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Aim: Inhibition of microRNA (miR)-132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR-132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment., Methods: The HF-REVERT (Phase 2, multicenter, randomized, parallel, 3-arm, placebo-controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post-acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N-terminal pro-B-type natriuretic peptide. The study consists of a 6-month double-blinded treatment period with the primary endpoint LV end-systolic volume index and relevant secondary endpoints, followed by a 6-month open-label observation period., Conclusion: The HF-REVERT trial may underpin the concept of miR-132 inhibition to prevent or reverse cardiac remodelling in post-MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Alzheimer disease (AD), the most common neurodegenerative disorder in the United States, disproportionately burdens minority populations., Objective: To explore barriers to AD clinical trial participation by Asian and Native Hawaiian patients diagnosed with AD or mild cognitive impairment., Method: We surveyed 187 patients with a Mini-Mental State Examination score ≥14 between January 2022 and June 2022. The score cutoff for clinical trial eligibility was set by the institution. Individuals also completed a 15-question telephone survey that assessed demographics, barriers to clinical trial participation, and clinical trial improvement methods., Results: Forty-nine patients responded, with a response rate of 26%. Asian and Native Hawaiian patients were less likely than White patients to participate in AD trials. The main barrier to participation was a lack of information about AD trials. Providing additional information regarding AD trials to patients and family members were listed as the top two reasons patients would consider participating in a clinical trial., Conclusion: Insufficient information about AD clinical trials is the primary barrier to participation among Asian and Native Hawaiian patients, followed by difficulty coordinating transportation and, in the case of Asians, the time required for clinical trials. Increased outreach, education, and assistance with logistics in these populations should be pursued to improve rates of participation in clinical trials., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The ability of nucleic acids for intramolecular interactions opens manifold opportunities for novel medicines that have the potential to treat intractable human disorders, including heart disease. In this context, microRNAs have been identified as pleiotropic regulators of disease pathways and consequently as powerful therapeutic targets. With antisense oligonucleotides novel drug modalities are available to specifically inhibit as well as correct derailed microRNAs including pathological downstream pathways potentially restoring hallmarks of disease. However, only a handful of microRNA-targeting drugs underwent clinical testing so far, and none in the cardiovascular field. In this paper, the authors introduce the first-ever microRNA-based therapy that entered clinical trials in heart disease and present the previous development from target identification to first-in-human studies., Competing Interests: This work was supported by Cardior Pharmaceuticals GmbH, where Dr Thum is founder and shareholder. Dr Viereck is a full-time employee of Cardior Pharmaceuticals GmbH. Dr Thum filed and licensed patents through the Hannover Medical School to Cardior Pharmaceuticals GmbH., (© 2023 The Authors.)

Introduction: Currently, there are limited accessible and cost-effective biomarkers for preclinical Alzheimer's disease (AD) patients. However, the apolipoprotein E (ApoE) polymorphic alleles can predict if someone is at high (e4), neutral (e3), or low (e2) genetic risk for developing AD. This study analyzed electroencephalogram (EEG) reports from individuals with various ApoE genotypes, aiming to identify EEG changes and patterns that could potentially serve as predictive markers for preclinical AD progression., Methods: Participants aged 64-78 were selected from the patient database at an outpatient neurology clinic. Genotype studies were performed to determine ApoE status, followed by EEG analysis to identify any apparent trends. A case-control design was used, categorizing participants into cases (e2e3, e2e4, e3e4, e4e4) and controls (e3e3). EEG recordings were compared between the groups to identify potential differences in EEG characteristics, including abnormal temporal slowing, frequency, and ApoE genotype association., Results: Among 43 participants, 49% demonstrated evidence of abnormal temporal slowing on EEG. Of these, 48% displayed focal left temporal slowing, and 52% displayed bilateral temporal slowing. The right-sided temporal slowing was not observed. Among participants with abnormal slowing, 95% exhibited theta frequency (4-8 Hz) slowing, while only 4.8% displayed delta frequency (0-4 Hz) slowing. Among participants with the ApoE4 allele, 61.5% demonstrated evidence of abnormal slowing, compared to 43.3% without it. Furthermore, the presence of an ApoE4 allele was associated with a significantly higher proportion of males (54%) compared to those without it (13%) (p=0.009)., Conclusions: Although we did not find a statistically significant difference in temporal EEG slowing among different ApoE genotypes, our findings suggest a potential association between temporal slowing on EEG and the presence of an ApoE4 allele in individuals with preclinical AD. These observations highlight the need for further exploration into the potential influence of the ApoE4 allele on EEG findings and the utility of EEG as a complementary diagnostic tool for AD. Longitudinal studies with large sample sizes are needed to establish the precise relationship between EEG patterns, ApoE genotypes, and AD progression., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Kim et al.)

