Using calcaneal plates in fixation of comminuted posterior wall acetabular fractures with cranial or posterior extension: a prospective case series and novel technique.

BACKGROUND: This study aims to evaluate the outcomes of using calcaneal plate in fixation of comminuted posterior wall (PW) acetabular fractures especially that have cranial (dome) or posterior extension (posterior column edge), and to evaluate its safety. To our knowledge, this is the first study that utilizes this off label implant technique in fixation of such fracture. METHODS: Twenty-two patients enrolled in the study with a minimum follow up of one year. After reducing the PW fragments sequentially, calcaneal plate was applied, fixing its distal part at ischial tuberosity upper ends using 3 screws in a triangular fashion, while its proximal part and radial wings were firmly fixed along the acetabular rim together with the classic longitudinal anchorage. Any fixation failure or head subluxation was recorded. RESULTS: Radiological outcome showed 18 cases scored as excellent, 2 were good, and 2 were poor. The functional outcome revealed 2 patients were excellent, 6 were very good and 14 were good. There was no loss of reduction or fixation failures throughout the follow up period. CONCLUSION: Calcaneal plate may offer an alternative method of fixation of comminuted PW fractures with acceptable radiological and functional results. Our study result may encourage the comprehensibility and replicability of this practice, however randomized multicentered studies should be conducted to validate this assumption. This method provides valuable trick strategy, stable and soft-tissue-friendly fracture fixation where modern implantations may be unavailable or of high cost. Calcaneal plates show some fascinating features that allow using them outside their field being flexible with large footprint area for fracture buttressing beside numerous hole choices with diverse paths providing suitable fixation, articular stability and wide zone of coverage in PW comminuted fracture patterns with cranial or posterior extensions. The plate proximal triangular configuration together with distal triangular screw fixation gives a stiff rigid anchorage and buttressing similar to a metal mesh covering and fixing any fragment numbers up to dome level.

STING activator 2'3'-cGAMP enhanced HSV-1-based oncolytic viral therapy.

Oncolytic viruses (OVs) can selectively replicate in tumor cells and remodel the microenvironment of immunologically cold tumors, making them a promising strategy to evoke antitumor immunity. Similarly, agonists of the stimulator of interferon genes (STING)-interferon (IFN) pathway, the main cellular antiviral system, provide antitumor benefits by inducing the activation of dendritic cells (DC). Considering how the activation of the STING-IFN pathway could potentially inhibit OV replication, the use of STING agonists alongside OV therapy remains largely unexplored. Here, we explored the antitumor efficacy of combining an HSV-1-based OV, C-REV, with a membrane-impermeable STING agonist, 2'3'-GAMP. Our results demonstrated that tumor cells harbor a largely defective STING-IFN pathway, thereby preventing significant antiviral IFN induction regardless of the permeability of the STING agonist. In vivo, the combination therapy induced more proliferative KLRG1-high PD1-low CD8+ T-cells and activated CD103+ DC in the tumor site and increased tumor-specific CD44+ CD8+ T-cells in the lymph node. Overall, the combination therapy of C-REV with 2'3'-cGAMP elicited antitumor immune memory responses and significantly enhanced systemic antitumor immunity in both treated and non-treated distal tumors.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants Compared with Warfarin in Patients with Low Bodyweight who have Atrial Fibrillation: A Systematic Review and Meta-analysis.

