Cell Context is the third axis of synergy for the combination of ATR inhibition and cisplatin in Ewing sarcoma.

PURPOSE: The importance of cellular context to the synergy of DNA Damage Response (DDR) targeted agents is important for tumors with mutations in DDR pathways, but less well-established for tumors driven by oncogenic transcription factors. In this study, we exploit the widespread transcriptional dysregulation of the EWS-FLI1 transcription factor to identify an effective DDR targeted combination therapy for Ewing Sarcoma (ES). EXPERIMENTAL DESIGN: We used matrix drug screening to evaluate synergy between a DNA-PK inhibitor (M9831) or an ATR inhibitor (berzosertib) and chemotherapy. The combination of berzosertib and cisplatin was selected for broad synergy, mechanistically evaluated for ES selectivity, and optimized for in vivo schedule. RESULTS: Berzosertib combined with cisplatin demonstrates profound synergy in multiple ES cell lines at clinically achievable concentrations. The synergy is due to loss of expression of the ATR downstream target CHEK1, loss of cell cycle checkpoints, and mitotic catastrophe. Consistent with the goals of the project, EWS-FLI1 drives the expression of CHEK1 and five other ATR pathway members. The loss of CHEK1 expression is not due to transcriptional repression and instead caused by degradation coupled with suppression of protein translation. The profound synergy is realized in vivo with a novel optimized schedule of this combination in subsets of ES models leading to durable complete responses in 50% of animals bearing two different ES xenografts. CONCLUSION: These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule.

Giant Chorioangioma of the Placenta as a Cause of Maternal, Foetal, and Neonatal Complications.

Chorioangioma is a benign placental neoplasm seen in about one percent of all pregnancies. The larger neoplasms generally cause severe foeto-maternal complications. We are reporting a case of a 33-year-old gravida three para two female who was incidentally diagnosed with chorioangioma at her routine 28-week antenatal follow-up. She delivered a preterm small-for-gestational-age female baby at 34 weeks with complications. Therefore, an early diagnosis warrants a close follow-up and timely intervention for a better outcome of the pregnancy.

Efficacy of bioadhesives in the management of oral mucositis in patients undergoing radio-chemotherapy for treatment of head and neck cancer-a systematic review and meta-analysis.

BACKGROUND: Management of head and neck cancers requires a multidisciplinary approach where surgery followed by radio and chemotherapy is the mainstay of treatment. The above-mentioned treatment can cause mucositis, a severely debilitating side effect. This can have a significant impact on quality of life. A recent advancing mode of drug delivery is the bioadhesive system. This interacts with mucosa by adhering to it and thereby improving the efficacy of the therapeutic agent delivered. AIM AND OBJECTIVE: The purpose of this systematic review is to evaluate the effectiveness of bioadhesives in reducing oral mucositis and relieving pain associated with mucositis in head and neck cancer patients receiving radio-chemotherapy. MATERIALS AND METHOD: Studies assessing the effectiveness of bioadhesives for the treatment of radiation-induced oral mucositis were retrieved from specialized databases (PubMed/MEDLINE, Scopus, ProQuest, Google Scholar, LILACS, OpenGrey) as well as institutional repositories. Data on incidence, pain reduction, resolution, and improvement of oral mucositis using bioadhesive were compiled. A Cochrane tool was used for randomized controlled trials and a JBI tool for non-randomized controlled trials and observational studies to assess the quality of included studies. Based on the eligible study data, a meta-analysis was conducted with STATA version 16, 2019 software, and 95% confidence intervals and p values greater than 0.05. RESULTS: A total of 15 studies were included which assessed the effectiveness of bioadhesives in managing mucositis and its associated pain. Studies included in the review described either reduction, resolution, or incidence of oral mucositis respectively. A total of three meta-analyses were conducted to assess the incidence of oral mucositis and the pain associated with it, as well as the reduction in incidence. Bioadhesives showed statistically significant differences in the incidence of severe mucositis (p = 0.04). A meta-analysis comparing bioadhesives efficacy in reducing mucositis and pain associated with it found no statistically significant differences (p = 0.36). CONCLUSION: Bioadhesives are emerging as a novel drug delivery method for treating radio-chemotherapy-induced oral mucositis because of their rapid absorption and easy application. Regardless of its benefits, clinical trials comparing it with conventional treatment methods are necessary to assess its efficacy in treating oral mucositis.

