Bayesian group testing with dilution effects.

A Bayesian framework for group testing under dilution effects has been developed, using lattice-based models. This work has particular relevance given the pressing public health need to enhance testing capacity for coronavirus disease 2019 and future pandemics, and the need for wide-scale and repeated testing for surveillance under constantly varying conditions. The proposed Bayesian approach allows for dilution effects in group testing and for general test response distributions beyond just binary outcomes. It is shown that even under strong dilution effects, an intuitive group testing selection rule that relies on the model order structure, referred to as the Bayesian halving algorithm, has attractive optimal convergence properties. Analogous look-ahead rules that can reduce the number of stages in classification by selecting several pooled tests at a time are proposed and evaluated as well. Group testing is demonstrated to provide great savings over individual testing in the number of tests needed, even for moderately high prevalence levels. However, there is a trade-off with higher number of testing stages, and increased variability. A web-based calculator is introduced to assist in weighing these factors and to guide decisions on when and how to pool under various conditions. High-performance distributed computing methods have also been implemented for considering larger pool sizes, when savings from group testing can be even more dramatic.

Normal CEA Levels After Neoadjuvant Chemotherapy and Cytoreduction with Hyperthermic Intraperitoneal Chemoperfusion Predict Improved Survival from Colorectal Peritoneal Metastases.

BACKGROUND: Normal carcinoembryonic antigen (CEA) levels (≤ 2.5 ng/ml) after resection of localized colorectal cancer or liver metastases are associated with improved survival, however, these trends are understudied for colorectal peritoneal metastases (CRPM). PATIENTS AND METHODS: We conducted a retrospective single-institution study of patients with CRPM undergoing cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) with and without neoadjuvant chemotherapy (NACT). CEA was measured before and after NACT and within 3 months after CRS/HIPEC. RESULTS: A total of 253 patients (mean age 55.3 years) with CRPM undergoing CRS/HIPEC had complete CEA data and 191 also underwent NACT with complete data. The median peritoneal carcinomatosis index score (PCI) of the overall cohort was 12 and 82.7% of patients had complete cytoreduction (CC0). In total, 64 (33.5%) patients had normal CEA levels after NACT with a median overall survival (OS) of 45.2 months compared with those with an elevated CEA (26.4 months, p = 0.004). Patients with normal CEA after NACT had a lower PCI found at the time of surgery than those with elevated CEA (10 versus 14, p < 0.001), 68 (26.9%) patients with an elevated preoperative CEA level experienced normalization after CRS/HIPEC, and 118 (46.6%) patients had elevated CEA after CRS/HIPEC. Patients who experienced normalization demonstrated similar OS to patients that had normal CEA levels pre- and post-surgery and improved OS compared with those with elevated postop CEA (median 41.9 versus 47 months versus 17.1 months, respectively, p < 0.001). CONCLUSIONS: Normal CEA levels after NACT and/or CRS/HIPEC are associated with improved survival for patients with CRPM. Patients that normalize CEA levels after surgery have similar survival to those with normal preoperative levels.

Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases.

Definitive diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrPSc). Our previous study revealed that PrPSc-seeding activity (PrPSc-SA) is detectable in skin of sCJD patients by an ultrasensitive PrPSc seed amplification assay (PrPSc-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2-3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls. The skin samples were analyzed for PrPSc-SA by RT-QuIC assay. The results were compared with demographic information, clinical manifestations, cerebrospinal fluid (CSF) PrPSc-SA, other laboratory tests, subtypes of prion diseases defined by the methionine (M) or valine (V) polymorphism at residue 129 of PrP, PrPSc types (#1 or #2), and gene mutations in deceased patients. RT-QuIC assays of the cohort #1 by two independent laboratories gave 87.3% or 91.3% sensitivity and 94.7% or 100% specificity, respectively. The cohort #2 showed sensitivity of 89.4% and specificity of 95.5%. RT-QuIC of CSF available from 212 cases gave 89.7% sensitivity and 94.1% specificity. The sensitivity of skin RT-QuIC was subtype dependent, being highest in sCJDVV1-2 subtype, followed by VV2, MV1-2, MV1, MV2, MM1, MM1-2, MM2, and VV1. The skin area next to the ear gave highest sensitivity, followed by lower back and apex of the head. Although no difference in brain PrPSc-SA was detected between the cases with false negative and true positive skin RT-QuIC results, the disease duration was significantly longer with the false negatives [12.0 ± 13.3 (months, SD) vs. 6.5 ± 6.4, p < 0.001]. Our study validates skin PrPSc-SA as a biomarker for the detection of prion diseases, which is influenced by the PrPSc types, PRNP 129 polymorphisms, dermatome sampled, and disease duration.

