Magnetization Transfer Rate Research Articles

Characterization of HER2 alterations in lung adenocarcinoma.

8534 Background: Mutations in the human epidermal growth factor receptor 2 (ERBB2; HER2) are oncogenic in lung adenocarcinoma (LUAD). An FDA-approved drug, trastuzumab deruxtecan, is now available as second line treatment (rx) of patients (pts) with HER2 mutated NSCLC. HER2 activation occurs via gene mutation (mt), gene amplification (amp), or protein overexpression. Further information is needed about HER2 alterations (alt) and the potential association with rx response. The purpose of this study is to describe the genomic landscape of a cohort of pts with HER2 alt LUAD in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC). Methods: In a cohort of 16,241 NSCLC LUAD pts available in GENIE v.13.0, we analyzed the association of HER2 alt (mt/amp) with alt in other driver genes. Also, we assessed the relationship between HER2 alt and expression levels using TCGA and CPTAC cohorts (566 and 110 pts), and prognosis using GENIE NSCLC BPC cohort (1,846 pts). Results: LUAD pts were classified as having KRASmt (K; 6426 pts; 31.9%), EGFRmt (E; 5256 pts; 26%) or EML4-ALK fusion (A; 102 pts; 0.5%). The remainder were classified as “KRAS/EGFR/ALK other (KEAother).” HER2mt (6.06%) and amp (2.06%) were more frequent in the KEAother cohort(p<0.001). HER2 amp were also found more frequently in the E deletion(del) mt cohort (1.63%), compared to KA cohorts (p<0.001). Additionally, there was significant co-occurrence of HER2 mt and HER2 amp (OR 6.49; p<0.001) in the KEAother cohort. HER2mt/amp had significant odds of co-occurrence with TP53 alt (OR 1.43; p<0.001), CDKN2A del (OR 2.15; p<0.001), TERT amp (OR 2.37; p<0.001), RB1 alt (OR 1.6; p<0.001). Additionally, HER2 amp co-occurred with TP53 alt (OR 4.0; p<0.001), CDKN2A del (OR 3.44; p<0.001), while HER2 mt co-occurred with CDKN2A del (OR 2.03; p<0.001), TERT amp (OR 2.43; p<0.001). BRAF mts were mutually exclusive with HER2 mt/amp (OR 2.31; p<0.001) and HER2 mt (OR 1.93; p<0.001). In the E cohort, there was a significant rate of HER2 mt or amp co-occurring with RB1 alt (OR 2.95; p<0.001). Despite limited survival data in the GENIE database, HER2 mt and amp had a trend toward inferior mOS (HER2mt 29.4 months vs HER2amp 27.8 months vs HER2wt 51.0 months), but this difference was not statistically significant. High HER2 mRNA expression is associated with increased age, while low expression is associated with stage IV disease. Pts with high HER2 expression that never smoked, have a trend toward inferior mOS (p=0.19), but this is based on a limited number of pts (n=18). Conclusions: HER2 mts are found in 1-4% of pts with NSCLC but can be identified in up to 6% of KEAother NSCLC. In contrast to prior reports, there was a significant rate of co-occurring HER2 mt and HER2 amp. BRAF mts were mutually exclusive with both HER2 mt and amp. Further analysis using the Caris database is planned to evaluate clinical outcomes by HER2 alt, co-mts, and prior rx received.

Computational analysis of heat and mass transfer flow of wall jet hybrid nanofluid with irregular heat source/sink effects and waste discharge concentration

Tailoring hybrid nanofluids to attain a specific and regulated heat transmission is done to fulfill the requirements of various applications, including cooling and cooling systems, as well as the automotive and aerospace sectors, among others. Because of its wide range of applications, the objective of this study is to present a numerically derived solution for a problem based on wall jet flow over a stretching surface. In this investigation, the authors have examined a non-Newtonian Eyring-Powell hybrid nanofluid consisting of water and nanoparticles of CoFe2O4 and TiO2. Additionally, the novelty of the paper is to investigate the influence of a magnetic field as well as the presence of an irregular heat sink/source and the waste discharge concentration. The numerical solution is obtained through the use of a similarity transformation technique and the “bvp4c solver implemented in MATLAB”. The higher values of external pollutant source variation parameter and local pollutant external source parameter causes MT rate to decrease. The temperature of the fluid increases significantly, as the heat source parameters become more dominant. The findings from this study hold relevance for a wide array of fields that make use of wall jet (WJ) applications. These fields include car defrosters, sluice gate flows, drying processes for vehicle or building spray paint applications, cooling systems for high-performance laptop CPUs, and cooling jets applied to turbo-machinery components, among others.

