The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates ...immune responses at the interface between the commensal microbiota and the host. CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease. As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref. 9), decreased epithelial CD1d expression--as observed in inflammatory bowel disease--may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP), as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite recent growth in healthcare delivery-based social risk screening, little is known about patient perspectives on these activities. This study evaluates patient and caregiver acceptability of ...social risk screening.
This was a cross-sectional survey of 969 adult patients and adult caregivers of pediatric patients recruited from 6 primary care clinics and 4 emergency departments across 9 states. Survey items included the Center for Medicare and Medicaid Innovation Accountable Health Communities’ social risk screening tool and questions about appropriateness of screening and comfort with including social risk data in electronic health records. Logistic regressions evaluated covariate associations with acceptability measures. Data collection occurred from July 2018 to February 2019; data analyses were conducted in February‒March 2019.
Screening was reported as appropriate by 79% of participants; 65% reported comfort including social risks in electronic health records. In adjusted models, higher perceived screening appropriateness was associated with previous exposure to healthcare-based social risk screening (AOR=1.82, 95% CI=1.16, 2.88), trust in clinicians (AOR=1.55, 95% CI=1.00, 2.40), and recruitment from a primary care setting (AOR=1.70, 95% CI=1.23, 2.38). Lower appropriateness was associated with previous experience of healthcare discrimination (AOR=0.66, 95% CI=0.45, 0.95). Higher comfort with electronic health record documentation was associated with previously receiving assistance with social risks in a healthcare setting (AOR=1.47, 95% CI=1.04, 2.07).
A strong majority of adult patients and caregivers of pediatric patients reported that social risk screening was appropriate. Most also felt comfortable including social risk data in electronic health records. Although multiple factors influenced acceptability, the effects were moderate to small. These findings suggest that lack of patient acceptability is unlikely to be a major implementation barrier.
This article is part of a supplement entitled Identifying and Intervening on Social Needs in Clinical Settings: Evidence and Evidence Gaps, which is sponsored by the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services, Kaiser Permanente, and the Robert Wood Johnson Foundation.
BACKGROUND:The literature comparing open and arthroscopic repair for glenohumeral instability is conflicting. We performed a prospective, expertise-based, randomized clinical trial to compare open ...shoulder stabilization with arthroscopic shoulder stabilization by measuring quality-of-life outcomes and recurrence rates at two years among patients treated for traumatic anterior shoulder instability.
METHODS:Computer-generated, variable-block-size, concealed randomization allocated 196 patients to either the open-repair group (n = 98) or the arthroscopic-repair group (n = 98). An expertise-based randomization design was employed to avoid a differential bias in terms of physician experience. Outcomes were measured at baseline, at three and six months postoperatively, and at one and two years postoperatively with use of the Western Ontario Shoulder Instability Index (WOSI) and the American Shoulder and Elbow Surgeons (ASES) functional outcome scale. Recurrent instability was also analyzed.
RESULTS:There were no significant differences in outcome scores at baseline. At two years, seventy-nine patients in the open group and eighty-three patients in the arthroscopic group were available for follow-up. There was no significant difference in mean WOSI scores between the groups; the mean WOSI score (and standard deviation) for the open group was 85.2 ± 20.4 (95% confidence interval CI = 80.5 to 89.8), and for the arthroscopic group, 81.9 ± 19.8 (95% CI = 77.4 to 86.4); p = 0.31. There was also no significant difference in mean ASES scores91.4 ± 12.7 (95% CI = 88.5 to 94.4) for the open group and 88.2 ± 15.9 (95% CI = 84.6 to 91.8) for the arthroscopic group; p = 0.17. Recurrence rates at two years were significantly different11% in the open group and 23% in the arthroscopic group (p = 0.05). Recurrent instability was more likely in patients with a preoperative Hill-Sachs lesion and in male patients who were twenty-five years old and younger. There was no significant difference in shoulder motion between the groups at two years.
CONCLUSIONS:There was no difference between open and arthroscopic repair in terms of patient quality of life. Open repair resulted in a significantly lower risk of recurrence. Secondary outcome data from this trial suggest that open surgical repair may be recommended to reduce the risk of recurrent instability in younger male patients with a Hill-Sachs lesion.
LEVEL OF EVIDENCE:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
OBJECTIVE:This article aims to provide the first systematic review of enhanced recovery after surgery (ERAS) programs for esophagectomy and generate guidelines.
BACKGROUND:ERAS programs use ...multimodal approaches to reduce complications and accelerate recovery. Although ERAS is well established in colorectal surgery, experience after esophagectomy has been minimal. However, esophagectomy remains an extremely high-risk operation, commonly performed in patients with significant comorbidities. Consequently, ERAS may have a significant role to play in improving outcomes. No guidelines or reviews have been published in esophagectomy.
