Dysregulated biodynamics in metabolic attractor systems precede the emergence of amyotrophic lateral sclerosis.
- 作者列表："Curtin P","Austin C","Curtin A","Gennings C","Figueroa-Romero C","Mikhail KA","Botero TM","Goutman SA","Feldman EL","Arora M
:Evolutionarily conserved mechanisms maintain homeostasis of essential elements, and are believed to be highly time-variant. However, current approaches measure elemental biomarkers at a few discrete time-points, ignoring complex higher-order dynamical features. To study dynamical properties of elemental homeostasis, we apply laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) to tooth samples to generate 500 temporally sequential measurements of elemental concentrations from birth to 10 years. We applied dynamical system and Information Theory-based analyses to reveal the longest-known attractor system in mammalian biology underlying the metabolism of nutrient elements, and identify distinct and consistent transitions between stable and unstable states throughout development. Extending these dynamical features to disease prediction, we find that attractor topography of nutrient metabolism is altered in amyotrophic lateral sclerosis (ALS), as early as childhood, suggesting these pathways are involved in disease risk. Mechanistic analysis was undertaken in a transgenic mouse model of ALS, where we find similar marked disruptions in elemental attractor systems as in humans. Our results demonstrate the application of a phenomological analysis of dynamical systems underlying elemental metabolism, and emphasize the utility of these measures in characterizing risk of disease.
: 进化保守机制维持必需元件的稳态，并且被认为是高度时变的。然而，目前的方法在几个离散的时间点测量元素生物标志物，忽略了复杂的高阶动力学特征。为了研究元素稳态的动力学性质，我们将激光烧蚀电感耦合等离子体质谱 (la-icp-ms) 应用于牙齿样品，以产生从出生到10年的元素浓度的500个时间顺序测量。我们应用动力系统和基于信息理论的分析，揭示了哺乳动物生物学中已知最长的吸引子系统，它是营养元素代谢的基础，并在整个发育过程中识别稳定和不稳定状态之间的明显和一致的转变。将这些动力学特征扩展到疾病预测，我们发现营养代谢的吸引子形貌早在儿童期就在肌萎缩侧索硬化 (ALS) 中发生了改变，表明这些途径与疾病风险有关。在ALS的转基因小鼠模型中进行了机理分析，其中我们发现元素吸引子系统中的显著破坏与人类相似。我们的研究结果证明了对元素代谢动力系统的物候分析的应用，并强调了这些措施在表征疾病风险方面的效用。
METHODS:BACKGROUND:Women with disabilities are increasingly becoming pregnant, and growing evidence suggests maternal disability may be associated with increased risk for perinatal complications. OBJECTIVE:A systematic review and meta-analysis were undertaken to examine the association between maternal disabilities and risk for perinatal complications. STUDY DESIGN:Medline, CINAHL, EMBASE, and PsycINFO were searched from inception to July 2018 for full-text publications in English on pregnancy, delivery, and postpartum complications in women with any disability and those with physical, sensory, and intellectual and developmental disabilities specifically. Searches were limited to quantitative studies with a comparison group of women without disabilities. Reviewers used standardized instruments to extract data from and assess the quality of included studies. Pooled odds ratios and 95% confidence intervals were generated using DerSimonian and Laird random effects models for outcomes with data available from ≥3 studies. RESULTS:The review included 23 studies, representing 8,514,356 women in 19 cohorts. Women with sensory (pooled unadjusted odds ratio, 2.85, 95% confidence interval, 0.79-10.31) and intellectual and developmental disabilities (pooled unadjusted odds ratio, 1.10, 95% confidence interval, 0.76-1.58) had elevated but not statistically significant risk for gestational diabetes. Women with any disability (pooled unadjusted odds ratio, 1.45, 95% confidence interval, 1.16-1.82) and intellectual and developmental disabilities (pooled unadjusted odds ratio, 1.77, 95% confidence interval, 1.21-2.60) had increased risk for hypertensive disorders of pregnancy; risk was elevated but not statistically significant for women with sensory disabilities (pooled unadjusted odds ratio, 2.84, 95% confidence interval, 0.85-9.43). Women with any (pooled unadjusted odds ratio, 1.31, 95% confidence interval, 1.02-1.68), physical (pooled unadjusted odds ratio, 1.60, 95% confidence interval, 1.21-2.13), and intellectual and developmental disabilities (pooled unadjusted odds ratio, 1.29, 95% confidence interval, 1.02-1.63) had increased risk for cesarean delivery; risk among women with sensory disabilities was elevated but not statistically significant (pooled unadjusted odds ratio, 1.28, 95% confidence interval, 0.84-1.93). There was heterogeneity in all analyses, and 13 studies had weak-quality ratings, with lack of control for confounding being the most common limitation. CONCLUSION:Evidence that maternal disability is associated with increased risk for perinatal complications demonstrates that more high-quality research is needed to examine the reasons for this risk and to determine what interventions could be implemented to support women with disabilities during the perinatal period.
