Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date. METHODS: We performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders. RESULTS: We confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10-13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders. DISCUSSION: Our gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms.

Investigation and modulation of interleukin-6 following subarachnoid hemorrhage: targeting inflammatory activation for cerebral vasospasm.

BACKGROUND: Cerebral vasospasm (CV) can contribute to significant morbidity in subarachnoid hemorrhage (SAH) patients. A key unknown is how CV induction is triggered following SAH. METHODS: Human aneurysmal blood and cerebral spinal fluid were collected for evaluation. To confirm mechanism, c57/bl6 wild type and c57/bl6 IL-6 female knockout (KO) mice were utilized with groups: saline injected, SAH, SAH + IL-6 blockade, SAH IL-6 KO, SAH IL-6 KO + IL-6 administration, SAH + p-STAT3 inhibition. Dual-labeled microglia/myeloid mice were used to show myeloid diapedesis. For SAH, 50 µm blood was collected from tail puncture and administered into basal cisterns. IL-6 blockade was given at various time points. Various markers of neuroinflammation were measured with western blot and immunohistochemistry. Cerebral blood flow was also measured. Vasospasm was measured via cardiac injection of India ink/gelatin. Turning test and Garcia's modified SAH score were utilized. P < 0.05 was considered significant. RESULTS: IL-6 expression peaked 3 days following SAH (p < 0.05). Human IL-6 was increased in aneurysmal blood (p < 0.05) and in cerebral spinal fluid (p < 0.01). Receptor upregulation was periventricular and perivascular. Microglia activation following SAH resulted in increased caveolin 3 and myeloid diapedesis. A significant increase in BBB markers endothelin 1 and occludin was noted following SAH, but reduced with IL-6 blockade (p < 0.01). CV occurred 5 days post-SAH, but was absent in IL-6 KO mice and mitigated with IL-6 blockade (p < 0.05). IL-6 blockade, and IL-6 KO mitigated effects of SAH on cerebral blood flow (p < 0.05). SAH mice had impaired performance on turn test and poor modified Garcia scores compared to saline and IL-6 blockade. A distinct microglia phenotype was noted day 5 in the SAH group (overlap coefficients r = 0.96 and r = 0.94) for Arg1 and iNOS, which was altered by IL-6 blockade. Day 7, a significant increase in toll-like receptor 4 and Stat3 was noted. This was mitigated by IL-6 blockade and IL-6 KO, which also reduced Caspase 3 (p < 0.05). To confirm the mechanism, we developed a p-STAT3 inhibitor that targets the IL-6 pathway and this reduced NFΚB, TLR4, and nitrotyrosine (p < 0.001). Ventricular dilation and increased Tunel positivity was noted day 9, but resolved by IL-6 blockade (p < 0.05). CONCLUSION: Correlation between IL-6 and CV has been well documented. We show that a mechanistic connection exists via the p-STAT3 pathway, and IL-6 blockade provides benefit in reducing CV and its consequences mediated by myeloid cell origin diapedesis.

NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage.

BACKGROUND: The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1ß production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. METHODS: We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. RESULTS: NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. CONCLUSIONS: We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.

Advanced breast cancer metastasized in the brain: treatment standards and innovations.

Breast cancer continues to be a difficult disease to treat due to high rates of metastasis. Metastasis to the brain presents a unique and often overlooked challenge. In this focused review, we discuss the epidemiology of breast cancer and which types frequently metastasize to the brain. Novel treatment approaches are highlighted with supporting scientific evidence. The role of the blood-brain barrier and how it may become altered with metastasis is addressed. We then highlight new innovations for Her2-positive and triple-negative breast cancer. Finally, recent directions for luminal breast cancer are discussed. This review serves to enhance understanding of pathophysiology, spark continued innovation, and provide a user-friendly resource through tables and easy-to-process figures.

Effects of therapeutic exercise on the motor function of adults with Down syndrome: a systematic review and meta-analysis.

