In vitro production of infectious Plasmodium falciparum sporozoites.

An effective vaccine is needed for the prevention and elimination of malaria. The only immunogens that have been shown to have a protective efficacy of more than 90% against human malaria are Plasmodium falciparum (Pf) sporozoites (PfSPZ) manufactured in mosquitoes (mPfSPZ)1-7. The ability to produce PfSPZ in vitro (iPfSPZ) without mosquitoes would substantially enhance the production of PfSPZ vaccines and mosquito-stage malaria research, but this ability is lacking. Here we report the production of hundreds of millions of iPfSPZ. iPfSPZ invaded human hepatocytes in culture and developed to mature liver-stage schizonts expressing P. falciparum merozoite surface protein 1 (PfMSP1) in numbers comparable to mPfSPZ. When injected into FRGhuHep mice containing humanized livers, iPfSPZ invaded the human hepatocytes and developed to PfMSP1-expressing late liver stage parasites at 45% the quantity of cryopreserved mPfSPZ. Human blood from FRGhuHep mice infected with iPfSPZ produced asexual and sexual erythrocytic-stage parasites in culture, and gametocytes developed to PfSPZ when fed to mosquitoes, completing the P. falciparum life cycle from infectious gametocyte to infectious gametocyte without mosquitoes or primates.

Endoplasmic reticulum localized TMEM33 domain-containing protein is crucial for all life cycle stages of the malaria parasite.

Endoplasmic reticulum (ER) plays a pivotal role in the regulation of stress responses in multiple eukaryotic cells. However, little is known about the effector mechanisms that regulate stress responses in ER of the malaria parasite. Herein, we aimed to identify the importance of a transmembrane protein 33 (TMEM33)-domain-containing protein in life cycle of the rodent malaria parasite Plasmodium berghei. TMEM33 is an ER membrane-resident protein that is involved in regulating stress responses in various eukaryotic cells. A C-terminal tagged TMEM33 was localized in the ER throughout the blood and mosquito stages of development. Targeted deletion of TMEM33 confirmed its importance for asexual blood stages and ookinete development, in addition to its essential role for sporozoite infectivity in the mammalian host. Pilot scale analysis shows that the loss of TMEM33 results in the initiation of ER stress response and induction of autophagy. Our findings conclude an important role of TMEM33 in the development of all life cycle stages of the malaria parasite, which indicates its potential as an antimalarial target.

Intranodal Lymphangiography and Embolization for Management of Iatrogenic Chylous Ascites after Oncological Surgery.

PURPOSE: To investigate the safety and effectiveness of intranodal lymphangiography (INL) and lymphatic embolization (LE) in management of chylous ascites after oncologic surgery. MATERIALS AND METHODS: Retrospective review of records of patients who underwent INL with or without LE from January 2017 to June 2022 was performed. Adult patients with chylous ascites after oncologic surgery referred to interventional radiology after failure of conservative treatment were included. Thirty-nine patients who underwent 55 procedures were included (34 males and 5 females). Data on patient demographics, procedural technique, outcomes, and follow-up were collected. Descriptive statistics were used to illustrate technical success, clinical success, and adverse events. Univariate logistic regression analysis was performed to evaluate factors predicting clinical success. RESULTS: INL was technically successful in 54 of 55 procedures (98%; 95% confidence interval [CI], 90%-100%). A lymphatic leak was identified in 40 procedures, and LE was attempted in 36. LE was technically successful in 33 of the 36 procedures (92%; 95% CI, 78%-98%). Clinical success, defined as resolution of ascites with no need for peritoneovenous shunt placement or additional surgery, was achieved in 22 of 39 patients (56%; 95% CI, 40%-72%). Clinical success was achieved in 18 patients after 1 procedure, and patients who required repeat procedures were less likely to achieve clinical success (odds ratio, 0.16; 95% CI, 0.04-0.66; P = .012). Four grade 1 procedural adverse events were recorded. CONCLUSIONS: INL with or without LE is a safe minimally invasive tool that can help patients with chylous ascites after oncologic surgery who failed conservative treatment avoid more invasive interventions.