Chronic Alcoholism and Its Health Implications: A Case Report.

Individuals with chronic alcohol use can be asymptomatic for a prolonged period of time and then exhibit signs of advanced heart and liver diseases with an abrupt onset. Herein, we present a case of a 60-year-old male with severe alcohol use disorder who presented with newly diagnosed atrial fibrillation (AF) with rapid ventricular response (RVR), dilated cardiomyopathy (DCM), and alcohol-associated cirrhosis following an episode of binge drinking.

Role of regional diffusion tensor imaging (DTI)-derived tensor metrics in the evaluation of intracranial gliomas and its histopathological correlation.

Background: The imaging of brain tumours has significantly improved with the use of advanced magnetic resonance (MR) techniques like diffusion tensor imaging (DTI). This study was conducted to analyse the utility of DTI-derived tensor metrics in the evaluation of intracranial gliomas with histopathological correlation and further adoption of these image-data analyses in clinical setting. Methods: A total of 50 patients with suspected diagnosis of intracranial gliomas underwent DTI along with conventional MR examination. The study correlated various DTI parameters in the enhancing part of the tumour and the peritumoral region with the histopathological grades of the intracranial gliomas. Results: The study revealed higher values of Cl (linear anisotropy), Cp (planar anisotropy), AD (axial diffusivity), FA (fractional anisotropy) and RA (relative anisotropy) and lower values of Cs (spherical anisotropy), MD (mean diffusivity) and RD (radial diffusivity) in the enhancing part of the tumour in case of high-grade gliomas. However, in the peritumoral region, the values of Cl, Cp, AD, FA and RA were less whereas values of Cs, MD and RD were more in high-grade gliomas than in the low-grade gliomas. The various cutoff values of these DTI-derived tensor metrics were found to be statistically significant. Conclusion: DTI-derived tensor metrics can be a valuable tool in differentiation between high-grade and low-grade gliomas which might be accepted in clinical practice in near future.

Importance of pharmacologic considerations in the development of targeted anticancer agents for children.

PURPOSE OF REVIEW: The purpose of this review is to describe key pharmacologic considerations to inform strategies in drug development for pediatric cancer. RECENT FINDINGS: Main themes that will be discussed include considering patient specific factors, epigenetic/genetic tumor context, and drug schedule when optimizing protocols to treat pediatric cancers. SUMMARY: Considering these factors will allow us to more effectively translate novel targeted therapies to benefit pediatric patients.

Synthesis, crystal structure, Hirshfeld surface analysis, energy frameworks and computational studies of Schiff base derivative.

The compound (E)-ethyl 3-(2-(2,4-dinitrophenyl)hydrazono)butanoate (3) was synthesised and crystallized using ethanol as a solvent. The compound was characterized by 1H NMR, and single crystal X-ray diffraction. The compound crystallizes in the monoclinic crystal system with the space group P21/c. The intermolecular interactions and the interaction energies responsible for the stabilization of the molecules were determined by Hirshfeld surface analysis and energy framework calculations. The structure of the compound was optimized by Density Functional Theory calculations and HOMO-LUMO energy gap was calculated. The non-covalent interactions were revealed by reduced density gradient analysis. The Mulliken atomic charges and natural atomic charges were calculated by density functional theory calculations. The reactive sites present in the molecule are shown by molecular electrostatic potential map. The inter and intra molecular charge transfer were investigated by NBO analysis.

Comparative evaluation of chelating efficacy of nano-chitosan, pomegranate extract, and ethylenediaminetetraacetic acid on primary radicular dentin: An in vitro study.

Background: Irrigation is a crucial aspect of root canal treatment, and it is imperative to employ chelating agents to eliminate the smear layer during biomechanical preparation. They in turn react with mineral content of dentin, leading to decreased strength and increased susceptibility to fracture. Aims: This study aimed to assess and compare mineral loss and microhardness from primary root canal dentin following the usage of different irrigating solutions and determine the least detrimental irrigant among the tested solutions. Materials and Methods: Sixty-six primary anterior teeth were divided into three groups with 22 in each- Group I: 17% ethylenediaminetetraacetic acid (EDTA) Group II: 0.2% Nano chitosan Group III: Pomegranate extract. The decoronated teeth were split longitudinally. Half of it was directly subjected to Vickers test, and the other half was immersed in a magnetic stirrer bath containing test solution to record the mineral loss from solution. Postmicrohardness values were recorded on the specimen and compared with initial values. Statistical Analysis Used: Statistical analysis was done using SPSS software (Version 20, SPSS, IBM, Armonk, NY, U. S. A). Results: Descriptive statistics were calculated, and the groups were compared using analysis of variance test and post hoc Tukey test. Pomegranate extract showed least effect on mineral content and microhardness compared to 17% EDTA and 0.2% nano chitosan. P ≤ 0.05 was considered statistically significant. Conclusion: Pomegranate aril extract showed better results with selected parameters.

