Synthesis, anticancer evaluation, molecular docking and ADME study of novel pyrido[4',3':3,4]pyrazolo[1,5-a]pyrimidines as potential tropomyosin receptor kinase A (TrKA) inhibitors.

The starting compound 3-amino-1,7-dihydro-4H-pyrazolo[4,3-c]pyridine-4,6(5H)-dione (1) is reacted with each of diketone and ß-ketoester, forming pyridopyrazolo[1,5-a]pyrimidines 4a,b and 14a,b, respectively. The compounds 4 and 14 reacted with each of aromatic aldehyde and arenediazonium salt to give the respective arylidenes and arylhydrazo derivatives, respectively. The structure of the new products was established using spectroscopic techniques. The cytotoxic activity of selected targets was tested in vitro against three cancer cell lines MCF7, HepG2 and HCT116. The data obtained from enzymatic assays of TrKA indicated that compounds 7b and 16c have the strongest inhibitory effects on TrKA with IC50 = 0.064 ± 0.0037 µg/ml and IC50 = 0.047 ± 0.0027 µg/ml, respectively, compared to the standard drug Larotrectinib with IC50 = 0.034 ± 0.0021 µg/ml for the HepG2 cancer cell line. In cell cycle analysis, compounds 7b, 15b, 16a and 16c caused the greatest arrest in cell cycle at the G2/M phase. In addition, compound 15b has a higher apoptosis-inducing effect (36.72%) than compounds 7b (34.70%), 16a (21.14) and 16c (26.54%). Compounds 7b, 16a and 16c were shown fit tightly into the active site of the TrKA kinase crystal structure (PDB: 5H3Q). Also, ADME study was performed on some selected potent anticancer compounds described in this study.

Predictors of outcomes in patients with obesity following mitral valve surgery.

Objective: Few studies have assessed the outcomes of mitral valve surgery in patients with obesity. We sought to study factors that determine the in-hospital outcomes of this population to help clinicians provide optimal care. Methods: A retrospective analysis of adult patients with obesity who underwent open mitral valve replacement or repair between January 1, 2012, and December 31, 2020, was conducted using the National Inpatient Sample. Weighted logistic regression and random forest analyses were performed to assess factors associated with mortality and the interaction of each variable. Results: Of the 48,775 patients with obesity, 34% had morbid obesity (body mass index ≥40), 55% were women, 66% underwent elective surgery, and 55% received isolated open mitral valve replacement or repair. In-hospital mortality was 5.0% (n = 2430). After adjusting for important covariates, a greater risk of mortality was associated with older patients (adjusted odds ratio [aOR], 1.24; 95% CI, 1.08-1.43), higher Elixhauser comorbidity score (aOR, 2.10; 95% CI, 1.87-2.36), prior valve surgery (aOR, 1.63; 95% CI, 1.01-2.63), and more than 2 concomitant procedures (aOR, 2.83; 95% CI, 2.07-3.85). Lower mortality was associated with elective admissions (aOR, 0.70; 95% CI, 0.56-0.87) and valve repair (aOR, 0.58; 95% CI, 0.46-0.73). Machine learning identified several interactions associated with early mortality, such as Elixhauser score, female sex, body mass index ≥40, and kidney failure. Conclusions: The complexity of presentation, comorbidities in older and female patients, and morbid obesity are independently associated with an increased risk of mortality in patients undergoing open mitral valve replacement or repair. Morbid obesity and sex disparity should be recognized in this population, and physicians should consider older patients and females with multiple comorbidities for earlier and more opportune treatment windows.

Does valve morphological type impact TAVR outcomes?

Appropriate treatment for the bicuspid aortic valve demands attention to detail across the spectrum of bicuspid morphological types. Transcatheter aortic valve replacement outcomes, while encouraging, require in-depth evaluation before generalization to improve the precision of care.

The influence of preoperative CT imaging on surgical delay in patients with acutely symptomatic abdominal wall hernias.

