Toward Quantifying the Chemical Sensitivity of Nuclear Spin Surface Relaxivity in Mesoporous Media.

Low-field nuclear magnetic resonance (NMR) relaxation is a promising non-invasive technique for characterizing solid-liquid interactions within functional porous materials. However, the ability of the solid-liquid interface to enhance adsorbate relaxation rates, known as the surface relaxivity, in the case of different solvents and reagents involved in various chemical processes has yet to be evaluated in a quantitative manner. In this study, we systematically explore the surface relaxation characteristics of 10 liquid adsorbates (cyclohexane, acetone, water, and 7 alcohols, including ethylene glycol) confined within mesoporous silicas with pore sizes between 6 and 50 nm using low-field (12.7 MHz) two-dimensional 1H T1-T2 relaxation measurements. Functional-group-specific relaxation phenomena associated with the alkyl and hydroxyl groups of the confined alcohols are clearly distinguished; we report the dependence of both longitudinal (T1) and transverse (T2) relaxation rates of these 1H-bearing moieties on pore surface-to-volume ratio, facilitating the quantification and assignment of surface relaxivity values to specific functional groups within the same adsorbate molecule for the first time. We further demonstrate that alkyl group transverse surface relaxivities correlate strongly with the alkyl/hydroxyl ratio of the adsorbates assessed, providing evidence for a simple, quantitative relationship between surface relaxivity and interfacial chemistry. Overall, our observations highlight potential pitfalls in the application of NMR relaxation for the evaluation of pore size distributions using hydroxylated probe molecules, and provide motivation for the exploration of nuclear spin relaxation measurements as a route to adsorbate identity within functional porous materials.

NMR Surface Relaxivity in a Time-Dependent Porous System.

We demonstrate an unexpected decay-recovery behavior in the time-dependent ^{1}H NMR relaxation times of water confined within a hydrating porous material. Our observations are rationalized by considering the combined effects of decreasing material pore size and evolving interfacial chemistry, which facilitate a transition between surface-limited and diffusion-limited relaxation regimes. Such behavior necessitates the realization of temporally evolving surface relaxivity, highlighting potential caveats in the classical interpretation of NMR relaxation data obtained from complex porous systems.

Detection of honey adulteration using benchtop 1H NMR spectroscopy.

High magnetic field NMR spectroscopy featuring the use of superconducting magnets is a powerful analytical technique for the detection of honey adulteration. Such high field NMR systems are, however, typically housed in specialised laboratories, require cryogenic coolants, and necessitate specialist training to operate. Benchtop NMR spectrometers featuring permanent magnets are, by comparison, significantly cheaper, more mobile and can be operated with minimal expertise. The lower magnetic fields used in such systems, however, result in limited spectral resolution, which diminishes their ability to perform quantitative composition analysis. These limitations may be overcome by implementing a recently developed field-invariant model-based fitting method which is defined by the underlying quantum mechanical properties of the nuclear spin system; this method is applied here to quantify the sugar composition of honey using benchtop 1H NMR (43 MHz) spectroscopy. The detection of adulteration of 26 honey samples with brown rice syrup is quantitatively demonstrated to a minimum adulterant concentration of 5 wt%. Honey adulteration with corn syrup, glucose syrup and wheat syrup was also quantitatively detected using this approach. Our NMR detection of adulteration was shown to be invariant with time over 60 days of storage.

Regulation of epidermal proliferation and hair follicle cycling by synthetic photostable retinoid EC23.

BACKGROUND: Retinoid signaling is an important regulator of the epidermis and skin appendages. Therefore, synthetic retinoids have been developed for therapeutic use for skin disorders such as psoriasis and acne. AIMS: In previous studies, we showed how the photostable retinoid EC23 induces neuronal differentiation in stem cell-like cell populations, and here, we aim to investigate its ability to influence epidermal and hair follicle growth. METHODS: EC23 influence on skin biology was investigated initially in cultures of monolayer keratinocytes and three-dimentional in vitro models of skin, and finally in in vivo studies of mice back skin. RESULTS: EC23 induces keratinocyte hyperproliferation in vitro and in vivo, and when applied to mouse skin increases the number of involucrin-positive suprabasal cell layers. These phenotypic changes are similar in skin treated with the natural retinoid all-trans retinoic acid (ATRA); however, EC23 is more potent; a tenfold lower dose of EC23 is sufficient to induce epidermal thickening, and resulting hyperproliferation is sustained for a longer time period after first dose. EC23 treatment resulted in a disorganized stratum corneum, reduced cell surface lipids and compromised barrier, similar to ATRA treatment. However, EC23 induces a rapid telogen to anagen transition and hair re-growth in 6-week-old mice with synchronously resting back skin follicles. The impact of EC23 on the hair cycle was surprising as similar results have not been seen with ATRA. CONCLUSIONS: These data suggest that synthetic retinoid EC23 is a useful tool in exploring the turnover and differentiation of cells and has a potent effect on skin physiology.