Synthesis of silicate clay minerals-based novel Mt/YF3:Eu3+ nanocomposites for regulated luminescent intensity-quantum yield-fluorescence lifetime

Rare earth luminescent materials have broad application prospects in the fields of white light LED lighting, flat panel display, biological imaging and so on. Here, we developed a novel silicate clay minerals-based montmorillonite nanosheet(Mt)/YF3:Eu3+ nanocomposites with strong luminescence performance. Mt carrier plays a three role: (1) reducing the size and improving dispersion of YF3: Eu3+ nanoparticles by surface effect; (2) narrowing down the band gap and increasing Urbach tail energy by interface effect; (3) reducing the shielding of the hole-electron Coulomb interactions while improving the exciton binding energy of YF3:Eu3+, thus improving the radiative recombination by dielectric effect. Therefore, orthogonal phase YF3: Eu3+ nanoparticles (diameter 20∼140 nm) binding to the surface of Mt via chemical bond interactions. The combination of Mt and YF3:Eu3+ not only enhanced luminescent intensity (about 2 times) but also improved the quantum yield (0.14% to 0.4%) and fluorescence lifetime (0.338 ns to 0.405 ns) of YF3:Eu3+ nanoparticles at 595 nm. In addition, the combination of Mt and YF3:Eu3+ give luminescent properties to Mt thereby improving the utilization rate of Mt and YF3: Eu3+ nanoparticles. It was found that the research supplies an insight on the development of new type luminescent materials, and hopefully it could promote them application in many fields.

Abstract Number ‐ 164: Clot Density as a Predictor for Successful Mechanical Thrombectomy

Introduction Switching mechanical thrombectomy techniques (ADAPT, SR or combination) mid procedure has the potential to prolong time to recanalization as well as increase associated healthcare costs. The basis of selecting the frontline technique still relies heavily on the operators’ preference. Conflicting results indicating the varying performance of techniques relative to clot composition have been reported. Clot composition can be estimated based on clot density calculated in Hounsfield Units (HU) on pre‐intervention CT. Identifying how various clot composites behave can aid in the decision making for selecting a frontline technique.Our objective is to determine if clot density as measured by Hounsfield units can predict successful recanalization with ADAPT and the need for rescue stentriever when using ADAPT as the first line technique. Methods Retrospective review of all patients undergoing mechanical thrombectomy with first pass ADAPT at a single urban tertiary care academic stroke center. Clot HU values were calculated on pre‐intervention scans. We evaluated the number of passes, the use of rescue SR, the post intervention TICI grade and mRS on final follow up. Results There were 167 patients that underwent MT with ADAPT as the frontline approach. 122 were excluded for inability to calculate HU on pre‐ intervention scans, most often due to contamination with contrast media. 45 patients were included in the final analysis. 18/45 (40%) required SR rescue due to incomplete recanalization with first pass ADAPT. HU were dichotomized around the mean to “high” and “low”. Higher HU value was associated higher likelihood of SR use and higher final mRS scores, these however did not reach statistical significance. There was no difference in the total number of passes or the final TICI grade. AUC and ROC did not show a correlation between HU value and the use of SR or a higher number of passes need to achieve TICI ≥ 2b recanalization. Conclusions In our patient cohort, HU value was not able to predetermine the success rate of MT using ADAPT. There was no correlation between HU value and functional outcomes of patients. Reliability of clot HU value in determining MT success with ADAPT could not be established. Other factors should be considered when selecting frontline technique in mechanical thrombectomy.

Differentiating active from Inactive Sacroiliitis in ankylosing spondylitis by combination of DWI and Magnetization Transfer Imaging.

