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OBJECTIVE Histology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I-III). In patterns I and II, a T-cell- and macrophage-associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers. METHODS We evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow-up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112). RESULTS A strong association of a ringlike enhancement and a hypointense T2-weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients. INTERPRETATION We provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440-454.

Crossbred Angus cow–calf pairs (n = 28 pairs) at the Central Grasslands Research Extension Center (Streeter, ND) were used to evaluate an electronic feeder to monitor individual mineral intake and feeding behavior and their relationship with growth performance and liver mineral concentrations. Cows and calves were fitted with radio frequency identification ear tags that allowed access to an electronic feeder (SmartFeed system; C-Lock Inc., Rapid City, SD) and were provided ad libitum minerals (Purina Wind and Rain Storm, Land O’Lakes, Inc., Arden Hills, MN). Mineral intake, number of visits, and duration at the feeder were recorded over a 95-d monitoring period while pairs were grazing native range. Liver biopsies were collected from a subset of cows on the final day of monitoring and analyzed for mineral concentrations. Data were analyzed with the GLM procedure in SAS for mineral intake and feeding behavior with age class (cows vs. calves), intake category (high vs. low), and the interaction between class and category in the model. Correlations were calculated among cow feeding behavior and calf intake and growth performance with the CORR procedure, and a comparison of liver mineral concentrations among cows of high (>90 g/d; average 125.4 g/d) and low (50 g/d; average 72.2 g/d) consumed greater (P < 0.001) amounts of minerals than low-intake calves (

Three experiments were conducted to evaluate supplementation strategies for beef cattle grazing in the Northern Great Plains. In experiment 1, 28 cow-calf pairs had access to electronic feeders (SmartFeed system; C-Lock Inc., Rapid City, SD) that monitored individual vitamin and mineral supplement (VTM) intake. Cows had greater VTM intakes (81.1 ± 8.2 g/d; P < 0.01) than calves (44.2 ± 8.6 g/d) but both attended feeders a similar (P = 0.71) proportion of days. Furthermore, we noted greater (P < 0.01) concentrations of Se, Cu, and Co in livers of HIGH intake cows compared to LOW intake cows. Experiment 2, we used the SmartFeed system to regulate intake of individual heifers (n = 60) in a group pasture scenario assigned to control (CON), VTM, or energy supplement (NRG) treatments, and evaluated supplement intake, and concentrations of liver mineral and metabolites. Though no differences were observed in BW and ADG, treatments that provided VTM enhanced liver concentrations of Se, Fe, Cu, and Co (P < 0.05). No differences (P = 0.85) were observed in concentrations of NEFA; however, NRG heifers had greater (P = 0.01) glucose concentrations than CON and VTM heifers. Experiment 3 objectives were to determine the influence of feeding VTM and NRG supplements to beef heifers (n = 35) during the first 84 days of pregnancy on concentrations of progesterone (P4), corpus luteum (CL) size and fetal body measurements. Providing NRG during early gestation resulted in heavier CLs (P = 0.003) that produced more P4 (P = 0.002) and greater fetal femur growth (P = 0.009) whereas providing VTM enhanced fetal liver growth (P = 0.05). Overall, we were able to successfully monitor and control individual mineral intake, corroborated those differences in liver mineral concentrations, and observed alterations in fetal growth after mineral and energy supplementation.

