Pyrimidine-fused Dinitrogenous Penta-heterocycles as a Privileged Scaffold for Anti-Cancer Drug Discovery

Pyrimidine-fused derivatives that are the inextricable part of DNA and RNA play a key role in the normal life cycle of cells. Pyrimidine-fused dinitrogenous penta-heterocycles including pyrazolopyrimidines and imidazopyrimidines is a special class of pyrimidine-fused compounds contributing to an important portion in anti-cancer drug discovery, which have been discovered as core structure for promising anti-cancer agents used in clinic or clinical evaluations. Pyrimidine-fused dinitrogenous penta-heterocycles have become one privileged scaffold for anti-cancer drug discovery. This review consists of the recent progress of pyrimidine-fused dinitrogenous penta-heterocycles as anti-cancer agents and their synthetic strategies. In addition, this review also summarizes some key structure-activity relationships (SARs) of pyrimidine-fused dinitrogenous penta-heterocycle derivatives as anti-cancer agents.

Study on the expression level of NF-κB and clinical evaluations in spinal tuberculosis patients

Spinal tuberculosis or tuberculous spondylitis is one of the most common types of skeletal tuberculosis. Complications of the spine and spinal cord tuberculosis include destruction of the vertebrae, deformity, and paraplegia. Since in some patients, the clinical manifestations of tuberculosis are unusual and timely diagnosis and treatment of this disease can prevent its serious consequences, so in the present study, some cases of rare manifestations of tuberculosis were investigated. The expression of the NF-κB gene in these patients was also evaluated. In this regard, 36 patients with spinal tuberculosis and 30 healthy individuals (as a control group) were assessed. Clinical symptoms, imaging, laboratory tests, pathology, and response to treatment related to patients with spinal tuberculosis and spinal cord tuberculosis were evaluated. NF-κB expression was also evaluated using the PCR technique in peripheral white blood cell samples. The obtained results were analyzed using SPSS ver. 16, χ2 and T-test statistical methods. Mann-Whitney U test and Kruskal–Wallis non-parametric tests were used to analyze non-parametric data. The results showed that out of 36 cases of spinal tuberculosis, 29 cases had spinal tuberculosis, five cases had tuberculous radiculomyelitis, one case had spinal intramedullary tuberculoma, and one case had syringomyelia. 52.78% of patients were male, and 70% of cases were observed between the ages of 35 and 55 years. Fever and back pain were seen in more than 80% of cases. The study of NF-κB expression in the control and case groups showed that the NF-κB expression in the case group increased compared to the control group. This increase was statistically significant (P = 0.0071). In general, in the present study, the methods of clinical diagnosis of spinal tuberculosis were evaluated. Also, the amount of NF-κB transcription factor was evaluated as an effective genetic factor in the diagnosis of this disease.

Effectiveness of immediate vs. delayed recall in detecting invalid performance in coached and uncoached simulators: Results of two experimental studies

Objective: Two experimental studies were conducted to compare the ability of immediate and delayed recall indicators to discriminate between performances of simulators and full-effort clinical and nonclinical participants. Methods: Three groups of simulators (uncoached, symptom-coached, and testcoached), one group of community controls, and one group of cognitively impaired patients were assessed with four experimental memory tests, in which the immediate and delayed recall tasks were separated by three other tasks. Results: Across both studies, delayed recall demonstrated higher accuracy than immediate recall in classifying simulated performances as invalid, as compared to performances of bona fide clinical participants. ROC curve results showed sensitivities below 50% for both indicators at specificities of ≥ 90%. Computing performance curves across recall trials revealed descending trends for all three simulator groups indicating a suppressed learning effect as a marker of noncredible performances. Among types of coaching, test-coaching proved to decrease differences between simulators and patients. Discussion: The effectiveness of such indicators in clinical evaluations and their vulnerability to information about test-taking strategies are discussed.