To evaluate lesions of sacroiliac joint (SIJ) by combination of diffusion-weighted imaging (DWI) and magnetization transfer (MT). A retrospective study was used in this study. Forty-nine ankylosing spondylitis (AS) patients admitted to The China Academy of Chinese Medical Sciences Xiyuan Hospital from May 2020 to October 2020 were collected into active and inactive groups. Twenty-two healthy volunteers were recruited. Apparent diffusion coefficient (ADC) values for bone marrow edema (BME), sclerosis area, fat deposit area, and normal-appearing bone marrow (NABM) (both patients and healthy volunteers) and the magnetization transfer (MT) rate of the cartilage (MTRc) were analyzed in the groups. The above five parameters (ADC (NABM), ADC (BME) and ADC (fat deposit) and MTRc) between the active group and the inactive group were compared. The effectiveness of each parameter in diagnosing sacroiliac arthritis of ankylosing spondylitis were analyzed, and the predictive value of the parameters was compared. ADC(BME), ADC(NABM) and MTRc showed statistically significant differences between the active and inactive groups (P <0.05). ADC (BME) and ADC (NABM) could predict the activity of AS sacroiliac arthritis (P <0.01). ADC (NABM) and MTRc were significantly different between healthy volunteers and the active group (P <0.01). The areas under the ROC curve (AUCs) of ADC (BME)_ADC(NABM), ADC(NABM)_MTR, and ADC(BME)_MTRc were 0.885 (cut-off value=0.69), 0.849 (cut-off value=0.56) and 0.864 (cut-off value=0.60), respectively. The predictive ability of the combined index ADC (BME)_MTRc and ADC(NABM)_MTRc was increased. The ability to diagnose and predict AS might be improved by the combination of diffusion-weighted imaging (DWI) and magnetization transfer (MT).

Sorption studies of Pb(II) onto montmorillonite clay

In this research, the lead (Pb(II)) removal rate of montmorillonite (Mt) was studied in aqueous solution. The adsorption conditions (contact time, pH, and temperature) were adjusted to study the effect of those factors on the removal rate of Pb(II) adsorption by Mt. The results indicated that the effect of temperature on the Pb(II) removal rate of Mt was not significant. The Pb(II) removal rate was found to be pH-dependent, improving with increasing pH in the range of 3 to 7. The equilibrium time of adsorption was attained after around 1 hour. The adsorption kinetics were analyzed by fitting to three models (pseudo-first-order (PFO) kinetic model, pseudo-second-order (PSO) kinetic model and intraparticle diffusion model. In comparison, R2 value (0.9952) of PSO kinetic model is better than PFO (0.9718), supposing that the adsorption process of Pb(II) onto Mt was chemisorption. The intraparticle diffusion model fitting showed that the Pb(II) adsorption process by Mt was controlled by three steps. Langmuir, Freundlich, Redlich-Peterson and Sips isotherm models were used to describe the adsorption mechanism of Pb(II) adsorbed onto Mt. The experiment results showed the adsorption isotherms are a perfect fit to the Sips model, indicating both homogeneous monolayer adsorption and heterogeneous multilayer adsorption were occurred in the Pb(II) adsorption process by Mt, and the adsorption was mainly controlled by heterogeneous multilayer adsorption.

Pattern of Altered Magnetization Transfer Rate in Alzheimer's Disease.

Biomarkers for Alzheimer's disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available. This study aims to quantify the forward magnetization transfer rate (kfor) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal kfor in AD and AD progression. From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups: 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCI/AD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study. We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCI/AD-to-AD and stable NC. Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression.

Chlorophyll retention reduces storability and pathogen defense in a novel citrus brown flavedo mutant

Residual chlorophylls in harvested crops induce “green seed problem”, which dramatically reduces seed shelf life and storage. However, the effect of residual chlorophylls on fruit storability was largely unexplored. Here, a novel citrus brown flavedo mutant ‘Zong Cheng’ (MT) was explored to understand the effect of residual chlorophylls on fruit postharvest disease and storage. MT fruit remained brown during long-term storage, and residual chlorophyll was observed in the flavedo of MT during the whole storage period. Compared with ‘Lane Late Navel Orange’ (WT), the firmness of MT decreased, while decay incidence, weight loss, respiratory intensity, and the release of ethanol in MT increased during low-temperature storage. The disease infection and decay rate of MT are obviously higher than WT during on-tree or natural storage. Inoculation experiments revealed reduced resistance against Penicillium italicum of MT, further confirming the worse pathogen defense of MT. Perturbations in many stress-responsive phytohormones, primary metabolites, and volatiles were associated with changes in storability and pathogen defense of MT fruit. Noticeably, compared with WT, the content of hydrogen peroxide (H2O2) and the activities of related enzymes were increased in the flavedo of MT during storage. Further studies indicated that chlorophyll retention was closely associated with fewer starch granules and decreased starch content in the flavedo of MT, which might result in decreased firmness and the worse storability of MT. Hence, residual chlorophyll in MT causes excessive ROS accumulation and firmness decrease, and thus reduces storability and pathogen defense in MT fruit. These findings contribute to our understanding of how residual chlorophylls affect fruit storability and disease infection, and help future citrus improvement with an enhanced intrinsic defense mechanism.

