The Women's Health Initiative: A Landmark Resource for Skeletal Research Since 1992

The Women's Health Initiative (WHI) is a large longitudinal study designed to investigate strategies for the prevention and control of common chronic diseases in postmenopausal women, including cardiovascular disease, cancer, and osteoporotic fractures. The WHI consisted of three overlapping clinical trials of hormone therapy, diet modification to reduce total dietary fat, and calcium/vitamin D supplementation. Women who were ineligible for the hormone therapy or diet modification trials or not interested were invited to participate in the observational study. Women were recruited into WHI from 1993 to 1998 at 40 US clinical centers. WHI enrolled 26,046 underrepresented minority women and 135,762 white women. Women could participate in each trial if eligible. The final enrollment included 27,347 women in the hormone trial; 48,835 women in the diet modification trial; 36,282 women in the calcium/vitamin D trial, and 93,676 in the observational study. After the main study ended in 2005, women were invited to continue follow-up for exposures and outcomes through two extensions to 2020. Proposals were recently submitted to continue follow-up through 2027. Information was collected on an extensive number of risk factors for fractures at baseline and over the follow-up, including fall and fracture history, weight patterns, comorbidities, diet, reproductive history, medications, anthropometry, and biomarkers. Bone mineral density was measured at three WHI clinical centers (n = 11,020) chosen to maximize race/ethnic diversity. WHI encourages outside investigators to make use of the publicly available WHI data and to access the biobank of specimens ( www.whi.org ). © 2020 American Society for Bone and Mineral Research.     

Comparison of Transcallosal Inhibition Between Hemispheres and Its Relationship with Motor Behavior in Patients with Severe Upper Extremity Impairment After Subacute Stroke

ObjectiveTo compare corticospinal excitability and transcallosal inhibition between contralesional primary motor cortex (M1) and ipsilesional M1. We also investigated the correlation between transcallosal inhibition and upper extremity motor behavior.Materials and methods19 individuals with unilateral ischemic subacute stroke who had severe upper extremity impairment participated in this study. Corticospinal excitability was assessed by measuring the resting motor threshold, active motor threshold and motor evoked potential amplitude. Transcallosal inhibition was investigated by measuring the duration and depth of the ipsilateral silent period (ISP). The data from the two hemispheres were compared and the relationships of transcallosal inhibition with upper extremity motor impairment, grip strength and pinch strength were analyzed.ResultsResting motor threshold (p = 0.001) and active motor threshold (p = 0.001) were lower and motor evoked potential amplitude was higher (p = 0.001) in the contralesional M1 compared to the ipsilesional M1. However, there were no differences between the two M1s in ISP duration (p = 0.297) or ISP depth (p =0. 229). Transcallosal inhibition from the contralesional M1 was positively associated with motor impairment (ISP duration, p = 0.003; ISP depth, p = 0.017) and grip strength (ISP duration, p = 0.016; ISP depth, p = 0.045).ConclusionsSymmetric transcallosal inhibition between hemispheres and positive association of transcallosal inhibition from contralesional M1 with upper extremity motor behavior indicate that recruitment of contralesional M1 may be necessary for recovery in patients with severe upper extremity impairment after subacute ischemic stroke.     

Efficacy of immunotherapy targeting the neoantigen derived from epidermal growth factor receptor T790M/C797S mutation in non–small cell lung cancer

Lung cancer is the leading cause of cancer‐related deaths worldwide. Epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) often have good clinical activity against non–small cell lung cancer (NSCLC) with activating EGFR mutations. Osimertinib, which is a third‐generation EGFR‐TKI, has a clinical effect even on NSCLC harboring the threonine to methionine change at codon 790 of EGFR (EGFR T790M) mutation that causes TKI resistance. However, most NSCLC patients develop acquired resistance to osimertinib within approximately 1 year, and 40% of these patients have the EGFR T790M and cysteine to serine change at codon 797 (C797S) mutations. Therefore, there is an urgent need for the development of novel treatment strategies for NSCLC patients with the EGFR T790M/C797S mutation. In this study, we identified the EGFR T790M/C797S mutation‐derived peptide (790‐799) (MQLMPFGSLL) that binds the human leukocyte antigen (HLA)‐A*02:01, and successfully established EGFR T790M/C797S‐peptide‐specific CTL clones from human PBMC of HLA‐A2 healthy donors. One established CTL clone demonstrated adequate cytotoxicity against T2 cells pulsed with the EGFR T790M/C797S peptide. This CTL clone also had high reactivity against cancer cells that expressed an endogenous EGFR T790M/C797S peptide using an interferon‐γ (IFN‐γ) enzyme‐linked immunospot (ELISPOT) assay. In addition, we demonstrated using a mouse model that EGFR T790M/C797S peptide‐specific CTL were induced by EGFR T790M/C797S peptide vaccine in vivo. These findings suggest that an immunotherapy targeting a neoantigen derived from EGFR T790M/C797S mutation could be a useful novel therapeutic strategy for NSCLC patients with EGFR‐TKI resistance, especially those resistant to osimertinib.     