Incorporating crystalline organic semiconductors into electronic devices requires understanding of heteroepitaxy given the ubiquity of heterojunctions in these devices. However, while rules for commensurate epitaxy of covalent or ionic inorganic material systems are known to be dictated by lattice matching constraints, rules for heteroepitaxy of molecular systems are still being written. Here, it is found that lattice matching alone is insufficient to achieve heteroepitaxy in molecular systems, owing to weak intermolecular forces that describe molecular crystals. It is found that, in addition, the lattice matched plane also must be the lowest energy surface of the adcrystal to achieve one-to-one commensurate molecular heteroepitaxy over a large area. Ultraviolet photoelectron spectroscopy demonstrates the lattice matched interface to be of higher electronic quality than a disordered interface of the same materials., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Intracranial artery calcification is a marker of vascular atherosclerosis and has a high prevalence worldwide. Both atherosclerosis of the internal carotid artery at the carotid sinus in the neck and intracranial calcification have been associated with ischemic stroke. The relationship between the two has not been well studied. The present study investigated how carotid sinus narrowing could relate to calcification located in the distal intracranial artery at the cavernous carotid. We examined a population not selected for cerebral disease. This retrospective study contained 179 subjects aged 18 years and older from the Hawaii Diagnostic Radiology database. Extracranial internal carotid artery stenosis was determined using the absolute diameter, North American Symptomatic Carotid Endarterectomy Trial, and common carotid artery methods. Calcification was scored using the modified Woodcock method. A positive correlation between intracranial calcification and extracranial carotid stenosis was found using all three methods. Individuals with intracranial calcification were more likely to be older, have a smaller internal carotid artery diameter, and have a greater percent stenosis at the internal carotid artery than those without intracranial artery calcification (p<0.001 for all). These results may help refocus interest in calcification in studies of cerebral vasculature and its correlation with extracranial carotid stenosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Jahansooz et al.)

Approximately 19% of the population is suffering from "Long COVID", also known as post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), which often results in exercise intolerance. As COVID infections continue to be common, studying the long-term consequences of coronavirus disease (COVID) on physical function has become increasingly important. This narrative review will aim to summarize the current literature surrounding exercise intolerance following COVID infection in terms of mechanism, current management approaches, and comparison with similar conditions and will aim to define limitations in the current literature. Multiple organ systems have been implicated in the onset of long-lasting exercise intolerance post-COVID, including cardiac impairment, endothelial dysfunction, decreased VO 2 max and oxygen extraction, deconditioning due to bed rest, and fatigue. Treatment modalities for severe COVID have also been shown to cause myopathy and/or worsen deconditioning. Besides COVID-specific pathophysiology, general febrile illness as commonly experienced during infection will cause hypermetabolic muscle catabolism, impaired cooling, and dehydration, which acutely cause exercise intolerance. The mechanisms of exercise intolerance seen with PASC also appear similar to post-infectious fatigue syndrome and infectious mononucleosis. However, the severity and duration of the exercise intolerance seen with PASC is greater than that of any of the isolated mechanisms described above and thus is likely a combination of the proposed mechanisms. Physicians should consider post-infectious fatigue syndrome (PIFS), especially if fatigue persists after six months following COVID recovery. It is important for physicians, patients, and social systems to anticipate exercise intolerance lasting for weeks to months in patients with long COVID. These findings underscore the importance of long-term management of patients with COVID and the need for ongoing research to identify effective treatments for exercise intolerance in this population. By recognizing and addressing exercise intolerance in patients with long COVID, clinicians can provide proper supportive interventions, such as exercise programs, physical therapy, and mental health counseling, to improve patient outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Weldon et al.)

The specialty of Pediatric Neurology emerged during the 20th century, a period in which many neurologists played significant roles in revolutionizing this field. Two acclaimed pediatric neurologists of Hispanic origin, Drs Manual Gomez and Arturo Lopez-Hernandez, made substantial contributions to the literature on pediatric neurology. One of their remarkable contributions was their discovery of a new, rare neurocutaneous syndrome with variable phenotype, the Gomez-Lopez-Hernandez syndrome (GLHS). Here, we describe the current understanding of GLHS and the historical background of how 2 celebrated Hispanic pediatric neurologists discovered this rare, sporadic syndrome during a time when there was a limited representation of minorities in the medical profession.

To promote health equity within the United States (US), randomized clinical trials should strive for unbiased representation. Thus, there is impetus to identify demographic disparities overall and by disease category in US clinical trial recruitment, by trial phase, level of masking, and multi-center status, relative to national demographics. A systematic review and meta-analysis were conducted using MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov, between 01/01/2008 to 12/30/2019. Clinical trials (N = 5,388) were identified based on the following inclusion criteria: study type, location, phase, and participant age. Each clinical trial was independently screened by two researchers. Data was pooled using a random-effects model. Median proportions for gender, race, and ethnicity of each trial were compared to the 2010 US Census proportions, matched by age. A second analysis was performed comparing gender, race, and ethnicity proportions by trial phase, multi-institutional status, quality, masking, and study start year. 2977 trials met inclusion criteria (participants, n = 607,181) for data extraction. 36% of trials reported ethnicity and 53% reported race. Three trials (0.10%) included transgender participants (n = 5). Compared with 2010 US Census data, females (48.3%, 95% CI 47.2-49.3, p < 0.0001), Hispanics (11.6%, 95% CI 10.8-12.4, p < 0.0001), American Indians and Alaskan Natives (AIAN, 0.19%, 95% CI 0.15-0.23, p < 0.0001), Asians (1.27%, 95% CI 1.13-1.42, p < 0.0001), Whites (77.6%, 95% CI 76.4-78.8, p < 0.0001), and multiracial participants (0.25%, 95% CI 0.21-0.31, p < 0.0001) were under-represented, while Native Hawaiians and Pacific Islanders (0.76%, 95% CI 0.71-0.82, p < 0.0001) and Blacks (17.0%, 95% CI 15.9-18.1, p < 0.0001) were over-represented. Inequitable representation was mirrored in analysis by phase, institutional status, quality assessment, and level of masking. Between 2008 to 2019 representation improved for only females and Hispanics. Analysis stratified by 44 disease categories (i.e., psychiatric, obstetric, neurological, etc.) exhibited significant yet varied disparities, with Asians, AIAN, and multiracial individuals the most under-represented. These results demonstrate disparities in US randomized clinical trial recruitment between 2008 to 2019, with the reporting of demographic data and representation of most minorities not having improved over time., (© 2022. The Author(s).)