METHODS::Aims: To estimate healthcare resource utilization (HRU) and costs among patients with spinal muscular atrophy (SMA) type 1 (SMA1) in real-world practice, overall and among patients treated with nusinersen. As a secondary objective, HRU and costs were estimated among patients with other SMA types (i.e. 2, 3, or 4 combined), overall and among patients treated with nusinersen.Materials and methods: Patients with SMA were identified from the Symphony Health's Integrated Dataverse (IDV) open claims database (September 1, 2016-August 31, 2018) and were classified into four cohorts based on SMA type and nusinersen treatment (i.e. SMA1, SMA1 nusinersen, other SMA, and other SMA nusinersen cohorts). The index date was the date of the first SMA diagnosis after December 23, 2016 or, for nusinersen cohorts, the date of nusinersen initiation. The study period spanned from the index date to the earlier among the end of clinical activity or data availability.Results: Patients in the SMA1 (n = 349) and SMA1 nusinersen (n = 45) cohorts experienced an average of 59.4 and 56.6 days with medical visits per-patient-per-year (PPPY), respectively, including 14.1 and 4.6 inpatient days. Excluding nusinersen-related costs, total mean healthcare costs were $137,627 and $92,618 PPPY in the SMA1 and SMA1 nusinersen cohorts, respectively. Mean nusinersen-related costs were $191,909 per-patient-per-month (PPPM) for the first 3 months post-initiation (i.e. loading phase) and $36,882 PPPM thereafter (i.e. maintenance phase). HRU and costs were also substantial among patients in the other SMA (n = 5,728) and other SMA nusinersen (n = 404) cohorts, with an average of 44.5 and 63.7 days with medical visits PPPY and total mean healthcare costs (excluding nusinersen-related costs) of $49,175 and $76,371 PPPY, respectively.Limitations: The database may contain inaccuracies or omissions in diagnoses, procedures, or costs, and does not capture medical services outside of the IDV network.Conclusions: HRU and healthcare costs were substantial in patients with SMA, including in nusinersen-treated patients.
METHODS:OBJECTIVES:To investigate the effect of cervical spondylosis (CS) in the brain with a combination of advanced neuroimaging techniques. METHODS:Twenty-seven patients with CS and 24 age- and gender-matched healthy controls were studied. Disease severity was quantified using the Modified Japanese Orthopaedic Association Scoring System (mJOHA). Magnetic resonance (MR) imaging of the brain and spinal cord, functional MR imaging (fMRI) with a bilateral rest/finger-tapping paradigm, brain diffusion tensor imaging (DTI), voxel-based morphometry (VBM), and MR spectroscopy of the sensorimotor cortex were performed. RESULTS:A total of 92.3% of patients had more than one herniated disc. In the MRI, 33.33% presented signs of myelopathy. The mJOHA score was 13.03 ± 2.83. Compared with controls, DTI results showed significant lower FA values in Corpus callosum, both corticospinal tracts and middle cerebellar peduncles (p < 0.05 corrected). Only in CS patients fMRI results showed activation in both globus pallidi, caudate nucleus, and left thalamus (p < 0.001). Subject-specific activation of the BOLD signal showed in CS patients lower activation in the sensorimotor cortex and increased activation in both cerebellum hemispheres (p < 0.05 corrected). VBM showed bilateral clusters of gray matter loss in the sensorimotor cortex and pulvinar nucleus (p < 0.05 corrected) of CS patients. NAA/Cr was reduced in the sensorimotor cortex of CS patients (p < 0.05). Linear discriminant and support vector machine analyses were able to classify > 97% of CS patients with parameters obtained from the fMRI, DTI, and MRS results. CONCLUSION:CS may lead to distal brain damage affecting the white and gray matter of the sensorimotor cortex causing brain atrophy and functional adaptive changes. KEY POINTS:• This study suggests that patients with cervical spondylosis may present anatomical and functional adaptive changes in the brain. • Cervical spondylosis may lead to white matter damage, gray matter volume loss, and functional adaptive changes in the sensorimotor cortex. • The results reported in this work may be of value to better understand the effect of prolonged cervical spine compression in the brain.