Zoonotic coronavirus (CoV) infections, such as those responsible for the current severe acute respiratory syndrome-CoV 2 (SARS-CoV-2) pandemic, cause grave international public health concern. In ...infected cells, the CoV RNA-synthesizing machinery associates with modified endoplasmic reticulum membranes that are transformed into the viral replication organelle (RO). Although double-membrane vesicles (DMVs) appear to be a pan-CoV RO element, studies to date describe an assortment of additional CoV-induced membrane structures. Despite much speculation, it remains unclear which RO element(s) accommodate viral RNA synthesis. Here we provide detailed 2D and 3D analyses of CoV ROs and show that diverse CoVs essentially induce the same membrane modifications, including the small open double-membrane spherules (DMSs) previously thought to be restricted to gamma- and delta-CoV infections and proposed as sites of replication. Metabolic labeling of newly synthesized viral RNA followed by quantitative electron microscopy (EM) autoradiography revealed abundant viral RNA synthesis associated with DMVs in cells infected with the beta-CoVs Middle East respiratory syndrome-CoV (MERS-CoV) and SARS-CoV and the gamma-CoV infectious bronchitis virus. RNA synthesis could not be linked to DMSs or any other cellular or virus-induced structure. Our results provide a unifying model of the CoV RO and clearly establish DMVs as the central hub for viral RNA synthesis and a potential drug target in CoV infection.
Background
Routine colonoscopy was traditionally recommended after acute diverticulitis to exclude coexistent malignancy. Improved CT imaging may make routine colonoscopy less required over time but ...most guidelines still recommend it. The aim of this review was to assess the role of colonoscopy in patients with CT‐proven acute diverticulitis.
Methods
PubMed and Embase were searched for studies reporting the prevalence of advanced colorectal neoplasia (ACN) or colorectal carcinoma in patients who underwent colonoscopy within 1 year after CT‐proven left‐sided acute diverticulitis. The prevalence was pooled using a random‐effects model and, if possible, compared with that among asymptomatic controls.
Results
Seventeen studies with 3296 patients were included. The pooled prevalence of ACN was 6·9 (95 per cent c.i. 5·0 to 9·4) per cent and that of colorectal carcinoma was 2·1 (1·5 to 3·1) per cent. Only two studies reported a comparison with asymptomatic controls, showing comparable risks (risk ratio 1·80, 95 per cent c.i. 0·66 to 4·96). In subgroup analysis of patients with uncomplicated acute diverticulitis, the prevalence of colorectal carcinoma was only 0·5 (0·2 to 1·2) per cent.
Conclusion
Routine colonoscopy may be omitted in patients with uncomplicated diverticulitis if CT imaging is otherwise clear. Patients with complicated disease or ongoing symptoms should undergo colonoscopy.
This systematic review demonstrates that the prevalence of colorectal cancer in all patients with diverticulitis is slightly higher than in controls, whereas patients with uncomplicated diverticulitis have a colorectal cancer prevalence comparable to that of asymptomatic controls from the literature. Therefore, routine colonoscopy should be omitted in those with uncomplicated diverticulitis and these patients may be referred back to the colorectal cancer screening programme. However, routine colonoscopy should remain the protocol for differential diagnosis after non‐surgical treatment of complicated diverticulitis.
Not needed routinely
Plasticity is concerned with understanding the behavior of metals and alloys when loaded beyond the elastic limit, whether as a result of being shaped or as they are employed for load bearing ...structures. Basic Engineering Plasticity delivers a comprehensive and accessible introduction to the theories of plasticity. It draws upon numerical techniques and theoretical developments to support detailed examples of the application of plasticity theory. This blend of topics and supporting textbook features ensure that this introduction to the science of plasticity will be valuable for a wide range of mechanical and manufacturing engineering students and professionals. * Brings together the elements of the mechanics of plasticity most pertinent to engineers, at both the micro- and macro-levels * Covers the theory and application of topics such as Limit Analysis, Slip Line Field theory, Crystal Plasticity, Sheet and Bulk Metal Forming, as well as the use of Finite Element Analysis * Clear and well-organized with extensive worked engineering application examples, and end of chapter exercises
Summary
Background
The rs738409 GG variant in patatin‐like phospholipase 3 (PNPLA3) is associated with non‐alcoholic fatty liver disease (NAFLD) and disease severity. However, it remains unclear if ...it contributes to the development of NAFLD through affecting dietary pattern.