The athletic characteristics of Olympic sports to assist anti-doping strategies.

The determinants of success in Olympic Games competition are specific to the athletic demands of the sporting event. A global evaluation to quantify the athletic demands across the spectrum of the Olympic Games sport events has not previously been conducted. Thus far, the interpretation and the comparison of sport physiological characteristics within anti-doping organisations (ADOs) risk assessments remains subjective without a standardised framework. Despite its subjective assessment, this information is a key component of any anti-doping programme. Sport characteristics inevitably influence the type of substances and/or methods used for doping purposes and should be captured through a comprehensive analysis. Seven applied sport scientists independently conducted an assessment to quantify the athletic demands across six preselected athletic variables. A principal component analysis was performed on the results of the panel's quantitative assessment for 160 Olympic sport events. Sport events were clustered using the Hierarchical Density Based Spatial Clustering of Applications with Noise (HDBSCAN) algorithm. The HDBSCAN identified 19 independent cluster groups; 36 sport events remained statistically unassigned to a cluster group representing unique and event-specific athletic demands. This investigation provides guidance to the anti-doping community to assist in the development of the sport specific physiology component of the risk assessment for Olympic Games disciplines. The dominant athletic characteristics to excel in each of these individual events will highlight areas of how athletes may strive to gain a competitive advantage through doping strategies, and inform the development of an effective and proportionate allocation of testing resources.

Low-Field NMR Relaxation Analysis of High-Pressure Ethane Adsorption in Mesoporous Silicas.

Understanding the behaviour of short-chain hydrocarbons confined to porous solids informs the targeted extraction of natural resources from geological features, and underpins rational developments in separation, storage and catalytic conversion processes. Herein, we report the application of low-field (12.7 MHz) 1 H nuclear magnetic resonance (NMR) relaxation measurements to characterise ethane dynamics within mesoporous silica materials exhibiting mean pore diameters between 6 and 50 nm. Our measurements provide NMR-based adsorption isotherms within the range 25-50 bar and at ambient temperature, incorporating the ethane condensation point (40.7 bar at our experimental temperature of 23.6 °C). The quantitative nature of the acquired data is validated via a direct comparison of NMR-derived excess adsorption capacities with ex situ gravimetric ethane adsorption measurements, which are demonstrated to agree to within 0.2 mmol g-1 of the observed ethane capacity. NMR T2 relaxation time distributions are further demonstrated as a means to decouple interparticle and mesopore dominated adsorption phenomena, with unexpectedly rapid relaxation rates associated with interparticle ethane gas confirmed via a direct comparison with NMR self-diffusion analysis.

A Brewed Awakening: Neuropsychiatric Effects of Caffeine in Older Adults.

This article provides a current review of the literature examining caffeine use in older adults. Caffeine use is prevalent among older adults; thus, providers need to be aware of the prevalence and diagnostic criteria of caffeine use disorder versus nonproblematic use. The relationship between caffeine and various neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, insomnia, and late-life depression, is reviewed. The neurobiological effects of caffeine are described, along with clinically relevant interactions between caffeine and common psychotropic medications.

Low-Field Functional Group Resolved Nuclear Spin Relaxation in Mesoporous Silica.