INTRODUCTION: oral anticoagulant (DOAC) agents are becoming the anticoagulation strategy of choice for most clinical risks for which they are indicated. However, residual uncertainty remains regarding their use in preventing stroke in patients with low bodyweight [< 60 kg or body mass index (BMI) < 18 kg/m2]. We have carried out pooled systematic analyses of published studies to determine the efficacy and safety of these agents compared with warfarin in stroke prevention in patients with low bodyweight. METHODS: We carried out a comprehensive search of electronic databases from inception to June 2023 for eligible studies reporting on the efficacy and safety of direct oral anticoagulants versus warfarin in patients with atrial fibrillation who had low bodyweight. These include PubMed, EMBASE, the Cochrane Database of Systematic Reviews, the Science Citation Index, and the Database of Abstracts of Reviews of Effectiveness. Using the random effects model, derived pooled odd ratios (with their corresponding confidence intervals) of mortality outcomes in patient cohorts exposed to direct oral anticoagulants versus warfarin in patients with atrial fibrillation who had low bodyweight. RESULTS: Nine studies (n = 159,514 patients) were included in our meta-analysis. DOAC analogs were associated with lower stroke recurrence compared with warfarin [odds ratio (OR) 0.66, 95% confidence interval (CI) 0.49-0.9]; however, there was no significant difference in the composite outcome (OR 0.81, 95% CI 0.59-1.09) and mortality (OR 0.82, 95% CI 0.48-1.41). Additionally, DOAC analogs showed a significant reduction in major bleeding events by 30% compared with warfarin (OR 0.70, 95% CI 0.62-0.80). CONCLUSION: In this pooled meta-analytical synthesis of studies comprising both real-world and randomized controlled data, the use of DOAC analogs in patients with atrial fibrillation and low bodyweight (< 60 kg or BMI < 18 kg/m2) was associated with a significant reduction in risks of stroke and major bleeding compared with patient cohorts stabilized on warfarin-based therapy. There was uncertainty regarding the composite outcome and mortality point estimate between these two anticoagulation strategies. This finding helps to resolve the uncertainty associated with the use of DOACs in this cohort. Additionally, it suggests the need for confirmatory non-inferiority randomized controlled trials evaluating DOACs versus warfarin in this cohort of patients.

Incidence, clinical features, and outcomes of posterior circulation ischemic stroke: insights from a large multiethnic stroke database.

Background: Posterior cerebral circulation ischemic stroke (PCS) comprises up to 25% of all strokes. It is characterized by variable presentation, leading to misdiagnosis and morbidity and mortality. We aim to describe PCS in large multiethnic cohorts. Methods: A retrospective review of a large national stroke database from its inception on the 1st of January 2014 till 31 December 2020. Incidence per 100,000 adult population/year, demographics, clinical features, stroke location, and outcomes were retrieved. We divided the cohort into patients from MENA (Middle East and North Africa) and others. Results: In total, 1,571 patients were identified. The incidence of PCS was observed to be rising and ranged from 6.3 to 13.2/100,000 adult population over the study period. Men were 82.4% of the total. The mean age was 54.9 ± 12.7 years (median 54 years, IQR 46, 63). MENA patients comprised 616 (39.2%) while others were 954 (60.7%); of these, the majority (80.5%) were from South Asia. Vascular risk factors were prevalent with 1,230 (78.3%) having hypertension, 970 (61.7%) with diabetes, and 872 (55.5%) having dyslipidemia. Weakness (944, 58.8%), dizziness (801, 50.5%), and slurred speech (584, 36.2%) were the most commonly presenting symptoms. The mean National Institute of Health Stroke Score (NIHSS) score was 3.8 ± 4.6 (median 3, IQR 1, 5). The overall most frequent stroke location was the distal location (568, 36.2%). The non-MENA cohort was younger, less vascularly burdened, and had more frequent proximal stroke location (p < 0.05). Dependency or death at discharge was seen in 39.5% and was associated with increasing age, and proximal and multilocation involvement; while at 90 days it was 27.4% and was associated with age, male sex, and having a MENA nationality (p < 0.05). Conclusion: In a multiethnic cohort of posterior circulation stroke patients from the MENA region and South Asia, we noted a rising incidence over time, high prevalence of vascular risk factors, and poor outcomes in older men from the MENA region. We also uncovered considerable disparities between the MENA and non-MENA groups in stroke location and outcome. These disparities are crucial factors to consider when tailoring individualized patient care plans. Further research is needed to thoroughly investigate the underlying reasons for these variations.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Low Body Weight Patients with Atrial Fibrillation: A Systematic Review and Meta-analysis.