Skin α-Synuclein Seeding Activity in Patients with Type 1 Gaucher Disease.

BACKGROUND: Patients with type 1 Gaucher disease (GD1) have a significantly increased risk of developing Parkinson's disease (PD). OBJECTIVE: The objective of this study was to evaluate skin α-synuclein (αSyn) seeding activity as a biomarker for GD1-related PD (GD1-PD). METHODS: This single-center study administered motor and cognitive examinations and questionnaires of nonmotor symptoms to adult patients with GD1. Optional skin biopsy was performed for skin αSyn seed amplification assay (αSyn SAA) using real-time quaking-induced conversion assay. RESULTS: Forty-nine patients were enrolled, and 36 underwent skin biopsy. Two study participants had PD. Ten participants were αSyn SAA positive (27.8%), 7 (19.4%) were intermediate, and 19 (52.8%) were negative. Positive αSyn seeding activity was observed in the single GD1-PD case who consented to biopsy. αSyn SAA positivity was associated with older age (p = 0.043), although αSyn SAA positivity was more prevalent in patients with GD1 than historic controls. CONCLUSIONS: Longitudinal follow-up is required to determine whether skin αSyn seeding activity can be an early biomarker for GD1-PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Interleukin 6 Blockade With Tocilizumab Diminishes Indices of Inflammation That Are Linked to Mortality in Treated Human Immunodeficiency Virus Infection.

BACKGROUND: People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine. METHODS: This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels. RESULTS: There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment. CONCLUSIONS: TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study. Clinical Trials Registration. NCT02049437.

Tau seeds occur before earliest Alzheimer's changes and are prevalent across neurodegenerative diseases.

Tau neurofibrillary tangles are a hallmark of Alzheimer's disease neuropathological change. However, it remains largely unclear how distinctive Alzheimer's disease tau seeds (i.e. 3R/4R) correlate with histological indicators of tau accumulation. Furthermore, AD tau co-pathology is thought to influence features and progression of other neurodegenerative diseases including Lewy body disease; yet measurements of different types of tau seeds in the setting of such diseases is an unmet need. Here, we use tau real-time quaking-induced conversion (RT-QuIC) assays to selectively quantitate 3R/4R tau seeds in the frontal lobe which accumulates histologically identifiable tau pathology at late disease stages of AD neuropathologic change. Seed quantitation across a spectrum of neurodegenerative disease cases and controls indicated tau seeding activity can be detected well before accompanying histopathological indication of tau deposits, and even prior to the earliest evidence of Alzheimer's-related tau accumulation anywhere in the brain. In later stages of AD, 3R/4R tau RT-QuIC measures correlated with immunohistochemical tau burden. In addition, Alzheimer's tau seeds occur in the vast majority of cases evaluated here inclusive of primary synucleinopathies, frontotemporal lobar degeneration and even controls albeit at multi-log lower levels than Alzheimer's cases. α-synuclein seeding activity confirmed synucleinopathy cases and further indicated the co-occurrence of α-synuclein seeds in some Alzheimer's disease and primary tauopathy cases. Our analysis indicates that 3R/4R tau seeds in the mid-frontal lobe correlate with the overall Braak stage and Alzheimer's disease neuropathologic change, supporting the quantitative predictive value of tau RT-QuIC assays. Our data also indicate 3R/4R tau seeds are elevated in females compared to males at high (≥ IV) Braak stages. This study suggests 3R/4R tau seeds are widespread even prior to the earliest stages of Alzheimer's disease changes, including in normal, and even young individuals, with prevalence across multiple neurodegenerative diseases to further define disease subtypes.