Excitability of motor and sensory axons in multifocal motor neuropathy

ObjectiveTo assess excitability differences between motor and sensory axons of affected nerves in patients with multifocal motor neuropathy (MMN).MethodsWe performed motor and sensory excitability tests in affected median nerves of 20 MMN patients and in 20 age-matched normal subjects. CMAPs were recorded from the thenar and SNAPs from the 3rd digit. Clinical tests included assessment of muscle strength, two-point discrimination and joint position.ResultsAll MMN patients had weakness of the thenar muscle and normal sensory tests. Motor excitability testing in MMN showed an increased threshold for a 50% CMAP, increased rheobase, decreased stimulus-response slope, fanning-out of threshold electrotonus, decreased resting I/V slope, shortened refractory period, and more pronounced superexcitability. Sensory excitability testing in MMN revealed decreased accommodation half-time and S2-accommodation and less pronounced subexcitability. Mathematical modeling indicated increased Barrett-Barrett conductance for motor fibers and increase in internodal fast potassium conductance for sensory fibers.ConclusionsExcitability findings in MMN suggest myelin sheath or paranodal seal involvement in motor fibers and, possibly, paranodal detachment in sensory fibers.SignificanceExcitability properties of affected nerves in MMN differ between motor and sensory nerve fibers.     

溃疡性结肠炎薄白苔和黄腻苔患者的肠道菌群特征分析

  目的：通过分析溃疡性结肠炎(UC)薄白苔、黄腻苔患者的肠道菌群特征,探讨UC患者舌苔与肠道菌群之间的关系。  方法：选取UC薄白苔患者、UC黄腻苔患者、健康对照者各35例,分别设为UC薄白苔组、UC黄腻苔组、健康对照组。收集粪便标本,采用16S rDNA基因测序分析技术和生物信息学方法分析比较各组肠道菌群的多样性和丰度。  结果：①与健康对照组比较,UC薄白苔、黄腻苔组患者肠道菌群物种的丰富度和多样性降低(P＜0.001),肠道菌群物种数量减少；与UC薄白苔组比较,UC黄腻苔组患者肠道菌群丰富度差异无统计学意义(P＞0.05),但肠道菌群物种数量减少。②门水平差异分析:与健康对照组比较,UC薄白苔、黄腻苔组患者肠道菌群中厚壁菌门(Firmicutes)减少(P＜0.05)；与UC薄白苔组比较,UC黄腻苔组患者肠道菌群中蓝细菌门(Cyanobacteria)增多(P＜0.05)。③属水平差异分析:与健康对照组比较,UC薄白苔组患者肠道菌群中埃希氏-志贺氏菌属(Escherichia-Shigella)、链球菌属(Streptococcus)等增多(P＜0.05),罕见小球菌属(Subdoligranulum)、多尔氏菌属(Dorea)、瘤胃球菌属(Ruminococcus)、罗氏菌属(Roseburia)等减少(P＜0.05)；UC黄腻苔组患者肠道菌群中埃希氏-志贺氏菌属(Escherichia-Shigella)、乳杆菌属(Lactobacillus)等增多(P＜0.05),多尔氏菌属(Dorea)、罕见小球菌属(Subdoligranulum)、瘤胃球菌属(Ruminococcus)、考拉杆菌属(Phascolarctobacterium)、罗氏菌属(Roseburia)等减少(P＜0.05)。与UC薄白苔组比较,UC黄腻苔组患者肠道菌群链球菌(Streptococcus)增多(P＜0.05),巨球型菌属(Megasphaera)、拟普氏菌属(Alloprevotella)、普氏菌属(Prevotella)、奈瑟氏菌属(Neisseria)等减少(P＜0.05)。④LDA判定(纲、目、科水平):UC薄白苔组患者肠道菌群中普氏菌科(f_Prevotellaceae)、奈瑟氏球菌目(o_Neisseriales)、奈瑟氏球菌科(f_Neisseriaceae)丰度显著多于UC黄腻苔组(LDA＞2.0),UC黄腻苔组患者肠道菌群中杆菌纲(c_Bacilli)、乳杆菌目(o_Lactobacillales)、链球菌科(f_Streptococcaceae)、消化链球菌科(f_Peptostreptococcaceae)丰度显著高于UC薄白苔组(LDA＞2.0)。  结论：UC薄白苔、黄腻苔患者肠道菌群丰富度和多样性均较健康者明显下降；UC薄白苔患者和UC黄腻苔患者在肠道菌群组成和细菌丰度上均存在差异,黄腻苔患者肠道致病性细菌增多而具有潜在保护作用的细菌减少；肠道菌群检测可以为舌诊现代化提供一定的信息。     