Solid-fluid interactions underpin the efficacy of functional porous materials across a diverse array of chemical reaction and separation processes. However, detailed characterization of interfacial phenomena within such systems is hampered by their optically opaque nature. Motivated by the need to bridge this capability gap, we report low-magnetic-field two-dimensional (2D) 1H nuclear spin relaxation measurements as a noninvasive probe of adsorbate identity and interfacial dynamics, exploring the relaxation characteristics exhibited by liquid hydrocarbon adsorbates confined to a model mesoporous silica. For the first time, we demonstrate the capacity of this approach in distinguishing functional group-specific relaxation phenomena across a diverse range of alcohols and carboxylic acids employed as solvents, reagents, and liquid hydrogen carriers, with distinct relaxation responses assigned to the alkyl and hydroxyl moieties of each confined liquid. Uniquely, this relaxation behavior is shown to correlate with adsorbate acidity, with the observed relationship rationalized on the basis of surface-adsorbate proton-exchange dynamics. Our results demonstrate that nuclear spin relaxation provides a molecular-level perspective on sorbent/sorbate interactions, motivating the exploration of such measurements as a unique probe of adsorbate identity within optically opaque porous media.

Rotator cuff repair in HIV-positive patients ages 65 and older: only slight increase in risk of general postoperative surgical complications.

PURPOSE: To examine postoperative complications associated with rotator cuff repair (RCR) in HIV-positive patients ages 65 and older. METHODS: Data were collected from the Medicare Standardized Analytic Files between 2005 and 2015 using the PearlDiver Patient Records Database. Subjects were selected using Current Procedural Terminology (CPT) and International Classification of Diseases (ICD) codes. Demographics including age, sex, medical comorbidities, and smoking status were collected. Complications were examined at 7-day, 30-day, and 90-day postoperative time points. Data were examined with univariate and multivariate analyses. RESULTS: The study included 152,114 patients who underwent RCR, with 24,486 (16.1%) patients who were HIV-positive. Following univariate analysis, patients with HIV were observed to be more likely to develop 7-day, 30-day, and 90-day postoperative complications. However, the absolute risk of each complication was quite low for HIV-positive patients. Univariate and multivariate analysis showed that within 7 days following surgery, patients with HIV were more likely to develop myocardial infarction (OR 2.5, AR 0.1%) and sepsis (OR 2.5, AR 0.04%). Within 30 days, HIV-positive patients were at increased risk for postoperative anemia (OR 2.8, AR 0.1%), blood transfusion (OR 3.3, AR 0.1%), heart failure (OR 2.3, AR 0.8%), and sepsis (OR 2.7, AR 0.1%). Within 90 days, mechanical complications (OR 2.1, AR 0.1%) were increased in the HIV-positive group. CONCLUSION: Postoperative complications of RCR occurred at increased rates in the HIV-positive group compared to the HIV-negative group in patients ages 65 and older. In particular, increased risk for myocardial infarction, sepsis, heart failure, anemia, and mechanical complications was noted in HIV-positive patients. However, the actual percentage of patients who experienced each complication was low, indicating RCR is likely safe to perform even in older HIV-positive patients. As more older adults living with HIV present for elective orthopedic procedures, the results of the present study may reassure physicians who are considering RCR as an option for patients in this particular population, while also informing providers about potential complications. LEVEL OF EVIDENCE: III.

Increased number of deaths within 24 h of admission during a period of social restriction related to the COVID-19 pandemic: A retrospective service evaluation in a metropolitan palliative care unit.

BACKGROUND: COVID-19 has led to implementation of wide-ranging social restriction measures with consequent impact on health care utilisation in many domains. There is little published data on the experience of palliative care services catering to a population with low case numbers of COVID-19. AIM: This study aimed to consider the impact of COVID-19 on utilisation of inpatient palliative care in the context of low community transmission, and low numbers of cases in hospital. DESIGN: A retrospective service evaluation examining differences in number of admissions, diagnoses, number of deaths and time from admission to death, across three discrete 8-week time periods spanning the early COVID-19 pandemic. SETTING/PARTICIPANTS: All admissions (n = 194) to a metropolitan tertiary hospital inpatient palliative care unit in Melbourne during the study period. RESULTS: An initial 16.9% fall in admissions was followed by a return to baseline admission numbers, with a 46.7% increase in number of deaths compared to baseline. The number of deaths within 24 h rose from 10.8% to 37.3% (p < 0.01). The number of patients with non-malignant diagnoses increased from 32.4% to 52%, and those with non-malignant diagnoses were more likely to die rapidly (p < 0.01). There were no patients with COVID-19 infection. CONCLUSION: Increased numbers of deaths within 24 h of admission occurred on the palliative care unit despite low COVID-19 case numbers in the wider community, and in the setting of widespread social restriction measures. More research is needed examining the health-related consequences of such restrictions for individuals not infected with COVID-19.

