Antipsychotics possess anti-glioblastoma activity by disrupting lysosomal function and inhibiting oncogenic signaling by stabilizing PTEN.

The repurposing of medications developed for central nervous system (CNS) disorders, possessing favorable safety profiles and blood-brain barrier permeability, represents a promising strategy for identifying new therapies to combat glioblastoma (GBM). In this study, we investigated the anti-GBM activity of specific antipsychotics and antidepressants in vitro and in vivo. Our results demonstrate that these compounds share a common mechanism of action in GBM, disrupting lysosomal function and subsequently inducing lysosomal membrane rupture and cell death. Notably, PTEN intact GBMs possess an increased sensitivity to these compounds. The inhibition of lysosomal function synergized with inhibitors targeting the EGFR-PI3K-Akt pathway, leading to an energetic and antioxidant collapse. These findings provide a foundation for the potential clinical application of CNS drugs in GBM treatment. Additionally, this work offers critical insights into the mechanisms and determinants of cytotoxicity for drugs currently undergoing clinical trials as repurposing agents for various cancers, including Fluoxetine, Sertraline, Thioridazine, Chlorpromazine, and Fluphenazine.

Detection of rat lungworm (Angiostrongylus cantonensis) infection by real-time PCR from the peripheral blood of animals: a preliminary study.

Rat lungworm disease or neuroangiostrongyliasis is a cerebral parasitic infection that affects humans and animals alike. Its clinical signs and symptoms can range from mild self-resolving to serious life-threatening conditions. Studies suggest therapeutic interventions during the early stages of infection to be more effective than in later stages. However, early diagnosis of infection is usually problematic without the knowledge of exposure and/or detection of the parasite's DNA or antibody against the parasite in the cerebrospinal fluid. This requires a lumbar puncture, which is an invasive procedure that generally requires hospitalization. This study evaluates an affordable and less invasive alternative to detect parasitic DNA by PCR from the peripheral blood of potentially infected animals. Blood samples from 58 animals (55 dogs and 3 cats) with clinical suspicion of infection were submitted to our lab between February 2019 and August 2022 by local, licensed veterinarians. DNA was extracted from whole blood, plasma, serum, and/or packed cells using the Qiagen DNeasy Blood & Tissue Kit as per the manufacturer's protocol. All 58 animals were tested by real-time PCR using the AcanITS1 assay and 32 of these animals (31dogs; 1 cat) were also tested using the AcanR3990 assay. The PCR results for both assays were classified into strongly positive > positive > weakly positive > negative, and equivocal for ambiguous results, based on the strength of the signal. The percent infection detected using the AcanITS1 and AcanR3990 assays was 12.72% (7/55) and 20.68% (6/29), respectively. The overall percent infection detected was 34.37% (11/32), with only two animals testing positive by both assays. The three cats involved in this study tested negative by both assays. These results are promising and warrant further investigations to increase sensitivity including variables that might affect detection in the blood, such as parasite load, and laboratory methodologies.

Robotic Magnetic Sphincter Augmentation Device Removal.

Although most patients with reflux can be managed with medical therapy, some require surgical intervention to manage their disease. Newer technologies, such as magnetic sphincter augmentation (MSA), have been promoted as the replacement of fundoplication. However, as time has elapsed, our institution noticed the need for the removal of MSA devices. Although a few reports have described MSA device removals, we provide a deeper explanation of how to perform a robotic device removal. Our article describes the technical steps and includes a video to demonstrate how to complete the surgery robotically.

Midlife health crisis of former competitive athletes: dissecting their experiences via qualitative study.