Hypoxemia events in preterm neonates are associated with urine oxidative biomarkers.

BACKGROUND: Intermittent hypoxemia (IH) events are common in preterm neonates and are associated with adverse outcomes. Animal IH models can induce oxidative stress. We hypothesized that an association exists between IH and elevated peroxidation products in preterm neonates. METHODS: Time in hypoxemia, frequency of IH, and duration of IH events were assessed from a prospective cohort of 170 neonates (<31 weeks gestation). Urine was collected at 1 week and 1 month. Samples were analyzed for lipid, protein, and DNA oxidation biomarkers. RESULTS: At 1 week, adjusted multiple quantile regression showed positive associations between several hypoxemia parameters with various individual quantiles of isofurans, neurofurans, dihomo-isoprostanes, dihomo-isofurans, and ortho-tyrosine and a negative correlation with dihomo-isoprostanes and meta-tyrosine. At 1 month, positive associations were found between several hypoxemia parameters with quantiles of isoprostanes, dihomo-isoprostanes and dihomo-isofurans and a negative correlation with isoprostanes, isofurans, neuroprostanes, and meta-tyrosine. CONCLUSIONS: Preterm neonates experience oxidative damage to lipids, proteins, and DNA that can be analyzed from urine samples. Our single-center data suggest that specific markers of oxidative stress may be related to IH exposure. Future studies are needed to better understand mechanisms and relationships to morbidities of prematurity. IMPACT: Hypoxemia events are frequent in preterm infants and are associated with poor outcomes. The mechanisms by which hypoxemia events result in adverse neural and respiratory outcomes may include oxidative stress to lipids, proteins, and DNA. This study begins to explore associations between hypoxemia parameters and products of oxidative stress in preterm infants. Oxidative stress biomarkers may assist in identifying high-risk neonates.

Plasma serotonergic biomarkers are associated with hypoxemia events in preterm neonates.

BACKGROUND: Hypoxemia is a physiological manifestation of immature respiratory control in preterm neonates, which is likely impacted by neurotransmitter imbalances. We investigated relationships between plasma levels of the neurotransmitter serotonin (5-HT), metabolites of tryptophan (TRP), and parameters of hypoxemia in preterm neonates. METHODS: TRP, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and kynurenic acid (KA) were analyzed in platelet-poor plasma at ~1 week and ~1 month of life from a prospective cohort of 168 preterm neonates <31 weeks gestational age (GA). Frequency of intermittent hypoxemia (IH) events and percent time hypoxemic (<80%) were analyzed in a 6 h window after the blood draw. RESULTS: At 1 week, infants with detectable plasma 5-HT had fewer IH events (OR (95% CI) = 0.52 (0.29, 0.31)) and less percent time <80% (OR (95% CI) = 0.54 (0.31, 0.95)) compared to infants with undetectable 5-HT. A similar relationship occurred at 1 month. At 1 week, infants with higher KA showed greater percent time <80% (OR (95% CI) = 1.90 (1.03, 3.50)). TRP, 5-HIAA or KA were not associated with IH frequency at either postnatal age. IH frequency and percent time <80% were positively associated with GA < 29 weeks. CONCLUSIONS: Circulating neuromodulators 5-HT and KA might represent biomarkers of immature respiratory control contributing to hypoxemia in preterm neonates. IMPACT: Hypoxemia events are frequent in preterm infants and are associated with poor outcomes. Mechanisms driving hypoxemia such as immature respiratory control may include central and peripheral imbalances in modulatory neurotransmitters. This study found associations between the plasma neuromodulators serotonin and kynurenic acid and parameters of hypoxemia in preterm neonates. Imbalances in plasma biomarkers affecting respiratory control may help identify neonates at risk of short- and long-term adverse outcomes.

