Reaction monitoring via benchtop nuclear magnetic resonance spectroscopy: A practical comparison of on-line stopped-flow and continuous-flow sampling methods.

The ability for nuclear magnetic resonance (NMR) spectroscopy to provide quantitative, structurally rich information makes this spectroscopic technique an attractive reaction monitoring tool. The practicality of NMR for this type of analysis has only increased in the recent years with the influx of commercially available benchtop NMR instruments and compatible flow systems. In this study, we aim to compare 19F NMR reaction profiles acquired under both on-line continuous-flow and stopped-flow sampling methods, with modern benchtop NMR instrumentation, and two reaction systems: a homogeneous imination reaction and a biphasic activation of a carboxylic acid to acyl fluoride. Reaction trends with higher data density can be acquired with on-line continuous-flow analyses, and this work highlights that representative reaction trends can be acquired without any correction when monitoring resonances with a shorter spin-lattice relaxation time (T1), and with the used flow conditions. On-line stopped-flow analyses resulted in representative reaction trends in all cases, including the monitoring of resonances with a long T1, without the need of any correction factors. The benefit of easier data analysis, however, comes with the cost of time, as the fresh reaction solution must be flowed into the NMR system, halted, and time must be provided for spins to become polarized in the instrument's external magnetic field prior to spectral measurement. Results for one of the reactions were additionally compared with the use of a high-field NMR.

The effect of tube quality on externally calibrated quantitative nuclear magnetic resonance analysis: How bad can it be?

Externally calibrated quantitative nuclear magnetic resonance (NMR) approaches offer practical means to simultaneously evaluate chemical identity and content without the addition of calibrants to the test sample. Despite continuous advances in external calibration over the last few decades, adoption of these approaches has been slower than expected. Variations in NMR tube geometry are a commonly overlooked factor that can have a substantial effect on externally calibrated quantitation methods. In this report, we investigate the extent to which tube-to-tube volume variability can affect quantitative NMR outcomes. The results highlight the importance of considering tube quality during the development stages of externally calibrated quantitative methods. In addition, we propose a simple, yet effective volume correction strategy using the residual protonated solvent signal that, based on experiments with mixed NMR tubes of varying quality, alleviates the effect of tube-to-tube variability.

A reliable external calibration method for reaction monitoring with benchtop NMR.

Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical technique with the ability to acquire both quantitative and structurally insightful data for multiple components in a test sample. This makes NMR spectroscopy a desirable tool to understand, monitor, and optimize chemical transformations. While quantitative NMR (qNMR) approaches relying on internal standards are well-established, using an absolute external calibration scheme is beneficial for reaction monitoring as resonance overlap complications from an added reference material to the sample can be avoided. Particularly, this type of qNMR technique is of interest with benchtop NMR spectrometers as the likelihood of resonance overlap is only enhanced with the lower magnetic field strengths of the used permanent magnets. The included study describes a simple yet robust methodology to determine concentration conversion factors for NMR systems using single- and multi-analyte linear regression models. This approach is leveraged to investigate a pharmaceutically relevant amide coupling batch reaction. An on-line stopped-flow (i.e., interrupted-flow or paused-flow) benchtop NMR system was used to monitor both the 1,1'-carbonyldiimidazole (CDI) promoted acid activation and the amide coupling. The results highlight how quantitative measurements in benchtop NMR systems can provide valuable information and enable analysts to make decisions in real time.

Globally invariant metabolism but density-diversity mismatch in springtails.

Soil life supports the functioning and biodiversity of terrestrial ecosystems. Springtails (Collembola) are among the most abundant soil arthropods regulating soil fertility and flow of energy through above- and belowground food webs. However, the global distribution of springtail diversity and density, and how these relate to energy fluxes remains unknown. Here, using a global dataset representing 2470 sites, we estimate the total soil springtail biomass at 27.5 megatons carbon, which is threefold higher than wild terrestrial vertebrates, and record peak densities up to 2 million individuals per square meter in the tundra. Despite a 20-fold biomass difference between the tundra and the tropics, springtail energy use (community metabolism) remains similar across the latitudinal gradient, owing to the changes in temperature with latitude. Neither springtail density nor community metabolism is predicted by local species richness, which is high in the tropics, but comparably high in some temperate forests and even tundra. Changes in springtail activity may emerge from latitudinal gradients in temperature, predation and resource limitation in soil communities. Contrasting relationships of biomass, diversity and activity of springtail communities with temperature suggest that climate warming will alter fundamental soil biodiversity metrics in different directions, potentially restructuring terrestrial food webs and affecting soil functioning.