Association of interleukin-enhanced factor 2 (ILF2) expression with prognosis and clinico-genomic features in breast cancer (BC).

1030 Background: Novel prognostic and predictive biomarkers beyond traditional histological subtypes are needed to better inform outcomes and enhance therapy guidance in breast cancer (BC). We have previously reported that ILF2 was overexpressed in TNBC cell lines and has a functional role in DNA and RNA metabolism, making it a promising biomarker for risk assessment and treatment decisions. Herein, we aim to leverage a large clinico-genomic dataset to further characterize ILF2 in BC patients (pts). Methods: A total of 9456 BC tissue samples underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Analyses included next generation sequencing of DNA (592 Gene Panel, or Whole Exome Sequencing), and RNA (Whole Transcriptome Sequencing), and immunohistochemistry (IHC). Wilcoxon and Fisher’s exact were used to determine statistical significance. Overall survival (OS) was obtained from insurance claims and Kaplan-Meier estimates were calculated. Spearman correlation was used to identify highly correlated genes (ρ&gt;0.6) with ILF2 and significant genes that were subsequently analyzed via pathway analysis using STRING. Results: BC pts were grouped into ILF2-High (H, top quartile) and ILF2-Low (L, bottom quartile) based on mRNA expression (TPM). ILF2-H pts were significantly younger (73 vs 80% for pts &gt;50), enriched in ductal histology (90.9 vs 77.7%), TNBC subtype (48.9 vs 18.9%), and had a higher CNS metastases rate (4.3 vs 1.4%) compared to ILF2-L pts (all q&lt;0.0001). ILF2 overexpression was associated with significantly inferior OS in all BC pts (HR 3.38, 95%CI: 2.97 – 3.84); when stratified into known BC hormonal receptor (HR) subtypes, ILF2 was prognostic in both HR+ BC (HR 1.7, 95 CI: 1.34-2.19) and TNBC (HR 3.8, 95 CI: 3.1-4.7), all p&lt;0.0001. In TNBC (n=2468), ILF2-H was associated with a higher frequency of TP53 mutations(mt), lower rate of PIK3CA mt and higher amplification of CCNE1 and FGF23; in HR+/HER2- BC (n = 5071), an association with a higher rate of TP53 mt, PD-L1 expression, NOTCH2 and CCND2 amplification was seen (Table). No significant molecular correlation with ILF2 was seen in HR-/HER2+ BC (n=682). In TNBC, ILF2 expression was significantly correlated with genes involved in spliceosome, cell cycle and RNA transport pathways. In HR+/HER2- BC, ILF2-correlated genes were significantly enriched in mismatch repair and DNA replication pathways (p&lt;0.05 for all factors individually). Conclusions: High expression of ILF2 is associated with a poorer prognosis independent of subtype in BC and our study warrants further investigation on ILF2 as a diagnostic and therapeutic target.[Table: see text]

Orientation dependence of inhomogeneous magnetization transfer and dipolar order relaxation rate in phospholipid bilayers

Inhomogeneous magnetization transfer (ihMT) is a novel MRI technique used to measure white matter myelination in the brain and spinal cord. In the brain, ihMT has a strong orientation dependence which is likely to arise from the anisotropy of dipolar couplings between protons on oriented lipids in the myelin bilayers. We measured the orientation dependence of the second moment (M2) of the lineshape, dipolar order relaxation rate (R1D), and ihMT ratio (ihMTR) in an oriented phospholipid bilayer at 9.4 T. We found a strong orientation dependence in all three parameters. ihMTR and R1D were maximized when the bilayers were aligned perpendicular to B0 and minimized near the magic angle (∼54.7°). M2 followed an orientation dependence given by the second Legendre polynomial squared as predicted by the form of the secular dipolar Hamiltonian. These results were used to calculate the orientation dependence of R1D and ihMTR in a diffusionless myelin sheath model, which showed ihMTR was maximised for fibers perpendicular to B0 and minimised at 45°, similar to ex-vivo spinal cord with a larger prepulse frequency offset, but in contrast to in vivo brain findings. Adding fiber dispersion to this model smoothed the orientation dependence curve as expected. Our results suggest the importance of the effects of lipid diffusion and prepulse offset frequency on ihMTR.