AAV vectors are promising delivery tools for human gene therapy. However, broad tissue tropism and pre-existing immunity against natural serotypes limit their clinical use. We identified two AAV capsid variants, AAV2-THGTPAD and AAV2-NLPGSGD, by in vivo AAV2 peptide display library screening in a murine model of pressure overload-induced cardiac hypertrophy. Both variants showed significantly improved efficacy in in vivo cardiomyocyte transduction compared with the parental serotype AAV2 as indicated by a higher number of AAV vector episomes in the nucleus and significant improved transduction efficiency. Both variants also outcompeted the reference serotype AAV9 regarding cardiomyocyte tropism, reaching comparable cardiac transduction efficiencies accompanied with liver de-targeting and decreased transduction efficiency of non-cardiac cells. Capsid modification influenced immunogenicity as sera of mice treated with AAV2-THGTPAD and AAV2-NLPGSGD demonstrated a poor neutralization capacity for the parental serotype and the novel variants. In a therapeutic setting, using the long non-coding RNA H19 in low vector dose conditions, novel AAV variants mediated superior anti-hypertrophic effects and revealed a further improved target-to-noise ratio, i.e., cardiomyocyte tropism. In conclusion, AAV2-THGTPAD and AAV2-NLPGSGD are promising novel tools for cardiac-directed gene therapy outperforming AAV9 regarding the specificity and therapeutic efficiency of in vivo cardiomyocyte transduction., Competing Interests: Declaration of interests L.R., C.B., T.T., and H.B. have filed and/or been granted patents in the field of AAV evolution for clinical applications. T.T. and J.V. have filed and been licensed a patent on the use of H19 in cardiovascular disease. T.T. is a founder of and holds shares in Cardior Pharmaceuticals GmbH., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Hawaii is a multicultural state with many different ethnicities, including Native Hawaiians and other Pacific Islanders (NHOPI). This demographic has not been thoroughly studied, despite its significantly higher prevalence of stroke. This study aimed to characterize risk factors for ischemic stroke in NHOPI compared to other ethnicities., Methods: An Institutional Review Board (IRB) sanctioned retrospective chart review was conducted at a multi-site community neurology clinic from June 2017 through June 2019. Prospective patients were identified from the database using the International Classification of Diseases 10th Edition (ICD-10) codes for ischemic stroke. 326 patients (99 NHOPI, 116 Asian, 111 Caucasian) with a history of ischemic stroke met the inclusion criteria. Risk factors were determined based on the American Stroke Association guidelines; ethno-racial grouping was based on self-identification; and average household income levels were estimated based on patient zip codes US Census Bureau data. Continuous variable risk factors were analyzed using an analysis of variance (ANOVA) and post-hoc pairwise comparisons using Tukey-Kramer; a multivariate analysis was conducted., Results: Compared to Asians and Caucasians, NHOPI patients were on average 11 years younger at the onset of stroke and more likely to be women. The NHOPI group also had the highest rates of diabetes and obesity. NHOPI average income was significantly lower compared to the Caucasian group. Hypertension and hyperlipidemia were found to be higher in the Asian population. Alcohol consumption was reported more frequently among Caucasian patients., Conclusions: These results better-characterized risk factors for ischemic stroke among NHOPI in Hawaii. The younger age of stroke onset in NHOPI patients is likely due to the higher burden of cardiovascular risk factors like obesity, smoking, and diabetes. Identifying such disparities in associated risk for NHOPI and other ethnicities can allow targeted stroke prevention and outpatient care in a multicultural setting., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Patients with psychogenic non-epileptic seizures (PNES) experience significant morbidity and early mortality, secondary to delayed diagnosis. Better characterizing risk factors and exploring how PNES differentially affects sex and racial strata may facilitate earlier diagnosis., Methods: From a Hawai'i neuroscience institution, 101 PNES patients were investigated in relation to sociodemographic and medical comorbidities. Cases were compared to 202 sex-, age-, and race-matched controls-representing patients with neurological disorders (general controls)-, as well as 404 unmatched epilepsy controls., Results: Relative to general controls, PNES patients had increased odds (p < 0.05) of being: female, younger age, Native Hawaiian or other Pacific Islander (NHPI), suburban origin, from the lowest income quartile, Medicaid beneficiaries, homeless, current/former smoker, illicit drug users (marijuana, opioids/narcotics, polysubstance abuse), have anxiety, depression, post-traumatic stress disorder, bipolar disorder, traumatic history, World Health Organization obesity class 3, traumatic brain injury, epilepsy, and somatoform disorder. In relation to epilepsy controls, PNES patients exhibited increased odds of being: employed, having attention-deficit/hyperactivity disorder, asthma, migraines, and chronic pain. Relative to females, male PNES patients exhibited increased odds of military insurance, diabetes mellitus type 2, and hypertension. Relative to Whites, the NHPI and Asian PNES patients presented increased odds of asthma, migraines, chronic