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r management translate into major patient benefit.Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain magnetic resonance imaging (MRI), in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important tool in the detection of PML. In clinical practice, standard MRI pulse sequences are utilized for screening, diagnosis, and monitoring of PML, but validated imaging-based outcome measures for use in prospective, interventional clinical trials for PML have yet to be established. We review the existing literature regarding the use of MRI and positron emission tomography imaging in PML and discuss the implications of PML histopathology for neuroradiology. MRI not only demonstrates the localization and extent of PML lesions, but also mirrors the tissue destruction, ongoing viral spread, and resulting inflammation. Finally, we explore the potential for imaging measures to serve as an outcome in PML clinical trials and provide recommendations for current and future imaging outcome measure development in this area.

This study aimed to understand the role of mTOR in CD8+ cells in the pathogenicity of rheumatoid arthritis (RA) and the changes after treatment with biologic drugs.

Peripheral blood mononuclear cells (PBMCs) were isolated from 17 healthy controls and 86 patients with RA. Phosphorylation of mTOR (p-mTOR) and its clinical relevance were evaluated. The role of mTOR in CD8+ cells was also examined in vitro.

Patients with RA who had a moderate or high disease activity, were biologic-naïve, and were refractory to MTX were enrolled in this study. The p-mTOR levels in CD8+ cells were higher in patients with RA than in healthy controls, and they positively correlated with the disease activity in such patients. However, after one year of treatment with TNF inhibitors, the p-mTOR levels in CD8+ cells were suppressed and showed a positive correlation with the treatment response, which was not observed in the abatacept-treatment group. In vitro stimulation of CD8+ cells with anti-CD3 and anti-CD28 antibodies induced mTOR phosphorylation and increased the production of granzyme B, GNLY, TNF-α, and IFN-γ but decreased the production of granzyme K. However, on treatment with TNF inhibitors, p-mTOR levels in CD8+ cells and granzyme B production decreased, while granzyme K production increased. The production of GNLY and IFN-γ was not affected by the TNF inhibitors.

These results suggested that mTOR activation in CD8+ cells may be a novel evaluation marker for RA disease activity and a predictive marker of therapeutic response to TNF inhibitors.

These results suggested that mTOR activation in CD8+ cells may be a novel evaluation marker for RA disease activity and a predictive marker of therapeutic response to TNF inhibitors.Blast-induced traumatic brain injury (bTBI) research is crucial in asymmetric warfare. The finite element analysis is an attractive option to simulate the blast wave interaction with the head. The popular blast simulation methods are ConWep-based pure Lagrangian, Arbitrary-Lagrangian-Eulerian, and coupling method. This study examines the accuracy and efficiency of ConWep and coupling methods in predicting the biomechanical response of the head. The simplified cylindrical, spherical surrogates and biofidelic human head models are subjected to field-relevant blast loads using these methods. The reflected overpressures at the surface and pressures inside the brain from the head models are qualitatively and quantitatively evaluated against the available experiments. Both methods capture the overall trends of experiments. Our results suggest that the accuracy of the ConWep method is mainly governed by the radius of curvature of the surrogate head. For the relatively smaller radius of curvature, such as cylindrical or spherical head surrogate, ConWep does not accurately capture decay of reflected blast overpressures and brain pressures. Selleckchem Adaptaquin For the larger radius of curvature, such as the biofidelic human head, the predictions from ConWep match reasonably well with the experiment. For all the head surrogates considered, the reflected overpressure-time histories predicted by the coupling method match reasonably well with the experiment. Coupling method uniquely captures the shadowing and union of shock waves governed by the geometry-driven flow dynamics around the head. Overall, these findings will assist the bTBI modeling community to judiciously select an objective-driven modeling methodology.

Intermetatarsal bursitis (IMB) represents juxta-articular synovial inflammation of the intermetatarsal bursae. Recent MRI-studies identified IMB as feature of early RA, but whether IMB already occurs in the pre-arthritic phase is unknown. We performed a large MRI-study in clinically suspect arthralgia (CSA) to assess the occurrence and prognostic value of IMB.

577 consecutive CSA-patients underwent contrast-enhanced MRI of the forefoot, metacarpophalangeal joints and wrist. MRIs were evaluated for subclinical synovitis/tenosynovitis/osteitis in line with the RA MRI scoring system (summed as RAMRIS-inflammation) and for IMB. IMB was considered present if uncommon in the general population at the same location (i.e. size scored above the 95th-percentile in age-matched symptom-free controls). The relation of IMB with other MRI-detected subclinical inflammation synovitis/tenosynovitis/osteitis) was studied. Cox-regression assessed the association with clinical arthritis development during median 25 months folovitis. IMB precedes development of clinical arthritis, particularly in ACPA-positive CSA. These results reinforce the notion that juxta-articular synovial inflammation is involved in the earliest phases of RA-development.

Robotic ventral hernia repair (VHR) has seen rapid adoption, but with limited data assessing clinical outcome or cost. This systematic review compared robotic VHR with laparoscopic and open approaches.