Sports participation confers many health benefits yet greatly increases injury risk. Long-term health outcomes in former athletes and transition to life after competitive sports are understudied. Ending a sport may pose physical and psychosocial challenges. The purpose was to determine the lived experiences of former competitive athletes and how their sports participation impacted their long-term health and well-being. Former college varsity athletes participated in semistructured interviews focusing on their experiences, including past and current health, the impact of injuries, activity, exercise, diet and transition to life after competitive sport. Thematic analysis was completed using a collaborative, iterative process. Thirty-one (16 female, 15 male) former college athletes aged 51.3±7.4 years were interviewed. Six themes emerged: (1) lifelong athlete identity; (2) structure, support and challenges of the college athlete experience; (3) a big transition to life beyond competitive sport; (4) impact of competitive sport on long-term health; (5) facilitators and barriers to long-term health after sport and (6) transferable life skills. Continuing sports eased the transition for many but often delayed their postathlete void. Challenges included managing pain and prior injury (eg, If I didn't have my knee injury, I would definitely be more active), reducing energy needs and intake (eg, When I was an athlete, I could eat anything; and unfortunately, that's carried into my regular life), lack of accountability, changed identity and lost resources and social support. Participants suggested a programme, toolkit, mentoring or exit course to facilitate the transition. While former athletes benefit from transferrable life skills and often continue sports and exercise, they face unique challenges such as managing pain and prior injury, staying active, reducing energy intake and changing identity. Future research should develop and evaluate a toolkit, programme and other resources to facilitate life after ending competitive sports under 'normal' conditions (eg, retirement) and after a career-ending injury.

Beta Blockers in Contemporary Cardiology: Is It Better to Cast Them Out?

Beta blockers are one of the commonest prescription drugs in medicine and they have been thought to revolutionize the treatment of heart failure (HF) with reduced ejection fraction (HFrEF) in the last century. In addition to HFrEF, they are prescribed for a variety of diseases in cardiology from hypertension to HF, angina, and stable coronary artery disease (CAD). The increased prescription of beta blockers in conditions like HF with preserved ejection fraction (HFpEF), and stable CAD may be doing more harm than good as per the data we have so far. The available data shows that beta blockers are associated with increased stroke risk and atrial fibrillation (AF) in hypertension and in patients with HFpEF, they have been associated with decreased exercise capacity. In patients with stable CAD and patients with myocardial infarction with normal systolic functions, beta blockers don't offer any mortality benefit. In this article, we critically review the common indications and the uses of beta blockers in patients with HFpEF, CAD, hypertension and AF and we propose that beta blockers are over-prescribed under the shadow of their beneficial effects in patients with HFrEF.

PTCH1-mutant human cerebellar organoids exhibit altered neural development and recapitulate early medulloblastoma tumorigenesis.

Patched 1 (PTCH1) is the primary receptor for the sonic hedgehog (SHH) ligand and negatively regulates SHH signalling, an essential pathway in human embryogenesis. Loss-of-function mutations in PTCH1 are associated with altered neuronal development and the malignant brain tumour medulloblastoma. As a result of differences between murine and human development, molecular and cellular perturbations that arise from human PTCH1 mutations remain poorly understood. Here, we used cerebellar organoids differentiated from human induced pluripotent stem cells combined with CRISPR/Cas9 gene editing to investigate the earliest molecular and cellular consequences of PTCH1 mutations on human cerebellar development. Our findings demonstrate that developmental mechanisms in cerebellar organoids reflect in vivo processes of regionalisation and SHH signalling, and offer new insights into early pathophysiological events of medulloblastoma tumorigenesis without the use of animal models.

Efficacy of X-Ray Phytosanitary Irradiation on the Infectivity and Reproduction of Angiostrongylus cantonensis in Experimentally Infected Rats.

Angiostrongylus cantonensis is a globally distributed nematode and the leading cause of eosinophilic meningitis in humans. As a global hotspot for this disease, Hawaii's agricultural exports may be contributing to the spread of A. cantonensis. Phytosanitary irradiation doses of 150 or 400 Gy provide quarantine security against multiple insect pests. We evaluated the in vitro and in vivo effects of phytosanitary irradiation on infectious, third-stage, A. cantonensis larvae. In vitro experiments directly exposed larvae to irradiation doses ranging from 200 to 1,000 Gy. Results showed low mortality and no dose response across all treatments 27 days post-irradiation. In vivo studies isolated larvae from wild-caught Parmarion martensi after exposure to x-ray irradiation at doses of 0, 150, and 400 Gy and infected them into laboratory rats. Fourteen rats were assigned to each treatment and infected with 50 larvae from their assigned irradiation dose. Results at 3 and 6 weeks post-infection demonstrated a significant negative dose response in regard to the number of larvae that migrated to the brain and adults found in the pulmonary artery. No irradiated larvae that grew into adults were able to produce eggs. These findings indicate that x-ray irradiation does not result in the direct mortality of A. cantonensis larvae; however, it does affect the infectivity and reproduction of A. cantonensis within its definitive host, the rat. Phytosanitary irradiation at doses ≥150 Gy appears to be an effective means of preventing the establishment of viable populations of A. cantonensis, thus reducing the potential for global spread due to agricultural exports from Hawaii.