pain, gastroesophageal reflux disease, and thyroid disease. Per multivariable logistic regression, anxiety was the only consistent predictor of PNES across all sex and race strata., Conclusion: Predictors of PNES's vary amongst the strata of race and sex. Lower socioeconomic status, along with several psychiatric and medical comorbidities, could increase a clinician's suspicion for earlier medical workup and diagnosis of PNES., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Better characterizing moyamoya disease (MMD) from ischemic strokes of other etiologies may facilitate earlier diagnosis by raising suspicion for a diagnostic work-up., Methods: To identify associated variables, MMD cases (n = 12) were compared against three sets of controls: age-, sex-, and race-matched controls of patients with general neurological disorders (n = 48), unmatched general controls (n = 48), and unmatched non-MMD ischemic stroke controls (n = 48)., Results: MMD patients were 32 years (p < 0.0001) younger than ischemic stroke controls. Relative to non-MMD ischemic strokes, MMD patients had greater odds of presenting with visual field defects (OR: 9.13, p = 0.09) or dizziness (OR: 9.13, p = 0.09), as well as being female (OR: 8.04, p = 0.008), Asian (OR: 3.68, p = 0.087), employed (OR: 6.96, p = 0.02), having migraines (OR: 21.61, p = 0.005), epilepsy (OR: 6.69, p = 0.01), insomnia (OR: 8.90, p = 0.099), and a lower Charlson Comorbidity Index (CCI; p = 0.002). Patients with MMD, compared to non-MMD ischemic strokes, also had a 4.67 kg/ m 2 greater body mass index (BMI) and larger odds (OR relative to normal BMI: 21.00, p = 0.03) of being from obesity class III (>40 kg/ m 2 ), yet reduced odds of coronary artery disease (OR: 0.13, p = 0.02). Relative to general controls, MMD patients had greater odds of diabetes mellitus type 2 (OR: 10.07, p = 0.006) and hypertension (OR: 7.28, p = 0.004)., Conclusion: MMD not only has a unique clinical presentation from other ischemic strokes, but also unique comorbidities, which may facilitate earlier work-up and treatment., Competing Interests: None., (© 2022 The Authors.)

In March 2020, Hawai'i instituted public health measures to prevent the spread of Coronavirus disease 2019 (COVID-19), including stay-at-home orders, closure of non-essential businesses and parks, use of facial coverings, social distancing, and a mandatory 14-day quarantine for travelers. In response to these measures, Hawai'i Pacific Neuroscience (HPN) modified practice processes to ensure continuity of neurological treatment. A survey of patients was performed to assess the impact of the COVID-19 pandemic and pandemic-related practice processes for quality improvement. Overall, 367 patients seen at HPN between April 22, 2020, and May 18, 2020, were surveyed via telephone. Almost half (49.6%) participated in a telemedicine appointment, with the majority finding it easy to use (87.4%) and as valuable as face-to-face appointments (68.7%). Many (44.5%) patients said they would have missed a health care appointment without the availability of telemedicine, and 47.3% indicated they might prefer to use telemedicine over in-person appointments in the future. Many reported new or worsening mental health problems, including depression (27.6%), anxiety (38.3%), or sleep disturbances (37.4%). A significant number reported worsening of their condition, with 33.1% of patients who experience migraines reporting increased symptom severity or frequency, 45.8% patients with Alzheimer's disease reporting worsened symptoms, 38.5% of patients with Parkinson's disease who had a recent fall, and 50.0% of patients with multiple sclerosis experiencing new or worsened symptoms. Insights from this survey applied to the practice's pandemic-related processes include emphasizing lifestyle modification, screening for changes in mental health, optimizing treatment plans, and continuing the option of telemedicine., (©Copyright 2022 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

Aims: Clinical trials for calcitonin gene-related peptide (CGRP) inhibitors excluded the concomitant use of onabotulinumtoxinA; thus, there is a lack of efficacy and safety data of the combined therapies. Our study aims to examine the effectiveness of CGRP inhibitors with onabotulinumtoxinA by evaluating migraine reductions in headache days and severity., Methods: Seventeen patients with chronic migraines were identified who had a partial or poor response to onabotulinumtoxinA, and were placed on dual therapy with a CGRP inhibitor. Patients' initial headache days and severity ratings were compared to final values taken 1-6 months after adding the CGRP inhibitor to their treatment regime. Comparisons between headache days and severity ratings prior to and during dual treatment were performed utilizing the Kruskal-Wallis test. The significance was set at p < 0.05., Results: Of 17 patients (16F/1 M), n = 9 were taking fremanezumab, n = 4 were taking erenumab, and n = 4 were taking galcanezumab. Patients' average headache days per month was reduced from 27.6 ± 4.8 initially to 18.6 ± 9.4 post-treatment (p = 0.00651), and their average pain level was reduced from 8.4 ± 1.4 out of 10 to 5.4 ± 2.5 (p = 0.00074). No serious adverse side effects were reported from patients on dual therapy., Conclusion: Patients with suboptimal response to onabotulinumtoxinA may benefit from CGRP inhibitors' addition to their migraine regimens. Placebo-controlled randomized studies are advised to corroborate this finding., (© 2021. Fondazione Società Italiana di Neurologia.)