PURPOSE: Abdominal wall hernias are common in the UK and many present in an emergent fashion. The widespread introduction of computed tomography (CT) imaging has transformed surgical practice but out of hours access can be limited by hospital resources and introduce delays. We investigated the influence of preoperative CT imaging in acutely symptomatic hernia and the association with surgical delay and risks of bowel ischemia. METHODS: A retrospective analysis of patients undergoing emergency hernia surgery between 2013 and 2021 in a busy UK district general hospital. We evaluated the role of preoperative CT and its influence on timing of surgery, postoperative complications, critical care admission and hospital length of stay. RESULTS: Five hundred and five patients were studied. Of these, 191 had a preoperative CT scan. Sites of hernia included inguinal in 164 patients (33%); umbilical in 164 (33%); femoral in 69 (14%); incisional in 69 (14%); epigastric in 30 (6%) and Spigelian hernia 9 (2%). Preoperative CT imaging was associated with surgical delay (22.0 h vs 13.0 h, p < 0.001) and an increased need for bowel resection (12% vs 6%, p = 0.027). Delay in surgery was not associated with increased postoperative complications (5% vs 4%, p = 0.474) but was associated with increased critical care admission (11.0% vs 4.8%, p = 0.014). CONCLUSIONS: Preoperative CT scan for emergent hernias can delay often inevitable surgery and is associated with an increasing need for more complex, resectional surgery .

An Online Management System for Streamlining and Enhancing the Quality of Learning Outcomes Assessment.

Learning outcomes assessment is an effective academic quality assurance tool that enables educators to review and enhance the alignment between planned, delivered, and experienced curricula. Accurately assessing what students know and are able to do after completing a learning module is the first step to decide on the strategies to implement and the proper actions to take in order to ensure the continuous improvement of the student learning experience. Nonetheless, learning outcomes assessment processes in higher education are still facing major challenges that affect their proper and effective implementation. Hence, faculty do not usually experience noticeable improvement in the students' performance over several assessment cycles, which causes their frustration and reluctance to continue participating in the assessment process. This paper discusses the main issues that affect the implementation of the assessment process and prevent the closure of the assessment loop. It also introduces a unified assessment process and an online management system that have been developed recently to address the discussed issues. The online management system streamlines the assessment process, while providing administrators and quality assurance officers with valuable infographics and reports to effectively oversee the implementation of the assessment process. The system has been deployed at the United Arab Emirates University since fall 2018, and has been successfully used by faculty to assess the learning outcomes for more than 1000 courses each semester. Moreover, collected statistics showed that the online features provided by the system allowed faculty to continue their assessment tasks seamlessly during the COVID-19 pandemic.

Perceived stigma and healthcare services in healthcare settings among people living with HIV in Egypt: a qualitative study.

BACKGROUND: The researchers conducted the current study to explore the perspectives of people living with HIV (PLHIV) on HIV-related discrimination and the delivery of healthcare services in healthcare settings. METHODS: An exploratory study using a qualitative approach was conducted among 46 PLHIV who were seeking HIV counselling and treatment from two HIV centres in the Cairo governorate using a purposive sampling technique. RESULTS: A thematic content analysis was used to examine the responses. Participants had a combination of positive and negative experiences. Some participants reported staff acceptance and friendliness towards HIV-positive patients on antiretroviral treatment. Most interviewees observed that staff took extra precautions when treating or caring for them. The majority stated that counselling about the effects of the treatment was inadequate and that testing was either too far from their homes or at overcrowded centres with long waiting times. All the interviewees recommended ongoing communication and HIV counselling skills for healthcare providers who are in contact with HIV patients. CONCLUSION: Most of the study participants were not satisfied with HIV services in the participating centres, as well as experiencing stigma. More investment in enhancing the quality of HIV service delivery and reinforcement of health worker competencies, mainly in HIV counselling, may improve satisfaction, bearing in mind HIV-related stigma in the centres involved.

Clinicopathologic features and therapy outcome in childhood Hodgkin's lymphoma: a report from tertiary care center in Saudi Arabia.