INTRODUCTION: Direct oral anticoagulant (DOAC) agents are established as the anticoagulation strategy of choice for a variety of clinical risks. Despite this, uncertainty still exists with regard to their efficacy and safety for the prevention of stroke and systemic embolism in some patient populations; most notably those with low body weight (LBW) (<60 kg or body mass index [BMI] <18 kg/m2). Currently, there is a paucity of trial and non-trial data to support a prescriptive recommendation for their use in these patient cohorts. We have carried out a pooled systematic review of the most up to date published data of patients stabilized on various DOAC analogs with the view to ascertaining the exact matrices of their efficacy and safety in these cohorts of patients. METHODS: We initially carried out a comprehensive search of databases from inception to June 2023 for eligible studies exploring the efficacy and safety of various analogs of direct oral anticoagulants in patients with atrial fibrillation who had low body weight. Databases accessed include PubMed, EMBASE, the Science Citation Index, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effectiveness. We carried out a weighted comparison of derived pooled odd ratios (with their corresponding confidence intervals) of mortality outcomes between various DOACs using the random effects model. RESULTS: Thirteen studies (n = 165,205 patients) were included in our meta-analysis. DOAC analogs were associated with increased stroke-related events, composite outcome, and mortality in low body weight patients compared to non-low body weight patients (odds ratio [OR] 1.50, 95% confidence interval [CI] 1.17-1.92), (OR 1.55, 95% CI 1.29-1.86), (OR 2.92, 95% CI 1.87-4.58), respectively. There was no significant difference in the safety outcome (major bleeding events) between the DOAC analogs (OR 1.19, 95% CI 0.93-1.52). DISCUSSION: In this meta-analytical review comprising both real-world and randomized controlled studies, the use of DOAC analogs in low body weight patients (body weight of <60 kg or BMI<18 kg/m2) with atrial fibrillation was associated with increased risks of stroke-related events, composite outcomes, and mortality compared to non-low body weight cohorts patients. At the same time, there was no significant difference in terms of major bleeding events. This finding has provided the first resolution of pervading uncertainty surrounding the use of DOAC analogs in these patient cohorts and suggests the need for follow-up confirmatory systematic studies in this group of patients.

Social networking and fear of missing out (FOMO) among medical students at University of Khartoum, Sudan 2021.

BACKGROUND: With students becoming more involved in the internet and social networking sites, they become more prone to their consequences. This study focuses on measuring the social networking intensity and the fear of missing out among the medical students of University of Khartoum, then examining the association between them. METHODS: Facility-based, descriptive, cross-sectional study was conducted at Faculty of Medicine, Khartoum University between January and March 2021. A total of 333 students were selected by simple random sampling. Data was collected from the participants using a structured self-administered questionnaire that involved the social networking intensity (SNI) scale and fear of missing out (FOMO) scale. The data was analyzed by the Statistical Package for Social Science (SPSS) software version 26. RESULTS: Moderate positive correlation between social networking intensity and fear of missing out was found (p-value < 0.01). Of the total participants; 51 participants (15.4%) experienced low SNI and low FOMO. Another 78 participants (23.6%) had moderate SNI and moderate FOMO and only 16 Participants (4.8%) showed high SNI and high FOMO. There were no significant differences in SNI or FOMO scores among the different socio-demographic variables, except for the SNI score which was positively correlated to the monthly income. CONCLUSION: An association between SNI and FOMO was found. SNI was not affected by socio-demographic factors except for the monthly income.

Practical Guidance on the Use of Cladribine Tablets in the Management or Relapsing Multiple Sclerosis: Expert Opinion from Qatar.

The increasing availability of high-efficacy disease-modifying therapies (DMT) for the management of relapsing multiple sclerosis (RMS) has increased the potential for individualised patient management but has added complexity to the design of treatment regimens. The long-term application of immune reconstitution therapy (IRT) is supported by an increasing database of real world studies that have added important information on the long-term safety and efficacy of this approach. Cladribine tablets (CladT) is an IRT given as two annual short courses of treatment, following which a majority of patients then demonstrate no significant MS disease activity over a period of years. Whether, and how, to treat patients beyond the first two years of treatment remains a matter for debate, as clinical evidence accumulates. We, a group of neurologists who manage people with RMS in Qatar, provide our expert consensus recommendations on the application and long-term management of CladT therapy based on our experience with treatment in the last 5 years. These include pragmatic recommendations for people with MS disease activity in years 3 and 4 (ie up to four years following first dose of CladT), and for people with or without MS disease activity in subsequent years. We believe our recommendations will help to ensure the optimal application of CladT-based IRT, with the potential benefit for the patient of achieving prolonged periods free of both MS disease symptoms and the burden of regular applications of immunosuppressive DMT.

Dosage, time, and polytherapy dependent effects of different levetiracetam regimens on cognitive function.