Intensive Versus Standard Blood Pressure Lowering and Days Free of Cardiovascular Events and Serious Adverse Events: a Post Hoc Analysis of Systolic Blood Pressure Intervention Trial.

BACKGROUND: Communication of the benefits and harms of blood pressure lowering strategy is crucial for shared decision-making. OBJECTIVES: To quantify the effect of intensive versus standard systolic blood pressure lowering in terms of the number of event-free days DESIGN: Post hoc analysis of the Systolic Blood Pressure Intervention Trial PARTICIPANTS: A total of 9361 adults 50 years or older without diabetes or stroke who had a systolic blood pressure of 130-180 mmHg and elevated cardiovascular risk INTERVENTIONS: Intensive (systolic blood pressure goal <120 mmHg) versus standard blood pressure lowering (<140 mmHg) MAIN MEASURES: Days free of major adverse cardiovascular events (MACE), serious adverse events (SAE), and monitored adverse events (hypotension, syncope, bradycardia, electrolyte abnormalities, injurious falls, or acute kidney injury) over a median follow-up of 3.33 years KEY RESULTS: The intensive treatment group gained 14.7 more MACE-free days over 4 years (difference, 14.7 [95% confidence interval: 5.1, 24.4] days) than the standard treatment group. The benefit of the intensive treatment varied by cognitive function (normal: difference, 40.7 [13.0, 68.4] days; moderate-to-severe impairment: difference, -15.0 [-56.5, 26.4] days; p-for-interaction=0.009) and self-rated health (excellent: difference, -22.7 [-51.5, 6.1] days; poor: difference, 156.1 [31.1, 281.2] days; p-for-interaction=0.001). The mean overall SAE-free days were not significantly different between the treatments (difference, -14.8 [-35.3, 5.7] days). However, the intensive treatment group had 28.5 fewer monitored adverse event-free days than the standard treatment group (difference, -28.5 [-40.3, -16.7] days), with significant variations by frailty status (non-frail: difference, 38.8 [8.4, 69.2] days; frail: difference, -15.5 [-46.6, 15.7] days) and self-rated health (excellent: difference, -12.9 [-45.5, 19.7] days; poor: difference, 180.6 [72.9, 288.4] days; p-for-interaction <0.001). CONCLUSIONS: Over 4 years, intensive systolic blood pressure lowering provides, on average, 14.7 more MACE-free days than standard treatment, without any difference in SAE-free days. Whether this time-based effect summary improves shared decision-making remains to be elucidated. TRIAL REGISTRATION: ClinicalTrials.gov Registration: NCT01206062.

Age-Related Differences in Medication Adherence, Symptoms, and Stigma in Poorly Adherent Adults With Bipolar Disorder.

OBJECTIVE: We present a secondary analysis of data reporting differences in medication adherence, psychiatric symptom severity, and internalized stigma levels in older (age ≥ 55 years) versus younger (age < 55 years) adults with bipolar disorder (BD) and poor medication adherence. METHODS: Data used for this analysis came from 184 participants in a National Institute of Mental Health-funded randomized controlled trial, comparing a customized adherence enhancement (CAE) intervention intended to promote BD medication adherence with a BD-specific educational program (EDU). At screen, study participants were ≥20% nonadherent with BD medications as measured by the Tablets Routine Questionnaire (TRQ). Psychiatric symptoms, functional status, and internalized stigma were measured using validated scales. RESULTS: Older adults had significantly lower anxiety disorder comorbidity (P < .01 for 1 or more anxiety disorders), depressive symptom severity scores (P = .011), and self-stigma scores (P = .001) compared to their younger counterparts. In the analyses evaluating change over time in TRQ between older and younger participants by treatment arm (ie, CAE and EDU), there was a significant finding of interaction between time, age-group, and treatment arm (P = .007). CONCLUSIONS: Older adults may be less anxious and depressed, with less self-stigma, compared to younger people with BD and poor adherence. With respect to medication adherence, older individuals in EDU appear to do less well than younger individuals over time.