Extended ischemic times during ex vivo lung perfusion is not associated with increased mortality.

BACKGROUND: The purpose of this study was to identify the association of increasing ischemic times in recipients who receive lungs evaluated by ex vivo lung perfusion (EVLP) and their association with outcomes following lung transplantation. METHODS: Lung transplant recipients who received an allograft evaluated by EVLP were identified from the United Network for Organ Sharing (UNOS) Database from 2016-2023. Recipients were stratified into three groups based on total ischemic time (TOT): short TOT (STOT, 0 to <7 h), medium TOT (MTOT, 7> to <14 h), and long TOT (LTOT, +14 h). The groups were assessed with comparative statistics and Kaplan-Meier methods. A Cox regression was created to determine the association of ischemic time in EVLP donors and long-term mortality. RESULTS: Recipients in the LTOT group had significantly longer length of stay and post-operative extracorporeal membrane use at 72 h (p < 0.05 for both). Additionally, they had nonsignificant increases in rate of stroke (4.7%, p = 0.05) and primary graft dysfunction grade 3 (PGD3, 27.5%, p = 0.082). However, there was no significant difference in hospital mortality or mid-term survival (p > 0.05 for both). On multivariable analysis, ischemic time was not associated with increased mortality whereas increasing recipient age, preoperative ECMO use and donation after circulatory death donors were (p < 0.05 for all). CONCLUSIONS: If EVLP technology is available, under certain circumstances, surgeons should not be dissuaded from using an allograft with extended ischemic time.

Drug-induced ER stress leads to induction of programmed cell death pathways of the malaria parasite.

The rapid emergence of drug resistance against the mainstream antimalarial drugs has increased the need for development of novel drugs. Recent approaches have embarked on the repurposing of existing drugs to induce cell death via programmed cell death pathways. However, little is known about the ER stress response and programmed cell death pathways of the malaria parasite. In this study, we treated ex vivo Plasmodium berghei cultures with tunicamycin, 5-fluorouracil, and chloroquine as known stress inducer drugs to probe the transcriptional changes of autophagy and apoptosis-related genes (PbATG5, PbATG8, PbATG12, and PbMCA2). Treatments with 5-fluorouracil and chloroquine resulted in the upregulation of all analyzed markers, yet the levels of PbATG5 and PbATG12 were dramatically higher in chloroquine-treated ex vivo cultures. In contrast, tunicamycin treatment resulted in the downregulation of both PbATG8 and PbATG12, and upregulation of PbMCA2. Our results indicate that the malaria parasite responds to various ER stressors by inducing autophagy- and/or apoptosis-like pathways.

Quantifying the impact of urban road traffic on air quality: activity pre-pandemic and during partial and full lockdowns.

The impact of partial and full COVID lockdowns in 2020 on vehicle miles traveled (VMT) in Kuwait was estimated using data extracted from the Directions API of Google Maps and a Python script running as a cronjob. This approach was validated by comparing the predictions based on the app to measuring traffic flows for 1 week across four road segments considered in this study. VMT during lockdown periods were compared to VMT for the same calendar weeks before the pandemic. NOx emissions were estimated based on VMT and were used to simulate the spatial patterns of NOx concentrations using an air quality model (AERMOD). Compared to pre-pandemic periods, VMT was reduced by up to 25.5% and 42.6% during the 2-week partial and full lockdown episodes, respectively. The largest reduction in the traffic flow rate occurred during the middle of these 2-week periods, when the traffic flow rate decreased by 35% and 49% during the partial and full lockdown periods, respectively. The AERMOD simulation results predicted a reduction in the average maximum concentration of emissions directly related to VMT across the region by up to 38%, with the maximum concentration shifting to less populous residential areas as a result of the lockdown.

A Candidate Bacterial-Type Amino Acid Decarboxylase Is Essential for Male Gamete Exflagellation and Mosquito Transmission of the Malaria Parasite.

