Introduction
Neurofilament light (NfL), chitinase‐3‐like protein 1 (YKL‐40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and ...synaptic degeneration, respectively.
Methods
We performed genome‐wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF‐AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates.
Results
We identify novel genome‐wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL‐40. We confirm previous work suggesting that YKL‐40 levels are associated with DNA variants in CHI3L1.
Discussion
Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD‐related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower ...morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization.
In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate.
Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 ).
Without visual feedback, humans perceive tilt when experiencing a sustained linear acceleration. This tilt illusion is commonly referred to as the somatogravic illusion. Although the physiological ...basis of the illusion seems to be well understood, the dynamic behavior is still subject to discussion. In this study, the dynamic behavior of the illusion was measured experimentally for three motion profiles with different frequency content. Subjects were exposed to pure centripetal accelerations in the lateral direction and were asked to indicate their tilt percept by means of a joystick. Variable-radius centrifugation during constant angular rotation was used to generate these motion profiles. Two self-motion perception models were fitted to the experimental data and were used to obtain the time constant of the somatogravic illusion. Results showed that the time constant of the somatogravic illusion was on the order of two seconds, in contrast to the higher time constant found in fixed-radius centrifugation studies. Furthermore, the time constant was significantly affected by the frequency content of the motion profiles. Motion profiles with higher frequency content revealed shorter time constants which cannot be explained by self-motion perception models that assume a fixed time constant. Therefore, these models need to be improved with a mechanism that deals with this variable time constant. Apart from the fundamental importance, these results also have practical consequences for the simulation of sustained accelerations in motion simulators.
Abstract Introduction Survivors of necrotizing enterocolitis (NEC) often develop a post-NEC intestinal stricture, causing severe and prolonged morbidity. Objectives We first aimed to determine the ...incidence of post-NEC strictures. Second, we aimed to determine risk factors associated with intestinal post-NEC strictures. Materials and Methods A total of 441 patients diagnosed with NEC Bell's stage ≥ 2 were retrospectively included in three academic pediatric surgical centers between January 2005 and January 2013. Clinical data were related to the occurrence of intestinal post-NEC strictures. Post-NEC strictures were defined as clinically relevant strictures with a radiological and/or surgical confirmation of this post-NEC stricture. Results The median gestational age of the 337 survivors of the acute phase of NEC was 29 weeks (range 24–41) and median birth weight was 1130 g (range 410–4130). Of the survivors, 37 (17%) medically treated NEC patients developed a post-NEC strictures versus 27 surgically treated NEC patients (24%; p = 0.001). Highest C-reactive protein (CRP) level measured during the NEC episode was associated with the development of post-NEC strictures (OR 1.20, 95% confidence interval 1.11–1.32; p = 0.03). No post-NEC strictures were detected in patients with CRP levels < 46 mg/L. Conclusion This multicenter retrospective cohort study demonstrates an overall incidence of clinical relevant post-NEC strictures of 19%, with a higher rate (24%) in NEC cases treated surgically. Increased CRP levels during the NEC episode were associated with the development of post-NEC strictures.
A light sphagnum peat mix inoculated with Trichoderma hamatum 382 consistently provided a significant (P = 0.05) degree of protection against bacterial spot of tomato and its pathogen Xanthomonas ...euvesicatoria 110c compared with the control peat mix, even though this biocontrol agent did not colonize aboveground plant parts. To gain insight into the mechanism by which T. hamatum 382 induced resistance in tomato, high-density oligonucleotide microarrays were used to determine its effect on the expression pattern of 15,925 genes in leaves just before they were inoculated with the pathogen. T. hamatum 382 consistently modulated the expression of genes in tomato leaves. We identified 45 genes to be differentially expressed across the replicated treatments, and 41 of these genes could be assigned to at least one of seven functional categories. T. hamatum 382-induced genes have functions associated with biotic or abiotic stress, as well as RNA, DNA, and protein metabolism. Four extensin and extensin-like proteins were induced. However, besides pathogenesis-related protein 5, the main markers of systemic acquired resistance were not significantly induced. This work showed that T. hamatum 382 actively induces systemic changes in plant physiology and disease resistance through systemic modulation of the expression of stress and metabolism genes.
Airway remodelling, characterised by increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia and mucus gland hypertrophy, is a feature of chronic asthma. Increased ...arginase activity could contribute to these features via increased formation of polyamines and l-proline downstream of the arginase product l-ornithine, and via reduced nitric oxide synthesis. Using the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH), we studied the role of arginase in airway remodelling using a guinea pig model of chronic asthma. Ovalbumin-sensitised guinea pigs were treated with ABH or PBS via inhalation before each of 12 weekly allergen or saline challenges, and indices of arginase activity, and airway remodelling, inflammation and responsiveness were studied 24 h after the final challenge. Pulmonary arginase activity of repeatedly allergen-challenged guinea pigs was increased. Allergen challenge also increased ASM mass and maximal contraction of denuded tracheal rings, which were prevented by ABH. ABH also attenuated allergen-induced pulmonary hydroxyproline (fibrosis) and putrescine, mucus gland hypertrophy, goblet cell hyperplasia, airway eosinophilia and interleukin-13, whereas an increased l-ornithine/l-citrulline ratio in the lung was normalised. Moreover, allergen-induced hyperresponsiveness of perfused tracheae was fully abrogated by ABH. These findings demonstrate that arginase is prominently involved in allergen-induced airway remodelling, inflammation and hyperresponsiveness in chronic asthma.
