International validation of meaningfulness of postural sway and gait to assess myeloneuropathy in adults with adrenoleukodystrophy.

BACKGROUND: The most common manifestation of X-linked adrenoleukodystrophy (ALD) is a slowly progressive myeloneuropathy, which leads to imbalance and gait disturbances. The variable progression of the disease complicates evaluation of its progression rate. Wearable sensors allow for easy and frequent balance and gait collection. This study reports baseline data from a longitudinal study on the quantitative assessment of balance and gait with wearable sensors and their clinical relevance. METHODS: Data were collected from adult patients in two institutions. Postural body sway and gait parameters were measured using accelerometers. Disease severity was measured by the Expanded Disability Severity Scale (EDSS). Falling frequency and quality of life (QOL) were collected in men. The relationship between sway and gait variables and EDSS score, participants' use of a walking aid, and falling frequency was evaluated. RESULTS: One hundred twenty individuals with ALD were included. Sway variables significantly differentiate participants' assistive device use. Sway and gait variables were correlated to the EDSS in both sexes. Both gait speed and sway were correlated with falling frequency in men from one institution. Select QOL subscores were correlated with the EDSS in males from one institution. Accelerometry generated comparable results across sites. DISCUSSION: This study confirms the clinical correlation between spinal cord disease and imbalance and gait in ALD. For the first time, this study shows clinically meaningful relationships for sway and gait with use of an assistive device, falling frequency and QOL. Wearable accelerometers are a valid means to measure sway and gait in ALD. These measures are promising outcomes for clinical trial designs to assess myeloneuropathy in ALD and to monitor disease progression in individuals.

Retrospective Use of Patients' Characteristics to Assess Variation in Prenatal Care Utilization.

OBJECTIVE: We used patients' medical and psychosocial risk factors to explore prenatal care utilization and health outcomes to inform prenatal care tailoring. STUDY DESIGN: This retrospective cohort study assessed patients who gave birth at an academic institution from January 1 to December 31, 2018, using electronic health record (EHR) data. Patients were categorized into four phenotypes based on medical/psychosocial risk factors available in the EHR: Completely low risk; High psychosocial risk only; High medical risk only; and Completely high risk. We examined patient characteristics, visit utilization, nonvisit utilization (e.g., phone calls), and outcomes (e.g., preterm birth, preeclampsia) across groups. RESULTS: Of 4,681 patients, the majority were age 18 to 35 (3,697, 79.0%), White (3,326, 70.9%), multiparous (3,263, 69.7%), and Completely high risk (2,752, 58.8%). More Black and Hispanic patients had psychosocial risk factors than White patients. Patients with psychosocial risk factors had fewer prenatal visits (10, interquartile range [IQR]: 8-12) than those without (11, IQR: 9-12). Patients with psychosocial risk factors experienced less time in prenatal care, more phone calls, and fewer EHR messages across the same medical risk group. Rates of preterm birth and gestational hypertension were incrementally higher with additional medical/psychosocial risk factors. CONCLUSION: Data readily available in the EHR can assess the compounding influence of medical/psychosocial risk factor on patients' care utilization and outcomes. KEY POINTS: · Medical and psychosocial needs in pregnancy can inform patient phenotypes and are associated with prenatal care use and outcomes.. · Patient phenotypes are associated with prenatal care use and outcomes.. · Patients with high psychosocial risk spent less time in prenatal care and had more phone calls in pregnancy.. · Tailored prenatal care models may proactively address differences in patient's needs..

A Phase 1 Study of Oral Vitamin D3 in Boys and Young Men With X-Linked Adrenoleukodystrophy.