Background: Previous studies of racial differences in Alzheimer disease (AD) presentation have not included Native Hawaiians and Pacific Islanders (NHPI)., Objective: To explore the presentation of AD and mild cognitive impairment (MCI) in NHPI., Method: We conducted a retrospective review of patient records from Hawaii with a diagnosis of unspecified AD or MCI from September 2000 to September 2019. Variables of interest included age at diagnosis, gender, race, marital status, insurance, comorbidities, and scores on the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA)., Results: We reviewed the medical records of 598 patients, including 224 Asians, 202 Whites, 87 NHPI, and 85 Other. AD was more dominant than MCI across all of the groups, with the highest percentage in NHPI. Among the mean ages of diagnosis, NHPI were the youngest. Across all groups, a higher proportion of women than men had AD, with the highest female prevalence among NHPI. Hypertension, hyperlipidemia, and type II diabetes were highest among NHPI compared with the other groups. Of individuals with MMSE/MoCA scores, there were significant variations in scores by racial group. The mean MMSE/MoCA score was highest among Whites and lowest among NHPI., Conclusion: Compared with other racial groups, NHPI have a higher proportion of AD than MCI at diagnosis, are diagnosed at a younger age, have a higher female prevalence, have more comorbidities that may contribute to AD/MCI onset, and present with lower MMSE scores., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Against the backdrop of the diverse minority-majority state of Hawaii, this study seeks to better characterize associations between idiopathic intracranial hypertension (IIH) with sociodemographic variables and medical comorbidities., Methods: A retrospective case-control study was conducted by utilizing 54 IIH patients and 216 age-, sex-, and race-matched controls, 216 unmatched controls, and 63 age-, sex-, and race-matched migraine patients., Results: Relative to controls, IIH were 25 years younger (p < 0.0001) and 10.18 kg/m 2 heavier (p < 0.0001), as well as exhibited greater odds of the following variables (p < 0.05): female (odds ratio [OR]: 8.87), the lowest income quartile (OR: 2.33), Native Hawaiian or other Pacific Islander (NHPI; OR: 2.23), Native American or Alaskan Native (OR: 16.50), obesity class 2 (35.0-39.9 kg/m 2 ; OR: 4.10), obesity class 3 (>40 kg/m 2 ; OR: 6.10), recent weight gain (OR: 11.66), current smoker (OR: 2.48), hypertensive (OR: 3.08), and peripheral vascular disease (OR: 16.42). Odds of IIH were reduced (p < 0.05) for patients who were Asian (OR: 0.27) or students (OR: 0.30;). Unique from Whites, NHPI IIH patients exhibited greater odds (p < 0.05) for being from lower socioeconomic status and currently smoking, as well as potential association with seizures (p = 0.08). Compared to migraines, IIH headaches were at increased odds of occurring (p < 0.05) occipitally, for greater than 15 days per month, aggravated by postural changes, and comorbid with dizziness and tinnitus., Conclusions: These results not only better characterize IIH, but also highlight socioeconomic and racial disparities in diagnosis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Given that the success of vaccines against coronavirus disease 2019 (COVID-19) relies on herd immunity, identifying patients at risk for vaccine hesitancy is imperative-particularly for those at high risk for severe COVID-19 (i.e., minorities and patients with neurological disorders)., Methods: Among patients from a large neuroscience institute in Hawaii, vaccine hesitancy was investigated in relation to over 30 sociodemographic variables and medical comorbidities, via a telephone quality improvement survey conducted between 23 January 2021 and 13 February 2021., Results: Vaccine willingness ( n = 363) was 81.3%. Univariate analysis identified that the odds of vaccine acceptance reduced for patients who do not regard COVID-19 as a severe illness, are of younger age, have a lower Charlson Comorbidity Index, use illicit drugs, or carry Medicaid insurance. Multivariable logistic regression identified the best predictors of vaccine hesitancy to be: social media use to obtain COVID-19 information, concerns regarding vaccine safety, self-perception of a preexisting medical condition contraindicated with vaccination, not having received the annual influenza vaccine, having some high school education only, being a current smoker, and not having a prior cerebrovascular accident. Unique amongst males, a conservative political view strongly predicted vaccine hesitancy. Specifically for Asians, a higher body mass index, while for Native Hawaiians and other Pacific Islanders (NHPI), a positive depression screen, both reduced the odds of vaccine acceptance., Conclusion: Upon identifying the variables associated with vaccine hesitancy amongst patients with neurological disorders, our clinic is now able to efficiently provide ancillary COVID-19 education to sub-populations at risk for vaccine hesitancy. While our results may be limited to the sub-population of patients with neurological disorders, the findings nonetheless provide valuable insight to understanding vaccine hesitancy.