Background : Our aim was to measure the impact of two cycles of standard chemotherapy on tumoral neoangiogenesis by [18F] Fluorine arginine-glycine-aspartic (RGD-K5) Positron Emission Tomography – Computed Tomography (PET) on patients presenting with lymphoma.Twenty one patients were prospectively included in Rouen’s Henri Becquerel Cancer Center. Fluorodeoxyglucose (FDG) and RGD-K5 PET were performed before (C0) and after (C2) two cycles of chemotherapy. End of treatment FDG PET was performed for final staging. Maximum Standardized Uptake Value (SUVmax), Mean SUV and Metabolic Tumor Volume (MTV) were measured for all lesions. RGD SUVmax and meanSUV were also analysed in 13 normal organs at C0 and C2. Patient’s treatment response was considered using Deauville score (DS) on end of treatment FDG PET. (DS 1 to 3 were considered as responders, DS 4 and 5 non-responders).Results : Nineteen patients had both C0 FDG and C0 RGD PET. Twelve patients had both C2 FDG and C2 RGD, completed treatment protocol and were included for end of treatment analysis. No statistical difference was found on normal organs RGD uptake before and after chemotherapy for SUVmax and SUVmean. On C0 RGD, apart from Classical Hodgkin lymphoma (cHL)and Grey Zone Lymphoma (GZL), other lymphoma sub-types had low RGD uptake (pConclusions : Our study showed significant higher initial RGD uptake in patients presenting with cHL and GZL compared to NHL. Non responder patients also had higher post chemotherapy RGD uptake compared to responder patients. Issues raised by RGD uptake, particularly in cHL, are yet to be explored and need to be confirmed in a larger population.

Nonenzymatic glycation (NEG) of human hemoglobin (Hb A) consists of initial non covalent, reversible steps involving glucose and amino acid residues, which may also involve effector reagent(s) in the formation of labile Hb A1c (the conjugate acid of the Schiff base). Labile Hb A1c can then undergo slow, largely irreversible, formation of stable Hb A1c (the Amadori product). Stable Hb A1c is measured to assess diabetic progression after labile Hb A1c removal. This study aimed to increase the understanding of the distinctions between labile and stable Hb A1c from a mechanistic perspective in the presence of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-Bisphosphoglycerate is an effector reagent that reversibly binds in the Hb A1c pocket and modestly enhances overall NEG rate. The deprotonation of C2 on labile Hb A1c in the formation of the Amadori product was previously proposed to be rate-limiting. Computational chemistry was used here to identify the mechanism(s) by which 2,3-BPG facilitates the deprotonation of C2 on labile Hb A1c. 2,3-Bisphosphoglycerate is capable of abstracting protons on C2 and the α-nitrogen of labile Hb A1c and can also deprotonate water and/or amino acid residues, therefore preparing these secondary reagents to deprotonate labile Hb A1c. Parallel reactions not leading to an Amadori product were found that include formation of the neutral Schiff base, dissociation of glucose from the protein, and cyclic glycosylamine formation. These heretofore under appreciated parallel reactions may help explain both the selective removal of labile from stable Hb A1c and the slow rate of NEG.

Purpose To determine host and pathogen factors predictive of outcomes in a large clinical cohort with keratoconjunctivitis. Design Retrospective analyses of the clinical and molecular data from a randomized, controlled, masked trial for auricloscene for keratoconjunctivitis (NVC-422 phase IIB, NovaBay; clinicaltrials.gov identifier, NCT01877694). Participants Five hundred participants from United States, India, Brazil, and Sri Lanka with clinical diagnosis of keratoconjunctivitis and positive rapid test results for adenovirus. Methods Clinical signs and symptoms and bilateral conjunctival swabs were obtained on days 1, 3, 6, 11, and 18. Polymerase chain reaction (PCR) analysis was performed to detect and quantify adenovirus in all samples. Regression models were used to evaluate the association of various variables with keratoconjunctivitis outcomes. Time to resolution of each symptom or sign was assessed by adenoviral species with Cox regression. Main Outcome Measures The difference in composite scores of clinical signs between days 1 and 18, mean visual acuity change between days 1 and 18, and time to resolution of each symptom or sign. Results Of 500 participants, 390 (78%) showed evidence of adenovirus by PCR. Among adenovirus-positive participants, adenovirus D species was most common (63% of total cases), but a total of 4 species and 21 different types of adenovirus were detected. Adenovirus D was associated with more severe signs and symptoms, a higher rate of subepithelial infiltrate development, and a slower decline in viral load compared with all other adenovirus species. The clinical courses of all patients with non–adenovirus D species infection and adenovirus-negative keratoconjunctivitis were similar. Mean change in visual acuity between days 1 and 18 was a gain of 1.9 letters; worse visual outcome was associated with older age. Conclusions A substantial proportion of keratoconjunctivitis is not associated with a detectable adenovirus. The clinical course of those with adenovirus D keratoconjunctivitis is significantly more severe than those with non–adenovirus D species infections or adenovirus-negative keratoconjunctivitis; high viral load at presentation and non-United States origin of participants is associated with poorer clinical outcome.