Challenges in the structure determination of a dimeric impurity found during development of GDC-0326.

While developing a synthetic route for GDC-0326, a PI3Kα selective inhibitor, a side product was identified which was adversely impacting process chemistry development. To aid in optimization of a viable synthetic pathway for the drug, it was decided to characterize this impurity. Initial efforts using typical high-resolution mass spectrometry data coupled with NMR analysis were unable to unambiguously identify the structure. The NMR analysis was hampered by a severe lack of protons in the core of the structure. While efforts were being made to produce suitable crystals for definitive x-ray analysis, Raman analysis was undertaken. The vibrational data were compared to DFT calculations for the two most likely structures. This data, along with chemical reasoning, eventually led to successful prediction of structure 2, which was ultimately confirmed by single crystal x-ray diffractometry data.

Global data on earthworm abundance, biomass, diversity and corresponding environmental properties.

Earthworms are an important soil taxon as ecosystem engineers, providing a variety of crucial ecosystem functions and services. Little is known about their diversity and distribution at large spatial scales, despite the availability of considerable amounts of local-scale data. Earthworm diversity data, obtained from the primary literature or provided directly by authors, were collated with information on site locations, including coordinates, habitat cover, and soil properties. Datasets were required, at a minimum, to include abundance or biomass of earthworms at a site. Where possible, site-level species lists were included, as well as the abundance and biomass of individual species and ecological groups. This global dataset contains 10,840 sites, with 184 species, from 60 countries and all continents except Antarctica. The data were obtained from 182 published articles, published between 1973 and 2017, and 17 unpublished datasets. Amalgamating data into a single global database will assist researchers in investigating and answering a wide variety of pressing questions, for example, jointly assessing aboveground and belowground biodiversity distributions and drivers of biodiversity change.

Survival in hospice patients with dementia: the effect of home hospice and nurse visits.

BACKGROUND: Hospice patients with dementia are at increased risk for live discharge and long lengths of stay (>180 days), causing patient and family caregiver stress and burden. The location and timing of clinician visits are important factors influencing whether someone dies as expected, in hospice, or experiences a live discharge or long length of stay. OBJECTIVE: Examine how home hospice and nurse visit frequency relate to dying in hospice within the Medicare-intended 6-month period. DESIGN: Retrospective cohort study. SETTING: Non-profit hospice agency. PARTICIPANTS: Three thousand eight hundred and thirty seven patients with dementia who received hospice services from 2013 to 2017. METHODS: Multivariable survival analyses examined the effects of receiving home hospice (vs. nursing home) and timing of nurse visits on death within 6 months of hospice enrollment, compared to live discharge or long length of stay. Models adjust for relevant demographic and clinical factors. RESULTS: Thirty-nine percent (39%) of patients experienced live discharge or long length of stay. Home hospice patients were more likely to experience live discharge or long length of stays (HR for death: 0.77, 95%CI: 0.69-0.86, p < 0.001). Frequency of nurse visits was inversely associated with live discharge and long lengths of stay (HR for death: 2.87, 95%CI: 2.47-3.33, p < 0.001). CONCLUSION: Nearly 40% of patients with dementia in our study experienced live discharge or a long length of stay. Additional research is needed to understand why home hospice may result in live discharge or a long length of stay for patients with dementia. Nurse visits were associated with death, suggesting their responsiveness to deteriorating patient health. Hospice guidelines may need to permit longer stays so community-dwelling patients with dementia, a growing segment of hospice patients, can remain continuously enrolled in hospice and avoid burden and costs associated with live discharge.

Race, Ethnicity, and Other Risks for Live Discharge Among Hospice Patients with Dementia.