OBJECTIVE: Cognitive impairment is a potential drawback of antiseizure medications. This study aimed to evaluate the impact of different levetiracetam drug regimens on cognitive function. METHODS: A retrospective analysis identified 221 patients diagnosed with seizures who underwent cognitive screening. Patients were categorized into four groups: no medications, non-levetiracetam medications, high and low dose levetiracetam. Composite scores determined low and high levetiracetam groups whereby one point was added for each increment in dosage, duration since uptake, and concurrent anti-seizure medication. Variables known to affect cognition were recorded and classified as demographic, seizure-related, diagnosis-related, and psychopathology. Logistic regression was used to identify variables associated with cognitive scores below cut-off. RESULTS: Multivariable analysis found being male, non-active in the community, less than 12 years of education, left temporal lobe epilepsy, high seizure frequency, and depression were associated with poor cognitive performance. In a final regression analysis, the high levetiracetam group exhibited a 4.5-fold higher likelihood of scoring below cut-off than the medication-free group (OR 4.5, CI 1.5-13.6, p<.08). Depression (OR 2.1, CI 1.1-3.9, p<.03), being male (OR 2.2, CI 1.1-4.3, p<.02), and not being active in the community (OR 3.8, 1.6-8.7, p <.003) remained significant contributors to the model. Language (p<.05), attention (p<.05), and delayed recall (p<.001) were the most affected cognitive domains. SIGNIFICANCE: When taken in small doses, for brief periods as monotherapy, levetiracetam minimally influences cognition. At higher doses, as part of long-term seizure management, in conjunction with multiple ASMs, LEV is associated with cognitive impairment.

The Impact of Metformin on Tumor-Infiltrated Immune Cells: Preclinical and Clinical Studies.

The tumor microenvironment (TME) plays a pivotal role in the fate of cancer cells, and tumor-infiltrating immune cells have emerged as key players in shaping this complex milieu. Cancer is one of the leading causes of death in the world. The most common standard treatments for cancer are surgery, radiation therapy, and chemotherapeutic drugs. In the last decade, immunotherapy has had a potential effect on the treatment of cancer patients with poor prognoses. One of the immune therapeutic targeted approaches that shows anticancer efficacy is a type 2 diabetes medication, metformin. Beyond its glycemic control properties, studies have revealed intriguing immunomodulatory properties of metformin. Meanwhile, several studies focus on the impact of metformin on tumor-infiltrating immune cells in various tumor models. In several tumor models, metformin can modulate tumor-infiltrated effector immune cells, CD8+, CD4+ T cells, and natural killer (NK) cells, as well as suppressor immune cells, T regulatory cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). In this review, we discuss the role of metformin in modulating tumor-infiltrating immune cells in different preclinical models and clinical trials. Both preclinical and clinical studies suggest that metformin holds promise as adjunctive therapy in cancer treatment by modulating the immune response within the tumor microenvironment. Nonetheless, both the tumor type and the combined therapy have an impact on the specific targets of metformin in the TME. Further investigations are warranted to elucidate the precise mechanisms underlying the immunomodulatory effects of metformin and to optimize its clinical application in cancer patients.

Internal fixator vs external fixator in the management of unstable pelvic ring injuries: A prospective comparative cohort study.

BACKGROUND: Reconstruction of the pelvic ring anatomy in unstable anterior pelvic ring injuries is a significant step to reduce the mortality rate associated with these injuries efficiently. There is a debate on using either an anterior subcutaneous pelvis internal fixator (INFIX) or an anterior supra-acetabular external fixator (EXFIX) to manage an unstable anterior pelvic ring fracture. AIM: To compare the functional and radiological outcomes and complications of INFIX vs EXFIX in managing unstable pelvic ring injuries. METHODS: A prospective cohort study included 54 patients with unstable pelvic ring fractures. The patients were divided into two groups; the INFIX group, in which 30 cases were fixed by INFIX, and the EXFIX group, in which 24 patients were treated by EXFIX. The average age in the EXFIX group was 31.17 years (16-57 years), while in the INFIX group, it was 34.5 years (17-53 years). The study included 20 (66.7%) males and 10 (33.3%) females in the INFIX group and 10 (41.7%) males and 14 (58.3%) females in the EXFIX group. The radiological outcomes were evaluated using Matta and Tornetta's score, and the functional outcomes using the Majeed score. RESULTS: The results revealed a statistically significant difference between both groups (P = 0.013) regarding radiological outcomes, according to Matta and Tornetta's score in favor of the INFIX group. Sitting, standing, and walking abilities were measured at a 3-mo follow-up visit using Majeed score modules. It was significantly better among the INFIX group than the EXFIX group in all three modules. At the final follow-up, both groups had no statistically significant difference according to the Majeed score; 92.35 in the INFIX group and 90.99 in the EXFIX group (P = 0.513). A lower surgical site infection rate was noticed in the INFIX group (P = 0.007). CONCLUSION: Anterior subcutaneous pelvis INFIX is associated with better radiological outcomes and a lower infection rate than anterior supra-acetabular EXFIX in managing patients with unstable anterior pelvic ring fractures.