Background: Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene Erbb4 is a common driving factor of PPCM., Methods: miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific Erbb4 mice ( Erbb4 F/+ αMHC-Cre + , n=9) with their age-matched nonpregnant CTRLs (n=9-10)., Results: Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (-29% to -50%; P <0.05). In addition, we demonstrate that genetic cardiomyocyte-specific downregulation of Erbb4 during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL; P <0.05), increased atrial natriuretic peptide (ANP) levels (4-fold increase versus HZ-CTRL mice, P <0.001), decreased VEGF (vascular endothelial growth factor) and VE-cadherin levels (-33±17%, P =0.07; -27±20%, P <0.05 versus HZ-CTRL), and histologically enlarged cardiomyocytes (+20±21%, versus HZ-CTRL, P <0.05) but without signs of myocardial apoptosis and inflammation., Conclusions: ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00998556.

Background: Pathological cardiac hypertrophy is a result of afterload-increasing pathologies including untreated hypertension and aortic stenosis. It features progressive adverse cardiac remodeling, myocardial dysfunction, capillary rarefaction, and interstitial fibrosis often leading to heart failure., Objectives: This study aimed to establish a novel porcine model of pressure-overload-induced heart failure and to determine the effect of inhibition of microribonucleic acid 132 (miR-132) on heart failure development in this model., Methods: This study developed a novel porcine model of percutaneous aortic constriction by implantation of a percutaneous reduction stent in the thoracic aorta, inducing progressive remodeling at day 56 (d56) after pressure-overload induction. In this study, an antisense oligonucleotide specifically inhibiting miR-132 (antimiR-132), was regionally applied via intracoronary injection at d0 (percutaneous transverse aortic constriction induction) and d28., Results: At d56, antimiR-132 treatment diminished cardiomyocyte cross-sectional area (188.9 ± 2.8 vs. 258.4 ± 9.0 μm 2 in untreated hypertrophic hearts) and improved global cardiac function (ejection fraction 48.9 ± 1.0% vs. 36.1 ± 1.7% in control hearts). Moreover, at d56 antimiR-132-treated hearts displayed less increase of interstitial fibrosis compared with sham-operated hearts (Δsham 1.8 ± 0.5%) than control hearts (Δsham 10.8 ± 0.6%). Of note, cardiac platelet and endothelial cell adhesion molecule 1 + capillary density was higher in the antimiR-132-treated hearts (647 ± 20 cells/mm 2 ) compared with in the control group (485 ± 23 cells/mm 2 )., Conclusions: The inhibition of miR-132 is a valid strategy in prevention of heart failure progression in hypertrophic heart disease and may be developed as a treatment for heart failure of nonischemic origin., Competing Interests: FUNDING SUPPORT AND AUTHOR DISCLOSURES This study was supported by the Deutsches Zentrum für Herz-Kreislauf-Forschung (German Centre for Cardiovascular Research) (to Drs. Hinkel, Weber, Engelhardt, Laugwitz, Moretti, and Kupatt) and, with regard to model development, by the Deutsche Forschungsgemeinschaft (German Research Foundation) (TRR 267 to Drs. Thum, Weber, Engelhardt, Laugwitz, and Kupatt.; and KFO311 to Dr. Thum.). Drs. Baktai and Thum are founders of Cardior Pharmaceuticals GmbH and hold shares. Dr. Thum filed and licensed patents in the field of noncoding ribonucleic acids including miR-132. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Although frequently prescribed, certain antibiotics such as trimethoprim-sulfamethoxazole carry the risk of a rare yet life-threatening adverse effect, termed drug-induced aseptic meningitis. Morbidity can be avoided if the medication is identified and discontinued. Patients in reported cases tend to be female and have an autoimmune disease or prior adverse reaction to the offending agent. As a rare and poorly characterized condition, the subset of patients using antibiotics at risk for aseptic meningitis remains unclear; hence, cataloging these adverse events remains critical for better elucidating the disease. Here, we report a 62-year-old man with psoriasis and no prior history of sulfa allergy, who presented with a sudden onset of fever, chills, vomiting, and muscle aches 5 hours after taking single doses of trimethoprim-sulfamethoxazole and ciprofloxacin. Common infectious causes were ruled out, and his medications were discontinued. Despite initial symptom resolution with discontinuation, the patient neurologically deteriorated over the next two days before eventually recovering with supportive care. This case highlights the variable presentation of drug-induced aseptic meningitis. In contrast to previous reports of drug-induced aseptic meningitis, our patient was male, older than the median age of 40 years, and did not have a prior adverse reaction to the antibiotic. Furthermore, to the best of our knowledge, we report a possible case of antibiotic-induced aseptic meningitis in a patient with psoriasis. Lastly, the case emphasizes not only the value of a thorough medication history but also the importance of recognizing that patients may deteriorate in the first 48 hours before resolution., (©Copyright 2021 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