Background and Objectives: There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD. Methods: In this open-label, multicenter, phase 1 study, we recruited boys and young men with ALD without brain lesions to a 12-month study of daily oral vitamin D3 supplementation. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80 ng/mL) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in the brain, measured with magnetic resonance spectroscopy, and blood, measured via mass spectrometry. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. After a midstudy safety assessment, we modified the dosing regimen, so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily. Results: Between October 2016 and June 2019, we enrolled 21 participants (n = 12, fixed-dose regimen; n = 9, weight-stratified regimen) with a median age of 6.7 years (range: 1.9-22 years) and median weight of 20 kg (range: 11.7-85.5 kg). The number of participants achieving target vitamin D levels was similar in both groups at 6 months (fixed dose: 92%; weight stratified: 78%) and 12 months (fixed dose: 67%; weight stratified: 67%). Among the 12 participants in the fixed-dose regimen, half had asymptomatic elevations in either urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels in the brain, but not the blood, increased significantly between baseline and 12 months. Discussion: Our vitamin D dosing regimens were well tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels warrant further study as a biomarker for vitamin D and ALD. Classification of Evidence: This study provides Class IV evidence that fixed or weight-stratified vitamin D supplementation achieved target levels of 25-hydroxyvitamin D in boys and young men with X-ALD without brain lesions.

Wearable sensors detect impaired gait and coordination in LBSL during remote assessments.

BACKGROUND: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare leukodystrophy with motor impairment due to biallelic mutations in DARS2, which encodes mitochondrial aspartyl tRNA synthetase. Progressive ataxia is the primary feature. OBJECTIVE: The study objective is to determine the feasibility of remotely collecting quantitative gait and balance measures in LBSL. METHODS: The study design uses wearable accelerometers and the scale for the assessment and rating of ataxia (SARA) scale to assess gait and postural sway in LBSL and control participants' homes through video conferencing. RESULTS: Lateral step variability (LSV), which indicates stride variability, and elevation of the step at mid-swing are increased for LBSL patients during brief walking tests. During stance with the eyes closed, LBSL participants show rapid accelerations and decelerations of body movement covering a large sway area and path. Both the LSV and sway area during stance with the feet together and eyes closed correlate strongly with the SARA. CONCLUSIONS: Wearable accelerometers are valid and sensitive for detecting ataxia in LBSL patients during remote assessments. The finding of large increases in the sway area during stance with the eyes closed is intriguing since dorsal column dysfunction is universally seen in LBSL. This approach can be applied to related rare diseases that feature ataxia.

MicroRNA and metabolomics signatures for adrenomyeloneuropathy disease severity.

Adrenomyeloneuropathy (AMN), the slow progressive phenotype of adrenoleukodystrophy (ALD), has no clinical plasma biomarker for disease progression. This feasibility study aimed to determine whether metabolomics and micro-RNA in blood plasma provide a potential source of biomarkers for AMN disease severity. Metabolomics and RNA-seq were performed on AMN and healthy human blood plasma. Biomarker discovery and pathway analyses were performed using clustering, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and regression against patient's clinical Expanded Disability Status Score (EDSS). Fourteen AMN and six healthy control samples were analyzed. AMN showed strong disease-severity-specific metabolic and miRNA clustering signatures. Strong, significant clinical correlations were shown for 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-HOCA) (r 2 = 0.83, p < 0.00001), dehydroepiandrosterone sulfate (DHEA-S; r 2 = 0.82, p < 0.00001), hypoxanthine (r 2 = 0.82, p < 0.00001), as well as miRNA-432-5p (r 2 = 0.68, p < 0.00001). KEGG pathway comparison of mild versus severe disease identified affected downstream systems: GAREM, IGF-1, CALCRL, SMAD2&3, glutathione peroxidase, LDH, and NOS. This feasibility study demonstrates that miRNA and metabolomics are a source of potential plasma biomarkers for disease severity in AMN, providing both a disease signature and individual markers with strong clinical correlations. Network analyses of affected systems implicate differentially altered vascular, inflammatory, and oxidative stress pathways, suggesting disease-severity-specific mechanisms as a function of disease severity.

Fornix white matter microstructure differentially predicts false recollection rates in older and younger adults.