METHODS:We undertook a systematic review of the PubMed, EMBASE, and the Cochrane databases in July 2012. The literature was searched for descriptions of ERAS in esophagectomy. Components of successful ERAS programs were determined, and when not directly available for esophagectomy, extrapolation from related evidence was made. Graded recommendations for each component were then generated.
RESULTS:Six retrospective studies have assessed ERAS for esophagectomy, demonstrating favorable morbidity, mortality, and length of stay. Methodological quality is, however, low. Overall, there is little direct evidence for components of ERAS, with much derived from nonesophageal thoracoabdominal surgery.
CONCLUSIONS:ERAS in principle seems logical and safe for esophagectomy. However, the underlying evidence is poor and lacking. Despite this, a number of recommendations for practice and research can be made.
Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole-exome sequencing (WES) of 42 TGCTs to comprehensively study the cancer's mutational profile. The ...mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per Mb) as compared with common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT, we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4 Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT.
Coronavirus disease 2019 has created unprecedented challenges for amyotrophic lateral sclerosis (ALS) clinical care and research in the United States. Traditional evaluations for making an ALS ...diagnosis, measuring progression, and planning interventions rely on in‐person visits that may now be unsafe or impossible. Evidence‐ and experience‐based treatment options, such as multidisciplinary team care, feeding tubes, wheelchairs, home health, and hospice, have become more difficult to obtain and in some places are unavailable. In addition, the pandemic has impacted ALS clinical trials by impairing the ability to obtain measurements for trial eligibility, to monitor safety and efficacy outcomes, and to dispense study drug, as these also often rely on in‐person visits. We review opportunities for overcoming some of these challenges through telemedicine and novel measurements. These can reoptimize ALS care and research in the current setting and during future events that may limit travel and face‐to‐face interactions.
A better understanding of the pathways that regulate regeneration of the coronary vasculature is of fundamental importance for the advancement of strategies to treat patients with heart disease. ...Here, we aimed to investigate the origin and clonal dynamics of endothelial cells (ECs) associated with neovascularization in the adult mouse heart following myocardial infarction (MI). Furthermore, we sought to define murine cardiac endothelial heterogeneity and to characterize the transcriptional profiles of pro-angiogenic resident ECs in the adult mouse heart, at single-cell resolution.
An EC-specific multispectral lineage-tracing mouse (Pdgfb-iCreERT2-R26R-Brainbow2.1) was used to demonstrate that structural integrity of adult cardiac endothelium following MI was maintained through clonal proliferation by resident ECs in the infarct border region, without significant contributions from bone marrow cells or endothelial-to-mesenchymal transition. Ten transcriptionally discrete heterogeneous EC states, as well as the pathways through which each endothelial state is likely to enhance neovasculogenesis and tissue regeneration following ischaemic injury were defined. Plasmalemma vesicle-associated protein (Plvap) was selected for further study, which showed an endothelial-specific and increased expression in both the ischaemic mouse and human heart, and played a direct role in regulating human endothelial proliferation in vitro.
We present a single-cell gene expression atlas of cardiac specific resident ECs, and the transcriptional hierarchy underpinning endogenous vascular repair following MI. These data provide a rich resource that could assist in the development of new therapeutic interventions to augment endogenous myocardial perfusion and enhance regeneration in the injured heart.
AbstractObjectiveTo determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease ...relapse.DesignDouble blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis.Setting125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres.Participants237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome.InterventionsChildren were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m2) or a standard eight week course of prednisolone (total dose 2240 mg/m2). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more).Main outcome measuresThe primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat.ResultsNo significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval −0.005 to 0.037) and cost savings (difference −£1673 ($2160; €1930), 95% confidence interval −£3455 to £109).ConclusionsClinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life.Trial registrationISRCTN16645249; EudraCT 2010-022489-29.
Purpose
PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO ...radioligand
11
CPK-11195 limits accurate quantification.
18
FGE-180, a novel TSPO ligand, displays superior binding to
11
CPK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of
18
FGE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures.
Methods
Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of
18
FGE-180. Kinetic modelling of time–activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (
V
T
) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region.
Results
The two-tissue compartment model was the best model. The average regional delivery rate constant (
K
1
) was 0.01 mL cm
−3
min
−1
indicating low extraction across the blood–brain barrier (1 %). The estimated median
V
T
across all ROIs was also low, ranging from 0.16 mL cm
−3
in the striatum to 0.38 mL cm
−3
in the thalamus. There were no significant differences in
V
T
between HABs and MABs across all ROIs.
Conclusion
A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low
V
T
estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of
18
FGE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.
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