Agricultural service providers often work closely with producers, and are well positioned to include weather and climate change information in the services they provide. By doing so, they can help ...producers reduce risks due to climate variability and change. A national survey of United States Department of Agriculture Farm Service Agency (FSA) field staff (n = 4621) was conducted in 2016. The survey was designed to assess FSA employees’ use of climate and weather-related data and explore their perspectives on climate change, attitudes toward adaptation and concerns regarding climate- and weather-driven risks. Two structural equation models were developed to explore relationships between these factors, and to predict respondents’ willingness to integrate climate and weather data into their professional services in the future. The two models were compared with assess the relative influence of respondents’ current use of weather and climate information. Findings suggest that respondents’ perceptions of weather-related risk in combination with their personal observations of weather variability help predict whether an individual intends to use weather and climate information in the future. Importantly, climate change belief is not a significant predictor of this intention; however, the belief that producers will have to adapt to climate change in order to remain viable is. Surprisingly, whether or not an individual currently uses weather and climate information is not a good predictor of whether they intend to in the future. This suggests that there are opportunities to increase employee exposure and proficiency with weather and climate information to meet the needs of American farmers by helping them to reduce risk.
Early studies of a cobalt-based alloy stent coated with the novel antiproliferative agent zotarolimus and a phosphorylcholine polymer have demonstrated significant reductions in angiographic ...restenosis and target vessel revascularization compared with bare metal stents. However, the generalizability of the angiographic outcomes and clinical benefit of zotarolimus-eluting stents (ZESs) to a more real-world patient population is undetermined. Clinical and angiographic outcomes in 1,317 patients treated with the ZES in the first 4 trials of the Endeavor ZES (Medtronic Vascular, Santa Rosa, CA) clinical trials program were pooled for systematic analysis. Protocol-specified follow-up angiography was performed at 8 or 12 months for a subset of 750 of these patients, and clinical follow-up was performed at 9 months after the index procedures in all patients. Diabetes mellitus was present in 22.5% of patients, the mean reference vessel diameter was 2.73 mm, and the mean lesion length was 14.59 mm. At 8 months (12 months for ENDEAVOR I), mean ± SD in-stent late luminal loss was 0.61 ± 0.49 mm. In-stent late luminal loss was greatest in larger caliber (>2.9 mm) vessels (0.65 ± 0.49 mm) and longer (>16.3 mm) lesions (0.70 ± 0.52 mm) but did not statistically vary according to diabetic status. At 9 months, overall rates of target lesion revascularization (TLR) and major adverse cardiac events (MACE) were 4.9% and 7.7%, respectively. The rate of TLR at 12 months was not significantly different relative to diabetes and lesion length >16.3 mm (7.2% and 7.7%, respectively), although TLR was significantly more common when reference vessel diameter was <2.5 mm (8.5%; p = 0.013). At 24 months, overall rates of TLR and MACE were 6.5% and 9.9%, respectively. The overall 24-month rate of stent thrombosis was 0.3%, with no events occurring >14 days after the procedure. Despite varied clinical and angiographic characteristics, treatment with the ZES is associated with consistently low rates of TLR and overall major adverse events, including stent thrombosis. Although these findings indicate the efficacy and safety of the ZES over the time course of the first 4 ENDEAVOR clinical trials, additional ongoing study with more open patient inclusion criteria (including long lesions, small vessels, bifurcations, etc) will be important for discerning whether comparable clinical outcomes can be extended to lesion subsets of higher complexity.
Structure of the β-Amyloid(10 - 35) Fibril Burkoth, Timothy S; Benzinger, Tammie L. S; Urban, Volker ...
Journal of the American Chemical Society,
08/2000, Letnik:
122, Številka:
33
Journal Article
Recenzirano
The primary component of the amyloid plaques in Alzheimer's disease (AD) is a highly ordered fibril composed of the 39−43 amino acid peptide, β-amyloid (Aβ). The presence of this fibril has been ...correlated with both the onset and severity of the disease. Using a combination of synthetic model peptides, solid-state NMR, electron microscopy, and small angle neutron scattering (SANS), methods that allowed fibrils to be studied directly both in solution and in the solid state, the three-dimensional structure of fibrils formed from Aβ(10 - 35) is assigned. The structure consists of six laminated β-sheets propagating and twisting along the fibril axis. Each peptide strand is oriented perpendicular to the helical axis in a parallel β-sheet, with each like amino acid residue in register along the sheet. The six sheets are laminated, probably also in parallel arrays, to give a fibril with dimensions of about 60 × 80 Å. Both the methodology developed and the structural insight gained here lay the foundation for strategies to characterize and design materials capable of amyloid-like self-assembly.
Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 ...microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
Abstract Adenovirus serotype 5 (Ad5) vectors are well suited for gene therapy. However, tissue-selective transduction by systemically administered Ad5-based vectors is confounded by viral particle ...sequestration in the liver. Hexon-modified Ad5 expressing reporter gene under transcriptional control by the immediate/early cytomegalovirus (CMV) or the Roundabout 4 receptor (Robo4) enhancer/promoter was characterized by growth in cell culture, stability in vitro, gene transfer in the presence of human coagulation factor X, and biodistribution in mice. The obtained data demonstrate the utility of the Robo4 promoter in an Ad5 vector context. Substitution of the hypervariable region 7 (HVR7) of the Ad5 hexon with HVR7 from Ad serotype 3 resulted in decreased liver tropism and dramatically altered biodistribution of gene expression. The results of these studies suggest that the combination of liver detargeting using a genetic modification of hexon with an endothelium-specific transcriptional control element produces an additive effect in the improvement of Ad5 biodistribution.