The Epidemiology of Intensive Care Unit Readmissions and Proposed Discharge Protocol for a Tertiary Care Hospital.

BACKGROUND: Intensive Care Unit (ICU) readmissions during the same hospitalization are associated with increased hospital stays, morbidity and mortality. Whereas mortality rates in patients admitted to the ICU for the first time may range from 10 to 20% depending on various factors, readmission mortality rates can be up to 50 to 70%. Factors leading to readmission in ICU in Indian Armed Forces Hospitals have not been well studied till date. METHODS: This was a record based cross sectional descriptive study conducted at the ICU of a tertiary care Armed Forces hospital. Demographic and clinical data of ICU patients were analysed. ICU admission and discharge data for the duration of last three years were acquired from admission and discharge registers and Hospital Informatics system (HIS) software. The primary outcome was readmission rates to ICU during the same hospitalization. Secondary outcomes included diagnosis at time of index admission (first time admission) to ICU and at readmission, multiple readmissions to ICU and mortality rates in readmitted patients. RESULTS: There were 3021 admissions to the ICU during the study period. 422 patients succumbed to illness during initial admission resulting in a mortality rate of 14%. 198 patients were readmitted to the ICU. The readmission rate to the ICU was 7.8%. The mortality rate in readmitted patients was 31% as compared to the ICU mortality rate of 14%. The triggering factors for readmission were usually respiratory or cardiac decompensations. CONCLUSION: Readmission to ICU occurred in about 7.8 % of all ICU patients in our study. ICU readmissions increase the risk of adverse outcomes. Objective measures in the form of a discharge protocol incorporating the stability and work index for transfer (SWIFT Score) may help minimizing readmission to ICU. Such protocols must be in place while shifting any patients from ICU so as to improve outcomes in patients of tertiary care hospitals.

Clinical outcomes of thyroid tumours with concurrent epithelial and mesenchymal components in 14 dogs (2006-2020).

BACKGROUND: While rare, multiple individual case reports have described mixed thyroid tumours in dogs containing both epithelial and mesenchymal neoplastic components. OBJECTIVES: In this retrospective case series, we describe the clinical presentation, treatment and outcome of 14 dogs of canine thyroid tumours with concurrent mesenchymal and epithelial neoplastic populations. METHODS: Fourteen cases were retrospectively abstracted from nine institutions. Histopathologic samples and reports were collected from 10/14 dogs and reviewed by a single board-certified anatomic pathologist. RESULTS: All 14 dogs had curative-intent surgery to remove the thyroid neoplasm. The most common surgery performed was a unilateral thyroidectomy (10/14 dogs). Postoperatively, systemic therapy was administered in eight dogs. Six dogs developed local recurrence with a median time to loco-regional recurrence of 53 days. Ten dogs developed metastatic disease with the most common metastatic site being the lungs (6/10 dogs), with a median time to metastasis of 93 days. Ten dogs were euthanised due to locoregional or distant progression of their mixed thyroid neoplasm. The overall median survival time was 156 days (95%CI: 49-244). The median survival time for dogs treated with adjuvant therapy was 189 days (95%CI: 24-244), whereas dogs without adjuvant therapy had a median survival time of 156 days (95%CI: 35-upper limit could not be calculated; p = 0.62). CONCLUSION: The thyroid tumours with both mesenchymal and epithelial components in this small sample set were associated with a poor prognosis after surgical excision with or without adjunctive therapy.

Improved accuracy and fewer outliers with a novel CT-free robotic THA system in matched-pair analysis with manual THA.