Aims: Cardiac miR-132 activation leads to adverse remodelling and pathological hypertrophy. CDR132L is a synthetic lead-optimized oligonucleotide inhibitor with proven preclinical efficacy and safety in heart failure (HF) early after myocardial infarction (MI), and recently completed clinical evaluation in a Phase 1b study (NCT04045405). The aim of the current study was to assess safety and efficacy of CDR132L in a clinically relevant large animal (pig) model of chronic heart failure following MI., Methods and Results: In a chronic model of post-MI HF, slow-growing pigs underwent 90 min left anterior descending artery occlusion followed by reperfusion. Animals were randomized and treatment started 1-month post-MI. Monthly intravenous (IV) treatments of CDR132L over 3 or 5 months (3× or 5×) were applied in a blinded randomized placebo-controlled fashion. Efficacy was evaluated based on serial magnetic resonance imaging, haemodynamic, and biomarker analyses. The treatment regime provided sufficient tissue exposure and CDR132L was well tolerated. Overall, CDR132L treatment significantly improved cardiac function and reversed cardiac remodelling. In addition to the systolic recovery, diastolic function was also ameliorated in this chronic model of HF., Conclusion: Monthly repeated dosing of CDR132L is safe and adequate to provide clinically relevant exposure and therapeutic efficacy in a model of chronic post-MI HF. CDR132L thus should be explored as treatment for the broad area of chronic heart failure., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: A survey was implemented for early assessment of pandemic-related practice processes and quality improvement (QI)., Background: In response to the public health measures in Hawaii to curtail the coronavirus 2019 pandemic, Hawaii Pacific Neuroscience (HPN) adapted their patient care to ensure continuity of neurological treatment., Methods: The telephone survey was conducted on patients seen at HPN during the period of April 22, 2020-May 18, 2020 to address four areas related to patients' outpatient experience: delivery of care, general well-being, experience with telemedicine, and disease-specific questions., Results: A total of 928 patients were contacted of which 429 (46.2%) patients responded and 367 (85.5%) agreed to participate. A total of 133 patients with migraine and 234 patients with other neurological conditions provided responses. Our migraine patients' survey responses suggest that their well-being was disproportionately negatively affected by the pandemic. Survey respondents with migraine were significantly more likely than their non-migraine peers to report worsening anxiety and sleep problems [62/132 (47.0%) vs. 78/234 (33.3%), χ 2  = 6.64, p = 0.010, and 64/132 (48.5%) vs. 73/234 (31.2%), χ 2  = 10.77, p = 0.001]; migraine patients also reported worsening of depression as a result of the pandemic more than patients with other diagnoses, though this was not statistically significant [44/132 (33.3%) vs. 57/234 (24.4%), χ 2  = 3.40, p = 0.065]. In regard to access to healthcare, significantly more migraine patients reported running out of medications than those with other diagnoses [20/133 (15.0%) vs. 18/234 (7.7%), χ 2  = 4.93, p = 0.026]. More avoided seeking medical help for new health problems because of the pandemic [30/133 (22.6%) vs. 30/234 (12.8%), χ 2  = 5.88, p = 0.015]. Migraine patients were also significantly impacted economically by the pandemic; 43/132 (32.4%) of migraine patients reported losing their jobs as the result of the pandemic versus 34/234 (14.5%) of their peers (χ 2  = 11.20, p < 0.001). An increase in headache severity or frequency was reported in 39/118 (33.1%) of respondents and 19/118 (16.1%) reported to using more abortive therapy than usual. Telemedicine was well received by almost all patients who took advantage of the option. Most of those patients found telemedicine to be easy to use and as valuable as an in-person visit. Migraine patients indicated with more frequency that without the telemedicine option, they would have missed their medical appointments [37/68 (54.4%) vs. 56/144 (38.6%), χ 2  = 4.31, p = 0.038]; a majority would prefer or consider telemedicine for future appointments over in-person visits., Conclusions: Insights gained from this QI survey to the practice's new pandemic-related processes include stressing lifestyle modification, optimizing treatment plans, and continuing the option of telemedicine., (© 2020 American Headache Society.)

Aims: Pathological cardiac remodelling and subsequent heart failure represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes, including that of heart diseases. Here, we report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy., Method and Results: Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase but strong sustained repression upon reaching the decompensated phase of heart failure. The translational potential of H19 is highlighted by its repression in a large animal (pig) model of left ventricular hypertrophy, in diseased human heart samples, in human stem cell-derived cardiomyocytes and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knock-out mice was aggravated compared to wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine and human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses and Chromatin ImmunoPrecipitation DNA-Sequencing, we identified a link between H19 and pro-hypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the anti-hypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity., Conclusion: H19 is highly conserved and down-regulated in failing hearts from mice, pigs and humans. H19 gene therapy prevents and reverses experimental pressure-overload-induced heart failure. H19 acts as an anti-hypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The valence band spectra of three cyano-ionic liquids based on 1-ethyl-3-methylimidazolium (Im 2,1 + ) paired with thiocyanate (SCN - ), dicyanamide (N(CN) 2 - ), and tricyanomethanide (C(CN) 3 - ) have been measured using ultraviolet and X-ray photoemission spectroscopy. Experimental spectra are compared to their corresponding density of states, weighted by photoemission cross sections, calculated for clusters of ions pairs of increasing size. Thus, this study bridges single ion approaches to 3D periodical DFT studies and enables the exploration of the different aspects of electronic structure establishment in ILs. Even for a relatively small cluster size, the relative energy of cation and anions states shifts by an amount that corresponds closely to that expected from the Madelung energy of a bulk IL, and the photoemission cross section-weighted DOS spectra are in good agreement with the measured valence bands. Trends in the relative energy and ionic character of the frontier orbitals across this series of cyano-ILs are discussed.