315
Background: Invasive procedures including biopsies in freshly irradiated tissue is a known risk factor for high-grade toxicity. Screening colonoscopies (CS) are often performed before ...radiotherapy given the need to rule out comorbid gastrointestinal conditions and avoid untoward post radiotherapy instrumentation of the pelvis. We investigate the association of pre-treatment CS and the colonic finding therein with subsequent GI toxicity following SBRT for prostate cancer. Methods: An institutional registry of patients undergoing five-fraction prostate SBRT was interrogated to identify those who underwent screening CS prior to radiotherapy from Feb. 2021 – May 2023. Patients were categorized into those who did and did not undergo CS within 6 months of SBRT. A detailed analysis of CS findings including polyp resection as well as presence of diverticulosis and hemorrhoids was performed. Post-SBRT toxicity was evaluated using CTCAE v 5.0. Groups were compared using the chi-square or Fisher’s exact test for categorical variables. The Mann-Whitney test was used to compare groups for time from CS to SBRT and presented as median (25
th
, 75
th
percentiles). A result was considered significant at p < 0.05. Results: In this cohort, a total of 156 patients underwent prostate SBRT with the distribution of risk grouping was as follows: low 9% (n = 14), intermediate 67% (n = 104), and high 24% (n = 38). Of the entire group, a total of 138 patients underwent pre-treatment CS with a median time from CS to SBRT of 4 months. There was no difference in grade 1+ GI toxicity (67% vs. 61%, p = 0.60) in patients who did and did not undergo pretreatment CS. However, there was a significantly higher grade 2+ GI toxicity in patients who did not undergo pretreatment CS (45% vs. 15%, p = 0.03). Of the 138 subjects who underwent CS, time from CS to SBRT was not different between those who did and did not have any GI toxicity (4.6 months versus 3.3 months, p = 0.08) or between those who had grade 1 vs. grade 2+ toxicity (4.6 versus 4.7 months, p = 0.65). Notably, there was not an increased rate of GI toxicity in patients found to have diverticulosis (61.1% vs. 74.2%, p = 0.11), hemorrhoids (62.3% vs. 70.6%, p = 0.31), or resected polyps (70% vs. 64.7%, p = 0.51) on pre-SBRT CS. Finally, patients who had polyps resected in the rectosigmoid did not have a higher rate of GI toxicity versus those who under polyp resection elsewhere in the colon (57.6% vs. 71.4% respectively, p = 0.23). Conclusions: Pretreatment CS was not associated with an increased risk of GI toxicity following prostate SBRT, and in fact was associated with a lower rate of grade 2+ GI toxicity. Moreover, identification of polyps requiring resection (in the rectosigmoid or elsewhere), diverticulosis, and hemorrhoids on pretreatment CS did not result in excess GI toxicity following SBRT.
In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (
p
= 0.003, log-rank test), while ...meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (
p
= 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (
n
) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang–Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.
Current healthcare systems do not effectively promote weight reduction in patients with obesity and gastroesophageal reflux disease (GERD). The Reflux Improvement and Monitoring (TRIM) program ...provides personalized, multidisciplinary, health education and monitoring over 6 months. In this study we aimed to (i) measure the effectiveness of TRIM on GERD symptoms, quality of life, and weight, and (ii) examine patient health beliefs related to TRIM.
This prospective mixed methods feasibility study was performed at a single center between September 2015 and February 2017, and included adult patients with GERD and a body mass index ≥30 kg/m
. Quantitative analysis consisted of a pre- to post-intervention analysis of TRIM participants (+TRIM Cohort) and a multivariable longitudinal mixed model analysis of +TRIM vs. patients who declined TRIM (-TRIM Cohort). Primary outcomes were change in patient-reported GERD symptom severity (GerdQ) and quality of life (GerdQ-DI), and change in percent excess body weight (%EBW). Qualitative analysis was based on two focus groups of TRIM participants.
Among the +TRIM cohort (n=52), mean baseline GerdQ scores (8.7±2.9) decreased at 3 months (7.5±2.2; P<0.01) and 6 months (7.4±1.9; P=0.02). Mean GerdQ-DI scores decreased, but did not reach statistical significance. Compared with the -TRIM cohort (n=89), reduction in %EBW was significantly greater at 3, 6, and 12 months among the +TRIM cohort (n=52). In qualitative analysis, patients unanimously appreciated the multidisciplinary approach and utilized weight loss effectively to improve GERD symptoms.
In this mixed methods feasibility study, participation in TRIM was associated with symptom improvement, weight reduction, and patient engagement.
Randomized controlled trials are the "gold standard" for estimating the causal effects of treatments. However, it is often not feasible to conduct such a trial because of ethical concerns or ...budgetary constraints. We expand upon an approach to the analysis of observational data sets that mimics a sequence of randomized studies by implementing propensity score models within each trial to achieve covariate balance, using weighting and matching. The methods are illustrated using data from a safety study of the relationship between second-generation antipsychotics and type 2 diabetes (outcome) in Medicaid-insured children aged 10-18 years across the United States from 2003 to 2007. Challenges in this data set include a rare outcome, a rare exposure, substantial and important differences between exposure groups, and a very large sample size.
Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and ...specific pathways, and the functional consequences.
Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro.
TSPAN12 was the gene most correlated with fibrostenosis (r = −0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34–0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = −0.41, P < .001), and genes enriched in cell cycle–related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti–IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell–fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling.
Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.
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We deciphered the role of TSPAN12 in fibrostenotic eosinophilic esophagitis by transcriptomic analysis across a multisite cohort, its association with clinical parameters and specific pathways, and the functional consequences in vitro.
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