Therapeutic exercise exerts positive effects by mitigating or reducing the motor or cognitive changes that people with Down syndrome undergo throughout their life. There are no updated systematic reviews that integrate the evidence available in a way that facilitates decision-making for physical rehabilitation teams. This study therefore aimed to consolidate the information available and compare the effects of different types of physical exercise on the motor function of adults with DS. We conducted a systematic review and meta-analysis of randomized clinical trials and quasi-experimental studies. The literature search was performed between January 2023 and February 2023 using the PubMed, SCIELO, Epistemonikos, and Lilacs databases. Studies were selected according to pre-determined inclusion and exclusion criteria. The risk-of-bias assessment was performed using the risk-of-bias rating tool for randomized clinical trial (RoB) and the risk of bias of non-randomized comparative studies was assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool. Risk-of-bias assessment and meta-analyses were performed using the RevMan software package. Sixteen studies met the eligibility criteria for the qualitative synthesis and 4 were included in the meta-analyses. Combined exercise significantly increased muscle strength both in the upper limbs (SMD = 0.74 [95% CI 0.25-1.22]) and lower limbs (SMD = 0.56[95% CI 0.08-1.04]). Aerobic exercise improved spatiotemporal gait parameters. Aerobic exercise showed significant improvements in dynamic balance while combined exercise significantly increased dynamic and static balance. The certainty of the evidence was low to moderate for all outcomes. There was low and moderate certainty of evidence for the outcomes proposed in this review. However, therapeutic exercise could be effective in improving muscle strength and gait functionality.

Combination release of chemokines from coated coils to target aneurysm healing.

BACKGROUND: Monocyte chemoattractant protein 1 (MCP-1) and osteopontin (OPN) have been identified separately as key mediators of the aneurysm healing process following coil embolization in the rodent model. The ability of protein coated coils to accelerate this process is currently unknown. OBJECTIVE: To create coils coated with both MCP-1 and OPN to target aneurysm healing. METHODS: We used a polymer (poly(glycolide-co-caprolactone)) (Rao pharmaceuticals) (CG910) to test whether coils could be dual coated with active proteins with sequential reliable release. Coils were coated with poly-DL-lactic glycolic acid (PLGA), CG910, and subsequently dipped with protein OPN (inner layer for delayed release) and MCP-1 (outer layer for initial release). Release assays were used to measure protein elution from coils over time. To test in vivo feasibility, coated coils were implanted into carotid aneurysms to determine the effect on aneurysm healing. RESULTS: The in vitro protein release assay demonstrated a significant amount of OPN and MCP-1 release within 2 days. Using a 200 µg/µL solution of MCP-1 in phosphate-buffered saline, we showed that CG910 coated coils provide effective release of MCP over time. In the carotid aneurysm model, MCP-1 and OPN coated coils significantly increased tissue ingrowth (74% and 80%) compared with PLGA and CG910 coated coils alone (58% and 53%). To determine synergistic impact of dual coating, we measured ingrowth for MCP-1/OPN coils (63%) as well as overlap coefficients for NOX4 and NFκB with CD31. CONCLUSIONS: This study demonstrates that MCP-1 and OPN coated coils are viable and may promote early aneurysm healing. Dual coated coils may have synergistic benefit given different location of protein interaction measured in vivo. Further work is warranted.

PheWAS and cross-disorder analysis reveal genetic architecture, pleiotropic loci and phenotypic correlations across 11 autoimmune disorders.

Introduction: Autoimmune disorders (ADs) are a group of about 80 disorders that occur when self-attacking autoantibodies are produced due to failure in the self-tolerance mechanisms. ADs are polygenic disorders and associations with genes both in the human leukocyte antigen (HLA) region and outside of it have been described. Previous studies have shown that they are highly comorbid with shared genetic risk factors, while epidemiological studies revealed associations between various lifestyle and health-related phenotypes and ADs. Methods: Here, for the first time, we performed a comparative polygenic risk score (PRS) - Phenome Wide Association Study (PheWAS) for 11 different ADs (Juvenile Idiopathic Arthritis, Primary Sclerosing Cholangitis, Celiac Disease, Multiple Sclerosis, Rheumatoid Arthritis, Psoriasis, Myasthenia Gravis, Type 1 Diabetes, Systemic Lupus Erythematosus, Vitiligo Late Onset, Vitiligo Early Onset) and 3,254 phenotypes available in the UK Biobank that include a wide range of socio-demographic, lifestyle and health-related outcomes. Additionally, we investigated the genetic relationships of the studied ADs, calculating their genetic correlation and conducting cross-disorder GWAS meta-analyses for the observed AD clusters. Results: In total, we identified 508 phenotypes significantly associated with at least one AD PRS. 272 phenotypes were significantly associated after excluding variants in the HLA region from the PRS estimation. Through genetic correlation and genetic factor analyses, we identified four genetic factors that run across studied ADs. Cross-trait meta-analyses within each factor revealed pleiotropic genome-wide significant loci. Discussion: Overall, our study confirms the association of different factors with genetic susceptibility for ADs and reveals novel observations that need to be further explored.