Nuclear spin relaxation as a probe of zeolite acidity: a combined NMR and TPD investigation of pyridine in HZSM-5.

The relative surface affinities of pyridine within microporous HZSM-5 zeolites are explored using two-dimensional 1H nuclear magnetic resonance (NMR) relaxation time measurements. The dimensionless ratio of longitudinal-to-transverse nuclear spin relaxation times T1/T2 is shown to exhibit strong sensitivity to the silica/alumina ratio (SAR) of these zeolites, which is indicative of material acidity. This trend is interpreted in terms of increased pyridine surface affinity with decreasing SAR. Temperature programmed desorption (TPD) analysis corroborates this observation, revealing a distinct increase in the heat of desorption associated with adsorbed pyridine as a function of decreasing SAR. A direct correlation between NMR and TPD data suggests NMR relaxation time analysis can be a valuable tool for the non-invasive characterisation of adsorption phenomena in microporous solids.

Laser-induced transient magnons in Sr3Ir2O7 throughout the Brillouin zone.

Although ultrafast manipulation of magnetism holds great promise for new physical phenomena and applications, targeting specific states is held back by our limited understanding of how magnetic correlations evolve on ultrafast timescales. Using ultrafast resonant inelastic X-ray scattering we demonstrate that femtosecond laser pulses can excite transient magnons at large wavevectors in gapped antiferromagnets and that they persist for several picoseconds, which is opposite to what is observed in nearly gapless magnets. Our work suggests that materials with isotropic magnetic interactions are preferred to achieve rapid manipulation of magnetism.

Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model.

Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile. Herein we report the synthesis of SMT022357, a second generation utrophin modulator preclinical candidate, and an asymmetric synthesis of its constituent enantiomers. The pharmacological properties of both enantiomers were evaluated in vitro and in vivo. No significant difference in the activity or efficacy was observed between the two enantiomers; activity was found to be comparable to the racemic mixture.

Low-field NMR relaxation-exchange measurements for the study of gas admission in microporous solids.

Understanding the uptake and storage of gases by microporous materials is important for our future energy security. As such, we demonstrate here the application of two-dimensional NMR relaxation experiments for probing the admission and corresponding exchange dynamics of methane within microporous zeolites. Specifically, we report low-field (12.7 MHz) 1H NMR relaxation-exchange correlation measurements of methane within commercial LTA zeolites (3A and 4A) at 25 and 35 bar and ambient temperature. Our results demonstrate the clear identification of bulk-pore and pore-pore exchange processes within zeolite 4A, facilitating the calculation and comparison of effective exchange rate dynamics across varying diffusion length scales and gas pressures. Additional data acquired for zeolite 3A reveals the sensitivity of NMR relaxation phenomena to size-exclusive gas admission phenomena, illustrating the potential of benchtop NMR protocols for material screening applications.

2-Arylbenzo[d]oxazole Phosphinate Esters as Second-Generation Modulators of Utrophin for the Treatment of Duchenne Muscular Dystrophy.

Utrophin modulation is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), which should be applicable to all patient populations. Following on from ezutromid, the first-generation utrophin modulator, we describe the development of a second generation of utrophin modulators, based on the bioisosteric replacement of the sulfone group with a phosphinate ester and substitution of the metabolically labile naphthalene with a haloaryl substituent. The improved physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties, further reflected in the enhanced pharmacokinetic profile of the most advanced compounds, 30 and 27, led to significantly better in vivo exposure compared to ezutromid and alleviation of the dystrophic phenotype in mdx mice. While 30 was found to have dose-limiting hepatotoxicity, 27 and its enantiomers exhibited limited off-target effects, resulting in a safe profile and highlighting their potential utility as next-generation utrophin modulators suitable for progression toward a future DMD therapy.

Prevalence Estimate of Blood Doping in Elite Track and Field Athletes During Two Major International Events.

