Phenotype and fate of liver-resident CD8 T cells during acute and chronic hepacivirus infection.

Immune correlates of hepatitis C virus (HCV) clearance and control remain poorly defined due to the lack of an informative animal model. We recently described acute and chronic rodent HCV-like virus (RHV) infections in lab mice. Here, we developed MHC class I and class II tetramers to characterize the serial changes in RHV-specific CD8 and CD4 T cells during acute and chronic infection in C57BL/6J mice. RHV infection induced rapid expansion of T cells targeting viral structural and nonstructural proteins. After virus clearance, the virus-specific T cells transitioned from effectors to long-lived liver-resident memory T cells (TRM). The effector and memory CD8 and CD4 T cells primarily produced Th1 cytokines, IFN-γ, TNF-α, and IL-2, upon ex vivo antigen stimulation, and their phenotype and transcriptome differed significantly between the liver and spleen. Rapid clearance of RHV reinfection coincided with the proliferation of virus-specific CD8 TRM cells in the liver. Chronic RHV infection was associated with the exhaustion of CD8 T cells (Tex) and the development of severe liver diseases. Interestingly, the virus-specific CD8 Tex cells continued proliferation in the liver despite the persistent high-titer viremia and retained partial antiviral functions, as evident from their ability to degranulate and produce IFN-γ upon ex vivo antigen stimulation. Thus, RHV infection in mice provides a unique model to study the function and fate of liver-resident T cells during acute and chronic hepatotropic infection.

The link between reversible cerebral vasoconstriction syndrome and transient global amnesia.

Reversible cerebral vasoconstriction syndrome (RCVS) and transient global amnesia (TGA) are acute and self-limiting intra-cerebral conditions. Although previously studied as independent phenomena, there are increasing reports of co-occurrence of these two pathologies. We report a 55-year-old male who presented to the hospital with recurrent thunderclap headaches over the course of 1 week with sudden onset of anterograde memory loss. His medications included a selective serotonin reuptake inhibitor and intermittent use of pseudoephedrine. On examination he was amnestic to recent events and notably perseverating. Magnetic resonance imaging of the brain without contrast showed a small, punctate focus of restricted diffusion in the left hippocampus. He was diagnosed with TGA based on his clinical presentation. His headaches and amnesia resolved over the next 12 h throughout the course of his stay with acetaminophen and oral verapamil and he was discharged. Repeat computed tomography angiogram at 2 weeks revealed diffuse and segmental narrowing of the anterior and posterior intracranial circulation, which resolved on follow-up imaging at 3 months, confirming RCVS. The acute and reversible nature of these conditions and increasing reports of co-occurrence suggests a common pathophysiologic link. We review the literature highlighting similar cases and the presumed pathophysiology.

Mechanical thrombectomy for acute large vessel occlusion stroke beyond 24 h.

BACKGROUND: Multiple trials have shown that mechanical thrombectomy (MT) is superior to medical therapy. However, no robust evidence is available regarding MT beyond 24 h. In this study, we aimed to determine the safety and efficacy of endovascular stroke therapy in this late window. METHODS: We conducted a retrospective study of prospectively collected data of patients who met extended window trial criteria, but underwent MT beyond 24 h. Safety and efficacy outcomes included symptomatic intracerebral hemorrhage (sICH), procedural complications, number of passes, successful recanalization (mTICI 2b - 3), delta (Δ) NIHSS (baseline-discharge), and favorable outcomes (mRS 0-2 at 90 days). RESULTS: A total of 39 patients were included with a median age of 69 years (IQR 61.5, 73.5); 54% were females. Hypertension was present in 76% of patients; 23% were smokers. Half of the patients had M1 occlusion (48.7%). Median preprocedural NIHSS was 11 (IQR 7.0, 19.5). Successful revascularization was achieved in 87%; median number of passes was 2 (IQR 1.0, 3.0). Median ΔNIHSS was 3.0 (IQR -1.5, 8.0). Favorable outcome was achieved in 49% (95% CI: 34%-64%), and 95% were free of complications. A total of 3 patients (7.7%) had sICH. In an exploratory analysis, posterior circulation occlusion was associated with higher mRS at 90 days (OR: 14.7, p = 0.016). Favorable discharge facility was associated with lower mRS at 90 days (OR: 0.11, p = 0.004). CONCLUSIONS: Our study showed comparable clinical outcomes of MT beyond 24 h compared to MT trials within 24 h in patients with favorable imaging profile, especially in anterior circulation occlusions.

Machine learning multi-omics analysis reveals cancer driver dysregulation in pan-cancer cell lines compared to primary tumors.