Accurate component orientation and restoration of hip biomechanics remains a continuing challenge in total hip arthroplasty (THA). The goal of this study was to analyze the accuracy/reproducibility of a novel CT-free and pin-less robotic-assisted THA (RA-THA) platform compared to manual THA (mTHA). This matched-pair cadaveric study compared this RA-THA system to mTHA (n = 33/arm), both using the assistance of fluoroscopic imaging, in a group of 14 high-volume arthroplasty surgeons. In both groups, surgeons were asked to aim for 40°/15° for cup inclination/version, and 0 mm of leg length discrepancy (LLD). A validated and accurate method using radio-opaque markers measured cup inclination/version and LLD. The accuracy and reproducibility (fewer outliers) of cup inclination was significantly improved in the robotic group (1.8° ± 1.3° vs 6.4° ± 4.9°, respectively, robotic vs manual; p < 0.001), with no significant difference between groups for version. The reproducibility of LLD was significantly improved in the robotic group (p = 0.003). For all parameters studied, the robotic group had an improved accuracy and lower variance (fewer outliers). The percentage of cases within the more restrictive Callanan safe zone was 100% for RA-THA vs 73% for mTHA (p = 0.002). The CT-free RA-THA platform, using only fluoroscopic imaging, demonstrated more accurate acetabular cup positioning, when compared to the mTHA procedures performed by high-volume hip surgeons (naive to this RA-THA platform), with respect to cup inclination and placement within the Lewinnek/Callanan safe zones. Future study must incorporate economic factors, lower volume surgeons, clinical and patient-centric outcomes, and other radiographic parameters in controlled studies in large sample sizes.

Improved accuracy and reproducibility of a novel CT-free robotic surgical assistant for medial unicompartmental knee arthroplasty compared to conventional instrumentation: a cadaveric study.

PURPOSE: Alignment errors in medial unicompartmental knee arthroplasty (UKA) predispose to premature implant loosening and polyethylene wear. The purpose of this study was to determine whether a novel CT-free robotic surgical assistant improves the accuracy and reproducibility of bone resections in UKA compared to conventional manual instrumentation. METHODS: Sixty matched cadaveric limbs received medial UKA with either the ROSA® Partial Knee System or conventional instrumentation. Fifteen board-certified orthopaedic surgeons with no prior experience with this robotic application performed the procedures with the same implant system. Bone resection angles in the coronal, sagittal and transverse planes were determined using optical navigation while resection depth was obtained using calliper measurements. Group comparison was performed using Student's t test (mean absolute error), F test (variance) and Fisher's exact test (% within a value), with significance at p < 0.05. RESULTS: Compared to conventional instrumentation, the accuracy of bone resections with CT-free robotic assistance was significantly improved for all bone resection parameters (p < 0.05), other than distal femoral resection depth, which did not differ significantly. Moreover, the variance was significantly lower (i.e. fewer chances of outliers) for five of seven parameters in the robotic group (p < 0.05). All values in the robotic group had a higher percentage of cases within 2° and 3° of the intraoperative plan. No re-cuts of the proximal tibia were required in the robotic group compared with 40% of cases in the conventional group. CONCLUSION: The ROSA® Partial Knee System was significantly more accurate, with fewer outliers, compared to conventional instrumentation. The data reported in our current study are comparable to other semiautonomous robotic devices and support the use of this robotic technology for medial UKA. LEVEL OF EVIDENCE: Cadaveric study, Level V.

Challenges in the Implementation of Competency-Based Medical Curriculum: Perspectives of Prospective Academicians.

Introduction The medical education system all over the world is witnessing a paradigm shift from traditional methods of teaching to competency-based medical education. With the current curricular change, teachers are supposed to play a catalyst role in terms of moderating the different frameworks of competency-based medical education (CBME). Following the implementation of the new curriculum in India (2019), the present study aims to understand the challenges that medical teachers face in its implementation. Materials and methods This nationwide cross-sectional study was conducted among 297 teaching faculty representing 91 medical colleges across 20 states between February and July 2020. A self-validated structured questionnaire on the views of the newly implemented competency-based medical curriculum was prepared, uploaded as a Google form link, and circulated to medical teachers through an electronic platform across the country The faculty responses were exported and analyzed using Microsoft Excel. Results Around 77.4% opined that making incremental changes to the old curriculum would have been better than the overhaul revision, and 85.6% have opined that input from more faculty must have been taken before implementing the new curriculum. Around 80% felt that the pace at which faculty are getting trained in the nodal/regional center is not adequate, and 75% of them believed that the faculty members are not adequate for preparatory work for CBME implementation. About 74.7% opined that framing specific learning objectives (SLOs) for all competencies is time-consuming. Conclusion It is the need of the hour for the curriculum to incorporate a systematic feedback mechanism built into the system. Despite the fact that many of the suggested changes are progressive, given the time and resource constraints, this can only be accomplished through the concerted and combined efforts of all those involved in medical education.