BACKGROUND: Hodgkin lymphoma (HL) is lymphoid neoplasm usually affecting lymphatic system; it accounts 3.6% of cancers in Saudi Arabia. Modern treatment protocols had shown particular success rates in overall-survival (OS) and event-free-survival (EFS). In our study, we reviewed the medical records of 80 pediatric and young adolescent patients diagnosed HL from January 2006 to July 2020, treated at tertiary care hospital in Riyadh, Saudi Arabia. Demographic, clinical, and pathological data were explored. First line therapy was ABVD, COG, COPP, R-CHOP, or radiotherapy alone in 53/80 (66.4%), 24/80 (30%), 1/80 (1.2%), 1/80 (1.2%), or 1/80 (1.2%) patients; respectively. Response assessment was done by CT + / - PET scan after first 2 cycles then every 2 cycle and end of therapy. Another assessment was done if any clinical suspicion of recurrence. RESULTS: Median age 11 (range 3-16) years. Males to females 1.3:1. Seventy-two out of eighty (90%) patients showed first complete remission (CR1) and maintained remission for median 40 (range 7-136) months. Eight out of eighty (10%) patients showed refractory disease. Nineteen patients received salvage therapy (ICE or ESHAP/brentuximab vedotin or gemcitabine/brentuximab vedotin), 14/19 (73.7%) had 2nd complete remission (CR2) for median time 24 (ranged 9-78) months, while 5/19 (26.3%) did not show any response. Five-year OS and EFS were 95% and 75%. Two patients had 2ry malignant neoplasms, one had AML and died, the other had malignant fibrous histocytoma and still alive. None of our patients had fertility problem. Also, they did not experience chronic pulmonary or cardiotoxicity. Classic Hodgkin's lymphoma: nodular sclerosis subtype was more prominent (55%) than mixed cellularity subtype (22.5%), which is similar to several European and US studies, lymphocyte rich (11.25%) and lymphocyte depleted (0%), while nodular lymphocyte predominant Hodgkin's lymphoma (11.25%). CONCLUSIONS: Our study provided unique descriptive study of childhood HL, in Saudi Arabia, with valuable insight into the long-term outcome and late toxicity. Our results are comparable to other studies in the Middle East and European countries.

Assessment of Health-related Quality of Life in Saudi Children with Cancer.

Advances in pediatric cancer treatment and dramatic improvement in long-term survival have made health-related quality of life (HRQOL) a priority. This study describes the HRQOL of Saudi children on cancer treatment, given the paucity of data on the subject. Parents of children undergoing cancer treatment between the ages of 2 and 12 years enrolled to answer the Arabic version of the parent proxy report PedsQL™ 3.0 cancer module. The module items were reverse-scored to a linear scale from 0 to 100, in which higher scores indicated a better HRQOL. Of the 95 study participants, 61 (64.2%) were hematological malignancies and 34 (35.8%) solid malignancies. The mean score of our sample's total HRQOL was 72.3, which is in line with the results of similar studies worldwide. The lowest scores were observed for procedural anxiety (60.14), perceived physical appearance (67.37), and treatment anxiety (67.58), while the highest were for communication (80.21), nausea (78.32), and cognitive problems (78.32). Significant associations were reported between the patients aged younger than 5 years and procedural anxiety, those aged 5 years or older and perceived physical appearance, and frequent hospital visits and worry. Healthcare professionals should consider the poor HRQOL sub-scales and their associated risks to improve treatment outcomes.

Rare tumors in pediatric age group: Single center experience from Saudi Arabia.

Rare pediatric tumors are heterogeneous group containing a variety of histopathological diseases, they represent approximately 10% of all childhood cancers. These rare tumors had a diversity of histology and clinical behaviors that pose different challenges to the investigators. Exploring different pediatric rare tumors. The data were reviewed, retrospectively, through the medical records of seven rare pediatric diseases between 2012 and 2019. Giant cell fibroblastoma (GCF) presented as painless swelling in the trunk, positive for CD34 with PTEN gene mutation. Neuroglial heterotopic tissue presented in 7 days old girl with facial asymmetry and bulging in the oral cavity, maximal de-bulking was done, histopathology was positive for GFAP and S100p. Left side neck mass, surgically excised revealed non-metastatic salivary grand mucoepidermoid carcinoma. Follow up without any chemotherapy or radiotherapy for 5 years with complete remission. Mesenchymal chondrosarcoma (MCS) presented in maxillofacial bones by persistent nasal bleeding, HEY1-NCOA2 fusion gene confirmed the diagnosis. Extra-osseous Ewing sarcoma (EES) presented as rubbery painless swelling in the scalp with fusion transcript involving EWSR1-FL11. Juvenile xanthogranuloma (JXG) presented by butter fly like skin patch in the face with foamy histiocytes in upper dermis with few Touton giant cells, extensive systemic involvement of lung and bone marrow. Metastatic ovarian choriocarcinoma with choriocarcinoma syndrome received induction two different lines of chemotherapy and consolidated with autologous stem cell transplant. Seven pediatric rare tumors, with different aspects of challenges in diagnosis and management, despite the absence of formal protocols and rarity of other center experiences.