Background The German clinical guideline on tobacco addiction recommends that general practitioners (GPs) provide brief stop-smoking advice to their patients according to the “5A” or the much briefer “ABC” method, but its implementation is insufficient. A lack of training is one barrier for GPs to provide such advice. Moreover, the respective effectiveness of a 5A or ABC training regarding subsequent delivery of stop-smoking advice has not been investigated. We developed a training for GPs according to both methods, and conducted a pilot study with process evaluation to optimize the trainings according to the needs of GPs. This study aims at evaluating the effectiveness of both trainings. Methods A pragmatic 2-arm cluster randomised controlled trial with a pre-post data collection will be conducted in 48 GP practices in North Rhine-Westphalia (Germany). GPs will be randomised to receive a 3.5-h-training in delivering either 5A or ABC, including peer coaching and intensive role plays with professional actors. The patient-reported primary outcome (receipt of GP advice to quit: yes/no) and secondary outcomes (recommendation rates of smoking cessation treatments, group comparison (5A versus ABC): receipt of GP advice to quit) will be collected in smoking patients routinely consulting their GP within 4 weeks prior, and 4 weeks following the training. Additional secondary outcomes will be collected at 4, 12 and 26 weeks following the consultation: use of cessation treatments during the last quit attempt (if so) since the GP consultation, and point-prevalence abstinence rates. The primary data analysis will be conducted using a mixed-effects logistic regression model with random effects for the cluster variable. Discussion If the training increases the rates of delivery of stop-smoking advice, it would offer a low-threshold strategy for the guideline implementation in German primary care. Should one method prove superior, a more specific guideline recommendation can be proposed. Trial registration German Clinical Trials Register (DRKS00012786); registered on 22th August 2017, prior to the first patient in. Open-Access-Publikationsfonds 2019

Nonenzymatic glycation (NEG) of human hemoglobin (Hb A) consists of initial non covalent, reversible steps involving glucose and amino acid residues, which may also involve effector reagent(s) in the formation of labile Hb A(1c) (the conjugate acid of the Schiff base). Labile Hb A(1c) can then undergo slow, largely irreversible, formation of stable Hb A(1c) (the Amadori product). Stable Hb A(1c) is measured to assess diabetic progression after labile Hb A(1c) removal. This study aimed to increase the understanding of the distinctions between labile and stable Hb A(1c) from a mechanistic perspective in the presence of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-Bisphosphoglycerate is an effector reagent that reversibly binds in the Hb A(1c) pocket and modestly enhances overall NEG rate. The deprotonation of C2 on labile Hb A(1c) in the formation of the Amadori product was previously proposed to be rate-limiting. Computational chemistry was used here to identify the mechanism(s) by which 2,3-BPG facilitates the deprotonation of C2 on labile Hb A(1c). 2,3-Bisphosphoglycerate is capable of abstracting protons on C2 and the α-nitrogen of labile Hb A(1c) and can also deprotonate water and/or amino acid residues, therefore preparing these secondary reagents to deprotonate labile Hb A(1c). Parallel reactions not leading to an Amadori product were found that include formation of the neutral Schiff base, dissociation of glucose from the protein, and cyclic glycosylamine formation. These heretofore under appreciated parallel reactions may help explain both the selective removal of labile from stable Hb A(1c) and the slow rate of NEG.

