Investigating home-based opioid use among youth with sickle cell disease using ecological momentary assessment.

BACKGROUND: Opioids are a common and essential treatment for acute sickle cell disease (SCD) pain. However, opioids carry well-known adverse side effects, including potential development of hyperalgesia and nociplastic pain. We characterized opioid use in youth with SCD using ecological momentary assessment (EMA) data, and investigated the relationships between home-based opioid use, pain, and a range of biopsychosocial factors. METHOD: Eighty-eight youth with SCD (aged 8-17 years) completed EMAs assessing home-based opioid use, pain, and related factors. Analyses consisted of descriptive and multilevel logistic regression to predict daily home opioid use. RESULTS: Youth averaged 3.64 weeks of EMAs. Approximately 35% of the sample (n = 31) took an opioid during the EMA period, and used them on only 24% of reported pain days. Youth who took opioids reported a higher percentage of pain days (t = -2.67, p < .05) and mean pain severity scores (t = -2.30, p < .05) than youth who did not take opioids. Multilevel logistic regression analyses indicated that high daily pain severity (odds ratio [OR] = 1.02, p < .01), older age (OR = 1.324, p < .01), and low positive affect (OR = 0.91, p < .01) were each related to an increased likelihood of opioid use. CONCLUSION: Youth with SCD take opioids appropriately in response to their pain, based on daily self-report. Beyond daily pain severity, age, and daily variation in positive affect were related to home-based opioid use. This suggests that behavioral interventions that enhance positive affect may promote reduced opioid use among youth with SCD.

Tissue-specific compensatory mechanisms maintain tissue architecture and body size independent of cell size in polyploid zebrafish.

Genome duplications and ploidy transitions have occurred in nearly every major taxon of eukaryotes, but they are far more common in plants than in animals. Due to the conservation of the nuclear:cytoplasmic volume ratio increased DNA content results in larger cells. In plants, polyploid organisms are larger than diploids as cell number remains relatively constant. Conversely, vertebrate body size does not correlate with cell size and ploidy as vertebrates compensate for increased cell size to maintain tissue architecture and body size. This has historically been explained by a simple reduction in cell number that matches the increase in cell size maintaining body size as ploidy increases, but here we show that the compensatory mechanisms that maintain body size in triploid zebrafish are tissue-specific: A) erythrocytes respond in the classical pattern with a reduced number of larger erythrocytes in circulation, B) muscle, a tissue comprised of polynucleated muscle fibers, compensates by reducing the number of larger nuclei such that myofiber and myotome size in unaffected by ploidy, and C) vascular tissue compensates by thickening blood vessel walls, possibly at the expense of luminal diameter. Understanding the physiological implications of ploidy on tissue function requires a detailed description of the specific mechanisms of morphological compensation occurring in each tissue to understand how ploidy changes affect development and physiology.

Experimental upper bound and theoretical expectations for parity-violating neutron spin rotation in 4He.

Neutron spin rotation is expected from quark-quark weak interactions in the standard model, which induce weak interactions among nucleons that violate parity. We present the results from an experiment searching for the effect of parity violation via the spin rotation of polarized neutrons in a liquid 4He medium. The value for the neutron spin rotation angle per unit length in 4He, d ϕ / d z = [ + 2.1 ± 8.3 (stat.) - 0.2 + 2.9 (sys.) ] × 10 - 7 rad/m, is consistent with zero. The result agrees with the best current theoretical estimates of the size of nucleon-nucleon weak amplitudes from other experiments and with the expectations from recent theoretical approaches to weak nucleon-nucleon interactions. In this paper we review the theoretical status of parity violation in the n → + 4He system and discuss details of the data analysis leading to the quoted result. Analysis tools are presented that quantify systematic uncertainties in this measurement and that are expected to be essential for future measurements.

MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling.

Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator with known links to a wide spectrum of neuropsychiatric disorders. Although postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of microRNAs (miRNAs) in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 short hairpin RNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development. Focusing on the most dysregulated miRNAs, we found miR-199 and miR-214 to be increased during early brain development and to differentially regulate extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase and protein kinase B (PKB/AKT) signaling. In parallel, we characterized the effects on human neurogenesis and neuronal differentiation brought about by MeCP2 deficiency using both monolayer and three-dimensional (cerebral organoid) patient-derived and MeCP2-deficient neuronal culture models. Inhibiting miR-199 or miR-214 expression in iPSC-derived neural progenitors deficient in MeCP2 restored AKT and ERK activation, respectively, and ameliorated the observed alterations in neuronal differentiation. Moreover, overexpression of miR-199 or miR-214 in the wild-type mouse embryonic brains was sufficient to disturb neurogenesis and neuronal migration in a similar manner to Mecp2 knockdown. Taken together, our data support a novel miRNA-mediated pathway downstream of MeCP2 that influences neurogenesis via interactions with central molecular hubs linked to autism spectrum disorders.

Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.

Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.

Severe psychosocial deprivation in early childhood is associated with increased DNA methylation across a region spanning the transcription start site of CYP2E1.

Exposure to adverse rearing environments including institutional deprivation and severe childhood abuse is associated with an increased risk for mental and physical health problems across the lifespan. Although the mechanisms mediating these effects are not known, recent work in rodent models suggests that epigenetic processes may be involved. We studied the impact of severe early-life adversity on epigenetic variation in a sample of adolescents adopted from the severely depriving orphanages of the Romanian communist era in the 1980s. We quantified buccal cell DNA methylation at ~400 000 sites across the genome in Romanian adoptees exposed to either extended (6-43 months; n=16) or limited duration (<6 months; n=17) of severe early-life deprivation, in addition to a matched sample of UK adoptees (n=16) not exposed to severe deprivation. Although no probe-wise differences remained significant after controlling for the number of probes tested, we identified an exposure-associated differentially methylated region (DMR) spanning nine sequential CpG sites in the promoter-regulatory region of the cytochrome P450 2E1 gene (CYP2E1) on chromosome 10 (corrected P=2.98 × 10(-5)). Elevated DNA methylation across this region was also associated with deprivation-related clinical markers of impaired social cognition. Our data suggest that environmental insults of sufficient biological impact during early development are associated with long-lasting epigenetic changes, potentially reflecting a biological mechanism linking the effects of early-life adversity to cognitive and neurobiological phenotypes.

A slow neutron polarimeter for the measurement of parity-odd neutron rotary power.

We present the design, description, calibration procedure, and an analysis of systematic effects for an apparatus designed to measure the rotation of the plane of polarization of a transversely polarized slow neutron beam as it passes through unpolarized matter. This device is the neutron optical equivalent of a crossed polarizer/analyzer pair familiar from light optics. This apparatus has been used to search for parity violation in the interaction of polarized slow neutrons in matter. Given the brightness of existing slow neutron sources, this apparatus is capable of measuring a neutron rotary power of dϕ/dz = 1 × 10(-7) rad/m.

Carnitine therapy for the treatment of metabolic syndrome and cardiovascular disease: evidence and controversies.

As the incidence of metabolic syndrome increases, there is also a growing interest in finding safe and inexpensive treatments to help lower associated risk factors. L-carntine, a natural dietary supplement with the potential to ameliorate atherosclerosis, has been the subject of recent investigation and controversy. A majority of studies have shown benefit of L-C supplementation in the metabolic syndrome or cardiovascular risk factors. However, recent work has suggested that dietary L-C may accelerate atherosclerosis via gut microbiota metabolites, complicating the role of L-C supplementation in health.

Disease correction by combined neonatal intracranial AAV and systemic lentiviral gene therapy in Sanfilippo Syndrome type B mice.

Mucopolysaccharidosis type IIIB (MPS IIIB) or Sanfilippo Syndrome type B is a lysosomal storage disease resulting from the deficiency of N-acetyl glucosaminidase (NAGLU) activity. We previously showed that intracranial adeno-associated virus (AAV)-based gene therapy results in partial improvements of several aspects of the disease. In an attempt to further correct the disease, MPS IIIB mice were treated at 2-4 days of age with intracranial AAV2/5-NAGLU (IC-AAV), intravenous lentiviral-NAGLU (IV-LENTI) or the combination of both (BOTH). The BOTH group had the most complete biochemical and histological improvements of any treatment group. Compared with untreated MPS IIIB animals, all treatments resulted in significant improvements in motor function (rotarod) and hearing (auditory-evoked brainstem response). In addition, each treatment group had a significantly increased median life span compared with the untreated group (322 days). The combination arm had the greatest increase (612 days), followed by IC-AAV (463 days) and IV-LENTI (358 days). Finally, the BOTH group had nearly normal circadian rhythm measures with improvement in time to activity onset. In summary, targeting both the systemic and central nervous system disease of MPS IIIB early in life appears to be the most efficacious approach for this inherited metabolic disorder.

Assessing fibromyalgia-related fatigue: content validity and psychometric performance of the Fatigue Visual Analog Scale in adult patients with fibromyalgia.

