statistically analyzed. A total of 275 liver biopsies were collected, 191 males and 84 females with mean age 41.22 ± 13.36 years. Etiological diagnosis made by histopathological evaluation was 48 drug-induced liver injury (DILI), 42 nonalcoholic fatty liver disease (NAFLD), 34 chronic hepatitis B, or C with cholestasis, 29 autoimmune hepatitis, 34 primary sclerosing cholangitis, 13 primary biliary cholangitis, 7 autoimmune overlap syndrome, 13 active bilharziasis and 10 Wilson's disease. Minor number of cases was diagnosed by different other etiologies. Initial diagnosis was made by liver biopsy and confirmed by clinical response and laboratory findings. Liver biopsy is still considered as the gold standard diagnostic measure of different liver diseases representing an integral component of management decisions in hepatology.

Clinical applications of heart rhythm monitoring tools in symptomatic patients and for screening in high-risk groups.

Recent technological advances have facilitated and diversified the options available for the diagnosis of cardiac arrhythmias. Ranging from simple resting or exercise electrocardiograms to more sophisticated and expensive smartphones and implantable cardiac monitors. These tests and devices may be used for varying periods of time depending on symptom frequency. The choice of the most appropriate heart rhythm test should be guided by clinical evaluation and optimized following accurate characterization of underlying symptoms, 'red flags', risk factors, and consideration of cost-effectiveness of the different tests. This review provides evidence-based guidance for assessing suspected arrhythmia in patients who present with symptoms or in the context of screening, such as atrial fibrillation or advanced conduction disturbances following transcatheter aortic valve implantation in high-risk groups. This is intended to help clinicians choose the most appropriate diagnostic tool to facilitate the management of patients with suspected arrhythmias.