miRNA-194-3p represses NF-κB in gliomas to attenuate iPSC genes and proneural to mesenchymal transition.

Severe tumor heterogeneity drives the aggressive and treatment refractory nature of glioblastomas (GBMs). While limiting GBM heterogeneity offers promising therapeutic potential, the underlying mechanisms that regulate GBM plasticity remain poorly understood. We utilized 14 patient-derived and four commercially available cell lines to uncover miR-194-3p as a key epigenetic determinant of stemness and transcriptional subtype in GBM. We demonstrate that miR-194-3p degrades TAB2, an important mediator of NF-κB activity, decreasing NF-κB transcriptional activity. The loss in NF-κB activity following miR-194-3p overexpression or TAB2 silencing decreased expression of induced pluripotent stem cell (iPSC) genes, inhibited the oncogenic IL-6/STAT3 signaling axis, suppressed the mesenchymal transcriptional subtype in relation to the proneural subtype, and induced differentiation from the glioma stem cell (GSC) to monolayer (ML) phenotype. miR-194-3p/TAB2/NF-κB signaling axis acts as an epigenetic switch that regulates GBM plasticity and targeting this signaling axis represents a potential strategy to limit transcriptional heterogeneity in GBMs.

Long-term function, body composition and cardiometabolic health in midlife former athletes: a scoping review.

While sports medicine has traditionally focused on recovering from injury and returning athletes to sport safely after injury, there is a growing interest in the long-term health of athletes. The purpose of this scoping review was to (1) summarise the literature (methodologies and findings) on physical function, body composition and cardiometabolic health in midlife (age 40-65 years) former competitive athletes compared with non-athlete controls, (2) identify areas for future study in long-term health in athletes and (3) determine outcomes that could be evaluated in a future systematic review(s). We searched PubMed, CINAHL, Web of Science and SPORTDiscus for studies published between 2000 and 2022 evaluating former athletes and controls on physical function, body composition and/or cardiometabolic measures using MeSH terms. We identified 20 articles that met our criteria. Outcomes varied considerably across studies, most of which were cross-sectional and evaluated only males. Limited data suggest that former endurance athletes have leaner body compositions, higher aerobic capacity and better cardiometabolic indicators than controls; former athletes who maintain higher physical activity (ie, self-reported exercise) are healthier than those who do not; and former team sport athletes, who have higher injury prevalence, may have poorer functional performance than controls who were recreationally active in college. Studies rarely evaluated functional performance, did not control for prior injury or diet and seldom assessed current physical activity levels. Future research should include females and evaluate sex differences, control for prior sports-related injury(ies), quantify physical activity, use standardised outcome measures including performance-based functional assessments and incorporate longitudinal designs.

Chlorthalidone-Induced Fixed-Drug Eruption: Unmasking an Uncommon Reaction to a Common Diuretic.

Fixed-drug eruptions (FDEs) are dermatological reactions characterized by specific skin lesions triggered by certain medications. Our case reports commonly used medications that can cause drug-induced skin reactions. Chlorthalidone, a widely used diuretic, had not been prominently linked to FDEs. Here, we present the case of a 45-year-old African-American male who developed classic FDE skin lesions following the initiation of chlorthalidone therapy. This case underscores the imperative for further investigation and heightened awareness among healthcare professionals regarding chlorthalidone-associated FDEs. Findings suggest that such reactions might be more prevalent than previously acknowledged, underscoring the significance of prompt diagnosis and effective management of drug-induced skin responses. Notably, the patient's lesions showed complete resolution upon discontinuing the diuretic, reinforcing the causal relationship. This case is an essential reminder of the importance of vigilance in monitoring patients for adverse drug reactions, even in unlikely medications, such as chlorthalidone.​​​​​​.