Metformin enhances the antitumor activity of oncolytic herpes simplex virus HF10 (canerpaturev) in a pancreatic cell cancer subcutaneous model.

Oncolytic virus (OV) therapy is a promising cancer immunotherapy, especially for cold tumors by inducing the direct lysis of cancer cells and initiation of potent antitumor response. Canerpaturev (C-REV) is an attenuated oncolytic herpes simplex virus-1, which demonstrated a potent antitumor effect in various preclinical models when used either alone or combined. Metformin is a commonly prescribed antidiabetic drug that demonstrated a potent immune modulator effect and antitumor response. We combined C-REV with metformin in a low immunogenic bilateral murine tumor model to enhance C-REV's antitumor efficacy. In vitro, metformin does not enhance the C-REV cell cytotoxic effect. However, in in vivo model, intratumoral administration of C-REV with the systemic administration of metformin led to synergistic antitumor effect on both sides of tumor and prolonged survival. Moreover, combination therapy increased the effector CD44+ CD8+ PD1- subset and decreased the proportion of terminally-differentiated CD103+ KLRG-1+ T-regulatory cells on both sides of tumor. Interestingly, combination therapy efficiently modulates conventional dendritic cells type-1 (cDC1) on tumors, and tumor-drained lymph nodes. Our findings suggest that combination of C-REV and metformin enhances systemic antitumor immunity. This study may provide insights into the mechanism of action of OV therapy plus metformin combination against various tumor models.

The impact of enteric coating of aspirin on aspirin responsiveness in patients with suspected or newly diagnosed ischemic stroke: prospective cohort study: results from the (ECASIS) study.

BACKGROUND AND PURPOSE: Uncertainty remains regarding the impact of enteric-coated aspirin (EC-ASA) on secondary prevention of ischemic stroke compared to plain aspirin (P-ASA). Hence, this study was designed to investigate the effect of EC formulation on ASA response via evaluating thromboxane B2 (TXB2) levels in patients with suspected or newly diagnosed stroke. METHODS: A prospective cohort study on suspected or newly diagnosed ischemic stroke patients who are aspirin-naive was conducted. Patients were received either EC aspirin or plain aspirin for at least 3 days. The primary outcome was the proportion of aspirin non-responsiveness between two groups (level of residual serum TXB2 associated with elevated thrombotic risk (< 99.0% inhibition or TXB2 > 3.1 ng/ml) within 72 h after three daily aspirin doses, while secondary outcomes were the incidence of early gastrointestinal tract (GIT) bleeding with the various aspirin preparations. (Trial registration: Clinicaltrials.gov NCT04330872 registered on 02 April 2020). RESULTS: Of 42 patients, ischemic strokes were confirmed in both P-ASA (81%) and EC-ASA (67%) arms. ASA non-responsiveness showed no significant difference between the two formulations (P-ASA vs. EC-ASA; 28.6% vs 23.8%; P = 0.726). Univariate and multivariate logistic regression analysis showed that patients treated with EC-ASA were more likely to have a lower rate of non-responders compared to P-ASA (unadjusted OR 0.78; 95% CI 0.20, 3.11); with the risk highest in type 2 diabetic patients with HBA1c > 6.5% (adjusted OR 6; 95% CI 1.02, 35.27; P = 0.047). No incidence of GIT bleeding observed throughout the study. CONCLUSION: A significant proportion of ASA non-responsiveness was recorded regardless of ASA formulation administered. The increased risk of ASA non-responsiveness in diabetic patients needs further exploration by larger prospective studies.