Can polygenic risk scores help explain disease prevalence differences around the world? A worldwide investigation.

Complex disorders are caused by a combination of genetic, environmental and lifestyle factors, and their prevalence can vary greatly across different populations. The extent to which genetic risk, as identified by Genome Wide Association Study (GWAS), correlates to disease prevalence in different populations has not been investigated systematically. Here, we studied 14 different complex disorders and explored whether polygenic risk scores (PRS) based on current GWAS correlate to disease prevalence within Europe and around the world. A clear variation in GWAS-based genetic risk was observed based on ancestry and we identified populations that have a higher genetic liability for developing certain disorders. We found that for four out of the 14 studied disorders, PRS significantly correlates to disease prevalence within Europe. We also found significant correlations between worldwide disease prevalence and PRS for eight of the studied disorders with Multiple Sclerosis genetic risk having the highest correlation to disease prevalence. Based on current GWAS results, the across population differences in genetic risk for certain disorders can potentially be used to understand differences in disease prevalence and identify populations with the highest genetic liability. The study highlights both the limitations of PRS based on current GWAS but also the fact that in some cases, PRS may already have high predictive power. This could be due to the genetic architecture of specific disorders or increased GWAS power in some cases.

Medication management: a case of brown bag-identified medication hoarding.

A 91-year-old woman living independently in the community presented along with her son for a medication therapy management (MTM) appointment with the clinical pharmacist at the University of Colorado Hospital Seniors Clinic. The purpose of the visit was to review the patient's medications, perform medication reconciliation, and identify ways to increase proper medication management. As requested for the MTM appointment, the patient and her son brought in several large bags of her over-the-counter (OTC) and prescription medications from her home, including those that she was not currently taking. The clinical pharmacist reviewed the medications and found multiple instances of duplicate therapies, nonadherence, discrepancies in her medication regimen, cost concerns, and other drug-therapy problems. In addition, the pharmacist's evaluation showed that the patient had been hoarding more than 100 medications, which increased her risk for drug-related problems. Most of the OTC and some prescription medications were voluntarily removed from the patient's possession to reduce the likelihood of potential overuse of medications.The pharmacist educated the patient and her son regarding her updated medication list and how to properly manage her medications. Finally, the patient's son volunteered to help his mother with medication management or hire someone to assist her. This case demonstrates the usefulness of requesting all medications-including OTC and prescription, active and inactive medications-be brought to the MTM appointment.The case also supports the need for family support for older adults struggling with managing polypharmacy.

Examining the role of astrogliosis and JNK signaling in post-traumatic epilepsy.