Nonenzymatic glycation (NEG) begins with the non-covalent binding of a glucopyranose to a protein. The bound glucopyranose must then undergo structural modification to generate a bound electrophile that can reversibly form a Schiff base, which can then lead to Amadori intermediates, and ultimately to glycated proteins. Inorganic phosphate (Pi) is known to accelerate the glycation of human hemoglobin (HbA), although the specific mechanism(s) of Pi as an effector reagent have not been determined. The aim of this study was to determine whether Pi and a glucopyranose can concomitantly bind to HbA and react while bound within the early, noncovalent stages to generate electrophilic species capable of progress in NEG. 31P and 1HNMR of model reactions confirm that bimolecular reactions between Pi and glucopyranose occur generating modified glucose electrophiles. Computations of protein/substrate interactions predict that Pi can concomitantly bind with a glucopyranose in HbA pockets with geometries suitable for multiple acid/base mechanisms that can generate any of four transient electrophiles. Pi-facilitated mechanisms in the noncovalent stages predict that the glycation of β-Val1 of HbA to HbA1c is a “hot spot” because the β-Val1 pocket facilitates many more mechanisms than any other site. The mechanistic diversity of the Pi effect within the early noncovalent stages of NEG predicts well the overall site selectivity observed from the in vivo glycation of HbA in the presence of Pi. These insights extend our basic understanding of the NEG process and may have clinical implications for diabetes mellitus and even normal aging.

The accurate simulation of stray light is essential for the verification of the contrast requirements in optical instruments. In a spectrometer, the scattering from reflective gratings is difficult to characterize while contributing significantly to the overall system stray light and reduction of the spectrometer contrast. In addition, the multiple diffraction orders create a ghost sensitive environment, which must be considered in the design of the instrument. In this article, we present an experimental setup for, and measurement results from, the characterization of the bidirectional scattering distribution function (BSDF) of a holographic grating for a spectrometer applied in a typical earth observation mission with demanding stray light requirements. We observed distinct stray light peaks out of the diffraction plane, which are called ‘satellites.’ The main challenges in the measurement of grating BSDFs arise from the near angle limit, the determination of the instrument signature and the selection of the appropriate sampling (2D or 3D). Following the grating characterization, the next step is to introduce these measured BSDFs into stray light simulation. We have done that by fitting appropriate functions to the measured BSDF and defining them in the optical analysis software ASAP as a user-defined BSDF. Ghost analysis is done at the spectrometer level as a sensitivity analysis of the tilts of the optical elements. Due to the ghosting of higher diffraction orders of the grating, a high sensitivity to the tilts of some of the optical elements can be seen.

Daily sperm production in bulls is determined by the size of the testicular Sertoli cell (SC) population established before puberty. Fine needle aspiration (FNA) is currently used as a diagnostic tool, but its value to determine SC and germ cell (GC) counts remains unexplored. The objectives were to compare three sampling techniques [(smears produced via 22G fine needle aspiration (SMR) vs. tissue sections collected via 14G aspiration (FNS) vs. conventional tissue sections (HIS)] and two stains [immunohistochemistry with GATA4 (IHC) and HE] to determine SC density in prepubertal bulls. Fourteen age-matched Angus bulls were surgically castrated. Testicular parenchyma samples and smears were stained using anti-GATA4 as a specific SC marker and HE. For stain comparison, mirrored tissue cuts were produced allowing cell counts of complementary seminiferous tubule (ST) cross sections. All data were analyzed using Pearson’s product moment correlations and linear regression. Testicular weights were correlated with IHC SC density (P = 0.018). High correlations existed for SC and GC counts done on ST cross sections using IHC (P < .0001) and HE (P < .0001). Within HIS and FNS, high correlations (r = 0.955; P ≤ 0.0001) existed between SC and automated GATA4+ cell densities. However, when comparing IHC SC density across techniques, no significant correlations (P ≤ 0.587) existed. The high correlation observed between SC counts done on mirrored ST cross sections for HE and IHC underlines the value of GATA4 as a specific SC marker in prepubertal bulls. Furthermore, the high correlation established between SC and GATA4+ cell densities within IHC HIS and FNS collection methods infers SC density determination can be automated. However, lack of correlation for SC density among techniques indicates that aspiration and conventional methods lead to different results. Research supported by North Dakota EPSCoR Doctoral Dissertation Assistantship (DDA) program.

