Histone H3K18 & H3K23 acetylation directs establishment of MLL-mediated H3K4 methylation.

In an unmodified state, positively charged histone N-terminal tails engage nucleosomal DNA in a manner which restricts access to not only the underlying DNA, but also key tail residues subject to binding and/or modification. Charge-neutralizing modifications, such as histone acetylation, serve to disrupt this DNA-tail interaction, facilitating access to such residues. We previously showed that a polyacetylation-mediated chromatin "switch" governs the read-write capability of H3K4me3 by the MLL1 methyltransferase complex. Here, we discern the relative contributions of site-specific acetylation states along the H3 tail and extend our interrogation to other chromatin modifiers. We show that the contributions of H3 tail acetylation to H3K4 methylation by MLL1 are highly variable, with H3K18 and H3K23 acetylation exhibiting robust stimulatory effects, and that this extends to the related H3K4 methyltransferase complex, MLL4. We show that H3K4me1 and H3K4me3 are found preferentially co-enriched with H3 N-terminal tail proteoforms bearing dual H3K18 and H3K23 acetylation (H3{K18acK23ac}). We further show that this effect is specific to H3K4 methylation, while methyltransferases targeting other H3 tail residues (H3K9, H3K27, & H3K36), a methyltransferase targeting the nucleosome core (H3K79), and a kinase targeting a residue directly adjacent to H3K4 (H3T3) are insensitive to tail acetylation. Together, these findings indicate a unique and robust stimulation of H3K4 methylation by H3K18 and H3K23 acetylation and provide key insight into why H3K4 methylation is often associated with histone acetylation in the context of active gene expression.

H3K18 & H3K23 acetylation directs establishment of MLL-mediated H3K4 methylation.

In an unmodified state, positively charged histone N-terminal tails engage nucleosomal DNA in a manner which restricts access to not only the underlying DNA, but also key tail residues subject to binding and/or modification. Charge-neutralizing modifications, such as histone acetylation, serve to disrupt this DNA-tail interaction, facilitating access to such residues. We previously showed that a polyacetylation-mediated chromatin "switch" governs the read-write capability of H3K4me3 by the MLL1 methyltransferase complex. Here, we discern the relative contributions of site-specific acetylation states along the H3 tail and extend our interrogation to other chromatin modifiers. We show that the contributions of H3 tail acetylation to H3K4 methylation by MLL1 are highly variable, with H3K18 and H3K23 acetylation exhibiting robust stimulatory effects, and that this extends to the related H3K4 methyltransferase complex, MLL4. We show that H3K4me1 and H3K4me3 are found preferentially co-enriched with H3 N-terminal tail proteoforms bearing dual H3K18 and H3K23 acetylation (H3{K18acK23ac}). We further show that this effect is specific to H3K4 methylation, while methyltransferases targeting other H3 tail residues (H3K9, H3K27, & H3K36), a methyltransferase targeting the nucleosome core (H3K79), and a kinase targeting a residue directly adjacent to H3K4 (H3T3) are insensitive to tail acetylation. Together, these findings indicate a unique and robust stimulation of H3K4 methylation by H3K18 and H3K23 acetylation and provide key insight into why H3K4 methylation is often associated with histone acetylation in the context of active gene expression.

Ethical issues of nosology in disorders of consciousness.

The current classification scheme for severe disorders of consciousness (DoC) has several shortcomings. First, there is no consensus on how to incorporate patients with covert consciousness. Second, there is a mismatch between the definitions of severe DoC, based on consciousness, and the diagnosis of these same DoC, which is based on observable motoric responsiveness. Third, current categories are grouped into large heterogeneous syndromes which share phenotype, but do not incorporate underlying pathophysiology. Here we discuss several ethical issues pertaining to the current nosology of severe DoC. We conclude by proposing a revised nosology which addresses these shortcomings.

Variant Sciatic Nerve Anatomy in Relation to the Piriformis Muscle on Magnetic Resonance Neurography: A Potential Etiology for Extraspinal Sciatica.

OBJECTIVE: To assess the prevalence and clinical implications of variant sciatic nerve anatomy in relation to the piriformis muscle on magnetic resonance neurography (MRN), in patients with lumbosacral neuropathic symptoms. MATERIALS AND METHODS: In this retrospective single-center study, 254 sciatic nerves, from 127 patients with clinical and imaging findings compatible with extra-spinal sciatica on MRN between 2003 and 2013, were evaluated for the presence and type of variant sciatic nerves, split sciatic nerve, abnormal T2-signal hyperintensity, asymmetric piriformis size and increased nerve caliber, and summarized using descriptive statistics. Two-tailed chi-square tests were performed to compare the anatomical variant type and clinical symptoms between imaging and clinical characteristics. RESULTS: Sixty-four variant sciatic nerves were identified with an equal number of right and left variants. Bilateral variants were noted in 15 cases. Abnormal T2-signal hyperintensity was seen significantly more often in variant compared to conventional anatomy (40/64 vs. 82/190; p = 0.01). A sciatic nerve split was seen significantly more often in variant compared to conventional anatomy (56/64 vs. 20/190; p < 0.0001). Increased nerve caliber, abnormal T2-signal hyperintensity, and asymmetric piriformis size were significantly associated with the clinically symptomatic side compared to the asymptomatic side (98:2, 98:2, and 97:3, respectively; p < 0.0001 for all). Clinical symptoms were correlated with variant compared to conventional sciatic nerve anatomy (64% vs. 46%; p = 0.01). CONCLUSION: Variant sciatic nerve anatomy, in relation to the piriformis muscle, is frequently identified with MRN and is more likely to be associated with nerve signal changes and symptomatology.

Black Patients Matter in Neurology: Race, Racism, and Race-Based Neurodisparities.

Black people living in the United States suffer disproportionate morbidity and mortality across a wide range of neurologic conditions. Despite common conceptions to the contrary, "race" is a socially defined construct with little genetic validity. Therefore, racial health inequities in neurology ("neurodisparities") are not a consequence of biologic differences between races. Instead, racism and associated social determinants of health are the root of neurodisparities. To date, many neurologists have neglected racism as a root cause of neurologic disease, further perpetuating the problem. Structural racism, largely ignored in current neurologic practice and policy, drives neurodisparities through mediators such as excessive poverty, inferior health insurance, and poorer access to neurologic and preventative care. Interpersonal racism (implicit or explicit) and associated discriminatory practices in neurologic research, workforce advancement, and medical education also exacerbate neurodisparities. Neurologists cannot fulfill their professional and ethical responsibility to care for Black patients without understanding how racism, not biologic race, drives neurodisparities. In our review of race, racism, and race-based disparities in neurology, we highlight the current literature on neurodisparities across a wide range of neurologic conditions and focus on racism as the root cause. We discuss why all neurologists are ethically and professionally obligated to actively promote measures to counteract racism. We conclude with a call for actions that should be implemented by individual neurologists and professional neurologic organizations to mitigate racism and work towards health equity in neurology.

Patient preference for virtual versus in-person visits in neuromuscular clinical practice.

INTRODUCTION/AIMS: It is unknown if patients with neuromuscular diseases prefer in-person or virtual telemedicine visits. We studied patient opinions and preference on virtual versus in-person visits, and the factors influencing such preferences. METHODS: Telephone surveys, consisting of 11 questions, of patients from 10 neuromuscular centers were completed. RESULTS: Five hundred and twenty surveys were completed. Twenty-six percent of respondents preferred virtual visits, while 50% preferred in-person visits. Sixty-four percent reported physical interaction as "very important." For receiving a new diagnosis, 55% preferred in-person vs 35% reporting no preference. Forty percent were concerned about a lack of physical examination vs 20% who were concerned about evaluating vital signs. Eighty four percent reported virtual visits were sufficiently private. Sixty eight percent did not consider expenses a factor in their preference. Although 92% were comfortable with virtual communication technology, 55% preferred video communications, and 19% preferred phone calls. Visit preference was not significantly associated with gender, diagnosis, disease severity, or symptom management. Patients who were concerned about a lack of physical exam or assessment of vitals had significantly higher odds of selecting in-person visits than no preference. DISCUSSION: Although neither technology, privacy, nor finance burdened patients in our study, more patients preferred in-person visits than virtual visits and 40% were concerned about a lack of physical examination. Interactions that occur with in-person encounters had high importance for patients, reflecting differences in the perception of the patient-physician relationship between virtual and in-person visits.

Associations of Lower Extremity Peripheral Nerve Impairment and Risk of Dementia in Black and White Older Adults.

BACKGROUND AND OBJECTIVES: Peripheral nerve impairments and dementia are common among older adults and share risk factors. However, few studies have examined whether peripheral nerve function and dementia are associated. We evaluated whether lower extremity peripheral nerve impairments were associated with higher incidence of dementia and whether associations differed by comorbidity subgroups (diabetes, low vitamin B12, and APOE ε4 allele carriers). METHODS: We studied Black and White Health, Aging, and Body Composition Study participants 70 to 79 years of age and without dementia at enrollment. Lower extremity sensory and motor peripheral nerve function was measured at year 4 (the analytic baseline of this study). Sensory nerve impairments were measured with monofilament (1.4 g, 10 g) and vibration threshold of the toe. Monofilament insensitivity was defined as unable to detect monofilament (3 of 4 touches), and vibration detection impairment was defined as >130 µm. Fibular motor impairments were defined as <1 mV compound motor action potential (CMAP) amplitude and slow nerve conduction velocity <40 m/s. Incident dementia over the following 11 years was determined from medical records, cognitive scores, and medications. Cox proportional hazard models adjusted for demographics and health conditions assessed associations of nerve impairments with incident dementia. RESULTS: Among 2,174 participants (52% women, 35% Black), 45% could not detect monofilament 1.4 g, 9% could not detect monofilament 10 g, 6% could not feel vibration, 10% had low CMAP amplitude, and 24% had slow conduction velocity. Monofilament 10 g (hazard ratio [HR] 1.35, 95% CI 0.99-1.84) and vibration detection insensitivity (HR 1.73, 95% CI 1.24-2.40) were associated/borderline associated with a higher risk of dementia after covariate adjustment. Estimates were elevated but not significant for monofilament 1.4 g, CMAP amplitude, and conduction velocity (p > 0.05). Increasing number of peripheral nerve impairments was associated with higher risk of dementia in a graded fashion; for ≥3 impairments, the HR was 2.37 (95% CI 1.29-4.38). In subgroup analyses, effect estimates were generally higher among those with diabetes, low vitamin B12, and APOE ε4 allele except for vibration detection. DISCUSSION: Peripheral nerve impairments, especially sensory, were associated with a higher risk of dementia even after adjustment for age and other health factors. These associations may represent a shared susceptibility to nervous system degeneration.

Reduced Peripheral Nerve Conduction Velocity is Associated with Alzheimer's Disease: A Cross-Sectional Study from China.

PURPOSE: Elderly individuals with degenerative diseases of the central nervous system are more likely to develop peripheral neuropathy; however, research is limited as to whether the decline in peripheral nerve conduction can be used as a biomarker of Alzheimer's disease (AD). PATIENTS AND METHODS: This study enrolled 74 patients with mild cognitive impairment (MCI), 21 with AD, and 82 healthy elderly individuals. All participants underwent a peripheral nerve conduction and neuropsychological evaluation. Nicolet EDX was used to assess peripheral nerve conduction in the limbs and comparisons were made between the three cognitive groups. Furthermore, the relationship between peripheral nerve conduction and cognitive function was investigated. RESULTS: A ladder-shaped difference was found in the median (p < 0.001) and common peroneal (p < 0.001) motor nerve velocity, with the control group > MCI group > AD group, even after controlling for variables. The median motor nerve amplitude in the AD group was lower than that in the control group (P = 0.017). After controlling for age, sex, education, and height, the median motor nerve velocity was positively correlated with the Montreal Cognitive Assessment (r = 0.196, p = 0.015), and the common peroneal motor nerve velocity was positively correlated with verbal fluency task-idioms (r = 0.184, p = 0.026). The median (AUC: 0.777, p < 0.001) and common peroneal motor nerve velocities (AUC: 0.862; p < 0.001) were significantly associated with the diagnosis of AD. The accuracy rate of these two motor nerve velocities to predict AD was 51.5%. CONCLUSION: Our study found that peripheral motor nerve velocity may correlate with early cognitive impairment in AD. However, the accuracy of different cognitive classifications and the value of early diagnosis are not ideal when peripheral motor nerve velocity is used alone. Whether peripheral nerve function can be used as a marker for early diagnosis of AD needs further clarification but provides a new possibility for the future of biomarker research.

Cardio-ankle vascular index of increased arterial wall stiffness is associated with neurocognitive impairment in well-controlled HIV.