Healthy aging is accompanied by increased false remembering in addition to reduced successful remembering in older adults. Neuroimaging studies implicate age-related differences in the involvement of medial temporal lobe and fronto-parietal regions in mediating highly confident false recollection. However, no studies have directly examined the relationship between white matter microstructure and false recollection in younger and older adults. Using diffusion-weighted imaging and probabilistic tractography, we examined how white matter microstructure within tracts connecting the hippocampus and the fronto-parietal retrieval network contribute to false recollection rates in healthy younger and older adults. We found only white matter microstructure within the fornix contributed to false recollection rates, and this relationship was specific to older adults. Fornix white matter microstructure did not contribute to true recollection rate, nor did common white matter contribute to false recollection, suggesting fornix microstructure is explicitly associated with highly confident false memories in our sample of older adults. These findings underlie the importance of examining microstructural correlates associated with false recollection in younger and older adults.

Shared neural recruitment across working memory and motor control tasks as a function of task difficulty and age.

Past research suggests that working memory (WM) and motor control may engage similar cognitive and neural mechanisms in older adults, particularly when task difficulty increases. However, much of this evidence arises from comparisons across behavioral and imaging studies that test only one of the foregoing functional domains. The current study used fMRI within the same group of older adults to investigate whether WM and motor control recruit common mechanisms, and whether recruitment increased with task demand and age. A conjunction analysis across WM and motor tasks revealed engagement of several frontoparietal regions as a function of increasing task demand. A separate conjunction analysis which included age as a predictor showed comparable regions exhibit increased recruitment with both increasing task demand and age. Results suggest that the recruitment of common frontoparietal regions across WM and motor tasks in response to task difficulty is maintained across the older adult lifespan.

Losing it in New Guinea: the voyage of HMS Rattlesnake.

The voyage of the HMS Rattlesnake to New Guinea and the archipelago to the east of it could have achieved so much for science. 'Make sure of what you do', enthused British hydrographer Francis Beaufort to the Rattlesnake's commander Owen Stanley in 1848. 'Do not leave interesting questions to be answered at the next visit - give names to Capes and Islands...and bring yourself and your people back without quarrels'. But for some reason Stanley wavered. There were several scientists on board the Rattlesnake desperate to ask interesting questions of these uncharted islands. But these natural historians, and in particular a young Thomas Henry Huxley, found their ambitions thwarted by their increasingly edgy captain.

From taxol to Taxol: the changing identities and ownership of an anti-cancer drug.

This paper analyzes the emergence and evolution of taxol, the world's bestselling anti-cancer drug. Over the years taxol has changed its identity, its status as property, and its association with different places (from the old-growth forests of Washington State to the government agencies of Washington, D.C., to laboratories in France). Taxol is not only a profitable pharmaceutical commodity and a substance injected into women with breast and/or ovarian cancer; it is also a natural product found in the bark of Taxus brevifolia (the Pacific yew, which is native to the North American Pacific Northwest) and a chemical substance that was discovered and brought to the point of commercial production in the public sector. We explore its role in several controversies: the destruction of old-growth forests, public participation in policy making, and the privatization of intellectual property and its effect on the price of drugs.

Does doping with aluminum alter the effects of ZnO nanoparticles on the metabolism of soil pseudomonads?

Doping of ZnO nanoparticles (NPs) is being used to increase their commercialization in the optical and semiconductor fields. This paper addresses whether doping with Al alters how ZnO NPs at nonlethal levels modifies the metabolism of soil-borne pseudomonads which are beneficial in performing bioremediation or promoting plant growth. The differences in X-ray diffraction (XRD) patterns, observed between commercial ZnO and Al-doped ZnO NPs indicated the aluminum was present as Al NPs. Both particles aggregated in the bacterial growth medium and formed colloids of different surface charges. They had similar effects on bacterial metabolism: rapid, dose-dependent loss in light output indicative of temporary toxicity in a biosensor constructed in Pseudomonas putida KT2440; increased production of a fluorescent pyoverdine-type siderophore, and decreased levels of indole acetic acid and phenazines in Pseudomonas chlororaphis O6. Solubilization of Zn and Al from the NPs contributed to these responses to different extents. These findings indicate that Al-doping of the ZnO NPs did not reduce the ability of the NPs to alter bacterial metabolism in ways that could influence performance of the pseudomonads in their soil environment.