An addition to the evolving spectrum of lipofibromatosis and lipofibromatosis-like neural tumor: Molecular findings in an unusual phenotype aid in accurate classification

Lipofibromatosis (LPF) and lipofibromatosis-like neural tumor (LPF-NT) are histologically and prognostically similar neoplasms having differences in immunophenotype as well as molecular biology. In most cases, LPF-NT is driven by fusions in the NTRK gene, whereas LPF has been associated with fusions in a variety of receptor tyrosine kinases. The distinction between the driver fusion event holds clinical significance because of the profound clinical response to tropomyosin receptor kinase (Trk) inhibitors (larotrectinib) in the NTRK-driven tumors. Immunohistochemically, and consistent with its namesake, to-date all reported cases classified as LPF-NT have shown positivity for S100-protein staining. Consequently, as S100-protein staining is widely available, it represents a cost-effective screening tool for LPF-NT where the more specific studies such as the pan-Trk stain or fluorescence in situ hybridization for NTRK rearrangement are not available. Herein, we present a case of presumed LPF-NT harboring the recurrent NTRK1-LMNA fusion, but which was negative for S100-protein immunostaining and was previously classified as classical LPF. This case reveals a potential pitfall in distinguishing these rare subcutaneous tumors by S100-protein staining and highlights the challenges in reconciling the rapid and novel discoveries made in the field of diagnostic pathology.     

丹蛭降糖胶囊通过mTOR/S6K1信号通路对糖尿病肾病大鼠的干预作用研究

目的研究丹蛭降糖胶囊对糖尿病肾病大鼠的肾脏病理改变和足细胞自噬水平的影响,初步探讨其相应的作用机制。方法选取GK大鼠40只,采用醋酸脱氧皮质酮-盐皮下注射联合高脂饲料喂养诱导糖尿病肾病模型。造模成功后随机分为模型组、丹蛭降糖胶囊低剂量组[0.54 g/(kg·d)]、高剂量组[1.08 g/(kg·d)]、缬沙坦组[10 mg/(kg·d)],每组10只。另选取10只同周龄正常Wistar大鼠作为正常组。模型组和正常组给予等容积生理盐水。连续灌胃10周后检测空腹血糖(FBG)、血肌酐(SCr)、尿素氮(BUN)和尿微量蛋白(U-mAlb)。Western Blot检测肾小球p-mTOR、p-S6K1、Beclin-1、LC3和Nephrin蛋白的表达,HE染色和PAS染色后于光镜下观察肾脏病理变化,电镜下观察各组亚细胞形态结构变化。结果与正常组比较,模型组FBG、SCr、BUN、U-mAlb水平升高(P<0.01);与模型组比较,丹蛭降糖胶囊低、高剂量组和缬沙坦组U-mAlb水平降低(P<0.01)。模型组可见肾小球基底膜增厚,系膜基质沉积,足细胞损伤,各用药组均有不同程度改善,丹蛭降糖胶囊高剂量组足细胞内有较多自噬体形成。与正常组比较,模型组p-mTOR、p-S6K1的表达增高,Nephrin、Beclin-1和LC3的表达水平降低(P<0.01);与模型组比较,各用药组p-mTOR、p-S6K1的表达下降,Nephrin、Beclin-1和LC3的表达增高(P<0.01)。丹蛭降糖胶囊高剂量组和缬沙坦组Beclin1、LC3Ⅱ/LC3Ⅰ水平较丹蛭降糖胶囊低剂量组升高(P<0.05)。结论丹蛭降糖胶囊具有减轻糖尿病肾病大鼠U-mAIb、足细胞损伤及相关肾脏病理改变的作用,其机制可能与抑制mTOR/S6K1信号通路进而提高足细胞的自噬活性有关。     