Cancer cell lines have been widely used for decades to study biological processes driving cancer development, and to identify biomarkers of response to therapeutic agents. Advances in genomic sequencing have made possible large-scale genomic characterizations of collections of cancer cell lines and primary tumors, such as the Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA). These studies allow for the first time a comprehensive evaluation of the comparability of cancer cell lines and primary tumors on the genomic and proteomic level. Here we employ bulk mRNA and micro-RNA sequencing data from thousands of samples in CCLE and TCGA, and proteomic data from partner studies in the MD Anderson Cell Line Project (MCLP) and The Cancer Proteome Atlas (TCPA), to characterize the extent to which cancer cell lines recapitulate tumors. We identify dysregulation of a long non-coding RNA and microRNA regulatory network in cancer cell lines, associated with differential expression between cell lines and primary tumors in four key cancer driver pathways: KRAS signaling, NFKB signaling, IL2/STAT5 signaling and TP53 signaling. Our results emphasize the necessity for careful interpretation of cancer cell line experiments, particularly with respect to therapeutic treatments targeting these important cancer pathways.

Ticagrelor Use in Stroke Patients: Past, Present, and Future.

Antiplatelet medications are the mainstay for secondary stroke treatment. Aspirin, clopidogrel, and aspirin-dipyridamole are commonly used antiplatelet medications. Other antiplatelet medications such as ticagrelor and prasugrel have been majorly used in cardiovascular or neuro-interventional specialties. Recent studies have paved a way to their use in secondary stroke prevention. In this review, we have briefly discussed the pharmacology of ticagrelor, published literature in cardiology and stroke trials, use of ticagrelor among patients with ischemic strokes, and compared its efficacy, limitations and side-effects with other antiplatelet medications.

A case of symptomatic spinal dural arteriovenous fistula after high-volume lumbar puncture.

BACKGROUND: Spinal dural arteriovenous fistulas (DAVFs) are rare lesions that lead to venous congestion and ischemic injury resulting in neurologic deterioration. Here we present a patient diagnosed with glioblastoma multiforme (GBM) who became symptomatic from a spinal DAVF after a diagnostic high-volume lumbar puncture (LP). CASE DESCRIPTION: When a 72-year-old female developed partial seizures in her left upper extremity without other focal neurological deficits, she underwent a magnetic resonance imaging (MRI) scan of the brain. The MRI revealed a right frontal/posterior corpus callosal lesion. She next had a MR-guided high-volume LP. A GBM was diagnosed following a biopsy. Postoperatively, after the LP, she was noted to have bilateral deltoid and bilateral 4/5 lower extremity weakness, with diffuse hyperreflexia. The MRI and magnetic resonance angiogram (MRA) of the cervical spine demonstrated a large venous varix at the C5-C6 level within the left neural foramen. She underwent successful complete embolization of two thyrocervical branches with direct communication to an enlarged anterior spinal artery. One month later, her neurological examination returned to baseline; she was walking independently with only 4+/5 residual weakness in her left lower extremity. CONCLUSIONS: Here we report a patient with a cranial GBM and an incidental cervical spinal C5-C6 DAVF that became symptomatic after a high-volume LP. It is possible that the high-volume LP increased vascular congestion, thus precipitating the onset of cervical myelopathy.

The attitude of physicians toward cold remedies for upper respiratory infection in infants and children: a questionnaire survey.

Over-the-counter cold remedies are widely used for symptomatic relief of upper respiratory tract infections. The safety of these drugs is not well established in infants and their efficacy is questionable. Our aim was to study the attitude of family physicians and pediatricians toward the use of cold remedies in infants and children. A questionnaire was sent to 400 family physicians and 100 pediatricians randomly selected across Ontario. The overall response rate was 53.2%. Sixteen percent of family physicians recommended cold remedies for infants 0 to 6 months of age compared to 4% of the pediatricians (P = 0.01). For infants 6 to 12 months of age, the difference between pediatricians and family physicians persisted (14% and 38% of, respectively; P < 0.001). Despite that cold remedies are not proven to be effective and some safety issues are associated with their use in the pediatric age group, physicians still recommend them. Continuing medical education programs should address the issue.

Vaccine hesitancy: understanding better to address better.

Vaccine hesitancy is an emerging term in the socio-medical literature which describes an approach to vaccine decision making. It recognizes that there is a continuum between full acceptance and outright refusal of some or all vaccines and challenges the previous understanding of individuals or groups, as being either anti-vaccine or pro-vaccine. The behaviours responsible for vaccine hesitancy can be related to confidence, convenience and complacency. The causes of vaccine hesitancy can be described by the epidemiological triad i.e. the complex interaction of environmental- (i.e. external), agent- (i.e. vaccine) and host (or parent)- specific factors. Vaccine hesitancy is a complex and dynamic issue; future vaccination programs need to reflect and address these context-specific factors in both their design and evaluation. Many experts are of the view that it is best to counter vaccine hesitancy at the population level. They believe that it can be done by introducing more transparency into policy decision-making before immunization programs, providing up-to-date information to the public and health providers about the rigorous procedures undertaken before introduction of new vaccines, and through diversified post-marketing surveillance of vaccine-related events.