The Relationship Between Medication Attitudes and Medication Adherence Behavior in Adults With Bipolar Disorder.

The relationship between medication attitudes and adherence as well as reliable measures of medication attitudes need further study. This study examined the psychometric properties of the Attitudes Toward Mood Stabilizers Questionnaire (AMSQ) in bipolar participants and the relationship between medication attitudes and adherence, measured by the self-reported Tablets Routine Questionnaire (TRQ). Inclusion criteria included mood stabilizer treatment and 20% or more medication nonadherence. Measures were given pretreatment and posttreatment. Average age was 47 years; majority were female (69%), African American (67%), and unmarried (53%). AMSQ's test-retest reliability was ρ = 0.73 (p < 0.001). AMSQ correlated with TRQ (rs = 0.20, p < 0.01) at baseline. Factor analysis identified three factors: positive/favorable attitudes, negative/critical attitudes, and unintentional nonadherence. Change in AMSQ across time correlated with change in TRQ. The AMSQ is valid psychometrically and is sensitive to change. Medication attitudes are related to adherence behavior. Interventions should include targeting specific domains of medication attitudes, such as illness knowledge.

Self-management for adults with epilepsy: Aggregate Managing Epilepsy Well Network findings on depressive symptoms.

OBJECTIVE: To assess depressive symptom outcomes in a pooled sample of epilepsy self-management randomized controlled trials (RCTs) from the Managing Epilepsy Well (MEW) Network integrated research database (MEW DB). METHODS: Five prospective RCTs involving 453 adults with epilepsy compared self-management intervention (n = 232) versus treatment as usual or wait-list control outcomes (n = 221). Depression was assessed with the nine-item Patient Health Questionnaire. Other variables included age, gender, race, ethnicity, education, income, marital status, seizure frequency, and quality of life. Follow-up assessments were collapsed into a visit 2 and a visit 3; these were conducted postbaseline. RESULTS: Mean age was 43.5 years (SD = 12.6), nearly two-thirds were women, and nearly one-third were African American. Baseline sample characteristics were mostly similar in the self-management intervention group versus controls. At follow-up, the self-management group had a significantly greater reduction in depression compared to controls at visit 2 (P < .0001) and visit 3 (P = .0002). Quality of life also significantly improved in the self-management group at visit 2 (P = .001) and visit 3 (P = .005). SIGNIFICANCE: Aggregate MEW DB analysis of five RCTs found depressive symptom severity and quality of life significantly improved in individuals randomized to self-management intervention versus controls. Evidence-based epilepsy self-management programs should be made more broadly available in neurology practices.

Understanding Aging in Bipolar Disorder by Integrating Archival Clinical Research Datasets.

OBJECTIVE: Although 25% of people with bipolar disorder (BD) are over age 60, there is a dearth of research on older age bipolar disorder (OABD). This report describes an initial effort to create an integrated OABD database using the U.S. National Institute of Mental Health Data Archive (NDA). Goals were to: 1) combine data from three BD studies in the United States that included overlapping data elements; 2) investigate research questions related to aims of the original studies; and 3) take an important first step toward combining existing datasets relevant to aging and BD. METHODS: Data were prepared and uploaded to the NDA, with a focus on data elements common to all studies. As appropriate, data were harmonized to select or collapse categories suitable for cross-walk analysis. Associations between age, BD symptoms, functioning, medication load, medication adherence, and medical comorbidities were assessed. The total sample comprised 451 individuals, mean age 57.7 (standard deviation: 13.1) years. RESULTS: Medical comorbidity was not significantly associated with either age or functioning and there did not appear to be an association between medication load, comorbidity, age, and adherence. Men and African-Americans were significantly more likely to have poor adherence. Both BD mania and depression symptoms were associated with functioning, but this differed across studies. CONCLUSION: Despite limitations including heterogeneity in study design and samples and cross-sectional methodology, integrated datasets represent an opportunity to better understand how aging may impact the presentation and evolution of chronic mental health disorders across the lifespan.