Understanding the Importance of Labile Fe(III) during Fe(II)-Catalyzed Transformation of Metastable Iron Oxyhydroxides.

Transformation of metastable Fe(III) oxyhydroxides is a prominent process in natural environments and can be significantly accelerated by the coexisting aqueous Fe(II) (Fe(II)aq). Recent evidence points to the solution mass transfer of labile Fe(III) (Fe(III)labile) as the primary intermediate species of general importance. However, a mechanistic aspect that remains unclear is the dependence of phase outcomes on the identity of the metastable Fe(III) oxyhydroxide precursor. Here, we compared the coupled evolution of Fe(II) species, solid phases, and Fe(III)labile throughout the Fe(II)-catalyzed transformation of lepidocrocite (Lp) versus ferrihydrite (Fh) at equal Fe(III) mass loadings with 0.2-1.0 mM Fe(II)aq at pH = 7.0. Similar to Fh, the conversion of Lp to product phases occurs by a dissolution-reprecipitation mechanism mediated by Fe(III)labile that seeds the nucleation of products. Though for Fh we observed a transformation to goethite (Gt), accompanied by the transient emergence and decline of Lp, for initial Lp we observed magnetite (Mt) as the main product. A linear correlation between the formation rate of Mt and the effective supersaturation in terms of Fe(III)labile concentration shows that Fe(II)-induced transformation of Lp into Mt is governed by the classical nucleation theory. When Lp is replaced by equimolar Gt, Mt formation is suppressed by opening a lower barrier pathway to Gt by heterogeneous nucleation and growth on the added Gt seeds. The collective findings add to the mechanistic understanding of factors governing phase selections that impact iron bioavailability, system redox potential, and the fate and transport of coupled elements.

EPIDEMIOLOGY OF MALIGNANT TUMORS OF THE RESPIRATORY ORGANS IN THE TRANSCARPATHIAN REGION DURING 2015-2019

The aim: Study and analysis of the epidemiological situation of malignant neoplasms of the respiratory system at the regional level during 2015-2019. Materials and methods: The study was based on the analysis of data from the state statistical reporting(forms №7, №35 - healthy) and the database of the National Cancer Registry during 2015 - 2019, which was approved by the conclusion of the bioethics commission of Uzhhorod National University (protocol №2/2 of 15.02.2021). Conclusions: The study found an increase in the level of malignant neoplasms of the respiratory system by 17,28%, as well as the uprise in the proportion of malignant neoplasms of the respiratory system in the structure of all tumours, by 11,98%; detection of malignant neoplasms of the respiratory organs in the late stages; the predominance of the death rate of men from MT over women, as well as mortality rate of the respiratory organs MT up to 1 year from the moment of diagnosis among men is higher over women.

Identification of water compartments in spinal cords by 2 H double quantum filtered NMR.

In 2 H double quantum filtered (DQF) NMR, the various water compartments are characterized by their different residual quadrupolar interactions. The spectral separation between the different signals enables the measurement of the relaxation of each compartment and the magnetization transfer (MT) between them. In the current study, five water compartments were identified in the 2 H DQF spectra of porcine spinal cord. The most prominent signal was the pair of satellites with a quadrupolar splitting of about 550 Hz. 2 H DQF MRI optimized for the 550 Hz quadrupolar splitting indicated that this signal originated mainly from the white matter and it was assigned to the myelin water. This splitting does not change upon changing the orientation of the spinal cord relative to the magnetic field, indicating a liquid crystalline nature. Another site exhibiting splitting of about 1500 Hz was assigned to collagenous connective tissue. The narrow central peak was assigned to a combination of intra- and inter-axonal water. The assignment of the other two sites is not certain and requires further study. The rates of MT between the various sites were recorded.

The impact of the COVID-19 outbreak on acute stroke care in Slovakia: Data from across the country.