Operative intervention of unstable paediatric pelvic fracture: radiological and functional assessment.

PURPOSE: The aim of the study was to add to the literature new data regarding the evaluation of surgical fixation of challenging unstable paediatric pelvic fractures, radiologically and clinically besides recording any complications through the follow-up period. METHODS: Prospective study was conducted at our hospital between 2012 and 2017 where 21 patients less than 16 years with unstable fracture pelvis were surgically fixed. The method of fixation varied between the external percutaneous fixation and internal fixation. The Infix system was used in for anterior ring fixation in some cases. Patients were evaluated radiologically and functionally using the functional independence measure questionnaire (FIM) and the modified Merle d'Aubigne and Postel (MDP) score. RESULTS: Twelve males and 9 females were fixed with mean age of 12.5 years. Motorcar accident was the main mode of trauma. Nine patients had fracture pelvis Tile's type B and 12 had Tile's type C injuries. All fractures united by 8 weeks. No patients suffered from pelvic asymmetry or leg length discrepancy at a mean follow-up of 2 years. The mean of FIM was 122.5 and the mean of MDP score was 16.2. CONCLUSION: Displaced unstable pelvic fractures in children need a systematic evaluation of the injury pattern. These serious fractures should be referred for anterior ± posterior ring stabilization. Promising clinical outcomes with surgical fixation can be reached with a low rate of complications. Further large-scale studies should be conducted for the calling literature.

Night-Time Non-dipping Blood Pressure and Heart Rate: An Association With the Risk of Silent Small Vessel Disease in Patients Presenting With Acute Ischemic Stroke.

Background and Purpose: Nocturnal non-dipping blood pressure and heart rate are associated with an increased risk of cardiovascular disease. The effects of such variance on cerebrovascular disease have not been well studied. Methods: The 24-h ambulatory blood pressure (ABPM) and heart rate were monitored with B-pro in patients with acute stroke within the initial week of hospital admission. The risk factor profiles, clinical presentation, imaging, and short-term prognosis were compared in nocturnal dippers and non-dippers (more than 10% nocturnal decrease) of blood pressure and heart rate. Results: We enrolled 234 patients in whom ABPM and MRI data were available. Heart rate data were available in 180 patients. Lacunar sub-cortical stroke was the most common acute lesion (58.9%), while hypertension (74%) and diabetes (41.5%) were the most common associated risk factors. ABPM revealed non-dipping in 69% of patients. On univariate analysis, Small Vessel Disease (SVD) was significantly more frequent in non-dippers vs. dippers (BP: 56.8 vs. 40.3% p = 0.02; heart rate: 57.9 vs. 40.7% p = 0.03). Silent strokes were also more frequent in non-dippers vs. dippers (BP: 40.7 vs. 26.4% p = 0.35; heart rate: 44.6 vs. 25.4% p = 0.01). Multivariate analysis revealed SVD to be significantly related to age, hypertension, blood pressure non-dipping, and severity of symptoms at index event. Conclusions: The presence of nocturnal non-dipping of blood pressure and heart rate are associated with an increased risk of silent stroke and SVD. Increased use of ABPM may allow for improved diagnosis of non-dippers.

S-1 facilitates canerpaturev (C-REV)-induced antitumor efficacy in a triple-negative breast cancer model.

Canerpaturev (C-REV) is a highly attenuated, replication-competent, mutant strain of oncolytic herpes simplex virus type 1 that may be an effective new cancer treatment option. S-1, an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, is used as a key chemotherapeutic agent for metastatic recurrent breast cancer. Although the antitumor effects of oncolytic viruses combined with 5-FU in vivo have been reported, the detailed mechanisms are unknown. Here, we investigated the antitumor mechanism of the combination of C-REV and S-1 in triple-negative breast cancer (TNBC) in the context of tumor immunity. The combined effect of C-REV and S-1 was evaluated in a bilateral tumor model of murine TNBC 4T1 in vivo. S-1 enhanced the TNBC growth inhibitory effects of C-REV, and decreased the number of tumor-infiltrating, myeloid-derived suppressor cells (MDSCs), which suppress both innate and adaptive immune responses. Moreover, C-REV alone and in combination with S-1 significantly increased the number of CD8+ T cells in the tumor and the production of interferon γ (IFNγ) from these cells. Our findings indicate that C-REV suppresses TNBC tumor growth by inducing the expansion of effector CD8+ T cell subsets in tumors in which S-1 can inhibit MDSC function. Our study suggests that MDSCs may be an important cellular target for breast cancer treatment. The combination of C-REV and S-1 is a new approach that might be directly translated into future clinical trials against TNBC.