OBJECTIVE: Post-traumatic epilepsy is a devastating complication of traumatic brain injury that has no targeted pharmacological therapy. Previous literature has explored the role of the c-Jun N-terminal kinase (JNK) pathway in epilepsy and the creation of epileptogenic foci by reactive astrogliosis; however, the relationship between reactive astrogliosis and the c-Jun N-terminal kinase signaling pathway in the development of post-traumatic epilepsy has not been thoroughly examined. METHODS: Four experimental groups, consisting of c57/b16 male mice, were examined: (1) control, (2) traumatic brain injury of graded severity (mild, moderate, severe), (3) sub-convulsive kainic acid alone without traumatic brain injury (15 mg/kg i.p.), and (4) sub-convulsive kainic acid administered 72 h after moderate traumatic brain injury. Modified Racine scale from 1 to 72 h and total beam breaks at 72 h were used to assess seizure activity. Immunohistochemistry and western blot were utilized to examine astrogliosis (GFAP), microglia activation (IBA-1), and phosphorylated JNK in prefrontal cortex samples collected from the contracoup side at 72 h post-injury. RESULTS: Astrogliosis, measured by GFAP, was increased after traumatic brain injury and increased commensurately based on the degree of injury. Mice with traumatic brain injury demonstrated a four-fold increase in phosphorylated JNK: p < 0.001. Sub-convulsive kainic acid administration did not increase seizure activity nor phosphorylation of JNK in mice without traumatic brain injury; however, sub-convulsive kainic acid administration in mice with moderate traumatic brain injury did increase phosphorylated JNK. Seizure activity was worse in mice, with traumatic brain injury, administered kainic acid than mice administered kainic acid. CONCLUSIONS: Reactive astrocytes may have dysfunctional glutamate regulation causing an increase in phosphorylated JNK after kainic acid administration. Future studies exploring the effects of JNK inhibition on post-traumatic epilepsy are recommended.

Increasing Health Literacy Among Residents at a Juvenile Temporary Detention Center.

INTRODUCTION: Health literacy is a nationwide public health concern. Low health literacy in adolescents is related to increased adolescent high-risk behaviors, which can negatively affect their overall health. METHOD: A quality improvement health literacy project was developed, implemented, and evaluated in a juvenile temporary detention center. Stakeholders identified pertinent health-related topics for discussion, including female body anatomy, sexual health, consent, pornography, sex trafficking, smoking, and anger management. Toolkits and pretest/posttest questionnaires guided weekly group sessions. Youth engaged in content during each session. RESULTS: Group health literacy scores were examined to evaluate the program. Group comments were debriefed by facilitators after each session; 119 youth residents participated. Positive increases in health literacy and health knowledge were observed in all sessions for all groups. DISCUSSION: Interactive health education programs for incarcerated youth can improve their health literacy and health knowledge and begin a path to decrease health inequities in this vulnerable population.

Inflammation and the role of infection: Complications and treatment options following neurotrauma.

Traumatic brain injury can have devastating consequences for patients and extended hospital stays and recovery course. Recent data indicate that the initial insult causes profound changes to the immune system and leads to a pro-inflammatory state. This alteration in homeostasis predisposes patients to an increased risk of infection and underlying autoimmune conditions. Increased emphasis has been placed on understanding this process both in the clinical and preclinical literature. This review highlights the intrinsic inflammatory conditions that can occur within the initial hospital stay, discusses long-term immune consequences, highlights emerging treatment options, and delves into important pathways currently being investigated with preclinical models.

Ovarian Cancer Metastasis to the Central Nervous System: A Literature Review.

Ovarian cancer is one of the leading causes of cancer-related deaths among women in the United States. Metastasis to the central nervous system has become more frequent in the previous decades, however, treatment options remain limited. In this review, we discuss the pathophysiology of ovarian cancer and how metastasis to the central nervous system typically occurs. We then discuss cases of metastasis presented in the literature to evaluate current treatment regimens and protocols. Finally, we highlight emerging treatment options that are being utilized in clinics to provide personalized treatment therapy for a patient's unique diagnosis. This review aims to further the understanding of pathophysiology, stimulate further innovative treatments, and present accessible resources through tables and figures.

Pediatric Subarachnoid Hemorrhage: Rare Events with Important Implications.

Rupture of an aneurysm is the leading cause of subarachnoid hemorrhage (SAH) which results in accumulation of blood between the arachnoid and pia mater, consequently increasing intracranial pressure. This often results in life threatening conditions like herniation or clinical presentations including focal neurological deficits. In children, these events, although rare, have significant implications. Pediatric SAH is associated with better outcomes in the hospital setting and may even be prevented proactively by the recognition of potential risk factors. Specifically, better recognition of genetic predispositions, metastatic lesions, and infectious causes of aneurysms is important to understand their growth and prevent hemorrhagic events. This review highlights the causes of pediatric SAH, reviews the models of current understanding of this etiology, and discusses the current treatment schema to provide a succinct summary and highlight gaps in current knowledge. This may lead to future investigations aimed at further improving prevention strategies, patient care, and patient outcomes.

