Health-Related Quality of Life in People with Advanced HIV Disease, from 1996 to 2021: Systematic Review and Meta-analysis.

The purpose of the study was to assess the effects of advanced HIV disease (AHD) on health-related quality of life (HRQoL) in PLHIV, the changes in HRQoL outcomes over the last 25 years, and the differences between countries according to level of economic development. We conducted a systematic review and meta-analysis. The search was conducted in PubMed and Web of Science using the terms: "health-related quality of life", "HQRoL", "HIV", "AIDS", "advanced HIV disease" and "low CD4 cells". Studies inclusion criteria were: adult population; initiated after 1996 and published before July 2021; clinical trials, cross-sectional, cohort, and case-control studies; studies analyzing the relationship between AHD and HRQoL; English or Spanish language. Standardized mean differences (d+) were calculated to estimate the effect size for the meta-analyses. Summary statistics were calculated using a random-effects model, and analyses of effect moderators, using mixed-effects models. The meta-analysis included 38 studies. The results indicated that HRQoL is worse in patients with AHD compared to those without. The main HRQoL domains affected were overall health perception and concern and physical and functional health and symptoms. We found a moderate impact for age and gender on some HRQoL domains. There were no differences in relation to socioeconomic inequities, country of residence, or time period analyzed. In conclusion, advanced HIV disease has a negative impact on health and well-being in PLHIV. Our results show that despite all the advances in antiretroviral treatments over the last 25 years, AHD persists as a source of extreme vulnerability, regardless of where PLHIV live.

RESUMEN: El objetivo del estudio fue evaluar los efectos de la enfermedad avanzada de sida (EAS) en la calidad de vida relacionada con la salud (CVRS) en personas que viven con el VIH (PVVIH), los cambios experimentados en la CVRS en los últimos 25 años y las diferencias entre países. Realizamos una revisión sistemática y metaanálisis. La búsqueda se llevó a cabo en PubMed y Web of Science utilizando los términos: "calidad de vida relacionada con la salud", "CVRS", "VIH", "SIDA", "enfermedad avanzada por VIH" y "células CD4 bajas". Los criterios de inclusión de los estudios fueron: población adulta; iniciado después de 1996 y publicado antes de julio de 2021; ensayos clínicos, estudios transversales, de cohorte y de casos y controles; estudios que analizan la relación entre EAS y CVRS; idioma inglés o español. Se calcularon diferencias de medias estandarizadas (d+) para estimar el tamaño del efecto para los metaanálisis. Los efectos promedios se calcularon utilizando un modelo de efectos aleatorios, y el análisis de moderadores utilizando modelos de efectos mixtos. El metaanálisis incluyó 38 estudios. Los resultados indicaron que la CVRS es peor en pacientes con EAS en comparación con aquellos sin EAS. Los principales dominios de CVRS afectados son la percepción de salud general y su preocupación, y la función física y de salud y los síntomas asociados. Encontramos un impacto moderado por edad y género en algunos dominios de CVRS. No encontramos diferencias en cuanto a las desigualdades socioeconómicas, país de residencia o período de tiempo analizado. En conclusión, la enfermedad avanzada por VIH tiene un impacto negativo en la salud y el bienestar en las personas con VIH. Nuestros resultados muestran que, a pesar de todos los avances en los tratamientos antirretrovirales en los últimos 25 años, el EAS persiste como una fuente de extrema vulnerabilidad, independientemente de dónde vivan las personas con VIH.

Multiple glass transitions in vapor-deposited orientational glasses of the most fragile plastic crystal Freon 113.

We investigate by fast-scanning nanocalorimetry the formation of Freon 113 films from the vapor phase at deposition temperatures ranging from 50 to 120 K, that is, spanning above and below the transition temperature of the glassy crystal to the plastic crystal (Tgc = 72 K). Analysis of the heat capacity curves indicates that vapor deposition at T < Tgc of the highly fragile Freon 113 yields structural and orientational glasses in the as-deposited state depending on the temperature range of deposition. Interestingly, growing above Tgc produces plastic crystals with a conformational ratio C1/Cs that changes with Tdep above and below 110-120 K, the temperature at which previous works have identified the arrest of the transformations between the C1 and Cs conformers.

Mitochondrial pore opening and loss of Ca2+ exchanger NCLX levels occur after frataxin depletion.