C-REV Retains High Infectivity Regardless of the Expression Levels of cGAS and STING in Cultured Pancreatic Cancer Cells.

Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)-TBK1-IRF3-IFN pathway is known to act as the central cellular host defense against viral infection. Recent reports have linked low expression levels of cGAS and STING in cancer cells to poor prognosis among patients. Moreover, downregulation of cGAS and STING has been linked to higher susceptibility to OV infection among several cancer cell lines. In this paper, we show that there is little correlation between levels of cGAS/STING expression and susceptibility to C-REV among human pancreatic cancer cell lines. Despite having a responsive STING pathway, BxPC-3 cells are highly susceptible to C-REV infection. Upon pre-activation of the STING pathway, BxPc-3 cells exhibited resistance to C-REV infection. However, without pre-activation, C-REV completely suppressed the STING pathway in BxPC-3 cells. Additionally, despite harboring defects in the STING pathway, other high-grade cancer cell lines, such as Capan-2, PANC-1 and MiaPaCa-2, still exhibited low susceptibility to C-REV infection. Furthermore, overexpression of STING in MiaPaCa-2 cells altered susceptibility to a limited extent. Taken together, our data suggest that the cGAS-STING pathway plays a minor role in the susceptibility of pancreatic cancer cell lines to C-REV infection.

Oncolytic herpes simplex virus HF10 (canerpaturev) promotes accumulation of CD8+ PD-1- tumor-infiltrating T cells in PD-L1-enriched tumor microenvironment.

Oncolytic viruses (OVs) remodel the tumor microenvironment by switching a "cold" tumor into a "hot" tumor with high CD8+ T-cell infiltration. CD8+ T-cell activity plays an essential role in the antitumor efficacy of OVs. However, the activity of T cells is impaired by the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction. To date, it remains unclear why OVs alone have a significant antitumor activity even when PD-L1 expression persists on tumor or immune cells. In this study, we found that canerpaturev (C-REV) treatment significantly suppressed tumor growth, even though it induced a significant increase in PD-L1 expression in tumors in vivo as well as persistence of high PD-L1 expression on antigen-presenting cells (macrophage and dendritic cells [DCs]). Surprisingly, we observed that C-REV treatment increased the abundance of activated CD8+ PD-1- tumor-infiltrating lymphocytes (TILs) in the tumor on both the injected and contralateral sides, although infiltration of CD8+ PD-1high TILs into the tumor was observed in the control group. Moreover, the difference in PD-1 expression was observed only in tumors after treatment with C-REV, whereas most CD8+ T cells in the spleen, tumor-draining lymph nodes and blood were PD-1-negative, and this did not change after C-REV treatment. In addition, changes in expression of T-cell immunoglobulin and mucin-domain containing-3 and T-cell immune-receptor with Ig and ITIM domains were not observed on CD8+ TILs after C-REV treatment. Taken together, our findings may reveal mechanisms that allow OVs to trigger an antitumor immune response, irrespective of a PD-L1-enriched tumor microenvironment, by recruitment of CD8+ PD-1- TILs.

Aerobic training, resistance training, or their combination as a means to fight against excess weight and metabolic syndrome in obese students - which is the most effective modality? A randomized controlled trial.