A few studies using data from regional databases have recently pointed to a decreased number of patients with stroke. The aim of the present study was to describe country-level data (the number of patients with stroke, the proportion of patients with acute stroke and transient ischemic attack (TIA), the proportion of patients treated with intravenous thrombolysis [IVT] or mechanical thrombectomy [MT], the door-to-needle times [DNT], and the onset-to-needle time [ONT]) during the COVID-19 pandemic in Slovakia. The study examined data from the stroke register at the National Health Information Centre. Data from three time periods (March to April 2020; March to April 2019; January to February 2020) were compared using an independent samples t-test and the Wilcoxon-Mann-Whitney two-sample rank-sum test. The number of stroke patients admitted to hospitals in Slovakia during the COVID-19 period showed a decrease (1673 vs. 2328 in period 2 and 2155 in period 3). The proportions of patients with TIA remained the same in periods 1 and 2 (9.7% vs. 11.7%) and in periods 1 and 3 (9.7 vs. 11.8%). The percentage of patients treated with IVT during the pandemic (22.4%) did not differ from period 2 (20.0%) or period 3 (21.4%). No difference was found in the rate of MT between the COVID-19 period (10.2%) and the same period in 2019 (10.7%) and in January to February 2020 (13.1%). The median DNT remained unchanged in periods 1 (30min), 2 (35min) and 3 (30min), and no differences were found in median ONT in periods 1 (130min), 2 (130min) and 3 (140min). We found a decreased number of stroke patients during the COVID-19 outbreak in Slovakia, but no evidence of achange in the quality of acute stroke care.

Murine typhus. How does it affect us in the 21st century? The epidemiology of inpatients in Spain (1997–2015)

ObjectiveThe aim of this study was to analyze the epidemiological impact of murine typhus in patients who required hospitalization in the National Health System (SNS) in Spain between 1997 and 2015. BackgroundMurine typhus (MT) is a zoonosis caused by Rickettsia typhi. MT is transmitted from rats, cats, dogs, and opossums to humans by their fleas. The clinical picture is characterized by headache, fever, rash, and liver function alteration. The prevalence of MT is considered underestimated since most cases are mild and self-limited. However, up to 10% of patients develop serious complications such as pneumonia or acute kidney injury and may even need admission to intensive care units. MethodsThis was a retrospective longitudinal descriptive study of inpatients diagnosed with Rickettsia typhi infection (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM], 081.0) in Spanish public hospitals between January 1, 1997, and December 31, 2015. Data were obtained from the Minimum Basic Data Set (MBDS, CMBD in Spanish), which includes information about inpatients admitted to the National Health System (NHS) hospitals provided by the Health Information Institute of the Ministry of Health and Equality. ResultsNinety-nine inpatients were included. The incidence rate of MT was 0.12 (95% CI, 0.09-0.14) cases per one million person-years. Cases were irregularly distributed throughout the period of study, with a slight upward trend between 2013 and 2015. The Canary Islands had the highest incidence rate: 2.17 (95% CI, 1.69–2.64) cases per one million person-years (80 cases). Most patients were men (63.6%). The mean age (±SD) was 46.4 years (±19). Five patients were under 15 years old. Approximately 85.9% of cases required urgent hospital admissions. The average hospital stay was 11 days (±9.9). Only 1 patient died. ConclusionsAlthough considered uncommon, the incidence of MT seems to be increasing slowly. Most cases occurred in middle-aged men between late summer and early autumn in Spain. The Canary Islands and Andalusia registered the highest number of cases. The MBDS is an appropriate approach to study MT hospital management.

Quantification of Monomer Units in Insoluble Polymeric Active Pharmaceutical Ingredients Using Solid-State NMR Spectroscopy I: Patiromer.