OBJECTIVES: The end-of-life trajectory for persons with dementia is often protracted and difficult to predict, placing these individuals at heightened risk of live discharge from hospice. Risks for live discharge due to condition stabilization or failure to decline among patients with dementia are not well established. Our aim was to identify demographic, health, and hospice service factors associated with live discharge due to condition stabilization or failure to decline among hospice patients with dementia. DESIGN: Retrospective cohort study. SETTING: A large not-for-profit agency in New York City. PARTICIPANTS: A total of 2629 hospice patients with dementia age 65 years and older. MEASUREMENTS: Primary outcome was live discharge from hospice due to condition stabilization or failure to decline (vs death). Measures include demographic factors (race/ethnicity, Medicaid, sex, age, marital status, parental status), health characteristics (primary dementia diagnosis, comorbidities, functional status, prior hospitalization), and hospice service (location, length of service, number and timing of nurse visits). RESULTS: Logistic regression models indicated that compared with white hospice patients with dementia, African American and Hispanic hospice patients with dementia experienced increased risk of live discharge (African American: adjusted odds ratio [aOR] = 2.42; 95% confidence interval [CI] = 1.34-4.38; Hispanic: aOR = 2.99; 95% CI = 1.81-4.94). Home hospice (aOR = 7.57; 95% CI = 4.04-14.18), longer length of service (aOR = 1.04; 95% CI = 1.04-1.05), and more days between nurse visits and discharge (aOR = 1.86; 95% CI = 1.56-2.21) were also associated with live discharge. CONCLUSION: To avoid burdensome and disruptive transitions out of hospice in patients with dementia, interventions to reduce live discharge due to condition stabilization or failure to decline should be tailored to meet the needs of African American, Hispanic, and home hospice patients. Policies regarding sustained hospice eligibility should account for the variable and protracted end-of-life trajectory of patients with dementia. J Am Geriatr Soc 68:551-558, 2020.

Towards an integrative understanding of soil biodiversity.

Soil is one of the most biodiverse terrestrial habitats. Yet, we lack an integrative conceptual framework for understanding the patterns and mechanisms driving soil biodiversity. One of the underlying reasons for our poor understanding of soil biodiversity patterns relates to whether key biodiversity theories (historically developed for aboveground and aquatic organisms) are applicable to patterns of soil biodiversity. Here, we present a systematic literature review to investigate whether and how key biodiversity theories (species-energy relationship, theory of island biogeography, metacommunity theory, niche theory and neutral theory) can explain observed patterns of soil biodiversity. We then discuss two spatial compartments nested within soil at which biodiversity theories can be applied to acknowledge the scale-dependent nature of soil biodiversity.

Impact of Surfactant and Surfactant-Polymer Interaction on Desupersaturation of Clotrimazole.

The impact of surfactants on supersaturation of clotrimazole solutions was systematically evaluated. Four clinically relevant surfactants, sodium dodecyl sulfate, vitamin E TPGS, Tween 80, and docusate sodium were studied. The induction time for nucleation and rate of desupersaturation were determined at a supersaturation ratio of 90% amorphous solubility. Measurement was also performed in the presence of predissolved hydroxypropyl methylcellulose acetate succinate to study the effect of surfactant-polymer interaction on desupersaturation. The 4 surfactants showed varied effects on desupersaturation. From supersaturation maintenance perspective, in the presence of hydroxypropyl methylcellulose acetate succinate, the rank order for the 4 surfactants was found to be: docusate sodium > vitamin E TPGS > sodium dodecyl sulfate > Tween 80. Given the importance of maintaining supersaturation and varied effect of surfactants on nucleation kinetics and desupersaturation rate, a careful examination of active pharmaceutical ingredient, polymer and surfactant interaction on an individual basis is recommended for selecting an appropriate surfactant for use in amorphous solid dispersion formulation.

Tocilizumab as a steroid sparing agent for the treatment of Graves' orbitopathy.

PURPOSE: To describe the effect of tocilizumab in two patients with thyroid associated orbitopathy (TAO). OBSERVATIONS: We present two patients with TAO who could not tolerate corticosteroids and had a reduction in clinical and laboratory markers of inflammatory activity with subsequent tocilizumab therapy. CONCLUSIONS AND IMPORTANCE: The IL-6 receptor antibody tocilizumab is a promising candidate for the treatment of TAO because it selectively targets a key inflammatory mediator and has a favorable side effect profile. Our report demonstrates that tocilizumab can achieve further reduction in inflammatory activity after treatment with corticosteroids. Importantly, we and others have observed a decrease in the level of thyroid stimulating immunoglobulin (TSI) with tocilizumab treatment. This suggests an upstream effect in the inflammatory cascade. Although the impact of tocilizumab on long-term outcome is unknown at this time, we believe that early disruption of the inflammatory process may prevent late complications and decrease the need for rehabilitative surgery.