This study aimed to determine the effects of either aerobic training (AT) or resistance training (RT) or both (A+RT) on obesity and its comorbidities in young adults. A total of 61 participants, aged 21.74 ± 1.42 years and with a body mass (BM) index (BMI) of 36.21 ± 2.43 kg/m2, were randomized for 12 weeks into control (CONT, n = 15), AT (n = 15), RT (n = 16), and A+RT (n = 15) groups. BM, body composition, and cardiovascular disease risk factors were assessed before and after intervention. BM did not change in the CONT and RT groups but decreased significantly by 7.5 kg in the AT (p ≤ 0.05) and 8.82 kg in the A+RT (p ≤ 0.05) groups, respectively. Significant reductions were also noted in waist circumference, BMI, and body fat percentage in the exercising groups. The most significant variations were in the A+RT group. High-density lipoprotein cholesterol (HDL-C) concentrations were increased after A+RT by 2.39 mg/dL. Significant reductions were also noted in very-low-density lipoprotein cholesterol (VLDL-C) concentrations (-2.84 mg/dL) in the A+RT group. AT alone is effective in improving BM and body composition, while RT alone improves the body composition and A+RT ensures better outcomes concerning BM, body composition, HDL-C, and VLDL-C. Novelty: Aerobic training alone is effective in improving BM and body composition. Resistance training alone improves the body composition. The combination of aerobic and resistance exercises ensures better outcomes for BM, body composition, HDL-C, and VLDL-C.

Anti-Inflammatory and Immunomodulatory Role of Bone Marrow-Derived MSCs in Mice with Acute Lung Injury.

Recently, studies suggested that the mesenchymal stem cells (MSCs) have anti-inflammatory and immune-modulatory roles in the induced acute lung injury in mice via controlling innate, humoral, and cell-mediated immunity. Sixty adult male mice were divided equally into three groups. Group A (control group) received an intraperitoneal (IP) phosphate-buffered saline. Group B was injected IP with lipopolysaccharide (LPS). Group C was injected IP with LPS, followed after 2 h by intravenous labeled bone marrow-derived MSCs (BM-MSCs). The plasma and bronchioalveolar lavage (BAL) fluid were collected at 12, 24, and 72 h postinjection. Estimation of total cell and neutrophils count and immunoglobulin M (IgM) in BAL fluid was performed. Enzyme-linked immunosorbent assay (ELISA) was used to analyze tumor necrosis factor-α (TNF-α) that is a proinflammatory cytokine and interleukin-10 (IL-10), which is an anti-inflammatory cytokine, in plasma. Lung samples were collected for histopathological examination at 12, 24, 72 h, and 1 week postinjection. Decreased TNF-α and increased IL-10 levels in the plasma of MSC-treated group compared to the LPS-infected group were observed. Also, decreased IgM level in BAL fluid of the MSC-treated group after 72 h compared to the LPS-infected group was detected with a resolution of inflammation and improvement in lung injury. Moreover, MSC-treated group showed a reduction in total leukocyte count and neutrophil percentage in comparison to control and LPS-infected groups. Histopathological improvement was detected in MSC-treated group as well. In conclusion, systemic MSCs injection has an anti-inflammatory and immune-modulatory effect in LPS-induced acute lung injury in mice.

Stroke in the adult Qatari population (Q-stroke) a hospital-based retrospective cohort study.

BACKGROUND: Studies assessing the burden of stroke in Qataris are limited. We aim to study stroke in the Qatari population. METHODS: A retrospective review was undertaken of all Qatari adults presenting with stroke to Hamad Medical Corporation over a 5-year period. Descriptive statistics were used to summarize demographic and all other clinical characteristics of the patients. The primary outcome was the incidence of stroke in the Qatari patients. Comparison was made between the sexes. RESULTS: 862 patients were included, with 58.9% being male. The average incidence of stroke over the 5-year period was 92.04 per 100,000 adult Qatari population. The mean age of the cohort was 64.3±14.4 years, (range 19-105 years). The mean age of first ever cerebrovascular event was 63.2±14.5 years. The diagnosis was ischemic stroke in (73.7%), transient ischemic attack in (13.8%), intracerebral hemorrhage (ICH) in (11.6%), subarachnoid hemorrhage in (0.7%) and (0.2%) cerebral venous sinus thrombosis. Small vessel disease was the most common cause of ischemic stroke accounting for (46.5%), followed by large artery atherosclerosis (24.5%). Hypertension (82.7%) and diabetes (71.6%) were particularly prevalent in this cohort. Females were older (65.8±14.1 vs 63.4±14.5 years), had more hypertension and diabetes and more disability or death at 90 days (p<0.05) compared to Qatari males. CONCLUSION: Stroke occurs at a significantly lower age in Qataris compared to the western population. This study has uncovered sex differences that need to be studied further.