Autonomic neurophysiologic implications of disorders comorbid with bladder pain syndrome vs myofascial pelvic pain.

AIMS: The neuropathophysiology of a debilitating chronic urologic pain condition, bladder pain syndrome (BPS), remains unknown. Our recent data suggests withdrawal of cardiovagal modulation in subjects with BPS, in contrast to sympathetic nervous system dysfunction in another chronic pelvic pain syndrome, myofascial pelvic pain (MPP). We evaluated whether comorbid disorders differentially associated with BPS vs MPP shed additional light on these autonomic differences. METHODS: We compared the presence and relative time of onset of 27 other medical conditions in women with BPS, MPP, both syndromes, and healthy subjects. Analysis included an adjustment for multiple comparisons. RESULTS: Among 107 female subjects (BPS alone = 32; BPS with MPP = 36; MPP alone = 9; healthy controls = 30), comorbidities differentially associated with BPS included irritable bowel syndrome (IBS), dyspepsia, and chronic nausea, whereas those associated with MPP included migraine headache and dyspepsia, consistent with the distinct autonomic neurophysiologic signatures of the two disorders. PTSD (earliest), anxiety, depression, migraine headache, fibromyalgia, chronic fatigue, and IBS usually preceded BPS or MPP. PTSD and the presence of both pelvic pain disorders in the same subject correlated with significantly increased comorbid burden. CONCLUSIONS: Our study suggests a distinct pattern of comorbid conditions in women with BPS. These findings further support our hypothesis of primary vagal defect in BPS as compared with primary sympathetic defect in MPP, suggesting a new model for chronic these pelvic pain syndromes. Chronologically, PTSD, migraine, dysmenorrhea, and IBS occurred early, supporting a role for PTSD or its trigger in the pathophysiology of chronic pelvic pain.

Depressive Symptom Severity in Individuals With Epilepsy and Recent Health Complications.

Identifying relationships between depression severity and clinical factors may help with appropriate recognition and management of neuropsychiatric conditions in persons with epilepsy (PWE). Demographic characteristics, epilepsy variables, and medical and psychiatric comorbidities were examined from a baseline randomized controlled trial sample of 120 PWE. Among demographic characteristics, only inability to work was significantly associated with depression severity (p = 0.05). Higher 30-day seizure frequency (p < 0.01) and lower quality of life (p < 0.0001) were associated with greater depression severity. Comorbid bipolar disorder (p = 0.02), panic disorder (p < 0.01), and obsessive-compulsive disorder (p < 0.01) were correlated with worse depression severity. The literature supports our findings of correlations between worse depression, seizure frequency, and lower quality of life. Less well studied is our finding of greater depression severity and selected psychiatric comorbidities in PWE.

Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum.