A frequent side effect of chemotherapy against malaria parasite blood infections is a dramatic induction of the sexual blood stages, thereby enhancing the risk of future malaria transmissions. The polyamine biosynthesis pathway has been suggested as a candidate target for transmission-blocking anti-malarial drug development. Herein, we describe the role of a bacterial-type amino acid decarboxylase (AAD) in the life cycle of the malaria model parasite Plasmodium yoelii. Hallmarks of AAD include a conserved catalytic lysine residue and high-level homology to arginine/lysine/ornithine decarboxylases of pathogenic bacteria. By targeted gene deletion, we show that AAD plays an essential role in the exflagellation of microgametes, resulting in complete absence of sporozoites in the mosquito vector. These data highlight the central role of the biosysthesis of polyamines in the final steps of male gamete sexual development of the malaria parasite and, hence, onward transmission to mosquitoes.

Stent Graft Placement for the Treatment of Hepatic Artery Injury in Patients with Cancer: Primary Patency and Clinical Outcomes.

PURPOSE: To evaluate the safety, primary patency, and clinical outcomes of hepatic artery stent graft (SG) placement for vascular injuries. MATERIALS AND METHODS: Patients treated with hepatic arterial SG placement for vascular injuries between September 2018 and September 2021 were reviewed. Data on demographic characteristics, indication, stent graft characteristics, antiplatelet/anticoagulant use, clinical success rate, complications, and type of follow-up imaging were collected. Follow-up images were reviewed by 2 independent reviewers to assess primary patency. A time-to-event analysis was performed. The median duration of stent graft patency was estimated using Kaplan-Meier curves. A Cox proportional hazard model was used to evaluate factors related to stent graft patency. RESULTS: Thirty-five patients were treated with hepatic arterial SG placement, 11 for postoperative bleeds and 24 for hepatic artery infusion pump catheter-related complications. Clinical success was achieved in 32 (91%) patients (95% CI, 77-98). The median primary patency was 87 days (95% CI, 73-293). Stent grafts of ≥6-mm diameter retained patency for a longer duration than that with stent grafts of smaller diameters (6 mm vs 5 mm; hazard ratio, 0.35; 95% CI, 0.14-0.88; P = .026; and 7+ mm vs 5 mm; hazard ratio, 0.27; 95% CI, 0.09-0.83; P = .023). Anticoagulation/antiplatelet regimen was not associated with increased stent graft patency duration (P > .05). Only minor complications were reported in 2 (5.7%) patients. CONCLUSIONS: Stent grafts can be used safely and effectively to treat injuries of the hepatic artery. Stent graft diameters of ≥6 mm seem to provide more durable patency.

Development of machine learning models for detection of vision threatening Behçet's disease (BD) using Egyptian College of Rheumatology (ECR)-BD cohort.

BACKGROUND: Eye lesions, occur in nearly half of patients with Behçet's Disease (BD), can lead to irreversible damage and vision loss; however, limited studies are available on identifying risk factors for the development of vision-threatening BD (VTBD). Using an Egyptian college of rheumatology (ECR)-BD, a national cohort of BD patients, we examined the performance of machine-learning (ML) models in predicting VTBD compared to logistic regression (LR) analysis. We identified the risk factors for the development of VTBD. METHODS: Patients with complete ocular data were included. VTBD was determined by the presence of any retinal disease, optic nerve involvement, or occurrence of blindness. Various ML-models were developed and examined for VTBD prediction. The Shapley additive explanation value was used for the interpretability of the predictors. RESULTS: A total of 1094 BD patients [71.5% were men, mean ± SD age 36.1 ± 10 years] were included. 549 (50.2%) individuals had VTBD. Extreme Gradient Boosting was the best-performing ML model (AUROC 0.85, 95% CI 0.81, 0.90) compared with logistic regression (AUROC 0.64, 95%CI 0.58, 0.71). Higher disease activity, thrombocytosis, ever smoking, and daily steroid dose were the top factors associated with VTBD. CONCLUSIONS: Using information obtained in the clinical settings, the Extreme Gradient Boosting identified patients at higher risk of VTBD better than the conventional statistical method. Further longitudinal studies to evaluate the clinical utility of the proposed prediction model are needed.