OBJECTIVES: HIV-associated neurocognitive disorders (HAND) remain prevalent in people living with HIV (PLWH) despite widespread use of combined antiretroviral therapy (ART). Vascular disease contributes to the pathogenesis of HAND, but traditional vascular risk factors do not fully explain the relation between vascular disease and HAND. A more direct measure of vascular dysfunction is needed. This cross-sectional study tested whether the cardio-ankle vascular index (CAVI), a novel method to assess arterial stiffness, is associated with HAND among PLWH. METHODS: Participants included 75 non-diabetic adults with well-controlled HIV from an outpatient HIV clinic. We assessed the relation between CAVI and neurocognitive impairment (NCI). The latter was primarily characterized by the Frascati criteria and secondarily (post hoc) using the Global Deficit Score (GDS). Logistic regression models tested whether high CAVI (≥ 8) was independently associated with NCI when controlling for potential confounders. RESULTS: Participants (Mage  = 45.6 ± 8.3 years; 30.1% male) had few traditional cardiovascular disease (CVD) risk factors (hypertension, n = 7; dyslipidaemia, n = 34; body mass index ≥ 25 kg/m2 , n = 12; smoking history, n = 13; 2.2% mean 10-year risk of CVD or stroke). Twelve (16%) participants had high CAVI, which was independently associated with meeting Frascati criteria for NCI [n = 39, odds ratio (OR) = 7.6, p = 0.04], accounting for age, education, gender, income, CD4 nadir, recent CD4 and traditional CVD risk factors. High CAVI was also associated with NCI as reflected by higher GDS (OR = 17.4, p = 0.02). CONCLUSIONS: Cardio-ankle vascular index is a promising measure of vascular dysfunction that may be independently associated with NCI in relatively healthy PLWH. Larger studies should test the utility of CAVI in predicting NCI/decline in PLWH.

Early nutritional influences of cardiovascular health.

INTRODUCTION: Increasing evidence shows that nutritional choices during children's formative years, including prenatally, impacts the development of adult onset cardiovascular diseases (CVDs), such as hypertension, myocardial infarction, or stroke. AREAS COVERED: This literature review aims to synthesize the current body of evidence on nutritional factors, from conception through adolescence, which may influence a person's risk factors for future development of CVD. EXPERT OPINION: Given the escalating healthcare costs associated with CVD, it is imperative that medical professionals and scientists remain steadfast in prioritizing and promoting early CVD prevention, even within the first few years of life. Though not the only contributing risk factor, diet is a modifiable risk factor and has been shown to have a profound impact on the reduction of cardiovascular morbidity and mortality in adult literature. Nutritional choices should be targeted on multiple levels: prenatally with the mother, individually with the patient, in conjunction with their family unit, and also within the broader community wherein they reside. Healthcare providers can play a key advocacy role for local and national food environment policy changes.

Psychometric utility of the international HIV dementia scale and Montreal Cognitive Assessment in HIV-associated asymptomatic neurocognitive impairment.

There is a growing need for brief screening measures for HIV Associated Neurocognitive Disorders (HAND). We compared two commonly used measures (the Montreal Cognitive Assessment [MoCA] and the International HIV Dementia Scale [IHDS]) in their ability to identify asymptomatic HAND (i.e., asymptomatic neurocognitive impairment [ANI]). Participants included 74 Thai PLWH: 38 met Frascati criteria for ANI and 36 were cognitively normal (CN). Participants completed Thai language versions of the MoCA (MoCA-T) and IHDS, and a validated neurocognitive battery. We examined between-group differences for MoCA-T and IHDS total scores, and scale subcomponents. We also conducted receiver operating characteristic (ROC) analyses to determine the ability of the MoCA-T and IHDS to discriminate between CN and ANI groups, and compared their area under the curve (AUC) values. Results revealed lower MoCA-T total score, as well as the Visuospatial/Executive and Delayed Recall subtask scores, in the ANI relative to CN group. Groups did not differ on the IHDS. For ROC analyses, the MoCA-T, but not the IHDS, significantly differentiated the ANI from CN group, and there was a significant difference in AUC values between the MoCA-T (AUC = .71) and IHDS (AUC = .56). Sensitivity and specificity statistics were poor for both screening measures. These data indicate while the MoCA-T functions better than the IHDS in detecting Thai PLWH with ANI, the mildest form of HAND, neither cognitive screener, showed strong utility. Our findings reflect the limited efficacy of common screening measures in detecting subtler cognitive deficits among Thai PLWH, and highlight the need for better screening tools.

Efficacy and Safety of the Telestroke Drip-And-Stay Model: A Systematic Review and Meta-Analysis.