Background: This study tested the null hypothesis that nonoperatively treated patients would not show disease progression of carpal tunnel syndrome (CTS) over time according to median nerve distal motor latency (DML) on two electrodiagnostic tests. Methods: This retrospective study analyzed sixty-two adult nonoperatively treated patients who were diagnosed with CTS confirmed by a minimum of two electrodiagnostic tests at our institution between December 2006 and tober 2012. A Wilcoxon signed-rank test was conducted to test the difference between electrodiagnostic measurements between the first and last test. Results: The mean time between the first and last electrodiagnostic test was 26±12 months (range, 12 to 55 months). The only electrodiagnostic measurement that increased significantly was the difference between median and ulnar DML on the same side (r=0.19, P =0.038). The time between the electrodiagnostic tests was significantly longer for patients with at least 10% worsening of the DML at the second test compared to cases of which the DML did not worsen or improve a minimum of 10% (P =0.015). Conclusions: There is evidence that—on average—idiopathic median neuropathy at the carpal tunnel slowly progresses over time, and this can be measured with electrodiagnostics, but studies with a much longer interval between lectrodiagnostic tests may be needed to determine if it always progresses.

On fluorine-18 fludeoxyglucose (Three phantoms containing five spheres filled withPhantoms: 4 min was required to obtain a stable quantification with the RRA method. The reference phase and the number of phases used for RRA did not affect the quantification which was similar on static acquisitions but different on ungated images. The results showed that the maximum standard uptake value (SUVSUVAccording to the results obtained using phantoms, RRA method is promising, showing a real impact on the lesion quantification on phantom data. With regard to the patient study, our results showed a trend towards an increase in the SUVs and a decrease in the volume between the ungated and RRA data. We also noticed a statistically significant correlation between the quantitative restoration obtained with RRA compared with ungated data and lesion displacement, indicating that the RRA approach should be reserved to patients with small lesions or nodes moving with a displacement larger than 1.2 cm. Advances in knowledge: This article investigates the performances of motion correction software recently introduced in PET. The conclusion revealed that such respiratory motion correction approach shows a real impact on the lesion quantification but must be reserved to the patient for whom lesion displacement was confirmed and high enough to clearly impact lesion evaluation.

The accuracy of the solution of dynamic general equilibrium models has become a major issue. Recent papers, in which second-order approximations have been substituted for first-order, indicate that this change may yield a significant improvement in accuracy. Second order approximations have been used with considerable success when solving for the decision variables in both small and large-scale models. Additionally, the issue of accuracy is relevant for the approximate solution of value functions. In numerous dynamic decision problems, welfare is usually computed via this same approximation procedure. However, Kim and Kim (Journal of International Economics, 60, 471---500, 2003) have found a reversal of welfare ordering when they moved from first- to second-order approximations. Other researchers, studying the impact of monetary and fiscal policy on welfare, have faced similar challenges with respect to the accuracy of approximations of the value function. Employing a base-line stochastic growth model, this paper compares the accuracy of second-order approximations and dynamic programming solutions for both the decision variable and the value function as well. We find that, in a neighborhood of the equilibrium, the second-order approximation method performs satisfactorily; however, on larger regions, dynamic programming performs significantly better with respect to both the decision variable and the value function.

We describe a new application for NLG technology: the generation of indicative, abstractive summaries of multi-party meetings. Based on the freely available AMI corpus of 100 hours of recorded meetings, we are developing a summarizer that uses the rich annotations in the AMI corpus.