Textbook outcomes after oesophagectomy: a single-centre observational study.

BACKGROUND: Textbook outcomes is a composite quality assurance tool assessing the ideal perioperative and postoperative course as a unified measure. Currently, its definition and application in the context of oesophagectomy in Australia is unknown. The aim of this study was to assess the textbook outcomes after oesophagectomy in a single referral centre of Australia and investigate the association between textbook outcomes and patient, tumour, and treatment characteristics. METHODS: An observational study was retrospectively performed on patients undergoing open, laparoscopic, or hybrid oesophagectomy between January 2010 and December 2019 in a single cancer referral centre. A textbook outcome was defined as the fulfillment of 10 criteria: R0 resection, retrieval of at least 15 lymph nodes, no intraoperative complications, no postoperative complications greater than Clavien-Dindo grade III, no anastomotic leak, no readmission to the ICU, no hospital stay beyond 21 days, no mortality within 90 days, no readmission related to the surgical procedure within 30 days from admission and no reintervention related to the surgical procedure. The proportion of patients who met each criterion for textbook outcome was calculated and compared. Selected patient-related parameters (age, gender, BMI, ASA score, CCI score), tumour-related factors (tumour location, tumour histology, AJCC clinical T and N stage and treatment-related factor [neoadjuvant chemotherapy and surgical approach]) were assessed. Disease recurrence and one year survival were also evaluated. RESULTS: 110 patients who underwent oesophagectomy were included. The overall textbook outcome rate was 24%. The difference in rates across the years was not statistically significant. The most achieved textbook outcome parameters were 'no mortality in 90 days' (96%) and 'R0 resection' (89%). The least frequently met textbook outcome parameter was 'no severe postoperative complications' (58%), followed by 'no hospital stays over 21 days' (61%). No significant association was found between patient, tumour and treatment characteristics and the rate of textbook outcome. Tumour recurrence rate and overall long term survival was similar between textbook outcome and non-textbook outcome groups. Patients with R0 resection, no intraoperative complication and a hospital stay less than 21 days had reduced mortality rates. CONCLUSIONS: Textbook outcome is a clinically relevant indicator and was achieved in 24% of patients. Severe complications and a prolonged hospital stay were the key criteria that limited the achievement of a textbook outcome. These findings provide meticulous evaluation of oesophagectomy perioperative care and provide a direction for the utilisation of this concept in identifying and improving surgical and oncological care across multiple healthcare levels.

Non-iatrogenic spontaneous acute spinal subdural haematoma after transforaminal lumbar interbody fusion.

PURPOSE: Reporting a rare case of a non-iatrogenic spontaneously resolved spinal subdural haematoma (SSDH) following revision of transforaminal lumbar interbody fusion (TLIF) and its possible explanation. METHODS: Case report of a 40-year-old man with a history of persistent lower back and left lower extremity radicular pain, secondary to recurrent disc prolapse, lumbar spondylosis with foraminal stenosis. He underwent an L5/S1 transforaminal interbody fusion via a right sided approach (through previous lumbar microdiscectomy incision). On post-operative day two, the patient developed headache and photophobia that were discovered to be secondary to an acute thoracolumbar subdural haematoma with no objective neurological deficit. RESULTS: After close observation of his neurological status and conservative management of the subdural haematoma, the patient fully recovered from his symptoms and remained problem-free at 2-year follow-up. CONCLUSIONS: Although the occurrence of acute spinal subdural haematoma after spinal surgery is a rare complication following spinal surgery, its appropriate management relies on early recognition if significant morbidity is to be avoided.

Description of Novel Technique for Managing Insufficient Nasal Skin Volume.