Aim
To examine the association among PNPLA3 gene polymorphism, dietary pattern, metabolic factors and NAFLD.
Methods
Liver fat and fibrosis were assessed by proton‐magnetic resonance spectroscopy and transient elastography in 920 subjects from a population screening project (251 had NAFLD). Dietary nutrient intake was recorded using a locally validated food‐frequency questionnaire.
Results
The prevalence of GG genotype in NAFLD subjects was 20.7%, compared to 10.6% in controls (P < 0.001). Macronutrient intake was similar among subjects with different PNPLA3 genotypes. The presence of G allele was a predictor of NAFLD independent of nutrient intake and other metabolic factors (adjusted odds ratio to CC: CG, 2.00; GG, 2.68). In subjects without metabolic syndrome, G allele was even more closely correlated with NAFLD diagnosis (adjusted odds ratio to CC: CG, 2.22; GG, 3.39). The prevalence of NAFLD was only 12% in subjects with CC genotype and no metabolic syndrome, and increased to 34% in those with GG genotype and no metabolic syndrome. While NAFLD subjects had significantly lower fibre intake, there was no significant interaction between PNPLA3 and dietary pattern.
Conclusions
The G allele in PNPLA3 rs738409 increases the risk of NAFLD in the general population, especially in subjects without metabolic syndrome, independent of dietary pattern and metabolic factors.
Magnesium is a lightweight structural metal but it exhibits low ductility-connected with unusual, mechanistically unexplained, dislocation and plasticity phenomena-which makes it difficult to form ...and use in energy-saving lightweight structures. We employ long-time molecular dynamics simulations utilizing a density-functional-theory-validated interatomic potential, and reveal the fundamental origins of the previously unexplained phenomena. Here we show that the key 〈c + a〉 dislocation (where 〈c + a〉 indicates the magnitude and direction of slip) is metastable on easy-glide pyramidal II planes; we find that it undergoes a thermally activated, stress-dependent transition to one of three lower-energy, basal-dissociated immobile dislocation structures, which cannot contribute to plastic straining and that serve as strong obstacles to the motion of all other dislocations. This transition is intrinsic to magnesium, driven by reduction in dislocation energy and predicted to occur at very high frequency at room temperature, thus eliminating all major dislocation slip systems able to contribute to c-axis strain and leading to the high hardening and low ductility of magnesium. Enhanced ductility can thus be achieved by increasing the time and temperature at which the transition from the easy-glide metastable dislocation to the immobile basal-dissociated structures occurs. Our results provide the underlying insights needed to guide the design of ductile magnesium alloys.
Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal ...cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients.
In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients.
The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery.
NCT02371304 , registration date: February 2015.
Reactivity of Metal Clusters Luo, Zhixun; Castleman, A. W; Khanna, Shiv N
Chemical reviews,
12/2016, Letnik:
116, Številka:
23
Journal Article
Recenzirano
Odprti dostop
We summarize here the research advances on the reactivity of metal clusters. After a simple introduction of apparatuses used for gas-phase cluster reactions, we focus on the reactivity of metal ...clusters with various polar and nonpolar molecules in the gas phase and illustrate how elementary reactions of metal clusters proceed one-step at a time under a combination of geometric and electronic reorganization. The topics discussed in this study include chemical adsorption, addition reaction, cleavage of chemical bonds, etching effect, spin effect, the harpoon mechanism, and the complementary active sites (CAS) mechanism, among others. Insights into the reactivity of metal clusters not only facilitate a better understanding of the fundamentals in condensed-phase chemistry but also provide a way to dissect the stability and reactivity of monolayer-protected clusters synthesized via wet chemistry.
Background
The shift from routine antibiotics towards omitting antibiotics for uncomplicated acute diverticulitis opens up the possibility for outpatient instead of inpatient treatment, potentially ...reducing the burden of one of the most common gastrointestinal diseases in the Western world.
Purpose
Assessing the safety and cost savings of outpatient treatment in acute colonic diverticulitis.