Giant right atrium: a long-term complication of rheumatic heart disease.

Giant right atrium (RA) is a rare entity often seen during childhood due to congenital anomalies. Limited literature has reported such finding in patients with rheumatic valvular heart disease. Here we present a case of a 68-year-old female with a history of rheumatic valve disease treated with a Starr Edwards mechanical ball-in-cage mitral valve replacement and tricuspid valve annuloplasty ring procedures. The patient developed heart failure and had multiple hospital admissions over three decades for heart failure exacerbations mostly triggered by medication and dietary non-compliance. She eventually developed a giant RA that filled most of her thorax. This case demonstrates an extreme form of cardiac remodeling caused by long-term rheumatic valvular heart disease.

Causes and Clinical Impact of Loss to Follow-Up in Patients with Proliferative Diabetic Retinopathy.

PURPOSE: This study determined the clinical impact and causes of loss to follow-up (LTFU) from the patients' perspective in individuals with proliferative diabetic retinopathy (PDR) who received panretinal photocoagulation (PRP) and/or intravitreal injections (IVIs) of antivascular endothelial growth factor (VEGF). METHODS: This prospective cohort study included 467 patients with PDR who received PRP and/or IVIs of anti-VEGF between May 2013 and June 2018. LTFU was defined as missing any follow-up visit for any interval exceeding 6 months, provided that patients eventually resumed care. Main outcome measures include rates and causes of LTFU. RESULTS: A total of 391 patients (83.7%) were followed up, and 76 patients (16.3%) were LTFU over the study period. Rates of LTFU decreased with age (P=0.005). Questionnaire analysis conducted for patients' LTFU showed a significant positive correlation between best corrected visual activity (BCVA) loss and patient's lack of trust and satisfaction with treatment (rs = 0.458, P=0.005). Questionnaire analysis conducted for patients' LTFU showed a significant positive correlation between best corrected visual activity (BCVA) loss and patient's lack of trust and satisfaction with treatment (rs = 0.458, P=0.005). Questionnaire analysis conducted for patients' LTFU showed a significant positive correlation between best corrected visual activity (BCVA) loss and patient's lack of trust and satisfaction with treatment (rs = 0.458, P=0.005). Questionnaire analysis conducted for patients' LTFU showed a significant positive correlation between best corrected visual activity (BCVA) loss and patient's lack of trust and satisfaction with treatment (rs = 0.458. CONCLUSIONS: LTFU threatens vision in PDR patients receiving PRP and/or IVIs of anti-VEGF. Possibly, patient-specific LTFU causes should be addressed before treatment in order to minimize the risk of LTFU. The clinical trial is registered with NCT04018326 (trial registration: ClinicalTrials.gov Identifier: NCT04018326, 10th of July 2019 "Retrospectively registered").

The Impact of COVID-19 Pandemic in Children With Cancer: A Report From Saudi Arabia.

In January 2020, the WHO declared the novel coronavirus (2019-nCoV) outbreak as a public health emergency of international concern. Due to the rapid spread of 2019-nCoV, all countries started preventive and precautionary measures to prevent COVID-19 infection spread. These measures limited the population mobility and services provided, which subsequently Impact of on children with cancer and cancer care delivery in the many health centers in Saudi Arabia. We did a cross-sectional study to assess the impact of this outbreak on children with cancer concerning all aspects of life including medical services provided, the specific precautions to prevent spread in cancer patients, mental, psychological effects, and its effect on the quality of life. We collected 204 responses during a survey that assessed the impact on the treatment of cancer children at a tertiary institution during the COVID-19 pandemic. The majority of patients were receiving ongoing chemotherapy for leukemia/lymphoma. The majority of these patients (60.5%) reported a delay in treatment received due to hospital cancellation of appointments due to the pandemic. Although the majority of patients in our cohort complained of delayed treatment, fortunately, none of the delays led to fatalities. In the context of global lockdowns and physical distancing to help flatten the COVID-19 curve, telemedicine has proved fundamental to keeping patients and their healthcare providers connected and safe. Children also faced multiple other difficulties such as psychosocial issues during the COVID-19 pandemic. Our long-term goals are to develop new programs that will enable children with cancer to emerge successfully during a pandemic.

