Interactive Associations of Neuropsychiatry Inventory-Questionnaire Assessed Sleep Disturbance and Vascular Risk on Alzheimer’s Disease Stage Progression in Clinically Normal Older Adults

Background: To determine whether sleep disturbance (SD) and vascular-risk interact to promote Alzheimer’s disease (AD) stage-progression in normal, community-dwelling older adults and evaluate their combined risk beyond that of established AD biomarkers.Methods: Longitudinal data from the National Alzheimer’s Coordinating Center Uniform-Dataset. SD data (i.e., SD+ vs. SD-), as characterized by the Neuropsychiatric Inventory-Questionnaire, were derived from 10,600 participants at baseline, with at-least one follow-up visit. A subset (n = 361) had baseline cerebrospinal fluid (CSF) biomarkers and MRI data. The Framingham heart study general cardiovascular disease (FHS-CVD) risk-score was used to quantify vascular risk. Amnestic mild cognitive impairment (aMCI) diagnosis during follow-up characterized AD stage-progression. Logistic mixed-effects models with random intercept and slope examined the interaction of SD and vascular risk on prospective aMCI diagnosis.Results: Of the 10,600 participants, 1,017 (9.6%) reported SD and 6,572 (62%) were female. The overall mean (SD) age was 70.5 (6.5), and follow-up time was 5.1 (2.7) years. SD and the FHS-CVD risk-score were each associated with incident aMCI (aOR: 1.42 and aOR: 2.11, p < 0.01 for both). The interaction of SD and FHS-CVD risk-score with time was significant (aOR: 2.87, p < 0.01), suggesting a synergistic effect. SD and FHS-CVD risk-score estimates remained significantly associated with incident aMCI even after adjusting for CSF (Aβ, T-tau, P-tau) and hippocampal volume (n = 361) (aOR: 2.55, p < 0.01), and approximated risk-estimates of each biomarker in the sample where data was available.Conclusions: Clinical measures of sleep and vascular risk may complement current AD biomarkers in assessing risk of cognitive decline in older adults.

MTHFD2 Expression Association with Bladder Cancer and Screening of its Potential Inhibitor

BackgroundBladder cancer is the most common urological malignancy. Genes of folate mediated 1 carbon metabolism are found to be highly up regulated in tumor cells and promotes tumor cell proliferation. Rationale and aim of the studyThe aim of the current study was to determine the expression of MTHFD2 gene and the impact of intronic SNP rs1667627 on MTHFD2 expression Furthermore, determination of potential ligand based inhibitors against MTHFD2. Methods & ResultsSemi-quantitative expression analysis and sanger sequencing were used for this purpose. Moreover, structure based virtual ligand library screening in order to find plausible inhibitors.MTHFD2 expression was significantly increased with tumor stage progression both in low and high-grade bladder cancer. However, the relative fold change difference in low grade bladder cancer in correlation with the tumor stage progression was more dramatic. Contrary to the TCGA dataset analysis, increased MTHFD2 expression was observed in papillary bladder cancer tumor. G to A transition in the intronic variant rs1667627 SNP was determined in tumor tissues as compared to control. Virtual ligand based library screening against the three dimensional MTHFD2 protein lead to identification of a plausible inhibitor MCULE-8027924848 that displayed lower binding free energy as compared to already documented LY345899. ConclusionMTHFD2 might be used as low-grade bladder cancer biomarker since its expression level changes drastically with tumor progression. Further, experimental studies are required to establish the potential mode of inhibition of MCULE-8027924848 ligand.

Patterns of Distribution of 18F-THK5351 Positron Emission Tomography in Alzheimer’s Disease Continuum

Background: Alzheimer’s disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. Objective: Using 18F-THK5351 as a tracer that binds to both tau and MAO-B, we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. Methods: We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. Results: On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. Conclusion: The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

Multimolecular-Targeted Agents for Intermediate-Stage Hepatocellular Carcinoma Influence Time to Stage Progression and Overall Survival

<b><i>Background &amp; Aims:</i></b> Intermediate hepatocellular carcinoma (HCC) treatment has become complicated due to the development of various molecular-targeted agents (MTAs). We aimed to determine whether the administration of MTAs in patients with intermediate-stage HCC contributed to the prevention of progression to an advanced stage. <b><i>Methods:</i></b> We enrolled and retrospectively examined 289 patients with Child-Pugh class A who had been diagnosed with intermediate-stage HCC and underwent initial trans-arterial chemoembolization (TACE). Patients were classified into 2 groups: a group in which MTAs were administered to patients whose condition was refractory to TACE (<i>n</i> = 65) and a group in which MTAs were not administered (<i>n</i> = 65) at intermediate-stage HCC after propensity score matching (PSM). Time to stage progression (TTSP) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM. <b><i>Results:</i></b> TTSP and OS of the group with MTA administration were significantly longer than those of the group without MTA administration (TTSP: 36.4 vs. 17.9 months, <i>p</i> &#x3c; 0.001; median survival time [MST]: 44.6 vs. 26.6 months, <i>p</i> = 0.001). Within the up-to-seven criteria and administration of MTAs at the intermediate-stage HCC were identified as independent factors for TTSP and OS in the multivariate analysis. TTSP and OS in the era of the multi-MTA group were significantly longer than those in the era of the mono-MTA group (TTSP: 44.8 vs. 27.4 months, <i>p</i> = 0.01; MST: 53.4 vs. 33.3 months, <i>p</i> = 0.01). <b><i>Conclusion:</i></b> The administration of MTAs in patients with intermediate-stage HCC contributes to the prevention of stage progression and prolongs OS.