This systematic review was undertaken in accordance with PRISMA guidelines. PubMed, MEDLINE, Embase, and Cochrane databases were searched for articles with terms relating to 'robot-assisted', 'cost effectiveness', and 'ventral hernia' or 'incisional hernia' from 1 January 2010 to 10 November 2020. Intraoperative and postoperative outcomes, pain, recurrence, and cost data were extracted for narrative analysis.

Of 25 studies that met the inclusion criteria, three were RCTs and 22 observational studies. Robotic VHR was associated with a longer duration of operation than open and laparoscopic repairs, but with fewer transfusions, shorter hospital stay, and lower complication rates than open repair. Robotic VHR was more expensive than laparoscopic repair, but not significantly different from open surgery in teed to weigh the clinical benefits against the cost of robotic VHR.

The optimal surgical weight loss procedure for patients with a BMI of 50 kg/m2 or more is uncertain. This study compared distal Roux-en-Y gastric bypass (RYGB) with standard RYGB.

In this double-blind RCT, patients aged 18-60 years with a BMI of 50-60 kg/m2 were allocated randomly to receive standard (150 cm alimentary, 50 cm biliopancreatic limb) or distal (150 cm common channel, 50 cm biliopancreatic limb) RYGB. The primary outcome (change in BMI at 2 years) has been reported previously. Secondary outcomes 5 years after surgery, such as weight loss, health-related quality of life, and nutritional outcomes are reported.

Between May 2011 and April 2013, 123 patients were randomized, 113 received an intervention, and 92 attended 5-year follow-up. Mean age was 40 (95 per cent c.i. 38 to 41) years and 73 patients (65 per cent) were women; 57 underwent standard RYGB and 56 distal RYGB. BMI was reduced by 15.1 (95 per cent c.i. 13.9 to 16.2) kg/m2 after standard and 15.7 (14.5 to 16.9) kg/m2 after distal RYGe of this procedure in patients with a BMI of 50-60 kg/m2. Registration number NCT00821197 (http//www.clinicaltrials.gov).Presented in part as abstract to the IFSO (International Federation for the Surgery of Obesity and Metabolic disorders) conference, Madrid, Spain, August 2019.

This paper assesses variation in rates of emergency surgery (ES) amongst emergency admissions to hospital in patients with acute appendicitis, cholelithiasis, diverticular disease, abdominal wall hernia, and intestinal obstruction.

Records of emergency admissions between 1 April 2010 and 31 December 2019 for the five conditions were extracted from Hospital Episode Statistics for 136 acute National Health Service (NHS) trusts in England. Patients who had ES were identified using Office of Population Censuses and Surveys (OPCS) procedure codes, selected by consensus of a clinical panel. The differences in ES rates according to patient characteristics, and unexplained variations across NHS trusts were estimated by multilevel logistic regression, adjusting for year of emergency admission, age, sex, ethnicity, diagnostic subcategories, index of multiple deprivation, number of co-morbidities, and frailty.

The cohort sizes ranged from 107 325 (hernia) to 268 253 (appendicitis) patients, and the proportion of pn NHS trusts remained after adjustment for demographic and clinical characteristics. Age was strongly associated with the likelihood of ES receipt for some procedures.Nuclear factor kappa B (NF-κB) transcriptionally regulates several genes involved in initiating uterine contractions. A key factor controlling NF-κB activity is its translocation to the nucleus. In myometrial smooth muscle cells (MSMCs), this translocation can be stimulated by the inflammatory molecule lipopolysaccharide (LPS) or by blocking the potassium calcium-activated channel subfamily M alpha 1 (KCNMA1 or BKCa) with paxilline (PAX). Here, we sought to determine the mechanism by which blocking BKCa causes NF-κB-p65 translocation to the nucleus in MSMCs. We show that LPS- and PAX-induced NF-κB-p65 translocation are similar in that neither depend on several mitogen-activated protein kinase pathways, but both require increased intracellular calcium (Ca2+). However, the nuclear transport inhibitor wheat germ agglutinin prevented NF-κB-p65 nuclear translocation in response to LPS but not in response to PAX. Blocking BKCa located on the plasma membrane resulted in a transient NF-κB-p65 nuclear translocation that was not sufficient to induce expression of its transcriptional target, suggesting a role for intracellular BKCa. We report that BKCa also localizes to the nucleus and that blocking nuclear BKCa results in an increase in nuclear Ca2+ in MSMCs. Together, these data suggest that BKCa localized on the nuclear membrane plays a key role in regulating nuclear Ca2+ and NF-κB-p65 nuclear translocation in MSMCs.

RNA 3D motifs are recurrent substructures, modeled as networks of base pair interactions, which are crucial for understanding structure-function relationships. The task of automatically identifying such motifs is computationally hard, and remains a key challenge in the field of RNA structural biology and network analysis. State of the art methods solve special cases of the motif problem by constraining the structural variability in occurrences of a motif, and narrowing the substructure search space.

Here, we relax these constraints by posing the motif finding problem as a graph representation learning and clustering task. This framing takes advantage of the continuous nature of graph representations to model the flexibility and variability of RNA motifs in an efficient manner. We propose a set of node similarity functions, clustering methods, and motif construction algorithms to recover flexible RNA motifs. Our tool, Vernal can be easily customized by users to desired levels of motif flexibility, abundance and size.