In elite sport, the Athlete Biological Passport (ABP) was invented to tackle cheaters by monitoring closely changes in biological parameters, flagging atypical variations. The hematological module of the ABP was indeed adopted in 2011 by World Athletics (WA). This study estimates the prevalence of blood doping based on hematological parameters in a large cohort of track and field athletes measured at two international major events (2011 and 2013 WA World Championships) with a hypothesized decrease in prevalence due to the ABP introduction. A total of 3683 blood samples were collected and analyzed from all participating athletes originating from 209 countries. The estimate of doping prevalence was obtained by using a Bayesian network with seven variables, as well as "blood doping" as a variable mimicking doping with low-doses of recombinant human erythropoietin (rhEPO), to generate reference cumulative distribution functions (CDFs) for the Abnormal Blood Profile Score (ABPS) from the ABP. Our results from robust hematological parameters indicate an estimation of an overall blood doping prevalence of 18% in 2011 and 15% in 2013 (non-significant difference) in average in endurance athletes [95% Confidence Interval (CI) 14-22 and 12-19% for 2011 and 2013, respectively]. A higher prevalence was observed in female athletes (22%, CI 16-28%) than in male athletes (15%, CI 9-20%) in 2011. In conclusion, this study presents the first comparison of blood doping prevalence in elite athletes based on biological measurements from major international events that may help scientists and experts to use the ABP in a more efficient and deterrent way.

Isolation, Structural Identification, Synthesis, and Pharmacological Profiling of 1,2-trans-Dihydro-1,2-diol Metabolites of the Utrophin Modulator Ezutromid.

5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles.

Anomalies in the pseudogap phase of the cuprates: competing ground states and the role of umklapp scattering.

Over the past two decades, advances in computational algorithms have revealed a curious property of the two-dimensional Hubbard model (and related theories) with hole doping: the presence of close-in-energy competing ground states that display very different physical properties. On the one hand, there is a complicated state exhibiting intertwined spin, charge, and pair density wave orders. We call this 'type A'. On the other hand, there is a uniform d-wave superconducting state that we denote as 'type B'. We advocate, with the support of both microscopic theoretical calculations and experimental data, dividing the high-temperature cuprate superconductors into two corresponding families, whose properties reflect either the type A or type B ground states at low temperatures. We review the anomalous properties of the pseudogap phase that led us to this picture, and present a modern perspective on the role that umklapp scattering plays in these phenomena in the type B materials. This reflects a consistent framework that has emerged over the last decade, in which Mott correlations at weak coupling drive the formation of the pseudogap. We discuss this development, recent theory and experiments, and open issues.

Nonthermal States Arising from Confinement in One and Two Dimensions.

We show that confinement in the quantum Ising model leads to nonthermal eigenstates, in both continuum and lattice theories, in both one (1D) and two dimensions (2D). In the ordered phase, the presence of a confining longitudinal field leads to a profound restructuring of the excitation spectrum, with the low-energy two-particle continuum being replaced by discrete "meson" modes (linearly confined pairs of domain walls). These modes exist far into the spectrum and are atypical, in the sense that expectation values in the state with energy E do not agree with the microcanonical (thermal) ensemble prediction. Single meson states persist above the two-meson threshold due to a surprising lack of hybridization with the (n≥4)-domain wall continuum, a result that survives into the thermodynamic limit and that can be understood from analytical calculations. The presence of such states is revealed in anomalous postquench dynamics, such as the lack of a light cone, the suppression of the growth of entanglement entropy, and the absence of thermalization for some initial states. The nonthermal states are confined to the ordered phase-the disordered (paramagnetic) phase exhibits typical thermalization patterns in both 1D and 2D in the absence of integrability.

Magnetism in iridate heterostructures leveraged by structural distortions.

Fundamental control of magnetic coupling through heterostructure morphology is a prerequisite for rational engineering of magnetic ground states. We report the tuning of magnetic interactions in superlattices composed of single and bilayers of SrIrO3 inter-spaced with SrTiO3 in analogy to the Ruddlesden-Popper series iridates. Magnetic scattering shows predominately c-axis antiferromagnetic orientation of the magnetic moments for the bilayer, as in Sr3Ir2O7. However, the magnetic excitation gap, measured by resonant inelastic x-ray scattering, is quite different between the two structures, evidencing a significant change in the stability of the competing magnetic phases. In contrast, the single layer iridate hosts a more bulk-like gap. We find these changes are driven by bending of the c-axis Ir-O-Ir bond, which is much weaker in the single layer, and subsequent local environment changes, evidenced through x-ray diffraction and magnetic excitation modeling. Our findings demonstrate how large changes in the magnetic interactions can be tailored and probed in spin-orbit coupled heterostructures by engineering subtle structural modulations.