Frataxin-deficient neonatal rat cardiomyocytes and dorsal root ganglia neurons have been used as cell models of Friedreich ataxia. In previous work we show that frataxin depletion resulted in mitochondrial swelling and lipid droplet accumulation in cardiomyocytes, and compromised DRG neurons survival. Now, we show that these cells display reduced levels of the mitochondrial calcium transporter NCLX that can be restored by calcium-chelating agents and by external addition of frataxin fused to TAT peptide. Also, the transcription factor NFAT3, involved in cardiac hypertrophy and apoptosis, becomes activated by dephosphorylation in both cardiomyocytes and DRG neurons. In cardiomyocytes, frataxin depletion also results in mitochondrial permeability transition pore opening. Since the pore opening can be inhibited by cyclosporin A, we show that this treatment reduces lipid droplets and mitochondrial swelling in cardiomyocytes, restores DRG neuron survival and inhibits NFAT dephosphorylation. These results highlight the importance of calcium homeostasis and that targeting mitochondrial pore by repurposing cyclosporin A, could be envisaged as a new strategy to treat the disease.

Glassy Anomalies in the Low-Temperature Thermal Properties of a Minimally Disordered Crystalline Solid.

The low-temperature thermal and transport properties of an unusual kind of crystal exhibiting minimal molecular positional and tilting disorder have been measured. The material, namely, low-dimensional, highly anisotropic pentachloronitrobenzene has a layered structure of rhombohedral parallel planes in which the molecules execute large-amplitude in-plane as well as concurrent out-of-plane librational motions. Our study reveals that low-temperature glassy anomalies can be found in a system with minimal disorder due to the freezing of (mostly in-plane) reorientational jumps of molecules between equivalent crystallographic positions with partial site occupation. Our findings will pave the way to a deeper understanding of the origin of the above-mentioned universal glassy properties at low temperature.

Thermodynamic and Kinetic Fragility of Freon 113: The Most Fragile Plastic Crystal.

We present a dynamic and thermodynamic study of the orientational glass former Freon 113 (1,1,2-trichloro-1,2,2-trifluoroethane, CCl_{2}F-CClF_{2}) in order to analyze its kinetic and thermodynamic fragilities. Freon 113 displays internal molecular degrees of freedom that promote a complex energy landscape. Experimental specific heat and its microscopic origin, the vibrational density of states from inelastic neutron scattering, together with the orientational dynamics obtained by means of dielectric spectroscopy have revealed the highest fragility value, both thermodynamic and kinetic, found for this orientational glass former. The excess in both Debye-reduced specific heat and density of states (boson peak) evidences the existence of glassy low-energy excitations. We demonstrate that early proposed correlations between the boson peak and the Debye specific heat value are elusive as revealed by the clear counterexample of the studied case.

On the microscopic mechanism behind the purely orientational disorder-disorder transition in the plastic phase of 1-chloroadamantane.

Globular molecules of 1-chloroadamantane form a plastic phase in which the molecules rotate in a restrained way, but with their centers of mass forming a crystalline ordered lattice. Plastic phases can be regarded as test cases for the study of disordered phases since, contrary to what happens in the liquid phase, there is a lack of stochastic translational degrees of freedom. When the temperature is increased, a hump in the specific heat curve is observed indicating a change in the energetic footprint of the dynamics of the molecules. This change takes place without a change in the symmetry of the crystalline lattice, i.e. no first-order transition is observed between temperatures below and above the calorimetric hump. This implies that subtle changes in the dynamics of the disordered plastic phase concerning purely orientational degrees of freedom should appear at the thermodynamic anomaly. Accordingly, we describe, for the first time, the microscopic mechanisms behind a disorder-disorder transition through the analysis of neutron diffraction and QENS experiments. The results evince a change in the molecular rotational dynamics accompanied by a continuous change in density.

Structure and reorientational dynamics of 1-F-adamantane.

The polymorphism and the dynamics of a simple rigid molecule (1-fluoro-adamantane) have been studied by means of X-ray powder diffraction and broadband dielectric spectroscopy. At temperatures below the melting point, the molecule forms an orientationally disordered Phase I with a cubic-centered structure (Phase I, Fm3¯m, Z = 4). This phase possesses eight equilibrium positions for the fluorine atom, with equal occupancy factors of 1/8. A solid-solid phase transition to a low-temperature tetragonal phase (Phase II, P4¯2(1)c, Z = 2) reduces the statistical disorder to only four possible equivalent sites for the fluorine atom, with fractional occupancies of 1/4. The dynamics has been rationalized under the constraints imposed by the space group of the crystal structure determined by powder X-ray diffraction. The dielectric spectroscopy study reveals that the statistical disorder in Phase II is dynamic in character and is associated with reorientational jumps along the two- and three-fold axes. In the dielectric loss spectra, the cooperative (α) relaxation exhibits a shoulder on the high-frequency side. This remarkable finding clearly reveals the existence of two intrinsic reorientational processes associated with the exchange of the F atom along the four sites. In addition to such "bimodal" relaxation, a secondary Johari-Goldstein relaxation is detected at lower temperatures.

Orientational relaxations in solid (1,1,2,2)tetrachloroethane.