Cross-realm assessment of climate change impacts on species' abundance trends.

Climate change, land-use change, pollution and exploitation are among the main drivers of species' population trends; however, their relative importance is much debated. We used a unique collection of over 1,000 local population time series in 22 communities across terrestrial, freshwater and marine realms within central Europe to compare the impacts of long-term temperature change and other environmental drivers from 1980 onwards. To disentangle different drivers, we related species' population trends to species- and driver-specific attributes, such as temperature and habitat preference or pollution tolerance. We found a consistent impact of temperature change on the local abundances of terrestrial species. Populations of warm-dwelling species increased more than those of cold-dwelling species. In contrast, impacts of temperature change on aquatic species' abundances were variable. Effects of temperature preference were more consistent in terrestrial communities than effects of habitat preference, suggesting that the impacts of temperature change have become widespread for recent changes in abundance within many terrestrial communities of central Europe.

Application of CRAFT in two-dimensional NMR data processing.

Two-dimensional (2D) data are typically truncated in both dimensions, but invariably and severely so in the indirect dimension. These truncated FIDs and/or interferograms are extensively zero filled, and Fourier transformation of such zero-filled data is always preceded by a rapidly decaying apodization function. Hence, the frequency line width in the spectrum (at least parallel to the evolution dimension) is almost always dominated by the apodization function. Such apodization-driven line broadening in the indirect (t1 ) dimension leads to the lack of clear resolution of cross peaks in the 2D spectrum. Time-domain analysis (i.e. extraction of frequency, amplitudes, line width, and phase parameters directly from the FID, in this case via Bayesian modeling into a tabular format) of NMR data is another approach for spectral resonance characterization and quantification. The recently published complete reduction to amplitude frequency table (CRAFT) technique converts the raw FID data (i.e. time-domain data) into a table of frequencies, amplitudes, decay rate constants, and phases. CRAFT analyses of time-domain data require minimal or no apodization prior to extraction of the four parameters. We used the CRAFT processing approach for the decimation of the interferograms and compared the results from a variety of 2D spectra against conventional processing with and without linear prediction. The results show that use of the CRAFT technique to decimate the t1 interferograms yields much narrower spectral line width of the resonances, circumventing the loss of resolution due to apodization. Copyright © 2016 John Wiley & Sons, Ltd.

Orbital Plasmacytoma Mimicking an Orbital Abscess.

An 83-year-old male with a 15-month history of multiple myeloma presented with acute onset of swelling, redness, and pain around his right eye. CT scan was consistent with an orbital abscess. The patient was taken to the operating room for drainage of the orbital abscess. Abnormal tissue was encountered intraoperatively so biopsies were taken. His cultures grew only one colony of coagulase-negative Staphylococcus aureus. The histopathology from the biopsies showed a CD-138 positive plasma cell neoplasia consistent with a plasmacytoma. Plasmacytomas have been reported to present as orbital cellulitis and as abscesses in other locations in the body, but to our knowledge, this is the first case of a plasmacytoma presenting as an orbital abscess.

Long-Term Results for Entropion Repair by Tarsal Margin Rotation With Posterior Lamella Superadvancement.

PURPOSE: To report the long-term stability of tarsal margin rotation and posterior lamellar superadvancement (TMR PLS) for the repair of upper eyelid cicatricial entropion. METHODS: A retrospective chart review was performed from January 2000 through December 2014 to identify all patients who had TMR PLS at the authors' institution. Charts were reviewed for demographic information, recurrence of entropion or trichiasis, and surgical complications. Failure was defined as return of entropion. Patients with greater than 24 months of follow up were included. RESULTS: A total of 30 TMR PLS procedures were performed during the review period. Nineteen cases from 14 patients were included in the final analysis. None of the 19 cases demonstrated recurrence of entropion over an average follow-up period of 78.3 months. Eight cases demonstrated trichiasis after TMR PLS, 5 of which required treatment. CONCLUSION: This case series suggests that TMR PLS for the treatment of upper eyelid cicatricial entropion has excellent long-term stability.

Meta-Analysis of Association Between Mediastinal Radiotherapy and Long-Term Heart Failure.

