Several conditions associated with reduced gastric acid secretion confer an altered risk of developing a gastric malignancy. Helicobacter pylori-induced atrophic gastritis predisposes to gastric ...adenocarcinoma, autoimmune atrophic gastritis is a precursor of type I gastric neuroendocrine tumours, whereas proton pump inhibitor (PPI) use does not affect stomach cancer risk. We hypothesised that each of these conditions was associated with specific alterations in the gastric microbiota and that this influenced subsequent tumour risk. 95 patients (in groups representing normal stomach, PPI treated, H. pylori gastritis, H. pylori-induced atrophic gastritis and autoimmune atrophic gastritis) were selected from a cohort of 1400. RNA extracted from gastric corpus biopsies was analysed using 16S rRNA sequencing (MiSeq). Samples from normal stomachs and patients treated with PPIs demonstrated similarly high microbial diversity. Patients with autoimmune atrophic gastritis also exhibited relatively high microbial diversity, but with samples dominated by Streptococcus. H. pylori colonisation was associated with decreased microbial diversity and reduced complexity of co-occurrence networks. H. pylori-induced atrophic gastritis resulted in lower bacterial abundances and diversity, whereas autoimmune atrophic gastritis resulted in greater bacterial abundance and equally high diversity compared to normal stomachs. Pathway analysis suggested that glucose-6-phospahte1-dehydrogenase and D-lactate dehydrogenase were over represented in H. pylori-induced atrophic gastritis versus autoimmune atrophic gastritis, and that both these groups showed increases in fumarate reductase. Autoimmune and H. pylori-induced atrophic gastritis were associated with different gastric microbial profiles. PPI treated patients showed relatively few alterations in the gastric microbiota compared to healthy subjects.
Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains ...poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare 'outlier' clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.
Virtual fracture clinics are an alternative to the traditional model of fracture care. Since their introduction in 2011, they have become increasingly used in the United Kingdom and Ireland. The ...coronavirus disease 2019 (COVID-19) health crisis has driven institutions to examine such innovative solutions to manage patient care. The current controversies include quantifying safety outcomes, such as potential delayed or missed injuries, inadequate treatment, and medicolegal claims. Questions also exist regarding the potential for cost reductions and efficiencies that may be achieved. Physical distancing has limited the number of face-to-face consultations, so this review was conducted to determine if virtual fracture clinics can provide an acceptable alternative in these challenging times.
The aim of this systematic review was to describe (1) adverse outcomes, (2) cost reductions, and (3) efficiencies associated with the virtual fracture clinic model.
A systematic review of the PubMed, MEDLINE, and Embase databases was conducted from database inception to March 2020. The keywords "virtual" or "telemedicine" or "telehealth" or "remote" or "electronic" AND "fracture" or "trauma" or "triage" AND "clinic" or "consultation" were entered, using the preferred reporting items for systematic reviews and meta-analyses. Inclusion criteria included adults and children treated for injuries by a virtual clinic model at the initial review. Eligible injuries included injuries deemed to not need surgical intervention, and those able to be treated remotely using defined protocols. Exclusion criteria consisted of patients reviewed by telemedicine using video links or in person at the initial review. Initially, 1065 articles were identified, with 665 excluded as they did not relate to virtual fracture clinics. In all, 400 articles were screened for eligibility, and 27 full-text reviews were conducted on 18 studies (30,512 virtual fracture clinic encounters). Three subdomains focusing on adverse outcomes, cost reductions, and efficiencies were recorded. The term adverse outcomes was used to describe any complications, further surgeries, re-referrals back to the clinic, or deviations from the protocols. Efficiency described the number of patients reviewed and discharged using the model, savings in clinic slots, reduced waiting times, or a reduction in consumption of resources such as radiographs. All studies were observational and the quality was assessed using Newcastle-Ottawa tool, which demonstrated a median score of 6 ± 1.8, indicating moderate quality.
Six studies reported adverse outcomes in detail, with events ranging from inappropriate splinting, deviations from protocols, and one patient underwent an osteotomy for a malunion. Efficiency varied from direct discharge proportions of 18% in early studies to 100% once the virtual fracture clinic model was more established. Cost reductions compared with estimates derived from conventional fracture clinics varied from USD 53 to USD 297 and USD 39,125 to USD 305876 compared with traditional fracture clinic visits.
Virtual fracture clinics may provide a means to treat patients remotely, using agreed-upon protocols. They have an important role in the current COVID-19 pandemic, due to the possibility to provide ongoing care in an otherwise challenging setting. More robust studies looking at this model of care will be needed to assess its long-term effects on patients, institutions, and health care systems.
Level IV, therapeutic study.