Cytochrome P450 27A1 (CYP27A1 or sterol 27-hydroxylase) is a ubiquitous, multifunctional enzyme catalyzing regio- and stereospecific hydroxylation of different sterols. In humans, complete CYP27A1 deficiency leads to cerebrotendinous xanthomatosis or nodule formation in tendons and brain (preferentially in the cerebellum) rich in cholesterol and cholestanol, the 5α-saturated analog of cholesterol. In Cyp27a1-/- mice, xanthomas are not formed, despite a significant cholestanol increase in the brain and cerebellum. The mechanism behind cholestanol production has been clarified, yet little is known about its metabolism, except that CYP27A1 might metabolize cholestanol. It also is unclear why CYP27A1 deficiency results in preferential cholestanol accumulation in the cerebellum. We hypothesized that cholestanol might be metabolized by CYP46A1, the principal cholesterol 24-hydroxylase in the brain. We quantified sterols along with CYP27A1 and CYP46A1 in mouse models (Cyp27a1-/-, Cyp46a1-/-, Cyp27a1-/-Cyp46a1-/-, and two wild type strains) and human brain specimens. In vitro experiments with purified P450s were conducted as well. We demonstrate that CYP46A1 is involved in cholestanol removal from the brain and that several factors contribute to the preferential increase in cholestanol in the cerebellum arising from CYP27A1 deficiency. These factors include (i) low cerebellar abundance of CYP46A1 and high cerebellar abundance of CYP27A1, the lack of which probably selectively increases the cerebellar cholestanol production; (ii) spatial separation in the cerebellum of cholesterol/cholestanol-metabolizing P450s from a pool of metabolically available cholestanol; and (iii) weak cerebellar regulation of cholesterol biosynthesis. We identified a new physiological role of CYP46A1, an important brain enzyme and cytochrome P450 that could be activated pharmacologically.

Diagnostic and prognostic value of human prion detection in cerebrospinal fluid.

OBJECTIVE: Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. METHODS: We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases that were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and type 1 or type 2 human prions on diagnostic performance. RESULTS: The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1-2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, whereas genetic prion diseases revealed distinct profiles for each PRNP gene mutation. INTERPRETATION: The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and tau proteins, and together with PRNP gene sequencing the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease-two important considerations for envisioned therapeutic interventions. ANN NEUROL 2017;81:79-92.

A 6-month prospective randomized controlled trial of remotely delivered group format epilepsy self-management versus waitlist control for high-risk people with epilepsy.

OBJECTIVE: Despite advances in care, many people with epilepsy have negative health events (NHEs) such as accidents, emergency department visits, and poor quality of life. "Self-management for people with epilepsy and a history of negative health events" (SMART) is a novel group format epilepsy self-management intervention. A community participatory approach informed the refinement of SMART, which was then tested in a 6-month randomized controlled trial of SMART (n = 60) versus waitlist control (WL, n = 60). METHODS: Participants were adults aged ≥18 years with epilepsy and an NHE within the past 6 months (seizure, accident, self-harm attempt, emergency department visit, or hospitalization). Assessments were conducted at screening, baseline, 10 weeks, and 24 weeks (6 months). Primary outcome was 6-month change in total NHE count. Additional outcomes included depression on the nine-item Patient Health Questionnaire and Montgomery-Asberg Depression Rating Scale, quality of life on the 10-item Quality of Life in Epilepsy, functioning on the 36-item Short-Form Health Survey, and seizure severity on the Liverpool Seizure Severity Scale. RESULTS: Mean age was 41.3 years (SD = 11.82), 69.9% were African American, 74.2% were unemployed, and 87.4% had an annual income < US$25 000; 57.5% had a seizure within 30 days of enrollment. Most NHEs were seizures. Six-month study attrition was 14.2% overall and similar between arms. Individuals randomized to SMART had greater reduction in total median NHEs from baseline to 6 months compared to WL (P = 0.04). SMART was also associated with improved nine-item Patient Health Questionnaire (P = 0.032), Montgomery-Asberg Depression Rating Scale (P = 0.002), 10-item Quality of Life in Epilepsy (P < 0.001), and 36-item Short-Form Health Survey (P = 0.015 physical health, P = 0.003 mental health) versus WL. There was no difference in seizure severity. SIGNIFICANCE: SMART is associated with reduced health complications and improved mood, quality of life, and health functioning in high-risk people with epilepsy. Additional efforts are needed to investigate potential for scale-up.

Depressive symptoms and suicidality among individuals with epilepsy enrolled in self-management studies: Results from the US Centers for Disease Control and Prevention Managing Epilepsy Well (MEW) Network.

Depression is a common comorbidity in people with epilepsy (PWE) that negatively affects self-management and a variety of health outcomes. Suicidal ideation is also more common among PWE than the general population. We examined correlates of depressive symptoms and suicidal ideation in adults using pooled data from epilepsy self-management studies conducted by sites in the Centers for Disease Control and Prevention (CDC) Research Center's Managing Epilepsy Well (MEW) Network that assessed depression severity with the 9-item Patient Health Questionnaire (PHQ-9). Of the 770 subjects in the analysis (mean age 42.4 ±â€¯13.0 years), the mean total PHQ-9 score was 9.4 ±â€¯6.6 and 334 subjects (43.4%) had moderate to severe depressive symptoms (PHQ-9 ≥ 10). Only ongoing seizures and low education were associated with moderate-severe depressive symptoms in multiple logistic regression analysis. Suicidality (PHQ-9, item 9 score ≥ 1) was endorsed by 155 subjects (20.1%). Only nonsuicidal depressive symptoms were associated with suicidality in multiple variable logistic regression analysis. We show in this large and regionally diverse dataset that both depression and suicidal ideation are common among PWE enrolled in self-management studies. Future studies are needed to examine whether suicidality exists independently of other depressive symptoms in some populations with epilepsy and investigate other correlates of suicidality that may inform screening practices.

Assessing depression severity with a self-rated vs. rater-administered instrument in patients with epilepsy.

RATIONALE: Up to 30-50% of individuals with epilepsy have depressive symptoms, which often complicate seizure management and reduce overall quality of life. To identify and manage depressive symptoms appropriately, clinicians need standardized instruments that can accurately identify and monitor those with clinically significant depression. The self-reported 9-item Patient Health Questionnaire (PHQ-9) has been used relatively widely to screen and monitor depression in epilepsy. The rater-administered Montgomery-Asberg Depression Rating Scale (MADRS) is a rater-administered instrument widely used in depression treatment trials but less widely applied in epilepsy. This secondary analysis from 2 epilepsy self-management clinical trials compared depression severity ratings using the PHQ-9 and the MADRS instruments. METHODS: Data for this analysis were derived from pooled baseline and longitudinal data from 2 prospective epilepsy self-management randomized controlled trials (RCTs). Both RCTs assessed depression with the PHQ-9 and the MADRS. For this analysis, total depression severity scores and case classification of individuals with no/minimal, mild, moderate/moderately severe, and severe depression were assessed using both PHQ-9 and MADRS. RESULTS: The sample contained 164 individuals with epilepsy. Demographic and clinical variables between the 2 studies were generally similar. There were 107 women (64.8%), 106 African-Americans (64.2%), and 51 Whites (30.9%). Individuals had epilepsy for an average of 22.1 (SD: 15.5). Mean past 30-day seizure frequency at baseline was 3.1 (SD: 11.6). Baseline mean PHQ-9 was 10.7 (SD: 6.80) with depression severity of 32 (19.6%) not or minimally depressed, 47 (28.8%) mildly depressed, 37 (22.7%) moderately depressed, 27 (16.6%) moderately severely depressed, and 20 (12.3%) severely depressed. Baseline mean MADRS severity was 18.5 (SD: 11.3) with 30 (18.8%) not or minimally depressed, 27 (16.9%) mildly depressed, 92 (56.1%) moderately depressed, and 11 (6.9%) severely depressed. The correlation between total PHQ-9 and total MADRS was 0.843 (p < .01) although case classification by depression severity varied somewhat between the two instruments. CONCLUSIONS: Standardized measures to evaluate depression severity in people with epilepsy can help identify cases and monitor treatment. The PHQ-9 and MADRS both perform well in assessing depression in people with epilepsy although administration burden is less with PHQ-9 thus making it likely preferable for settings where time and epilepsy specialty resources are limited.