Detection of Microorganisms in Body Fluids via MTT-PMS Assay

Early detection of microorganisms is essential for the management of infectious diseases. However, this is challenging, as traditional culture methods are labor-intensive and time-consuming. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-phenazine methosulfate (MTT-PMS) assay has been used to evaluate the metabolic activity in live cells and can thus be used for detecting living microorganisms. With the addition of NaOH and Tris-EDTA, the same approach can be accelerated (within 15 min) and used for the quick detection of common bacterial pathogens. The assay results can be evaluated colorimetrically or semi-quantitatively. Here, the quick detection by MTT-PMS assay was further investigated. The assay had a detection limit of approximately 104 CFU/mL. In clinical evaluations, we used the MTT-PMS assay to detect clinical samples and bacteriuria (>105 CFU/mL). The negative predictive value of the MTT-PMS assay for determining bacteriuria was 79.59% but was 100% when the interference of abnormal blood was excluded. Thus, the MTT-PMS assay might be a potential “rule-out” tool for bacterial detection in clinical samples, at a cost of approximately USD 1 per test. Owing to its low cost, rapid results, and easy-to-use characteristics, the MTT-PMS assay may be a potential tool for microorganism detection.

Analytical sensitivity of seven SARS-CoV-2 antigen-detecting rapid tests for Omicron variant

The emergence of novel SARS-CoV-2 variants of concern (VOCs) requires investigation of a potential impact on diagnostic performance, especially on Antigen-detecting rapid antigenic tests (Ag-RDT). Although anecdotal reports have been circulating that Omicron is in principle detected by several Ag-RDTs, no published data are a yet available for the newly emerged Omicron variant. Here, we have performed an analytical sensitivity testing with cultured virus in seven Ag-RDTs for their sensitivity to Omicron compared to data earlier obtained on VOCs Alpha, Beta Gamma and Delta and a pre-VOC isolate of SARS-CoV-2. Overall, we have found a tendency towards lower sensitivity for Omicron compared to pre-VOC SARS-CoV-2 and the other VOCs across tests. Importantly, while analytical testing with cultured virus may be a proxy for clinical sensitivity, is not a replacement for clinical evaluations which are urgently needed for Ag-RDT performance in Omicron-infected individuals.

The Development of the Extravascular Defibrillator with Substernal Lead Placement: A New Frontier for Device-Based Treatment of Sudden Cardiac Arrest

Introduction: The extravascular ICD (EV ICD) system with substernal lead placement is a novel non-transvenous alternative to current commercially available ICD systems. The EV ICD provides defibrillation and pacing therapies without the potential long-term complications of endovascular lead placement. Methods: This paper summarizes the development of the EV ICD, including the pre-clinical and clinical evaluations that have contributed to system and procedural refinements to date. Results: Extensive pre-clinical research evaluations and 4 human clinical studies with >140 combined acute and chronic implants have enabled the development and refinement of the EV ICD system, currently in worldwide pivotal study. Conclusion: The EV ICD may represent a clinically valuable solution in protecting patients from sudden cardiac death while avoiding the long-term consequences of transvenous hardware. The EV ICD offers advantages over transvenous and subcutaneous systems by avoiding placement in the heart and vasculature; relative to subcutaneous systems, EV ICD requires less energy for defibrillation, enabling a smaller device, and provides pacing features such as anti-tachycardia and asystole pacing in a single system.