OBJECTIVES: To compare outcomes between two models of acute ischemic stroke care. Namely 1) "drip-and-stay", i.e. IV tissue plasminogen activator (tPA) administered at a spoke hospital in a telestroke network, with the patient remaining at the spoke, versus 2) "drip-and-ship", i.e. tPA administered at a spoke hospital with subsequent patient transfer to a hub hospital, and 3) "hub", i.e. tPA and subsequent treatment at a hub hospital. MATERIALS AND METHODS: We performed a systematic review and meta-analysis according to PRISMA guidelines. Literature searches of MEDLINE, Embase, and Cochrane from inception-October 2019 included randomized control trials and observational cohort studies comparing the drip-and-stay model to hub and drip-and-ship models. Outcomes of interest were functional independence (modified Rankin Scale ≤ 1), symptomatic intracranial hemorrhage (sICH), mortality, and length of stay. Pooled effect estimates were calculated using a fixed-effects meta-analysis and random-effects Bayesian meta-analysis. Non-inferiority was calculated using a fixed-margin method. RESULTS: Of 2806 unique records identified, 10 studies, totaling 4,164 patients, fulfilled the eligibility criteria. Meta-analysis found no significant difference in functional outcomes (mRS0-1) (6 studies, RR=1.09, 95%CI 0.98-1.22, p=0.123), sICH (8 studies, RR=0.98, 95%CI 0.64-1.51, p=0.942), or 90-day mortality (5 studies, RR=0.98, 95%CI 0.73-1.32, p=0.911, respectively) between patients treated in a drip-and-stay model compared to patients treated in drip-and-ship or hub models. There was no significant heterogeneity in these outcomes. Drip-and-stay outcomes (mRS 0-1, sICH) were non-inferior when compared to the combined group. CONCLUSIONS: Our findings indicate that drip-and-stay is non-inferior to current models of drip-and-ship or hub stroke care, and may be as safe and as effective as either.

Financial Conflicts of Interest of United States-Based Authors in Neurology Journals: Cross-Sectional Study Using the Open Payments Database.

OBJECTIVE: To detail the scope, nature, and disclosure of financial conflicts of interest (COI) between the pharmaceutical and medical device industries (Industry) and authors in high-impact clinical neurology journals. METHODS: Using the Centers for Medicare and Medicaid Services Open Payments Database (OPD), we retrieved information on payments from Industry to 2,000 authors from randomly selected 2016 articles in 5 journals. We categorized payments by type (research, general, and associated research/institutional), sponsoring entity, and year (from 2013 to 2016). Each author's self-disclosures were compared to OPD-listed Industry relationships to measure discordance. Payments were manually reviewed to identify those from manufacturers of products that were directly tested or discussed in the article. We also quantified the prevalence and value of these nondisclosed, relevant COI. RESULTS: Two hundred authors from 158 articles had at least 1 OPD payment. Median/mean annual payments per author were $4,229/$19,586 (general); $1,702/$5,966 (research); and $67,512/$362,102 (associated research). Most neurologists received <$1,000/y (74.6%, 93.0%, and 79.5% for general, research, and associated research, respectively), but a sizeable minority (>10% of authors) received more than $10,000 per year, and several received over $1 million. Of 3,013 payments deemed directly relevant to the article, 50.9% were not self-disclosed by the authors, totaling $5,782,197 ($1,665,603 general; $25,532 research; $4,091,062 associated research). CONCLUSION: Industry-related financial relationships are prevalent among United States-based physicians publishing in major neurology journals, and incomplete self-disclosure is common. As a profession, academic and other neurologists must work to establish firm rules to ensure and manage disclosure of financial COI.

A Novel SPAST/SPG4 Splice-Site Variant in a Family with Dominant Hereditary Spastic Paraplegia.

Some causes of spastic paraplegia are treatable and many are not. Diagnostic work-up to determine the etiology can be costly and invasive. Here we report the case of a man with slowly progressive spastic paraparesis. Using a multigene next-generation sequencing (NGS) panel, we identified a novel variant in the consensus splice site of the SPAST gene (exon 13, c.1536G>A, heterozygous), affecting codon 512 of the SPAST mRNA. The observed variant segregated with the disease in four tested family members. In this case, genetic confirmation obviated the need for additional testing such as MRI and lumbar puncture and helped the patient and his family understand his condition and prognosis. We conclude with a brief discussion of the SPG4/SPAST gene and the role of multigene panels in the diagnosis and management of hereditary spastic paraplegia.

What Should We Do About the Mismatch Between Legal Criteria for Death and How Brain Death Is Diagnosed?

Mismatch between whole-brain death criteria embedded in statutes and accepted tests physicians use to diagnose brain death have clinical and ethical implications that could undermine public trust in death pronouncements. We consider merits and drawbacks of 4 ways to address this problem.