Orthostatic Hypotension in Middle-Age and Risk of Falls

One-third of older adults fall each year. Orthostatic hypotension (OH) has been hypothesized as an important risk factor for falls, but findings from prior studies have been inconsistent

A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells

A minor population of glioblastoma stem-like cells (GSCs) has been implicated in the relapse and resistance of glioblastoma to therapeutic treatments. Based on knowledge of the involvement of multiple microRNAs in GSC propagation, we designed a combinational approach to target the GSC population with multiple miRNA-based therapeutics. As carriers for the targeted delivery we took advantage of two aptamers that bind to, and inhibit, the receptor tyrosine kinases, Axl and PDGFRβ. We showed that the aptamer conjugates are transported through an in vitro blood-brain barrier (BBB) model. Furthermore, combining miR-137 and antimiR-10b synergizes with the receptor inhibitory function of aptamer carriers and prevents GSC expansion. Results highlighted the potential of combining multifunctional RNA-based therapeutics for selective targeting of GSCs and offer a proof of principle strategy to potentially fulfill the still unmet need for effective and safe treatment of glioma

Remembrances of Steve Ellmann, Still Present

In Memoriam: Steven Ellman

Clinical characterization of a hypersensitivity mixed bacterial and fungal dermatitis in a translational model of porcine NASH

IntroductionThe development of animal models of chronic liver disease via diet modification is a promising avenue for translational research but can lead to unexpected side effects that impact model adoption. While these side effects are well characterized in rodent models of nonalcoholic steatohepatitis (NASH), limited knowledge of these effects exists for novel porcine models of NASH. To close this gap, the present study investigates the side effects of diet-based NASH induction in pigs, with a systematic analysis of the pathologic mechanisms underlying dermatitis development and evaluation of treatment approaches.MethodTwelve pigs (10 large domestic pigs, 2 Goettingen minipigs) were fed a methionine- and choline-deficient, high-fat diet for 8 weeks to induce NASH. A retrospective review of each animal’s clinical record was performed to identify the side effects of the diet. Following the identification of diet-associated dermatitis, severity was judged by using a novel gradation system that characterized the individual lesions and body regions resulting in a cumulative evaluation. In addition to this clinical assessment, the etiology of the dermatitis was investigated via histopathologic and microbiologic testing. Furthermore, the success of prophylactic and therapeutic treatment approaches was evaluated by considering dermatitis development and clinical course.ResultsAll study animals demonstrated unexpected side effects of the methionine- and choline-deficient, high fat diet. In addition to marked dermatitis, study pigs showed impaired weight gain and developed steatorrhea and anemia. Based on the skin gradation system, five animals developed severe dermatitis, four animals moderate dermatitis, and three animals mild diet-associated dermatitis. Histological and microbiological evaluation of the affected skin showed signs of a hypersensitivity reaction with secondary infection by bacteria and fungi. The analysis showed that preemptive bathing extended the lesion-free duration by nearly 20 days. Furthermore, bathing in combination with a targeted antibiotic treatment represented a helpful treatment approach for diet-associated dermatitis.ConclusionThe provision of a methionine- and choline-deficient, high fat diet represents an effective approach for inducing NASH liver disease in pigs but predisposes study animals to multiple side effects. These side effects are universal to animals on study but can be adequately managed and do not represent a significant limitation of this model

The IMPROVE guidelines (Ischaemia Models: Procedural Refinements Of in Vivo Experiments)

Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information)

Circulating tumor DNA is readily detectable among Ghanaian breast cancer patients supporting non-invasive cancer genomic studies in Africa.

Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. In 15 patient plasma samples collected at the time of diagnosis as part of the Ghana Breast Health Study and unselected for tumor grade and subtype, ctDNA was detected in a majority of patients based on whole- genome sequencing at high (30×) and low (0.1×) depths. Breast cancer driver copy number alterations were observed in the majority of patients

Perioperative Factors Associated With Postoperative Delirium in Patients Undergoing Noncardiac Surgery:An Individual Patient Data Meta-Analysis

IMPORTANCE: Postoperative delirium (POD) is a common and serious complication after surgery. Various predisposing factors are associated with POD, but their magnitude and importance using an individual patient data (IPD) meta-analysis have not been assessed.OBJECTIVE: To identify perioperative factors associated with POD and assess their relative prognostic value among adults undergoing noncardiac surgery.DATA SOURCES: MEDLINE, EMBASE, and CINAHL from inception to May 2020.STUDY SELECTION: Studies were included that (1) enrolled adult patients undergoing noncardiac surgery, (2) assessed perioperative risk factors for POD, and (3) measured the incidence of delirium (measured using a validated approach). Data were analyzed in 2020.DATA EXTRACTION AND SYNTHESIS: Individual patient data were pooled from 21 studies and 1-stage meta-analysis was performed using multilevel mixed-effects logistic regression after a multivariable imputation via chained equations model to impute missing data.MAIN OUTCOMES AND MEASURES: The end point of interest was POD diagnosed up to 10 days after a procedure. A wide range of perioperative risk factors was considered as potentially associated with POD.RESULTS: A total of 192 studies met the eligibility criteria, and IPD were acquired from 21 studies that enrolled 8382 patients. Almost 1 in 5 patients developed POD (18%), and an increased risk of POD was associated with American Society of Anesthesiologists (ASA) status 4 (odds ratio [OR], 2.43; 95% CI, 1.42-4.14), older age (OR for 65-85 years, 2.67; 95% CI, 2.16-3.29; OR for &gt;85 years, 6.24; 95% CI, 4.65-8.37), low body mass index (OR for body mass index &lt;18.5, 2.25; 95% CI, 1.64-3.09), history of delirium (OR, 3.9; 95% CI, 2.69-5.66), preoperative cognitive impairment (OR, 3.99; 95% CI, 2.94-5.43), and preoperative C-reactive protein levels (OR for 5-10 mg/dL, 2.35; 95% CI, 1.59-3.50; OR for &gt;10 mg/dL, 3.56; 95% CI, 2.46-5.17). Completing a college degree or higher was associated with a decreased likelihood of developing POD (OR 0.45; 95% CI, 0.28-0.72).CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis of individual patient data, several important factors associated with POD were found that may help identify patients at high risk and may have utility in clinical practice to inform patients and caregivers about the expected risk of developing delirium after surgery. Future studies should explore strategies to reduce delirium after surgery.</p

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts