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BackgroundInternational guidelines on the prevention and treatment of parastomal hernias are lacking. The European Hernia Society therefore implemented a Clinical Practice Guideline development project.MethodsThe guidelines development group consisted of general, hernia and colorectal surgeons, a biostatistician and a biologist, from 14 European countries. These guidelines conformed to the AGREE II standards and the GRADE methodology. The databases of MEDLINE, CINAHL, CENTRAL and the gray literature through OpenGrey were searched. Quality assessment was performed using Scottish Intercollegiate Guidelines Network checklists. The guidelines were presented at the 38th European Hernia Society Congress and each key question was evaluated in a consensus voting of congress participants.ResultsEnd colostomy is associated with a higher incidence of parastomal hernia, compared to other types of stomas. Clinical examination is necessary for the diagnosis of parastomal hernia, whereas computed tomography scan or ultrasonography may be performed in cases of diagnostic uncertainty. Currently available classifications are not validated; however, we suggest the use of the European Hernia Society classification for uniform research reporting. There is insufficient evidence on the policy of watchful waiting, the route and location of stoma construction, and the size of the aperture. The use of a prophylactic synthetic non-absorbable mesh upon construction of an end colostomy is strongly recommended. No such recommendation can be made for other types of stomas at present. It is strongly recommended to avoid performing a suture repair for elective parastomal hernia. So far, there is no sufficient comparative evidence on specific techniques, open or laparoscopic surgery and specific mesh types. However, a mesh without a hole is suggested in preference to a keyhole mesh when laparoscopic repair is performed.ConclusionAn evidence-based approach to the diagnosis and management of parastomal hernias reveals the lack of evidence on several topics, which need to be addressed by multicenter trials. Parastomal hernia prevention using a prophylactic mesh for end colostomies reduces parastomal herniation. Clinical outcomes should be audited and adverse events must be reported.

Our understanding of conventional dendritic cell (cDC) development and the functional specializations of distinct subsets in the peripheral tissues has increased greatly in recent years. Here, we review cDC development from the distinct progenitors in the bone marrow through to the distinct cDC subsets found in barrier tissues, providing an overview of the different subsets described in each location. In addition, we detail the transcription factors and local signals that have been proposed to control this developmental process. Importantly, despite these significant advances, numerous questions remain to be answered regarding cDC development. For example, it remains unclear whether the different subsets described, such as the CD103+CD11b+ and CD103−CD11b+ cDCs in the intestines, truly represent different populations or rather distinct developmental or activation stages. Furthermore, whether distinct progenitors exist for these cDC subsets remains to be determined. Thus in the last part of this review we discuss what we believe will be the main questions facing the field for the coming years.

The airway epithelium regulates responses to aeroallergens, acting as a physical and immunological barrier. In asthma, epithelial barrier function and the expression of adherens junction protein E-cadherin is compromised, but it is unknown whether this is cause or consequence of the disease. We hypothesized that airway epithelial loss of E-cadherin is a critical step in the development of manifestations of asthma. We generated a transgenic mouse model with conditional loss of E-cadherin in lung epithelial cells at birth and onwards. We observed normal lung development at the time of birth in mice lacking E-cadherin in the lung epithelium. However, E-cadherin deficiency led to progressive epithelial damage in mice growing into adulthood, as evidenced by airway epithelial denudation, decreased zonula occludens (ZO)-1 expression, loss of ciliated cells, and enlarged alveolar spaces. In addition, spontaneous goblet cell metaplasia with mucus production was observed. These epithelial changes were accompanied by elevated levels of the epithelial-derived chemokine CCL17, infiltration of eosinophils and dendritic cells, and mucus production. In conclusion, loss of E-cadherin induces features in the lung reminiscent of those observed in asthma, indicating that the disruption of E-cadherin-mediated cell-cell contacts may play a key role in the development of asthma manifestations.

Communicating weather-related hazards to the public can be a challenge for meteorologists, particularly given the nature of confidence levels in forecasting science. Despite these challenges, communicating high-impact weather remains extremely important because it has implications for the safety, health, and resilience of impacted communities. Because the dynamics of this issue are complex, solutions to weather hazard communication benefit from interdisciplinary solutions and multiple types of expertise. Our work demonstrates how rhetoric, a foundational communication discipline, can be applied to improving weather forecast communication. Applying a rhetorical framework allows the identification of communication strategies that not only invite public involvement but encourage users to act as conduits for weather information distribution. As a result, trust can be developed between the National Weather Service (NWS) and public audiences. The initial results support the hypothesis that effective public communication from NWS messaging can be improved by incorporating the concept of “commonplaces,” which are the expressions of beliefs, values, and norms that construct community attitudes toward weather or natural hazard forecasts, into visual communication techniques such as NWS Weather Stories.

Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation. Roquin-1 is a posttranscriptional regulator that controls the expression of many immune-related genes such as ICOS and TNFA . Here, the authors report a homozygous R688* loss of function mutation in Roquin-1 in a patient with syndromic uncontrolled hyperinflammation associated with immune cell activation and hypercytokinemia.

The identification of intestinal macrophages (mφs) and dendritic cells (DCs) is a matter of intense debate. Although CD103+ mononuclear phagocytes (MPs) appear to be genuine DCs, the nature and origins of CD103− MPs remain controversial. We show here that intestinal CD103−CD11b+ MPs can be separated clearly into DCs and mφs based on phenotype, gene profile, and kinetics. CD64−CD103−CD11b+ MPs are classical DCs, being derived from Flt3 ligand-dependent, DC-committed precursors, not Ly6Chi monocytes. Surprisingly, a significant proportion of these CD103−CD11b+ DCs express CCR2 and there is a selective decrease in CD103−CD11b+ DCs in mice lacking this chemokine receptor. CCR2+CD103− DCs are present in both the murine and human intestine, drive interleukin (IL)-17a production by T cells in vitro, and show constitutive expression of IL-12/IL-23p40. These data highlight the heterogeneity of intestinal DCs and reveal a bona fide population of CCR2+ DCs that is involved in priming mucosal T helper type 17 (Th17) responses.

Upper-limb amputation can cause a great deal of functional impairment for patients, particularly for those with amputation at or above the elbow. Our long-term objective is to improve functional outcomes for patients with amputation by integrating a fully implanted electromyographic (EMG) recording system with a wireless telemetry system that communicates with the patient's prosthesis. We believe that this should generate a scheme that will allow patients to robustly control multiple degrees of freedom simultaneously. The goal of this study is to evaluate the feasibility of predicting dynamic arm movements (both flexion/extension and pronation/supination) based on EMG signals from a set of muscles that would likely be intact in patients with transhumeral amputation. We recorded movement kinematics and EMG signals from seven muscles during a variety of movements with different complexities. Time-delayed artificial neural networks were then trained offline to predict the measured arm trajectories based on features extracted from the measured EMG signals. We evaluated the relative effectiveness of various muscle subsets. Predicted movement trajectories had average root-mean-square errors of approximately 15.7° and 24.9° and average R(2) values of approximately 0.81 and 0.46 for elbow flexion/extension and forearm pronation/supination, respectively.

Purpose In 10–24% of patients with rectal cancer who are treated with neoadjuvant chemoradiation, no residual tumor is found after surgery (ypT0). When accurately selected, these complete responders might be considered for less invasive treatments instead of standard surgery. So far, no imaging method has proven reliable. This study was designed to assess the accuracy of diffusion-weighted MRI (DWI) in addition to standard rectal MRI for selection of complete responders after chemoradiation. Methods A total of 120 patients with locally advanced rectal cancer from three university hospitals underwent chemoradiation followed by a restaging MRI (1.5T), consisting of standard T2W-MRI and DWI (b0-1000). Three independent readers first scored the standard MRI only for the likelihood of a complete response using a 5-point confidence score, after which the DWI images were added and the scoring was repeated. Histology (ypT0 vs. ypT1-4) was the standard reference. Diagnostic performance for selection of complete responders and interobserver agreement were compared for the two readings. Results Twenty-five of 120 patients had a complete response (ypT0). Areas under the ROC-curve for the three readers improved from 0.76, 0.68, and 0.58, using only standard MRI, to 0.8, 0.8, and 0.78 after addition of DWI ( P  = 0.39, 0.02, and 0.002). Sensitivity for selection of complete responders ranged from 0–40% on standard MRI versus 52–64% after addition of DWI. Specificity was equally high (89–98%) for both reading sessions. Interobserver agreement improved from κ 0.2–0.32 on standard MRI to 0.51–0.55 after addition of DWI. Conclusions Addition of DWI to standard rectal MRI improves the selection of complete responders after chemoradiation.

Autoimmune myocarditis often leads to dilated cardiomyopathy (DCM). Although T cell reactivity to cardiac self-antigen is common in the disease, it is unknown which antigen presenting cell (APC) triggers autoimmunity. Experimental autoimmune myocarditis (EAM) was induced by immunizing mice with α-myosin loaded bone marrow APCs cultured in GM-CSF. APCs found in such cultures include conventional type 2 CD11b cDCs (GM-cDC2s) and monocyte-derived cells (GM-MCs). However, only α-myosin loaded GM-cDC2s could induce EAM. We also studied antigen presenting capacity of endogenous type 1 CD24 cDCs (cDC1s), cDC2s, and MCs for α-myosin-specific TCR-transgenic TCR-M CD4 T cells. After EAM induction, all cardiac APCs significantly increased and cDCs migrated to the heart-draining mediastinal lymph node (LN). Primarily cDC2s presented α-myosin to TCR-M cells and induced Th1/Th17 differentiation. Loss of IRF4 in mice reduced MHCII expression on GM-cDC2s and cDC2 migration . However, partly defective cDC2 functions in mice did not suppress EAM. MCs were the largest APC subset in the inflamed heart and produced pro-inflammatory cytokines. Targeting APC populations could be exploited in the design of new therapies for cardiac autoimmunity.