Methods
PubMed and EMBASE were searched for studies on outpatient treatment of colonic diverticulitis, confirmed with computed tomography or ultrasound. Outcomes were readmission rate, need for emergency surgery or percutaneous abscess drainage, and healthcare costs.
Results
A total of 19 studies with 2303 outpatient treated patients were included. These studies predominantly excluded patients with comorbidity or immunosuppression, inability to tolerate oral intake, or lack of an adequate social network. The pooled incidence rate of readmission for outpatient treatment was 7% (95%CI 6–9%,
I
2
48%). Only 0.2% (2/1288) of patients underwent emergency surgery, and 0.2% (2/1082) of patients underwent percutaneous abscess drainage. Only two studies compared readmission rates outpatients that had similar characteristics as a control group of inpatients; 4.5% (3/66) and 6.3% (2/32) readmissions in outpatient groups versus 6.1% (4/66) and 0.0% (0/44) readmissions in inpatient groups (
p
= 0.619 and
p
= 0.174, respectively). Average healthcare cost savings for outpatient compared with inpatient treatment ranged between 42 and 82%.
Conclusion
Outpatient treatment of uncomplicated diverticulitis resulted in low readmission rates and very low rates of complications. Furthermore, healthcare cost savings were substantial. Therefore, outpatient treatment of uncomplicated diverticulitis seems to be a safe option for most patients.
The analysis of high-precision timing observations of an array of ∼20 millisecond pulsars (a so-called ‘timing array’) may ultimately result in the detection of a stochastic gravitational-wave ...background. The feasibility of such a detection and the required duration of this type of experiment are determined by the achievable rms of the timing residuals and the timing stability of the pulsars involved. We present results of the first long-term, high-precision timing campaign on a large sample of millisecond pulsars used in gravitational-wave detection projects. We show that the timing residuals of most pulsars in our sample do not contain significant low-frequency noise that could limit the use of these pulsars for decade-long gravitational-wave detection efforts. For our most precisely timed pulsars, intrinsic instabilities of the pulsars or the observing system are shown to contribute to timing irregularities on a 5-year time-scale below the 100 ns level. Based on those results, realistic sensitivity curves for planned and ongoing timing array efforts are determined. We conclude that prospects for detection of a gravitational-wave background through pulsar timing array efforts within 5 years to a decade are good.
Purpose:
Platelet-derived growth factors (PDGF) are regulators of fibroblast activity that may be involved in the pathophysiology of Graves' ophthalmopathy (GO). We unraveled the expression and ...origin of PDGF family members in GO orbital tissue and investigated the effect of PDGF isoforms on IL-6 and hyaluronan production and proliferation by orbital fibroblasts.
Methods:
PDGF-A, PDGF-B, PDGF-C, PDGF-D, PDGF-Rα, and PDGF-Rβ expression was determined by real-time quantitative PCR and PDGF-A and PDGF-B protein expression was determined by Western blot in orbital tissues. Orbital tissues were immunohistochemically stained for PDGF-A and PDGF-B expression, together with stainings for T cells, monocytes, B cells, macrophages, and mast cells. Effects of PDGF-AA, PDGF-AB, and PDGF-BB on orbital fibroblast proliferation and IL-6 and hyaluronan production were examined. Finally, effects of PDGF-BB- and PDGF-AA-neutralizing antibodies on IL-6 and hyaluronan production in GO whole orbital tissue cultures were tested.
Results:
GO orbital tissue showed increased PDGF-A and PDGF-B mRNA and protein levels. Increased numbers of PDGF-A- and PDGF-B-positive monocytes, macrophages, and mast cells were present in GO orbital tissue. PDGF-BB stimulated proliferation and hyaluronan and IL-6 production by orbital fibroblasts the most, followed by PDGF-AB and PDGF-AA. Finally, in particular imatinib mesylate and PDGF-BB-neutralizing antibodies reduced IL-6 and hyaluronan production by whole orbital tissue cultures from GO patients.
Conclusions:
In GO, mast cells, monocytes, and macrophages may activate orbital fibroblasts via secretion of especially PDGF-AB and PDGF-BB. Preclinical studies with whole orbital tissue cultures show that blocking PDGF-B chain containing isoforms can be a promising treatment for GO.
PDF