Challenges in an X + Y ambulatory model.

BACKGROUND: Internal medicine training requires significant exposure to ambulatory practice. Ensuring continuity of patient care is challenging, especially with intermittent ambulatory resident assignments. A popular scheduling model is an X + Y block system where residents rotate for X weeks on inpatient rotations followed by Y weeks on ambulatory clinics. Although benefits exist with the X + Y model, it has drawbacks, particularly for continuity of care: residents struggle to obtain follow-up test results and return patient calls promptly. To provide patients with seamless continuity the programme assigned two Managing Clinic Continuity Care Residents (MCCCRs) to cover all tasks. The MCCCRs were soon overwhelmed by the number of tasks and became dissatisfied with the workflow, however, resulting in a low task-completion rate. METHOD: In our 4 + 1 model residents are divided into five cohorts, we created mini-practice groups (MPGs) consisting of one resident from each cohort. Each week the resident in the clinic is assigned to act as the Practice Clinic Continuity of Care Resident (PCCCR) for the MPG. This individual is responsible for addressing the patient tasks of the other four residents in the MPG. For optimal performance, the previous two MCCCRs are now assigned for oversight only each week. We tracked task-completion rates weekly and surveyed residents for satisfaction. RESULTS: Following the redistribution of responsibilities, the task-completion rates improved from 75 to 97%. The MCCCR satisfaction rate for the workflow increased from zero to 63%, and the on-time note completion rates increased from 21 to 67%. CONCLUSION: Modification of the X + Y model using the MPG structure ensured the timely completion of patient-related tasks, and improved the overall experience for both patients and providers. Modification of the X + Y model using the MPG structure ensured the timely completion of patient-related tasks, and improved the overall experience for both patients and providers.

Pattern of Intermediate Uveitis in an Egyptian Cohort.

Purpose: To describe the clinical experience with intermediate uveitis at six Egyptian tertiary eye centers.Methods: A multicenter retrospective chart review of all patients with intermediate uveitis seen at six ocular inflammation referral clinics in Egypt between January 2010 and January 2017.Results: The study included a total of 781 patients with intermediate uveitis. The study cohort comprised of 282 male and 499 female patients. In over half of our cohort (58.77%), no specific cause could be confirmed. The remaining patients had sarcoidosis (16.26%), tuberculosis (14.85%), multiple sclerosis (9.09%), and TINU (1.02%). By the end of our study, 62% of the affected eyes had a BCVA better than 20/40Conclusion: More than 40% of our patients with intermediate uveitis had sarcoidosis, tuberculosis, multiple sclerosis, or TINU as the underlying etiology. Owing to their potential morbidity, these diseases need to be considered in Egyptian patients presenting with intermediate uveitis.

Impella-Induced Incessant Ventricular Tachycardia.

Background: The Impella 2.5 and Impella Cardiac Power (CP) devices (ABIOMED) are used to provide mechanical circulatory support for high-risk percutaneous coronary interventions or cardiogenic shock as a bridge to recovery or destination therapy. The Impella device has shown both efficacy and safety in patients presenting with cardiogenic shock. Performing clinical and hemodynamic assessments of patients presenting with cardiogenic shock is an important step to determine if mechanical circulatory support with an Impella device is indicated. Case Report: A 62-year-old male presented with cardiogenic shock requiring Impella device support. Two days later, the patient developed incessant ventricular tachycardia. Transthoracic echocardiography showed that the Impella device had migrated out of the ventricular cavity. Once the position of the Impella device was adjusted, ventricular tachycardia immediately resolved. Conclusion: Our case emphasizes the importance of using imaging modalities such as transthoracic echocardiography to ensure correct positioning of an Impella device in the left ventricle to avoid complications.