Knowledge, Attitude, and Practice among the Healthcare Professionals regarding the myths on COVID-19 vaccination - Demystified.

BackgroundCOVID-19 vaccine is the mighty weapon opted by all the countries across the globe in an attempt to eradicate the fatal COVID-19 pandemic. The myths on the COVID-19 vaccine are spreading widely, causing a hindrance to this noble preventive measure. The prevalence of such myths among the healthcare professionals may be toxic and deadly. Aim & ObjectivesTo assess the knowledge, attitude, and practice of the healthcare professionals regarding the myths on COVID-19 vaccination and to demystify them. Materials and MethodsAn 18-item questionnaire evaluating knowledge, attitude, and practice based on the existing myths on COVID-19 vaccination was circulated through Google Forms(R) among the 412 healthcare professionals of six disciplines belonging to a private University. The responses obtained were subjected to statistical analysis using SPSS(R) 20 software package. ResultsA total of 385 health professionals participated in this study. The majority of them had medium knowledge (165) and positive attitude (273) with the mean knowledge and attitude scores of 3.82 {+/-} 1.55 out of 6 and 4.3 {+/-} 1.58 out of 7 respectively. Even though 312 participants got vaccinated, 72 of them failed to receive it. The knowledge scores showed a high statistically significant difference among the participants of different designations (p=0.001), but not with gender, field, and staff with different years of experience (p>0.05). The attitude scores were statistically different among participants of fields and designation (p<0.05) but not among genders (p=0.31) and staff with different years of experience (p=0.87). Knowledge and attitude scores showed a positive linear correlation and a high statistically significant difference (p<0.001). ConclusionThis study recommends more enhanced education programs on COVID-19 vaccination for the health professionals and demands an improved knowledge, attitude, and practice among them to achieve the goal of 100% vaccination so as to completely eradicate the COVID-19 pandemic.

Synthesis, structural characterization, and DFT studies of anti-cancer drug N-(2-Aminophenyl)-2-(4-bromophenoxy)acetamide.

Drug design is an integrated and developing system that portends an era of a novel and safe tailored drugs. It involves studying the effects of biologically active synthetic, semi-synthetic, and natural compounds based on molecular interactions in terms of molecular structure with activated functional groups or its unique physicochemical properties involved. The title compound, N-(2-aminophenyl)-2-(4-bromophenoxy) acetamide (c), was synthesized in a good yield and characterized by different spectroscopic techniques (1H, 13CNMR, and LC-MS) and finally, the structure was confirmed by X-ray diffraction (XRD) studies. The XRD data confirms that the cryatal structure is orthorhombic with space group of Pca2 1 . The intermolecular interactions (N-H … O and N-H … Cg) inside the molecule stabilizes the crystal structure. The existence of this intermolecular interactions are computed by the Hirshfeld surfaces (HS) and two-dimensional (2D) fingerprints plot analysis. In addition to this, Energy frame work analysis is performed to quantify the interaction energies between the molecular pairs in a crystal by incorporating new version of CrystalExplorer17 using the energy model of HF/3-21G. Also to calculate the HOMO and LUMO energies, DFT calculations were carried out.

Canine leishmaniasis in Northern California-A case report.

A 3-year-old dog was referred to the Veterinary Medical Teaching Hospital of the University of California-Davis for further evaluation of episodes of epistaxis of 1-year duration and peripheral lymphadenopathy. The patient had a history of atopic dermatitis with no travel history outside of California. Hyperglobulinemia with a polyclonal gammopathy was noted on serum protein electrophoresis. Microscopic evaluation of a bone marrow aspirate sample revealed many free and intra-cellular amastigotes of Leishmania sp. that was further confirmed by qPCR as L infantum. This is, to the best of our knowledge, the first reported case of canine leishmaniasis in the state of California. The patient is believed to have been vertically infected from the dam who is from Serbia and remained subclinical until presentation. Because the clinical progression of leishmaniasis is variable, it is important that precautions be discussed with owners acquiring puppies with dams from endemic regions of leishmaniasis to prevent zoonotic exposure in states where competent vectors are present.