A short nose is a common esthetic problem faced by facial plastic surgeons. Rhinoplasty of the short nose has been recognized as a complex procedure to perform for achieving satisfactory results. The authors presented 4 cases of short nose in 4 Saudi men who underwent rhinoplasty using septal extension graft and closure the skin with secondary intention as an option to control skin tension after graft placement and to increase nose skin volume to prevent skin retraction, which may occur postoperatively during the healing process. Furthermore, the authors have also discussed the surgical outcomes of these 4 cases and overall satisfaction. Finally, the authors reviewed the literature to identify published papers on correcting the short nose technique.

Implementing Nanovesicles for Boosting the Skin Permeation of Non-steroidal Anti-inflammatory Drugs.

The consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have increased lately around the world, as they are considered essential and popular drugs for effective reduction of pain and inflammation. They have analgesic, antipyretic, and anti-inflammatory activities; also, it was reported recently that they protect against various critical disorders like heart attacks and cancer. However, oral use of NSAIDs may cause several pulmonary, gastrointestinal, hepatic, cardiovascular, cerebral, and renal complications. Therefore, topical NSAIDs were recommended as a substitute to oral NSAIDs for the treatment of inflammation and pain. Still, the skin permeation of NSAIDs is considered a challenge, as the skin have an effective barrier function. Therefore, this review investigates various advanced vesicular nanocarriers and their applications through the skin, to augment the topical delivery of NSAIDs through stratum corneum over the conventional systems, enhance their effectiveness, and reduce the unwanted side effects. These innovative systems can manage bioavailability, solubility, stability, safety, and efficacy issues present in conventional systems.

An Alternative Autophagy-Related Mechanism of Chloroquine Drug Resistance in the Malaria Parasite.

We generated highly chloroquine (CQ)-resistant (ResCQ) Plasmodium yoelii parasites by stepwise exposure to increasing concentrations of CQ and CQ-sensitive parasites (SenCQ) by parallel mock treatments. No mutations in genes that are associated with drug resistance were detected in ResCQ clones. Autophagy-related genes were highly upregulated in SenCQ compared to ResCQ parasites during CQ treatment. This indicates that CQ resistance can be developed in the malaria parasite by the inhibition of autophagy as an alternative drug resistance mechanism.

Lymphatic Interventions in the Cancer Patient.

PURPOSE OF REVIEW: The incidence of lymphatic leakage (iatrogenic and non-iatrogenic) is growing in cancer population due to the increased complexity of the surgical procedures and improved overall survival in cancer patients. The purpose of this article is to review the contemporary approach in the field of percutaneous lymphatic embolization in cancer patients with lymphatic leaks. RECENT FINDINGS: Since the advent of intranodal lymphangiography in 2011 alongside with the MR and CT lymphangiography, the accuracy of diagnosis of the lymphatic diseases has significantly improved significantly. These advancements have triggered a revival of minimally invasive lymphatic interventions. Lymphatic embolization is expanding from the classic indication, thoracic duct embolization, to other lymphatic disorders (chylous ascites, lymphoceles, liver lymphorrhea, protein-losing enteropathy). The growth of lymphatic research and the standardization of the lymphatic interventions require a multidisciplinary and collaborative approach between physicians and researchers.

Comparison of the efficacy of two doses of dexmedetomidine as an adjunct to levobupivacaine in infraclavicular brachial plexus block: prospective double-blinded randomized controlled trial.