Electrocardiographic lead reversals.

Misplacement of cables during the recording of a 12-lead electrocardiogram [ECG] poses a non-negligible risk of creating panic and confusion at the bedside in daily clinical practice. Clinical awareness about the manifestations of commonly encountered electrode misplacements is imperative for avoiding misdiagnosis. A basic understanding of the electrophysiology behind these anomalous ECG tracings is likely to aid in prompt suspicion, accurate detection, and appropriate rectification in most cases. We discuss the abnormalities produced on 12-lead ECG tracings by the misplacement of electrode cables, with a focus on the clinical implications of the same. We suggest a mnemonic - 'SPIRAL' - as a quick screening criterion to detect commonly encountered lead reversals.

Does Cardiac Arrhythmia Predict Worse Outcome in Mild or Moderate Covid-19 Infection?

Covid-19 is a multisystem disease with the lungs being predominantly affected. Cardiac involvement is mostly seen as a rise in troponins, arrhythmias, and ventricular dysfunction. This study aimed to estimate the incidence of arrhythmias seen in Covid-19 infection and assess if arrhythmias predict worsening or mortality. Prospective observational study involving patients with mild to moderate Covid illness admitted in a tertiary care centre. Among the 85 patients (Mean age 45.8 + 14.1 years; 75.31% men), worsening of Covid-19 illness was seen in 29 (34.1%) patients. New onset arrhythmias were detected on Holter in 9 (10.5%) patients. Supraventricular tachycardia was seen in 7 (8.2%) patients of whom 6 showed worsening which was statistically significant (p-value-0.006). Risk factors associated with worsening on univariate analysis were male gender (OR [95%CI] = 6.93(1.49-32.31), p-value - 0.014), new onset supraventricular tachycardia (OR [95% CI] = 14.35 [1.64-125.94], p-value - 0.016) and D-dimer elevation (OR [95% CI] = 1.00(1.00-1.01), p-value - 0.02). On multivariate analysis D-dimer (OR [95% CI] = 1.00(1.00-1.01; p-value 0.046) and supraventricular arrhythmias (OR [95% CI] = 11.12 (1.22-101.14); p-value - 0.033) were independently associated with worsening. Covid-19 infection can lead to cardiac arrhythmias. The development of supraventricular tachycardia in patients with Covid-19 infection predicts higher morbidity and worsening.

Management of Type 3c Diabetes in an Elite Tactical Athlete.

The presentation of Type 3c diabetes is atypical, accounting for 0.5-1% of all types of diabetes. Combining this with the healthy Special Operations community is even more profound. A 38-year-old active-duty male in Special Operations developed acute abdominal pain and vomiting while deployed. He was diagnosed with severe acute necrotizing pancreatitis secondary to Type 3c diabetes, and the management of his condition became increasingly difficult. This case highlights Type 3c diabetes and the complexity of formulating a comprehensive treatment plan for a tactical athlete.

Economic Evaluation Comparing Virtual Reality with Child Life Programming for Non-sedated Pediatric Medical Imaging: A Cost-Consequence Analysis.