Myocardial ischemia induces a multifaceted remodeling process in the heart. Novel therapeutic entry points to counteract maladaptive signalling include the modulation of non-coding RNA molecules such as long non-coding RNA (lncRNA). We here questioned if the lncRNA candidate H19 exhibits regulatory potential in the setting of myocardial infarction. Initial profiling of H19 expression revealed a dynamic expression profile of H19 with upregulation in the acute phase after murine cardiac ischemia. In vitro, we found that oxygen deficiency leads to H19 upregulation in several cardiac cell types. Repression of endogenous H19 caused multiple phenotypes in cultivated murine cardiomyocytes including enhanced cardiomyocyte apoptosis, at least partly through attenuated vitamin D signalling. Unbiased proteome analysis revealed further involvement of H19 in mRNA splicing and translation as well as inflammatory signalling pathways. To study H19 function more precisely, we investigated the phenotype of systemic H19 loss in a genetic mouse model of H19 deletion (H19 KO). Infarcted heart tissue of H19 KO mice showed a massive increase of pro-inflammatory cytokines after ischemia-reperfusion injury (I/R) without significant effects on scar formation or cardiac function but exaggerated cardiac hypertrophy indicating pathological cardiac remodeling. H19-dependent changes in cardiomyocyte-derived extracellular vesicle release and alterations in NF-κB signalling were evident. Cardiac cell fractionation experiments revealed that enhanced H19 expression in the proliferative phase after MI derived mainly from cardiac fibroblasts. Here further research is needed to elucidate its role in fibroblast activation and function. In conclusion, the lncRNA H19 is dynamically regulated after MI and involved in multiple pathways of different cardiac cell types including cardiomyocyte apoptosis and cardiac inflammation., Competing Interests: Declaration of Competing Interest TT and JF have filed patents in the field of cardiovascular non-coding RNA diagnostics and therapeutics. TT is founder and shareholder of Cardior Pharmaceuticals GmbH., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Currently, predicting and preventing idiopathic normal pressure hydrocephalus (iNPH) remains challenging, especially for patients without a history of cerebrovascular disease. By exploring the role of cardiovascular and psychiatric history, demographics, and socioeconomic status in iNPH, will provide better direction for elucidating the etiology or addressing healthcare inequalities., Patients and Methods: To investigate iNPH with respect to the selected risk factors, we conducted a retrospective case-control study from a neuroscience institute in Hawaii with a patient pool of 25,843. After excluding patients with a history of cerebrovascular disease, we identified 29 cases which meet the American-European guidelines for iNPH diagnosis. Meanwhile, 116 controls matched to age, sex, and race were also randomly selected., Results: Median age at diagnosis was 83 (IQR: 74-88), with cases estimated 22 years older than controls (95 % CI: 14.00-29.00; p = 0.0000001). Patients with iNPH were more likely to be White (OR 4.01, 95 % CI: 1.59-10.11; p = 0.0042) and less likely Native Hawaiian and other Pacific Islander (OR 0.010, 95 % CI: 0.00-0.78; p = 0.014). Median household income was $2874 (95 % CI: 0.000089-6905; p = 0.088) greater amongst iNPH cases. Effect size amongst cardiovascular risk factors was not found statistically significant (i.e., body mass index, hyperlipidemia, type 2 diabetes mellitus, hypertension, coronary artery disease or prior myocardial infarction history, peripheral vascular disease, smoking status, congestive heart failure, atrial fibrillation/flutter, and history of prosthetic valve replacement). However, iNPH patients were more likely to have a history of alcohol use disorder (OR 8.29, 95 % CI: 0.99-453.87; p = 0.050) and history of a psychiatric disorder (OR 2.48; 95 % CI: 1.08-5.68; p = 0.029). Odds ratio for autoimmune disorder, thyroid disorder, glaucoma, and seizures did not reach statistical significance., Conclusion: Patient race (i.e., White; Native Hawaiian or other Pacific Islander) was found associated with iNPH development. Meanwhile, after excluding those with cerebrovascular disease, cardiovascular risk factors were not found associated with iNPH. Lastly, iNPH cases were more inclined to have a history of alcohol use disorder and prior psychiatric disorder. Overall, this data reveals that a racial disparity exists amongst iNPH, as well as highlights the role of various cardiovascular and psychiatric risk factors, which can potentially provide direction in etiology elucidation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)