Early-Phase Urine Output and Severe-Stage Progression of Oliguric Acute Kidney Injury in Critical Care

Background: The relationship between urine output (UO) and severe-stage progression in the early phase of acute kidney injury (AKI) remains unclear. This study aimed to investigate the relationship between early-phase UO6−12h [UO within 6 h after diagnosis of stage 1 AKI by Kidney Disease: Improving Global Outcomes (KDIGO) UO criteria] and severe-stage progression of AKI and to identify a reference value of early-phase UO6−12h for guiding initial therapy in critical care.Methods: Adult patients with UO &lt; 0.5 ml/kg/h for the first 6 h after intensive care unit (ICU) admission (meeting stage 1 AKI by UO) and UO6−12h ≥ 0.5 ml/kg/h were identified from the Medical Information Mart for Intensive Care (MIMIC) III database. The primary outcome was progression to stage 2/3 AKI by UO. After other variables were adjusted through multivariate analysis, generalized additive model (GAM) was used to visualize the relationship between early-phase UO6−12h and progression to stage 2/3 AKI by UO. A two-piecewise linear regression model was employed to identify the inflection point of early-phase UO6−12h above which progression risk significantly leveled off. Sensitivity and subgroup analyses were performed to assess the robustness of our findings.Results: Of 2,984 individuals, 1,870 (62.7%) with KDIGO stage 1 UO criteria progressed to stage 2/3 AKI. In the multivariate analysis, early-phase UO6−12h showed a significant association with progression to stage 2/3 AKI by UO (odds ratio, 0.40; 95% confidence interval, 0.34–0.46; p &lt; 0.001). There was a non-linear relationship between early-phase UO6−12h and progression of AKI. Early-phase UO6−12h of 1.1 ml/kg/h was identified as the inflection point, above which progression risk significantly leveled off (p = 0.780). Patients with early-phase UO6−12h ≥ 1.1 ml/kg/h had significantly shorter length of ICU stay (3.82 vs. 4.17 days, p &lt; 0.001) and hospital stay (9.28 vs. 10.43 days, p &lt; 0.001) and lower 30-day mortality (11.05 vs. 18.42%, p &lt; 0.001). The robustness of our findings was confirmed by sensitivity and subgroup analyses.Conclusions: Among early-stage AKI patients in critical care, there was a non-linear relationship between early-phase UO6−12h and progression of AKI. Early-phase UO6−12h of 1.1 ml/kg/h was the inflection point above which progression risk significantly leveled off.

Comparison of cell therapy and other novel adjunctive therapies combined with core decompression for the treatment of osteonecrosis of the femoral head

Aims The value of core decompression (CD) in the treatment of osteonecrosis of the femoral head (ONFH) remains controversial. We conducted a systematic review and meta-analysis to evaluate whether CD combined with other treatments could improve the clinical and radiological outcomes of ONFH patients compared with CD alone. Methods We searched the PubMed, Embase, Web of Science, and Cochrane Library databases until June 2020. All randomized controlled trials (RCTs) and clinical controlled trials (CCTs) comparing CD alone and CD combined with other measures (CD + cell therapy, CD + bone grafting, CD + porous tantalum rod, etc.) for the treatment of ONFH were considered eligible for inclusion. The primary outcomes of interest were Harris Hip Score (HHS), ONFH stage progression, structural failure (collapse) of the femoral head, and conversion to total hip arthroplasty (THA). The pooled data were analyzed using Review Manager 5.3 software. Results A total of 20 studies with 2,123 hips were included (CD alone = 768, CD combined with other treatments = 1,355). The combination of CD with other therapeutic interventions resulted in a higher HHS (mean difference (MD) = 6.46, 95% confidence interval (CI) = 2.10 to 10.83, p = 0.004) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score (MD = −10.92, 95% CI = -21.41 to -4.03, p = 0.040) and a lower visual analogue scale (VAS) score (MD = −0.99, 95% CI = -1.56 to -0.42, p < 0.001) than CD alone. For the rates of disease stage progression, 91 (20%) progressed in the intervention group compared to 146 (36%) in the control group (odds ratio (OR) = 0.32, 95% CI = 0.16 to 0.64, p = 0.001). In addition, the intervention group had a more significant advantage in delaying femoral head progression to the collapsed stage (OR = 0.32, 95% CI = 0.17 to 0.61, p < 0.001) and reducing the odds of conversion to THA (OR = 0.35, 95% CI = 0.23 to 0.55, p < 0.001) compared to the control group. There were no serious adverse events in either group. Subgroup analysis showed that the addition of cell therapy significantly improved clinical and radiological outcomes compared to CD alone, and this approach appeared to be more effective than other therapies, particularly in precollapse (stage I to II) ONFH patients. Conclusion There was marked heterogeneity in the studies. There is a trend towards improved clinical outcomes with the addition of stem cell therapy to CD. Cite this article: Bone Joint Res 2021;10(7):445–458.