Understanding the genetics of intracranial aneurysms: A primer.

The genetics of intracranial aneurysms is complex. Much work has been done looking at the extracellular matrix surrounding cerebral vasculature as well as the role of matrix metalloproteinases. This comprehensive review summarizes what is known to date about the important genetic components that predispose to aneurysm formation and critically discusses the published findings. We discuss promising pre-clinical models of aneurysm formation and subarachnoid hemorrhage, and highlight avenues for future discovery, while considering limitations in the research to date. This review will further serve as a comprehensive reference guide to understand the genetic underpinnings for aneurysm pathophysiology and act as a primer for further investigation.

Spinal Cord Injury: A Review of Current Management Considerations and Emerging Treatments.

Traumatic spinal cord injuries can have devastating outcomes for patients. In this focused review, we discuss the epidemiology of spinal cord injuries, associated neurologic exam findings, and primary and secondary injury progression. We then delve into the emerging treatment approaches and relevance to improving outcomes. The disease is multifactorial and has many management considerations. This concise user-friendly resource can help guide clinicians caring for these patients. Also, it points to the need for continued scientific discovery and improved pharmaceutical and device innovations.

Interleukin-6: Important Mediator of Vasospasm Following Subarachnoid Hemorrhage.

The correlation of neuroinflammation with the development of cerebral vasospasm following subarachnoid hemorrhage has been well documented in the literature; both clinical and preclinical. The exact mechanisms by which this process occurs, however, are poorly elucidated. Recent evidence indicates that interleukin-6 is not only an important prognostic biomarker for subarachnoid hemorrhage and subsequent vasospasm development but also an integral component in the progression of injury following initial insult. In this review, we briefly highlight other pathways under investigation and focus heavily on what has been discovered regarding the role of interleukin 6 and cerebral vasospasm following subarachnoid hemorrhage. A proposed mechanistic pathway is highlighted in written and graphical format. A discussion regarding the human correlative findings and initial pre-clinical mechanistic studies is addressed. Finally, in the future investigation section, innovative developments and a clear description of areas warranting further scientific inquiry are emphasized. This review will catalyze continued discovery in this area of emerging significance and aid in the quest for effective vasospasm treatment where limited clinical therapeutics currently exist.

Study of the Vaginal Microbiota in Healthy Women of Reproductive Age.

Understanding the characteristics of the vaginal microbiota of our patients allows us to carry out both a personalized therapeutic approach and a closer follow-up in those with microbiota susceptible to dysbiosis. This trial pursues the analysis of the vaginal microbiota of premenopausal women and its fluctuations within a four-week follow-up period. Vaginal samples of 76 fertile women were taken at a baseline visit and at a final visit (day 28 ± 5). To perform a phylogenetic study, we employed massive sequencing techniques to detect the 16S rRNA gene of the vaginal microbiota. The most prevalent vaginal microbial community was type I (34.87%), dominated by Lactobacillus crispatus. Vaginal microbial community types II (Lactobacillus gasseri) and V (Lactobacillus jensenii) were underrepresented in our population. When repeating the sampling process four weeks later, 75% of our patients maintained their initial bacterial community. In the follicular phase, the most recurrent microbiota was type III (Lactobacillus iners); in the periovulatory phase, types III and IV (microbial diversity); finally, in the luteal phase, the most frequent type was IV. The most prevalent vaginal bacterial community in our population was dominated by L. crispatus. The vaginal microbiota was resistant to changes in its bacterial community in 75% of our patients, even between consecutive menstrual cycles.

Prenatal diagnosis and molecular cytogenetic characterization of a de novo duplication of 15q24.3-q26.1.

Reported cases of distal 15q interstitial duplications are uncommon and do not result in a recognizable pattern of abnormalities. Some studies report prenatal overgrowth, while others describe growth retardation. We present molecular cytogenetic characterization of a 14 Mb interstitial duplication, encompassing 81 Online Mendelian Inheritance in Man (OMIM) genes, in a fetus with single umbilical artery and short limbs. We propose that growth restriction, previously described and present in our patient, may be due to duplication of a gene or genes contained in the 15q24 region.