Although extensive precautions are taken to limit batch-to-batch variation in pharmaceutical manufacturing, differences between lots may still exist, particularly in complex formulations. When polymerization is used in the production process, the potential for varying chain lengths and incorporation of different monomers increases the likelihood of batch-to-batch variation. This poses a significant challenge for demonstrating active pharmaceutical ingredient (API) sameness between the innovator and generic drug under development. Therefore, the ability to accurately analyze and quantify the relative amounts of active ingredients present in a formulated product is critically important. Solid-state nuclear magnetic resonance (SSNMR) spectroscopy was used to identify, quantify, and compare the relative amounts of the three polymer groups in the amorphous block copolymer drug, patiromer (Veltassa®). Techniques such as cross polarization (CP) and magic angle spinning were used to quantify each polymer group while the importance of understanding CP dynamics to obtain quantitative data was also addressed. It was found that the magnetization transfer rate and chemical shift anisotropy for different functional groups present in patiromer play a large role when optimizing parameters for spectral acquisition. Once accounted for, the average patiromer lot contained 90.9%, 7.6%, and 1.5% carboxylate, aromatic, and aliphatic blocks, respectively, with little lot-to-lot variation between different dosage strengths and expiration dates. SSNMR proved to be a sensitive analytical technique for evaluating and quantifying different monomer groups present in patiromer. This procedure may serve as a guide for similar quantitation studies on complex drug products and for demonstrating API sameness during generic drug development.

Multiparametric qMTI Assessment and Monitoring of Normal Appearing White Matter and Classified T1 Hypointense Lesions in Relapsing-Remitting Multiple Sclerosis

BackgroundQuantitative magnetization transfer imaging (qMTI)1 is an efficient technique that is sensitive to the density of the macromolecular protons which are found mainly in white matter myelin. ObjectiveThe aim of this study is to investigate the statistical significance of complementary qMTI parameters including magnetization transfer rate (Ksat)2 and longitudinal relaxation time under MT saturation pulse (T1sat)3 compared to magnetization transfer ratio (MTR)4 and longitudinal relaxation time (T1)5 in relapsing remitting multiple sclerosis (RRMS)6 patients. MethodsIn this study, conventional MRI protocols as well as MT-3DSPGR imaging were performed on twelve clinically definite RRMS patients and twelve age-matched controls. Two general methodologies were utilized for qMTI calculations, including global volumetric measurement of MTI-T1 parameters using a pixel-based analysis method throughout the brain white matter and the regional assessments within classified MS lesions with respect to their hypointensities on T1-weighted scans. MTI-T1 parameters of segmented lesions and normal appearing white matter (NAWM)7 in RRMS patients were evaluated in comparison with normal white matter (NWM)8 of control subjects. ResultsSignificant reductions of MTR and Ksat values in isointense (p<0.0001), mild (p<0.0001) and severe hypointense lesions in comparison with NAWM on T1-weighted scans, were associated with considerable increases in both tissue relaxation times with and without MT pulse, T1sat (p<0.0001) and T1 (p<0.0001) respectively. Similar significant changes of quantitative MT imaging parameters and T1 values were also seen in non-lesion areas of NAWM in MS patients compared to those of NWM in healthy volunteers. ConclusionComplementary qMT imaging parameter contributes to the magnetization transfer phenomenon including Ksat and T1sat can provide more reliable information about the magnitudes and mechanisms of myelin destruction in multiple sclerosis compared to the conventional MTR and T1 relaxation time values.

The origin of negative cross-peaks in proton-spin diffusion spectrum of fully protonated solids at fast MAS: Coherent or incoherent effect?

Spin-diffusion (SD) is amongst the first methods proposed to spatially transfer polarization between dipolar-coupled nuclear spins. Lab-frame SD has proved particularly useful in structural characterization of a large variety of molecules. During SD, the rate of magnetization transfer between the two nuclei depends on the square of the dipolar coupling and the zero-quantum lineshape of the two spins. The relative sign of the diagonal and cross-peaks is determined by the spin part of the dipolar Hamiltonian. Practically, SD experiments are used in two ways: (a) SD transfer amongst only the protons (known as proton spin-diffusion or PSD) and b) SD amongst rare nuclei, coupled to a strong proton bath, known as proton driven spin-diffusion (PDSD). It is well established that the diagonal and cross-peaks have the same sign during SD based polarization transfer. 2D PSD experiments recorded on Histidine.HCl.H2O sample at fast magic angle spinning (MAS) show that some of the cross-peaks in the 2D spectrum are negative with respect to the diagonal peaks. Cross-relaxation due to stochastic motion is generally believed to give rise to such negative peaks. Herein, we use theoretical calculations, numerical simulations and experiments to show that the origin of the negative cross-peaks in PSD spectrum is due to coherent interactions. The origin of negative peaks can be specifically ascribed to a four spin, double-flip-double flop term, in the third-order Hamiltonian. These terms become the dominant terms at fast spinning when additional — conditions are satisfied.