OBJECTIVES: To document 1) the content validity and 2) measure improvements in fatigue, using the Fatigue Visual Analogue Scale (VAS) assessment tool in patients with fibromyalgia. METHODS: The relevance and comprehensiveness of the Fatigue VAS were tested through a qualitative analysis of 20 subjects' verbatim transcripts from semi-structured qualitative interviews. Data from two randomised, controller trials in fibromyalgia (n=1121) were used to conduct correlation analyses with the Fatigue and Tiredness items from the Fibromyalgia Impact Questionnaire (FIQ) and the Short Form-36 Vitality scale. Known-groups and cross classification analyses were conducted to demonstrate the ability to measure improvement in fatigue using the Fatigue VAS. RESULTS: All subjects spontaneously reported that fatigue was an important symptom to capture in fibromyalgia. The Fatigue VAS was well understood by most subjects (n=18/20). High correlations (Pearson r>0.75) and good agreement (k>0.66) were found between the Fatigue VAS and the FIQ tiredness items no. 16 and 17 and SF-36™ Vitality scale. In both clinical trials there was a substantial separation of approximately 20 points on the mean change in the Fatigue VAS score between responders (>30% improvement in pain VAS) and non-responders. CONCLUSIONS: Previous studies have confirmed that fatigue is a major component of the fibromyalgia experience. This current study reports that fibromyalgia patients spontaneously rated fatigue as a highly significant feature of their illness, and supports the use of the Fatigue VAS as a valid questionnaire in fibromyalgia clinical trials.

Assessing sleep in fibromyalgia: investigation of an alternative scoring method for the Jenkins Sleep Scale based on data from randomized controlled studies.

OBJECTIVES: To investigate the validity of a rescored version of the Jenkins Sleep Scale (JSS) to assess the extent of possible bias of a 4-week recall period in assessing sleep in patients with fibromyalgia. METHODS: A rescoring algorithm of the JSS was developed. The psychometric properties of the rescored JSS were examined using blinded, observed data from a Phase 2 trial (n=195) in subjects with fibromyalgia. In addition, data from two Phase 3, randomised, controlled trials (n=1,121) in subjects with fibromyalgia were used to further validate the rescored JSS by conducting correlation analyses with other assessments expected to correlate with sleep. These included fatigue and tiredness items from the Fibromyalgia Impact Questionnaire (FIQ), the Functional Outcomes of Sleep Questionnaire (FOSQ), and the Short Form-36 (SF-36™) Vitality scale. RESULTS: Construct validity of the rescored JSS was found to be acceptable, with an internal consistency reliability of α=0.70. Test-retest reliability on stable subjects, defined using the FIQ total score, was also acceptable (ICC=0.70). Moderate to high correlations (Pearson r>0.66) were found with two FIQ items, addressing fatigue and non-restorative sleep, and the SF-36™ Vitality scale; correlations with the original JSS were similar. Both JSS versions were found to be responsive (p<0.0001), and the rescored version accounted for 90% of the variance captured in the original version. CONCLUSIONS: These results showed the rescored JSS performed similarly to the original scale, suggesting the original scale's 4-week recall period did not introduce substantial bias in capturing the experience of fibromyalgia-related sleep disturbances.

Use of "spydergrams" to present and interpret SF-36 health-related quality of life data across rheumatic diseases.

The Medical Outcomes Study Short Form-36 (SF-36) is a generic measure of health-related quality of life (HRQOL), validated and cross-culturally translated, which has been extensively utilised in rheumatology. In randomised controlled trials and observational studies, SF-36 provides rich data regarding HRQOL; but as typically portrayed, patterns of disease and treatment-associated effects can be difficult to discern. "Spydergrams" offer a simplified means to visualise complex results across all domains of SF-36 in a single figure: depicting disease and population-specific patterns of decrements in HRQOL compared with age and gender-matched normative data, as well as providing a tool for interpreting complex treatment-associated or longitudinal changes. Utilising spydergrams as a standard format to illustrate and report changes in SF-36 across different rheumatic diseases can greatly facilitate analyses and interpretations of clinical trial results, as well as providing patients an accessible means to compare baseline scores and treatment-associated improvements with normative data from individuals without arthritis. Furthermore, SF-6D utility scores based on mean changes across all eight domains of SF-36 are suggested as a quantitative means of summarising changes illustrated by spydergrams, offering a universal metric for cost-effectiveness analyses of therapeutic interventions.