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 goal of this study is to investigate the immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in former pneumococcal CAP patients. We hypothesize that an impaired or suboptimal ...humoral immune response against (specific) pneumococcal serotypes might explain the vulnerability for pneumococcal disease.
Hospitalised adult CAP patients who participated in two trials (2004–2006 (n=201) and, 2007–2009 (n=304)) were screened. Patients eligible for inclusion had CAP caused by either S. pneumoniae (pneuCAP) or due to another well-defined pathogen (otherCAP). Serotype-specific pneumococcal antibody concentrations (total IgG and IgG2/IgG1) before and 3–4weeks after PCV13 administration were measured (Luminex) and compared between pneuCAP and otherCAP patients.
We vaccinated 60 patients:i.e. 34 pneuCAP and 26 otherCAP patients. In the pneuCAP group, 74% of patients were categorized as good responders (≥9/13 serotypes with concentration≥1300ng/ml), versus 77% in the otherCAP group. Significantly fewer full responders (i.e. 13/13 serotypes with a concentration≥1300ng/mL) were identified in the pneuCAP group (15% vs 42% respectively, p=0.02). For serotype 1, total IgG and IgG2/IgG1 subset post-vaccination concentrations were significantly lower among pneuCAP patients. Our additional case-series showed that of 16 pneuCAP patients who were infected by a serotype included in PCV13 three patients did not respond against the serotype originally responsible for their CAP episode, including one former bacteraemic pneumococcal CAP patient who also failed to show a response against the serotype responsible for CAP during infection. Thirteen patients did respond to the previously infecting serotype following PCV13 including three patients who had bacteraemic pneumococcal pneumonia and did not show a response during infection against the serotype responsible for CAP.
Our results confirm the immunogenic properties of PCV13 in former pneumococcal CAP patients including patients previously regarded as potential hyporesponders. A slightly diminished overall humoral response to polysaccharides characterizes the former pneumococcal CAP patients.
ClinicalTrials.gov Identifier: NCT02141009.
In the field of motion-based simulation, it was found that a visual amplitude equal to the inertial amplitude does not always provide the best perceived match between visual and inertial motion. This ...result is thought to be caused by the “quality” of the motion cues delivered by the simulator motion and visual systems. This paper studies how different visual characteristics, like field of view (FoV) and size and depth cues, influence the scaling between visual and inertial motion in a simulation environment. Subjects were exposed to simulator visuals with different fields of view and different visual scenes and were asked to vary the visual amplitude until it matched the perceived inertial amplitude. This was done for motion profiles in surge, sway, and yaw. Results showed that the subjective visual amplitude was significantly affected by the FoV, visual scene, and degree-of-freedom. When the FoV and visual scene were closer to what one expects in the real world, the scaling between the visual and inertial cues was closer to one. For yaw motion, the subjective visual amplitudes were approximately the same as the real inertial amplitudes, whereas for sway and especially surge, the subjective visual amplitudes were higher than the inertial amplitudes. This study demonstrated that visual characteristics affect the scaling between visual and inertial motion which leads to the hypothesis that this scaling may be a good metric to quantify the effect of different visual properties in motion-based simulation.
Coffee consumption has been associated with a reduced risk of developing colorectal cancer (CRC). However, it is not clear whether coffee consumption is related to CRC progression. Hence, we assessed ...the association of coffee consumption with CRC recurrence and all‐cause mortality using data from a prospective cohort study of 1719 stage I–III CRC patients in the Netherlands. Coffee consumption and other lifestyle characteristics were self‐reported using questionnaires at the time of diagnosis. We retrieved recurrence and all‐cause mortality data from the Netherlands Cancer Registry and the Personal Records Database, respectively. Cox proportional hazard regression models with and without restricted cubic splines were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age, sex, education, smoking status, cancer stage and tumor location. We observed 257 recurrences during a 6.2‐year median follow‐up and 309 deaths during a 6.6‐year median follow‐up. Consuming more than 4 cups/d of coffee compared to an intake of <2 cups/d was associated with a 32% lower risk of CRC recurrence (95% CI: 0.49, 0.94,). The association between coffee consumption and all‐cause mortality was U‐shaped; coffee intake seemed optimal at 3–5 cups/d with the lowest risk at 4 cups/d (HR: 0.68, 95% CI: 0.53, 0.88). Our results suggest that coffee consumption may be associated with a lower risk of CRC recurrence and all‐cause mortality. The association between coffee consumption and all‐cause mortality appeared nonlinear. More studies are needed to understand the mechanism by which coffee consumption might improve CRC prognosis.
What's new?
Although existing evidence suggests that coffee consumption may lower colorectal cancer risk, the association with colorectal cancer prognosis remains unclear. This large prospective study of stage I–III patients in a country with a relatively high coffee intake revealed a strong inverse association between coffee consumption and colorectal cancer recurrence. The association between coffee consumption and all‐cause mortality in colorectal cancer patients was nonlinear, suggesting an optimal intake of three to five cups per day. The findings could potentially inform future intervention studies as well as dietary guidelines for colorectal cancer patients.
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