Bacterial infection is highly prevalent in patients who have had a stroke. Despite the potential contribution of micro-aspiration in post-stroke pneumonia, we found that the majority of the ...microorganisms detected in the patients who developed infections after having a stroke were common commensal bacteria that normally reside in the intestinal tracts. In a mouse model of ischemic stroke, post-stroke infection was only observed in mice that were born and raised in specific-pathogen-free facilities; this was not seen in mice that were born and raised in germ-free facilities. Using high-throughput 16S rRNA gene amplicon sequencing and bioinformatics analyses, we provide evidence demonstrating that the source of the bacteria forming the microbial community in the lungs of post-stroke mice was indeed the host small intestine. Additionally, stroke-induced gut barrier permeability and dysfunction preceded the dissemination of orally inoculated bacteria to peripheral tissues. This study identifies a novel pathway in which stroke promotes the translocation and dissemination of selective strains of bacteria that originated from the host gut microbiota.
Tissue-resident macrophages, such as microglia, Kupffer cells, and Langerhans cells, derive from Myb-independent yolk sac (YS) progenitors generated before the emergence of hematopoietic stem cells ...(HSCs). Myb-independent YS-derived resident macrophages self-renew locally, independently of circulating monocytes and HSCs. In contrast, adult blood monocytes, as well as infiltrating, gut, and dermal macrophages, derive from Myb-dependent HSCs. These findings are derived from the mouse, using gene knockouts and lineage tracing, but their applicability to human development has not been formally demonstrated. Here, we use human induced pluripotent stem cells (iPSCs) as a tool to model human hematopoietic development. By using a CRISPR-Cas9 knockout strategy, we show that human iPSC-derived monocytes/macrophages develop in an MYB-independent, RUNX1-, and SPI1 (PU.1)-dependent fashion. This result makes human iPSC-derived macrophages developmentally related to and a good model for MYB-independent tissue-resident macrophages, such as alveolar and kidney macrophages, microglia, Kupffer cells, and Langerhans cells.
•Human iPSC-derived macrophages are MYB independent but RUNX1 and SPI1 dependent•Transcription factor dependence genetically uncovers ontogeny of hiPSC macrophages
Macrophages are highly plastic multifunctional immune cells that play an essential role in mammalian tissues and their dysregulation is implicated in many pathological conditions. In this article, Buchrieser and colleagues define that iPSC-derived macrophages are of the same ontogeny as mouse tissue-resident macrophages, and are MYB independent. This work lays the foundation for the generation of authentic tissue-specialized macrophage subtypes.
Purpose
Most US inflammatory bowel disease (IBD) epidemiology studies conducted to date have sampled small, geographically restricted populations and have not examined time trends. The aim of our ...study was to determine the prevalence of Crohn’s disease (CD) and ulcerative colitis (UC) in a commercially insured US population and compare prevalences across sociodemographic characteristics and time.
Methods
Using claims data from approximately 12 million Americans, we performed three consecutive 2-year cross-sectional studies. Cases of CD and UC were identified using a previously described algorithm. Prevalence was estimated by dividing cases by individuals in the source population. Logistic regression was used to compare prevalences by region, age, and sex.
Results
In 2009, the prevalences of CD and UC in children were 58 95 % confidence interval (CI) 55–60 and 34 (95 % CI 32–36), respectively. In adults, the respective prevalences were 241 (95 % CI 238–245) and 263 (95 % CI 260–266). Data analysis revealed that IBD prevalences have slightly increased over time. Based on census data, an estimated 1,171,000 Americans have IBD (565,000 CD and 593,000 UC).
Conclusions
Analysis of the epidemiological data revealed an increasing burden of IBD in recent years, which may be used to inform policy.
We examined if resistance training affected muscle NAD
and NADH concentrations as well as nicotinamide phosphoribosyltransferase (NAMPT) protein levels and sirtuin (SIRT) activity markers in ...middle-aged, untrained (MA) individuals. MA participants (59±4 years old; n=16) completed 10 weeks of full-body resistance training (2 d/wk). Body composition, knee extensor strength, and vastus lateralis muscle biopsies were obtained prior to training (Pre) and 72 hours following the last training bout (Post). Data from trained college-aged men (22±3 years old, training age: 6±2 years old; n=15) were also obtained for comparative purposes. Muscle NAD
(+127%, p<0.001), NADH (+99%, p=0.002), global SIRT activity (+13%, p=0.036), and NAMPT protein (+15%, p=0.014) increased from Pre to Post in MA participants. Additionally, Pre muscle NAD
and NADH in MA participants were lower than college-aged participants (p<0.05), whereas Post values were similar between cohorts (p>0.10). Interestingly, muscle citrate synthase activity levels (i.e., mitochondrial density) increased in MA participants from Pre to Post (+183%, p<0.001), and this increase was significantly associated with increases in muscle NAD
(r
=0.592, p=0.001). In summary, muscle NAD
, NADH, and global SIRT activity are positively affected by resistance training in middle-aged, untrained individuals. Whether these adaptations facilitated mitochondrial biogenesis remains to be determined.
In the Carotid Revascularization Endarterectomy versus Stenting Trial, we found no significant difference between the stenting group and the endarterectomy group with respect to the primary composite ...end point of stroke, myocardial infarction, or death during the periprocedural period or any subsequent ipsilateral stroke during 4 years of follow-up. We now extend the results to 10 years.
Among patients with carotid-artery stenosis who had been randomly assigned to stenting or endarterectomy, we evaluated outcomes every 6 months for up to 10 years at 117 centers. In addition to assessing the primary composite end point, we assessed the primary end point for the long-term extension study, which was ipsilateral stroke after the periprocedural period.
Among 2502 patients, there was no significant difference in the rate of the primary composite end point between the stenting group (11.8%; 95% confidence interval CI, 9.1 to 14.8) and the endarterectomy group (9.9%; 95% CI, 7.9 to 12.2) over 10 years of follow-up (hazard ratio, 1.10; 95% CI, 0.83 to 1.44). With respect to the primary long-term end point, postprocedural ipsilateral stroke over the 10-year follow-up occurred in 6.9% (95% CI, 4.4 to 9.7) of the patients in the stenting group and in 5.6% (95% CI, 3.7 to 7.6) of those in the endarterectomy group; the rates did not differ significantly between the groups (hazard ratio, 0.99; 95% CI, 0.64 to 1.52). No significant between-group differences with respect to either end point were detected when symptomatic patients and asymptomatic patients were analyzed separately.
Over 10 years of follow-up, we did not find a significant difference between patients who underwent stenting and those who underwent endarterectomy with respect to the risk of periprocedural stroke, myocardial infarction, or death and subsequent ipsilateral stroke. The rate of postprocedural ipsilateral stroke also did not differ between groups. (Funded by the National Institutes of Health and Abbott Vascular Solutions; CREST ClinicalTrials.gov number, NCT00004732.).
Trauma-induced coagulopathy is a major driver of mortality following severe injury. Viscoelastic goal-directed resuscitation can reduce mortality after injury. The TEG 5000 system is widely used for ...viscoelastic testing. However, the TEG 6s system incorporates newer technology, with encouraging results in cardiovascular interventions. The purpose of this study was to validate the TEG 6s system for use in trauma patients.
Multicenter noninvasive observational study for method comparison conducted at 12 US Levels I and II trauma centers. Agreement between the TEG 6s and TEG 5000 systems was examined using citrated kaolin reaction time (CK.R), citrated functional fibrinogen maximum amplitude (CFF.MA), citrated kaolin percent clot lysis at 30 minutes (CK.LY30), citrated RapidTEG maximum amplitude (CRT.MA), and citrated kaolin maximum amplitude (CK.MA) parameters in adults meeting full or limited trauma team criteria. Blood was drawn ≤1 hour after admission. Assays were repeated in duplicate. Reliability (TEG 5000 vs. TEG 6s analyzers) and repeatability (interdevice comparison) was quantified. Linear regression was used to define the relationship between TEG 6s and TEG 5000 devices.
A total of 475 patients were enrolled. The cohort was predominantly male (68.6%) with a median age of 49 years. Regression line slope estimates (ß) and linear correlation estimates (p) were as follows: CK.R (ß = 1.05, ρ = 0.9), CFF.MA (ß = 0.99, ρ = 0.95), CK.LY30 (ß = 1.01, ρ = 0.91), CRT.MA (TEG 6s) versus CK.MA (TEG 5000) (ß = 1.06, ρ = 0.86) as well as versus CRT.MA (TEG 5000) (ß = 0.93, ρ = 0.93), indicating strong reliability between the devices. Overall, within-device repeatability was better for TEG 6s versus TEG 5000, particularly for CFF.MA and CK.LY30.
The TEG 6s device appears to be highly reliable for use in trauma patients, with close correlation to the TEG 5000 device and equivalent/improved within-device reliability. Given the potential advantages of using the TEG 6s device at the site of care, confirmation of agreement between the devices represents an important advance in diagnostic testing.
Diagnostic test, level II.
Genome-wide association studies (GWAS) have identified thousands of SNPs that are associated with human traits and diseases. But, because the vast majority of these SNPs are located in non-coding ...regions of the genome, the mechanisms by which they promote disease risk have remained elusive. Employing a new methodology that combines cistromics, epigenomics and genotype imputation, we annotate the non-coding regions of the genome in breast cancer cells and systematically identify the functional nature of SNPs associated with breast cancer risk. Our results show that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 and ESR1 and the epigenome of histone H3 lysine 4 monomethylation (H3K4me1) in a cancer- and cell type-specific manner. Furthermore, the majority of the risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the rs4784227 SNP on the TOX3 gene within the 16q12.1 risk locus.
PDF