BACKGROUND: This prospective, double-blind, randomized, controlled trial compared the efficacy of two dexmedetomidine doses (50 and 100-µg) combined with levobupivacaine on sensory block duration in infraclavicular brachial plexus block. We hypothesized that perineural dexmedetomidine would extend sensory block duration dose-dependently. METHODS: The study included 60 patients aged 20 to 60 years of both sex with an ASA I/II undergoing forearm and hand surgery. The patients were randomly assigned into three equal groups (n = 20) for ultrasound-guided infraclavicular brachial plexus block. The L group received 35-mL 0.5% levobupivacaine plus normal saline, the LD50 group received 35-mL 0.5% levobupivacaine plus 50-µg dexmedetomidine, and the LD100 group received 35-mL 0.5% levobupivacaine plus 100-µg dexmedetomidine. Patients were investigated for onset and duration of sensory blockade, time to first postoperative rescue analgesia, and the total 24-h postoperative morphine requirement. RESULTS: The LD100 group had a longer sensory block duration (15.55 ± 1.1 h; 95% confidence interval (CI), 15.04-16.06) than the LD50 group (12.8 ± 1.2 h; 95% CI, 12.24-13.36 h) (p < 0.001) or the L group (9.95 ± 1.05 h; 95% CI, 9.46-10.44 h) (p < 0.001). The LD100 group took longer to request postoperative rescue analgesia and required fewer postoperative morphine doses than the LD50 and L groups (P < 0.001). CONCLUSIONS: Sensory block duration was longer with perineural 100-µg dexmedetomidine as an adjunct to levobupivacaine than with 50-µg dexmedetomidine. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Aswan University Hospital (approval number: aswu/125/4/17) (date of registration: 04/04/2017). Furthermore, the trial was retrospectively registered at ClinicalTrial.gov (NCT04729868) with a verification date of January 2021.

Systemic inflammation in COVID-19 patients may induce various types of venous and arterial thrombosis: A systematic review.

COVID-19 is a global pandemic with a daily increasing number of affected individuals. Thrombosis is a severe complication of COVID-19 that leads to a worse clinical course with higher rates of mortality. Multiple lines of evidence suggest that hyperinflammation plays a crucial role in disease progression. This review compiles clinical data of COVID-19 patients who developed thrombotic complications to investigate the possible role of hyperinflammation in inducing hypercoagulation. A systematic literature search was performed using PubMed, Embase, Medline and Scopus to identify relevant clinical studies that investigated thrombotic manifestations and reported inflammatory and coagulation biomarkers in COVID-19 patients. Only 54 studies met our inclusion criteria, the majority of which demonstrated significantly elevated inflammatory markers. In the cohort studies with control, D-dimer was significantly higher in COVID-19 patients with thrombosis as compared to the control. Pulmonary embolism, deep vein thrombosis and strokes were frequently reported which could be attributed to the hyperinflammatory response associated with COVID-19 and/or to the direct viral activation of platelets and endothelial cells, two mechanisms that are discussed in this review. It is recommended that all admitted COVID-19 patients should be assessed for hypercoagulation. Furthermore, several studies have suggested that anticoagulation may be beneficial, especially in hospitalized non-ICU patients. Although vaccines against SARS-CoV-2 have been approved and distributed in several countries, research should continue in the field of prevention and treatment of COVID-19 and its severe complications including thrombosis due to the emergence of new variants against which the efficacy of the vaccines is not yet clear.

Surveillance Study of Acute Neurological Manifestations among 439 Egyptian Patients with COVID-19 in Assiut and Aswan University Hospitals.

BACKGROUND: COVID-19 can be accompanied by acute neurological complications of both central and peripheral nervous systems (CNS and PNS). In this study, we estimate the frequency of such complications among hospital inpatients with COVID-19 in Assiut and Aswan university hospitals. MATERIALS AND METHODS: We screened all patients with suspected COVID-19 admitted from 1 June to 10 August 2020 to the university hospitals of Assiut and Aswan in Upper Egypt. Clinical and laboratory tests, CT/MRI of the chest and brain, and neurophysiology study were performed for each patient if indicated. RESULTS: 439 patients had confirmed/probable COVID-19; neurological manifestations occurred in 222. Of these, 117 had acute neurological disease and the remainder had nonspecific neuropsychiatric symptoms such as headache, vertigo, and depression. The CNS was affected in 75 patients: 55 had stroke and the others had convulsions (5), encephalitis (6), hypoxic encephalopathy (4), cord myelopathy (2), relapse of multiple sclerosis (2), and meningoencephalitis (1). The PNS was affected in 42 patients: the majority had anosmia and ageusia (31) and the others had Guillain-Barré syndrome (4), peripheral neuropathy (3), myasthenia gravis (MG, 2), or myositis (2). Fever, respiratory symptoms, and headache were the most common general symptoms. Hypertension, diabetes mellitus, and ischemic heart disease were the most common comorbidities in patients with CNS affection. CONCLUSION: In COVID-19, both the CNS and PNS are affected. Stroke was the most common complication for CNS, and anosmia and/or ageusia were common for PNS diseases. However, there were 6 cases of encephalitis, 2 cases of spinal cord myelopathy, 2 cases of MG, and 2 cases of myositis.

Novel thienopyrimidine analogues as potential metabotropic glutamate receptors inhibitors and anticancer activity: Synthesis, In-vitro, In-silico, and SAR approaches.

There is a continuous need in drug development approach for synthetic anticancer analogues with new therapeutic targets to diminish chemotherapeutic resistance of cancer cells. This study presents new group of synthetic thienopyrimidine analogues (1-9) aims as mGluR-1 inhibitors with anticancer activity. In-vitro antiproliferative assessment was carried out using viability assay against cancer cell lines (MCF-7, A-549 and PC-3) compared to WI-38 normal cell line. Analogues showed variable anticancer activity with IC50 ranging from 6.60 to 121 µg/mL with compound 7b is the most potent analogue against the three cancer cell lines (MCF-7; 6.57 ± 0.200, A-549; 6.31 ± 0.400, PC-3;7.39 ± 0.500 µg/mL) compared to Doxorubicin, 5-Flurouracil and Riluzole controls. Selected compounds were tested as mGluR-1 inhibitors in MCF-7 cell line and results revealed compound 7b induced significant reduction in extracellular glutamate release (IC50; 4.96 ± 0.700 µM) compared to other analogues and next to Riluzole (IC50; 2.80 ± 0.500 µM) of the same suggested mode of action. Furthermore, both cell cycle and apoptosis assays confirmed the potency of compound 7b for early apoptosis of MCF-7 at G2/M phase and apoptotic positive cell shift to (91.4%) compared to untreated control (19.6%) and Raptinal positive control (51.4%). On gene expression level, compound 7b induced over-expression of extrinsic (FasL, TNF-α and Casp-8), intrinsic (Cyt-C, Casp-3, Bax) apoptotic genes with down-regulation of anti-apoptotic Bcl-2 gene with boosted Bax/Bcl-2 ratio to 2.6-fold increase. Molecular docking and dynamic studies confirmed the biological potency through strong binding and stability modes of 7b where it was faster in reaching the equilibrium point and achieving the stability than Riluzole over 20 ns MD. These results suggest compound 7b as a promising mGluR inhibitory scaffold with anticancer activity that deserves further optimization and in-depth In-vivo and clinical investigations.

Neurosurgery activity levels in the United Kingdom and republic of Ireland during the first wave of the covid-19 pandemic - a retrospective cross-sectional cohort study.

The impact of Covid-19 on surgical patients worldwide has been substantial. In the United Kingdom (UK) and the Republic of Ireland (RoI), the first wave of the pandemic occurred in March 2020. The aims of this study were to: (1) evaluate the volume of neurosurgical operative activity levels, Covid-19 infection rate and mortality rate in April 2020 with a retrospective cross-sectional cohort study conducted across 16 UK and RoI neurosurgical centres, and (2) compare patient outcomes in a single institution in April-June 2020 with a comparative cohort in 2019. Across the UK and RoI, 818 patients were included. There were 594 emergency and 224 elective operations. The incidence rate of Covid-19 infection was 2.6% (21/818). The overall mortality rate in patients with a Covid-19 infection was 28.6% (6/21). In the single centre cohort analysis, an overall reduction in neurosurgical operative activity by 65% was observed between 2020 (n = 304) and 2019 (n = 868). The current and future impact on UK neurosurgical operative activity has implications for service delivery and neurosurgical training.