This investigation sought to identify and quantify any increased risk of long-term heart failure (HF) after thoracic radiotherapy (RT) for cancer and identify any population covariates that corresponded with increased risk. Electronic databases were systematically searched for studies reporting relative risk, odds ratio, and hazard ratio (HR) for symptomatic HF more than 5 years after RT administration. Clinical characteristics, study design, univariable effect sizes, and associated 95% CIs were extracted. Univariable effect size was pooled and computed in a meta-analysis using random-effects model weighted by inverse variance. Six studies (45,669 patients) with weighted median follow-up duration of 13.9 years were included, each data-linkage study that reported HRs for HF. Pooled HR for long-term HF was significant (HR 1.83 [1.09 to 3.08], p = 0.022), with significant between-study heterogeneity (Q 43.38, df = 5, p <0.001, I2 88.47%). Statistical significance was lost when excluding studies of malignancies other than breast cancer or hematological malignancies and excluding studies with Newcastle-Ottawa scores <8, but the direction of effect and magnitude remained approximately the same. Subgroup and meta-regression analyses demonstrated that study differences in age at time of RT administration and duration of follow-up explained approximately 80% of observed heterogeneity. Earlier publication date was associated with increased HF risk. Other variables, including female proportion, proportion of adjuvant chemotherapy use, and sample size did not significantly impact the conclusions. In conclusion, RT approximately doubled the long-term risk of HF. This finding was associated with younger age at time of RT and longer follow-up duration, which explained approximately 80% of interstudy heterogeneity.

Long-term Risk of Heart Failure and Myocardial Dysfunction After Thoracic Radiotherapy: A Systematic Review.

BACKGROUND: Chest irradiation is a commonly used treatment for malignancy, with demonstrated symptomatic and survival benefit. The frequency and presentation of cardiovascular complications of radiotherapy remains unclear. METHODS: We performed a systematic review to evaluate the prevalence and manifestations of myocardial dysfunction (asymptomatic and symptomatic) in long-term cancer survivors treated with radiotherapy. RESULTS: Thoracic radiotherapy is associated with increased risk of heart failure in long-term follow-up, with hazard ratios ranging from 2.7 to 7.4 for Hodgkin lymphoma, and 1.5-2.4 for breast cancer. Although ejection fraction is often normal, systolic dysfunction has been more widely reported with modern techniques including 2-dimensional speckle strain and cardiac magnetic resonance. This might have implications for the selection of patients for cardioprotection. Despite common emphasis, diastolic functional abnormalities were infrequent in the long term. A limited amount of data suggest that right ventricular dysfunction is important in this population. CONCLUSIONS: The reports were heterogeneous, used different treatments, end points, and definitions of myocardial dysfunction, and most studies on the cardiac consequences of radiotherapy involved small numbers of patients and were published decades ago, making it difficult to formulate definitive conclusions for the current era.

A comprehensive model for correcting RNFL readings of varying signal strengths in cirrus optical coherence tomography.

PURPOSE: To develop a model for the Cirrus HD-OCT that allows for the comparison of retinal nerve fiber layer (RNFL) thickness measurements with dissimilar signal strengths (SS) and accounts for test-retest variability. METHODS: Retinal nerve fiber layers were obtained in normals using the Cirrus optic disc cube 200 × 200 protocol during a single encounter. Five RNFL scans were obtained with a SS of 9 or 10. Diffusion lens filters were used to degrade SS to obtain five scans at each SS group of 7 or 8, 5 or 6, and 3 or 4. The relationship between average RNFL thickness and SS was established, and an equation was developed to allow for adjustment of an RNFL measurement had it been a SS of 7. Intravisit interclass correlation coefficient (ICC) and coefficient of variation (CV) parameter estimates for each SS group were calculated. Repeatability and upper tolerance limit were calculated as 1.96 × âˆš2 × within-subject standard deviation (Sw) and 1.645 × âˆš2 × Sw, respectively. RESULTS: There was a linear relationship between average RNFL and SS. RNFLadj = RNFL - 1.03*SS + 7.21 allows for the adjustment of RNFL readings to the same SS. Interclass correlation coefficients and CVs were good for all measurements down to SS of 3 or 4. Repeatability and upper tolerance limit were 5.24 and 4.40 µm, respectively. CONCLUSIONS: Our model adjusts RNFL readings based on SS and includes an upper tolerance limit of 5 µm. If validated, this model could improve the detection of real RNFL changes. Further study to validate this model should be performed before widespread use is adopted.