This study provides further evidence of the mutational and clinical spectrum of PTHS and confirms its important role in the differential diagnosis of severe mental retardation.

Background and Purpose-The characteristics of intracerebral hemorrhage (ICH) may vary by ICH location because of differences in the distribution of underlying cerebral small vessel diseases. Therefore, we investigated the incidence, characteristics, and outcome of lobar and nonlobar ICH. Methods-In a population-based, prospective inception cohort study of ICH, we used multiple overlapping sources of case ascertainment and follow-up to identify and validate ICH diagnoses in 2010 to 2011 in an adult population of 695 335. Results-There were 128 participants with first-ever primary ICH. The overall incidence of lobar ICH was similar to nonlobar ICH (9.

Polymorph detection and quantification in crystalline materials is a principle interest of the pharmaceutical industry. Terahertz (THz) spectroscopy can be used for such analytical applications since this technique is sensitive to the intermolecular interactions of molecules in the solid state. Understanding the fundamental nature of the lattice vibrational motions leading to absorptions in THz spectra is challenging, but may be achieved through computational approaches. In this study, the THz spectra of two diclofenac acid polymorphs were obtained by THz spectroscopy, and the vibrational characters of the observed absorptions were analyzed using solid-state density functional theory (DFT). The results demonstrate the quantitative capacity of THz spectroscopy and the reliability and utility of solid-state DFT in the calculation of low-frequency vibrational motions.

Introduction Increased mortality has been demonstrated in older adults with COVID-19, but the effect of frailty has been unclear. Methods This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty, and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation, and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS), and delirium on risk of increased care requirements on discharge, adjusting for the same variables. Results Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, IQR 54–83; 55.2% male). The risk of death increased independently with increasing age (>80 vs 18–49: HR 3.57, CI 2.54–5.02), frailty (CFS 8 vs 1–3: HR 3.03, CI 2.29–4.00) inflammation, renal disease, cardiovascular disease, and cancer, but not delirium. Age, frailty (CFS 7 vs 1–3: OR 7.00, CI 5.27–9.32), delirium, dementia, and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9. Conclusions Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.

The effects of applying an empirical dispersion correction to solid-state density functional theory methods were evaluated in the simulation of the crystal structure and low-frequency (10 to 90 cm(-1)) terahertz spectrum of the non-steroidal anti-inflammatory drug, naproxen. The naproxen molecular crystal is bound largely by weak London force interactions, as well as by more prominent interactions such as hydrogen bonding, and thus serves as a good model for the assessment of the pair-wise dispersion correction term in systems influenced by intermolecular interactions of various strengths. Modifications to the dispersion parameters were tested in both fully optimized unit cell dimensions and those determined by X-ray crystallography, with subsequent simulations of the THz spectrum being performed. Use of the unmodified PBE density functional leads to an unrealistic expansion of the unit cell volume and the poor representation of the THz spectrum. Inclusion of a modified dispersion correction enabled a high-quality simulation of the THz spectrum and crystal structure of naproxen to be achieved without the need for artificially constraining the unit cell dimensions.

The endoplasmic reticulum, the cytoplasmic organelle that matures a massive amount of nascent secretory polypeptides, is particularly sensitive to stress. Endoplasmic reticulum stress causes unfolded proteins to populate the organelle, eliciting the unfolded protein response. During the unfolded protein response, GRP78—an endoplasmic reticulum master stress regulator—detaches from three endoplasmic reticulum stress sensors (IRE1α, PERK, and ATF6) and allows them to activate the apoptotic signaling pathway. Fortilin, a pro-survival molecule, is known to inhibit apoptosis by binding and inhibiting p53, but its role in endoplasmic reticulum stress-induced apoptosis remains unknown. Here, we report that fortilin directly interacts with the cytoplasmic domain of IRE1α, inhibits both kinase and endoribonuclease (RNase) activities of the stress sensor, and protects cells against apoptotic cell death at both cellular and whole animal levels. Our data support a role of fortilin in the unfolded protein response and its potential participation in human diseases caused by unfolded protein response.

Oxalic acid and oxalic acid dihydrate were studied using terahertz spectroscopy and solid-state density functional theory (DFT) in the spectral range 10-100 cm(-1). The size of the oxalic acid molecule and its limited internal degrees of freedom make it ideal for evaluating the performance of computational methods for the structural and dynamical simulation of strongly hydrogen-bonded solids. Calculations of the solid-state structures and terahertz spectra of oxalic acid and oxalic acid dihydrate were performed using the hybrid B3LYP and B3PW91 and the nonhybrid BLYP and PW91 density functionals employing the 6-311G(2d,2p) basis set. When these simulations were compared to the experimental spectra of the oxalic acid solids, a constant overprediction of the dihydrate frequencies was observed in contrast to the results of the anhydrous system. This change in behavior is connected to the nature of the vibrational motions being accessed. The primary molecular motion contributions to the terahertz vibrations of oxalic acid dihydrate were found to originate in the external motions of the cocrystallized H(2)O molecules. The observed overestimation of the vibrational energies in the simulated terahertz spectra is attributed to increased anharmonicity of the vibrational motions in the dihydrate system versus the anhydrous, resulting from weaker hydrogen bonding through the networked water molecules.

The terahertz (THz, far-infrared) spectra of enantiomerically pure and racemic crystalline serine were investigated using time-domain THz spectroscopy and solid-state density functional theory (DFT) in the spectral range of 10-90 cm(-1). The experimental THz spectra of L- and DL-serine at 78 K appear quite similar despite the significant differences in arrangement of the molecules in their crystal structures. Structural analyses of the two systems and calculation of the vibrational modes and intensities were performed using DFT with periodic boundary conditions employing the B3LYP and PW91 density functionals with the 6-31G(d,p) and 6-311G(d,p) basis sets. The applied computational methods produced simulations of the THz spectra in good agreement with experiment, with accurate predictions of the subtle differences in the THz spectra of the two chiral solid-state mixtures of serine. The observed spectral features are assigned as primarily external lattice translations and rotations with lesser contributions due to intramolecular torsions of the -NH(3)(+) and -COO(-) groups modified by intermolecular hydrogen bonding.