Development of Sacral Ratio Percentile Card for Children: A Preliminary Report

Introduction Sacrospinal anomalies that may accompany anorectal malformations may cause fecal and urinary incontinence despite proper anomaly treatment. The sacral ratio has been suggested in the determination of both the prognosis in terms of incontinence and the need for further examination for sacrospinal anomalies. The normal and clinically decisive values of sacral ratio are given differently in publications. We aimed to determine the distribution of the sacral ratio in children under 12 months and to develop the sacral ratio percentile card that will enable one to give an age-independent parametric result in clinical evaluations. Materials and Methods The files of patients under 1 year of age who had anteroposterior direct radiography including pelvis were reviewed retrospectively. Sacral ratio was studied for 360 patients, 30 patients per month. Percentile card was developed with LMS software and reference values were used as 1, 2, 3, 4, and 10%. Results The lowest sacral ratio value was 0.514 and the highest value was 0.936. There was no statistical difference between the mean sacral ratio of the cases when they were classified on a monthly basis (p = 0.191). Low percentile values were found slightly different at first 4 months of age. Conclusion Although the mean of sacral ratio does not change significantly during the first year of life, values that are considered pathological for patients are within different percentile limits depending on age. Instead of using sacral ratio with some clinically decisive values, we think that parametric evaluation with the help of the percentile card will increase its clinical value.

Small airway dysfunction on impulse oscillometry and pathological signs on lung ultrasound are frequent in post-COVID-19 patients with persistent respiratory symptoms

Background Thousands of people worldwide are suffering the consequences of coronavirus disease-2019 (COVID-19), and impulse oscillometry (IOS) and lung ultrasound (LUS) might be important tools for the follow-up of this population. Our objective was to prospectively evaluate abnormalities detected using these two methods in a cohort of COVID-19 survivors with respiratory symptoms. Methods In this follow-up study, 59 patients underwent clinical evaluations, spirometry, IOS and LUS in the 2nd (M1) and 5th (M2) months after diagnostic confirmation of COVID-19 by real-time reverse transcriptase–polymerase chain reaction. Aeration scores were obtained from the LUS exams based on the following findings: B-lines >2, coalescent B-lines, and subpleural consolidations. Results Fifty-nine (100%) participants had cough and/or dyspnea at M1, which decreased to 38 (64.4%) at M2 (p = 0.0001). Spirometry was abnormal in 26 (44.1%) and 20 (33.9%) participants at M1 and M2, respectively, although without statistical significance (p = 0.10). Normal examination, restrictive patterns, and obstructive patterns were observed in 33 (55.9%), 18 (30.5%), and 8 (13.6%) participants, respectively, at M1 and in 39 (66.1%), 13 (22%), and 7 (11.9%) participants at M2 (p = 0.14). Regarding IOS, considering changes in resistive and reactive parameters, abnormal exams were detected in 52 (88.1%) and 42 (71.2%) participants at M1 and M2, respectively (p = 0.002). Heterogeneity of resistance between 4 and 20 Hz >20% was observed in 38 (64.4%) and 33 (55.9%) participants at M1 and M2, respectively (p = 0.30). Abnormal LUS was observed in 46 (78%) and 36 (61%) participants at M1 and M2, respectively (p = 0.002), with a reduction in aeration scores between M1 and M2 [5 (2–8) vs. 3 (0–6) points, p<0.0001]. Conclusions IOS and LUS abnormalities are frequent in the first 5 months post-COVID-19 infection; however, when prospectively evaluated, significant improvement is evident in the parameters measured by these two methods.

Prospective Factors that Predict American Board of Surgery In-Training Examination Performance: A Systematic Review

Introduction American Board of Surgery In-Training Examination (ABSITE) performance has become an important factor when monitoring resident progress. Understanding which prospective factors predict performance can help identify residents at risk. Methods A literature search was conducted searching PubMed, EMBASE, and JAMA Network from June 2011 to June 2021, in accordance with the PRISMA guidelines. Searches were performed for the terms “ABSITE” and “American Board of Surgery In-Training Examination.” Prospective factors such as prior examination performance, clinical evaluations, and demographics were evaluated. Results A final 35 studies were included. The prospective factor most consistently found to predict ABSITE performance is performance on prior knowledge-based examinations such as the USMLE step exams. The ACGME Medical Knowledge 1 milestone evaluation also appears to correlate to ABSITE performance, although clinical evaluations, in general, do not. Demographics have no significant correlation to ABSITE performance. Discussion Using performance on prior knowledge-based examinations programs may be able to identify residents at risk for failing ABSITE. It may be possible to initiate early intervention before rather than only remediation after poor performance.