Behavioral and Biochemical Features of the Course and Surgical Treatment of Experimental Obstructive Hydrocephalus in Young Rats

Introduction: Hydrocephalus is a multifactorial disease, affecting the dynamics of cerebrospinal fluid (CSF) and leading to severe neurological impairment in children; in spite of the recent advances in hydrocephalus research, it has many physiopathological aspects that still remain poorly understood, especially after treatment. Objectives: To analyze the clinical, radiological, histopathological, and biochemical aspects of kaolin-induced hydrocephalus in an experimental model, both in the acute phase and after shunt treatment, by means of behavioral tests, magnetic resonance imaging (MRI) scans, histopathological studies, and level of inflammatory interleukins in the CSF. Methods: Seven-day-old Wistar rats were used and subdivided into three subgroups: treated hydrocephalic (n = 24), untreated hydrocephalic (n = 17), and controls (n = 5). The hydrocephalic groups underwent cisternal injection of 15% kaolin for induction of hydrocephalus at 7 days of age. The treated group was submitted to a ventricular-subcutaneous shunt (VSCS) 1 week after induction. All animals were euthanized at 21 days of age. They underwent motor function and memory testing as well as brain MRI scans. Histopathological analysis for glial fibrillary acidic protein and Ki-67 was done, and CSF was collected for measurement of IL-1β, IL-6, and TNF-α. Results: The average time to reach the water maze platform was highest in the untreated hydrocephalic group. The magnetization transfer rates were 37.21 and 33.76 before and after shunting, respectively. The mean astrocyte counts were 2.45, 1.36, and 90.5 for shunted, untreated, and control animals, respectively. The mean CSF IL-1β concentrations were 62.3 and 249.6 pg/mL, the average IL-6 levels were 104.2 and 364.7 pg/mL, and the average TNF-α values were 4.9 and 170.5 pg/mL for the treated hydrocephalic group and the untreated group, respectively. Conclusions: Pups treated with a CSF shunt showed better performance on memory tests. VSCS did not revert demyelination caused by hydrocephalus. Likewise, reactive astrocytosis and cell proliferation over the germinal matrix were not reversed after shunting. Hydrocephalic animals had raised levels of inflammatory interleukins, which returned to normal after treatment.

Distribution and evolution of acute interventional ischemic stroke treatment in Germany from 2010 to 2016

BackgroundMechanical thrombectomy (MT) is a new evidence-based treatment option for large vessel occlusion in the anterior brain circulation. Using comprehensive administrative data from Germany, we analysed the nationwide development of intravenous thrombolysis (IVT) and MT in Germany between 2010 and 2016.MethodsWe considered all documented cases (n = 1,515,634) with a main diagnosis of the ICD-10-GM code I63 (ischemic stroke) and identified specific stroke recanalization therapy by using the corresponding Operating and Procedure Key for systemic thrombolysis and mechanical thrombectomy out of the DRG statistics. Regional analyses are based on data from the 413 German administrative districts and cities and the obligatory quality reports of all hospitals. We distinguished between rates of MT related to place of residence of patients and place of treatment.ResultsCoded ischemic strokes increased by 10.2% from 2010 (n = 206.688) to 2016 (n = 227.687). The rate of IVT increased from 8.9% in 2010 to 14.9% in 2016 and the rate of MT increased from 0.8% in 2010 to 4.7% in 2016 with a strong increase in 2015 and 2016. There was a high regional variability of MT according to place of residence of patients between 0 and 11.2% in 2016 with significant lower treatment rates in rural compared to urban areas (3.8 vs 5.4%). Mean age of patients treated with MT increased from 67.8 years in 2010 to 73.3 years in 2016 and almost reached the mean age of IVT treated patients (74.4 years). The number of hospitals coding MT increased from 91 to 193 from 2010 to 2016, but 80% of all MT procedures were performed in neurointerventional centers with ≥50 procedures/year in 2016.ConclusionsThe rate of IVT in patients with acute ischemic stroke in Germany continues to rise and has reached 14.9% nationwide. The increase of MT is even more pronounced and was triggered by the evidence after publication of the MT randomized trials. There is still a high regional variability with significant lower MT rates in rural areas.