INTRODUCTION: Effective preparation of children for hospital procedures, including non-sedated medical imaging, is an important clinical issue. This study aimed to assess the costs and consequences (effects) of preparing pediatric patients using two methods of delivering preparation for a scheduled magnetic resonance image (MRI)-virtual reality (VR-MRI) and a certified Child Life Program (CLP). METHODS: A cost-consequence analysis (CCA) was performed using a societal perspective in Canada. The CCA catalogs a wide range of costs and consequences of VR-MRI compared with a CLP. The evaluation uses data from a prior randomized clinical trial evaluating VR and a CLP in a simulated trial. The economic evaluation encompassed health-related effects, including anxiety, safety and adverse events, and non-health effects, including preparation time, displaced time from usual activities, workload capacity, patient-specific adaptation, administrative burden, and user-experience metrics. The costs have been categorized into hospital operational costs, travel costs, other patient costs, and societal costs. RESULTS: VR-MRI has similar benefits to the CLP in managing anxiety, safety and adverse events, as well as converting patients to non-sedated medical imaging. Preparation time and patient-specific adaptation are in favor of the CLP, while displaced time from usual activities, potential workload capacity, and administrative burden are in favor of VR-MRI. Both programs rank favorably in terms of user experience. The hospital operational costs ranged in Canadian dollars (CAN$) from CAN$32.07 for the CLP to between CAN$107.37 and CAN$129.73 for VR-MRI. Travel costs ranged from CAN$50.58 to CAN$2365.18 depending on travel distance for the CLP, and CAN$0 for VR-MRI. Other patient costs involved caregiver time off, and ranged from CAN$190.69 to CAN$$1144.16 for the CLP and CAN$47.67 for VR-MRI. The total cost for the CLP ranged from CAN$315.16 (CAN$277.91-$426.64) to CAN$3843.41 (CAN$3196.59-$4849.91) per patient depending on travel distance and amount of administrative support required, while VR-MRI preparation ranged from CAN$178.30 (CAN$178.20-$188.76) to CAN$283.85 (CAN$283.71-$298.40) per patient. For every instance where patient travel to visit a Certified Child Life Specialist (CCLS) onsite was replaced with VR-MRI, between CAN$119.01 and CAN$3364.62 total costs could be saved per patient. CONCLUSIONS: While it is neither feasible nor appropriate to replace all preparation with VR, using VR to reach children who cannot otherwise visit the CLP onsite could increase access to quality preparation, and using VR in place of the CLP where clinically indicated could reduce the overall costs for patients, the hospital, and society. Our CCA gives decision makers a cost analysis and the relevant effects of each preparation program so they can value the VR and CLP programs more broadly within the potential health and non-health outcomes of pediatric patients scheduled for MRI at their facilities.

Neuroangiostrongyliasis: Updated Provisional Guidelines for Diagnosis and Case Definitions.

Angiostrongylus cantonensis is the main causative agent for eosinophilic meningoencephalitis in humans. Larvae are rarely found in the cerebral spinal fluid (CSF). Consequently, serology and DNA detection represent important diagnostic tools. However, interpretation of the results obtained from these tools requires that more extensive accuracy studies be conducted. The aim of the present study is to update guidelines for diagnosis and case definitions of neuroangiostrongyliasis (NA) as provided by a working group of a recently established International Network on Angiostrongyliasis. A literature review, a discussion regarding criteria and diagnostic categories, recommendations issued by health authorities in China and an expert panel in Hawaii (USA), and the experience of Thailand were considered. Classification of NA cases and corresponding criteria are proposed as follows: minor (exposure history, positive serology, and blood eosinophilia); major (headache or other neurological signs or symptoms, CSF eosinophilia); and confirmatory (parasite detection in tissues, ocular chambers, or CSF, or DNA detection by PCR and sequencing). In addition, diagnostic categories or suspected, probable, and confirmatory are proposed. Updated guidelines should improve clinical study design, epidemiological surveillance, and the proper characterization of biological samples. Moreover, the latter will further facilitate accuracy studies of diagnostic tools for NA to provide better detection and treatment.

Comparison of Antibody Isotype Response to Angiostrongylus cantonensis in Experimentally Infected Rats (Rattus norvegicus) Using Hawai'i 31 kDa Antigen in an Indirect ELISA.