Comparison of fiber tract low frequency stimulation to focal and ANT stimulation in an acute rat model of focal cortical seizures

BackgroundCurrent implementations of direct brain stimulation for epilepsy in patients involve high-frequency (HFS) electrical current and targeting of grey matter. Studies have shown that low-frequency (LFS) fiber-tract stimulation may also prove effective. To compare the efficacy of high-frequency grey matter stimulation to the low-frequency fiber tract stimulation technique a well-controlled set of experiments using a single animal model of epilepsy is needed.ObjectiveThe goal of this study was to determine the relative efficacy of different direct brain stimulation techniques for suppressing seizures using an acute rat model of focal cortical seizures.Methods4-AP was injected into the S1 region of cortex in rodents over 3 h. LFPs were recorded from the seizure focus and mirror focus to monitor seizure frequency during the experiments. CC-LFS, HFS-ANT, Focal-HFS, or a transection of the CC was applied.ResultsStimulation of the CC yielded a 65% ±14% (p = 0.0014) reduction of seizures in the focus and a 97% ±15% (p = 0.0026) reduction in the mirror focus (n = 7). By comparison transection of the CC produced a 65% ±18% reduction in the focus and a non-statistically significant reduction of 57% ±18% (p = 0.1381) in the mirror focus (n = 5). All other methods of stimulation failed to have a statistically significant effect on seizure suppression.ConclusionsLFS of the CC is the only method of stimulation to significantly reduce seizure frequency in this model of focal cortical seizures. These results support the hypothesis that LFSof fiber tracts has significant potential for seizure control.     

Meeting 24-h Movement Guidelines is Related to Better Academic Achievement: Findings from the YRBS 2019 Cycle

This research is designed to investigate the relationship between the 24-h movement guidelines (24-HMG) and self-reported academic achievement (AA) using nationally representative data derived from the 2019 U.S. National Youth Risk Behaviour Survey. A multiple-stage cluster sampling procedure has been adopted to ensure a representative sample (N = 9127 adolescents; mean age = 15.7 years old; male% = 49.8%). Logistic regression has been adopted to obtain the odds ratio (OR) regarding the associations between adherence to 24-HMG and AA while controlling for ethnicity, body mass index, sex and age. The prevalence of meeting the 24-h movement guidelines in isolation and combination varied greatly (physical activity = 23.3%, screen time = 32.5%, sleep = 22.3%, and 24-HMG = 2.8%), while the percentage of highest-class AA was 42.5%. Compared with the situation when none of 24-HMG is met, the achievement of any of the combined guidelines (except for meeting the physical activity guidelines) was significantly associated with higher odds of achieving first-class AA. Meeting the sleep guideline had 1.42 times increased likelihood to achieve highest-class AA as compared with not meeting the sleep guideline. Meeting screen time guidelines and physical activity guidelines, respectively, were 1.32 and 1.13 times more likely to report first-class AA; but meeting the guidelines of physical activity was not significantly related to AA. Meeting the 24-HMG had the highest odds of achieving first-class AA (OR = 2.01, 95%CI: 1.47– 2.73). In both sexes, adolescents who met 24-HMG self-reported better AA (boys OR = 2.05, 95%CI: 1.34–3.15; girls OR = 2.26, 95%CI: 1.36–3.76). Significant relationships were observed in adolescents from 9–10th grade, but not higher grades. Our research findings suggest that optimal movement behaviours can be seen as an important This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.32604/IJMHP.2021.017660 ARTICLE Tech Science Press Published Online: 26 October 2021 element to better academic achievement among U.S. adolescents. Future studies can adopt our discoveries to promote adolescents’ academic achievement through implementing optimal 24-h movement behaviour patterns.