Neuroangiostrongyliasis (NAS) is an emerging tropical disease in humans and some animals which is caused by infection with the parasitic nematode Angiostrongylus cantonensis. It is the leading cause of eosinophilic meningitis worldwide. Diagnoses in humans and susceptible animals are generally presumptive and easily confused with other central nervous system disorders. The 31 kDa antigen is currently the only NAS immunodiagnostic assay that has achieved 100% sensitivity. However, little is known about the humoral immune response against the 31 kDa antigen in NAS infections, which would be critical for widespread adoption of this assay. We used the Hawai'i 31 kDa isolate in an indirect ELISA assay to confirm the presence of immunoglobulin IgG, IgM, IgA, and IgE isotypes in six-week post-infection plasma from lab-reared rats infected with 50 live, third-stage, A. cantonensis larvae isolated from a wild Parmarion martensi semi-slug. Our results confirmed the presence of all four isotypes against the Hawaii 31 kDa isolate, with sensitivity ranging from 22-100%. The IgG isotype showed 100% sensitivity in detecting A. cantonensis infection, which validates the use of IgG indirect ELISA with 31 kDa antigen as an effective immunodiagnostic assay for rats six weeks post-infection. Given each isotype may be present at different times during NAS infections, our data provides preliminary information on the humoral immune response to A. cantonensis infection in lab-reared rats and serves as a baseline for future studies.

Exploring the value of three-dimensional printing and virtualization in paediatric healthcare: A multi-case quality improvement study.

Background: Three-dimensional printing is being utilized in clinical medicine to support activities including surgical planning, education, and medical device fabrication. To better understand the impacts of this technology, a survey was implemented with radiologists, specialist physicians, and surgeons at a tertiary care hospital in Canada, examining multidimensional value and considerations for uptake. Objectives: To examine how three-dimensional printing can be integrated into the paediatric context and highlight areas of impact and value to the healthcare system using Kirkpatrick's Model. Secondarily, to explore the perspective of clinicians utilizing three-dimensional models and how they make decisions about whether or not to use the technology in patient care. Methods: A post-case survey. Descriptive statistics are provided for Likert-style questions, and a thematic analysis was conducted to identify common patterns in open-ended responses. Results: In total, 37 respondents were surveyed across 19 clinical cases, providing their perspectives on model reaction, learning, behaviour, and results. We found surgeons and specialists to consider the models more beneficial than radiologists. Results further showed that the models were more helpful when used to assess the likelihood of success or failure of clinical management strategies, and for intraoperative orientation. We demonstrate that three-dimensional printed models could improve perioperative metrics, including a reduction in operating room time, but with a reciprocal effect on pre-procedural planning time. Clinicians who shared the models with patients and families thought it increased understanding of the disease and surgical procedure, and had no effect on their consultation time. Conclusions: Three-dimensional printing and virtualization were used in preoperative planning and for communication among the clinical care team, trainees, patients, and families. Three-dimensional models provide multidimensional value to clinical teams, patients, and the health system. Further investigation is warranted to assess value in other clinical areas, across disciplines, and from a health economics and outcomes perspective.

Early dose of Adenosine, postRadiofrequency abLation of accessory pathwaY in determining acute procedural success (EARLY study).

INTRODUCTION: Post ablation of the accessory pathway (AP), the patient is observed in the catheterization laboratory for a variable period for resumption of pathway conduction. Aim of the study was to determine whether the administration of intravenous adenosine at 10 min after ablation of AP would have the same diagnostic accuracy as waiting for 30 min in predicting the resumption of AP conduction. METHODS: This was a prospective interventional study conducted in two centers. Post ablation of the AP, intravenous adenosine was administered at 10 min to look for dormant pathway conduction. The response was recorded as positive (presence of pathway conduction), negative (absence), or indeterminate (not able to demonstrate AV and VA block and inability to ascertain AP conduction). RESULTS: The study included 110 procedures performed in 109 patients. Adenosine administration at 10 min showed positive result in 3 cases (2.7%), negative result in 99 cases (90%) and indeterminate result in 8 cases (7.3%). Reconnection of accessory pathway at 30 min postablation was seen in 8 cases (7.3%). Of these 8 cases, 10 min adenosine administration showed positive test in 3 patients and negative test in 5 patients. Adenosine test at 10 min has a sensitivity, specificity, positive predictive value, and negative predictive value of 37.5%, 100%, 100%, and 94.9% in identifying the recurrence of accessory pathway conduction at 30 min, respectively. CONCLUSION: Absence of pathway conduction on administration of adenosine 10 min postablation does not help predict the absence of resumption of conduction thereafter.