We employ dielectric spectroscopy and molecular dynamic simulations to investigate the dipolar dynamics in the orientationally disordered solid phase of (1,1,2,2)tetrachloroethane. Three distinct orientational dynamics are observed as separate dielectric loss features, all characterized by a simply activated temperature dependence. The slower process, associated to a glassy transition at 156 ± 1 K, corresponds to a cooperative motion by which each molecule rotates by 180° around the molecular symmetry axis through an intermediate state in which the symmetry axis is oriented roughly orthogonally to the initial and final states. Of the other two dipolar relaxations, the intermediate one is the Johari-Goldstein precursor relaxation of the cooperative dynamics, while the fastest process corresponds to an orientational fluctuation of single molecules into a higher-energy orientation. The Kirkwood correlation factor of the cooperative relaxation is of the order of one tenth, indicating that the molecular dipoles maintain on average a strong antiparallel alignment during their collective motion. These findings show that the combination of dielectric spectroscopy and molecular simulations allows studying in great detail the orientational dynamics in molecular solids.

Molecular diffusion and dc conductivity perfectly correlated with molecular rotational dynamics in a plastic crystalline electrolyte.

We probe the ionic conduction and the molecular dynamics in a pure and lithium-salt doped dinitrile molecular plastic crystal. While the diffusion of the Li(+) ions is decoupled from the molecular reorientational dynamics, in the undoped plastic crystal the temperature dependence of the mobility of dinitrile ions and thus of the conductivity is virtually identical to that of on-site molecular rotations. The undoped material is found to obey the Walden and Stokes-Einstein rules typical of ideal liquid electrolytes, implying that an effective viscosity against diffusion can be defined even for a plastic crystalline phase. These surprising results, never reported before in a translationally ordered solid, indicate that in this dinitrile plastic crystalline material the timescale of translational diffusion is perfectly correlated with that of the purely reorientational on-site dynamics.

Thermal properties of halogen-ethane glassy crystals: Effects of orientational disorder and the role of internal molecular degrees of freedom.

The thermal conductivity, specific heat, and specific volume of the orientational glass former 1,1,2-trichloro-1,2,2-trifluoroethane (CCl2F-CClF2, F-113) have been measured under equilibrium pressure within the low-temperature range, showing thermodynamic anomalies at ca. 120, 72, and 20 K. The results are discussed together with those pertaining to the structurally related 1,1,2,2-tetrachloro-1,2-difluoroethane (CCl2F-CCl2F, F-112), which also shows anomalies at 130, 90, and 60 K. The rich phase behavior of these compounds can be accounted for by the interplay between several of their degrees of freedom. The arrest of the degrees of freedom corresponding to the internal molecular rotation, responsible for the existence of two energetically distinct isomers, and the overall molecular orientation, source of the characteristic orientational disorder of plastic phases, can explain the anomalies at higher and intermediate temperatures, respectively. The soft-potential model has been used as the framework to describe the thermal properties at low temperatures. We show that the low-temperature anomaly of the compounds corresponds to a secondary relaxation, which can be associated with the appearance of Umklapp processes, i.e., anharmonic phonon-phonon scattering, that dominate thermal transport in that temperature range.

A continuous mixture of two different dimers in liquid water.

It is hitherto thought that liquid water is composed of tetrahedrally coordinated molecules with an asymmetric interaction of the central molecule with neighboring molecules. Kühne et al., Nat. Commun., 2013, 4, 1450 suggested that this asymmetry, energetic rather than geometric, is the cornerstone to reconcile the homogeneous and inhomogeneous viewpoints of liquid water. In order to investigate the geometric origin of that asymmetry, we have scrutinized Molecular Dynamics (MD) simulations of water through a careful analysis of the five-dimensional probability distribution function of Euler angles in which the relative positions and orientations of water molecules are obtained. We demonstrate that, beyond the ubiquitous tetrahedral structure with well-defined molecular dimers, there is a series of possible molecular orientations that define the structure. These orientations are generated by rotating the neighboring molecule around the O-H axis that is involved in the hydrogen bond scheme. Two of the possible orientations have a higher probability, giving rise to two kinds of dimers: one close to the lowest energy of a water dimer in vacuum with an almost perpendicular alignment of the dipole moment, and another one with a parallel orientation of the dipole moment which is less tightly bound. These two different dimers have an effect on the orientation of further water dipole moments up to a distance of ≈6 Å. Liquid water can therefore be described as a continuous mixture of two kinds of dimers where the hydrogen bonds have the same geometry but the interaction energies are different due to a different mutual orientation of the dipoles of the participating water molecules.

An unexpected high-pressure stability domain for a lower density polymorph of benzophenone.

For over a century, it was thought that the crystalline polymorph II of benzophenone does not possess a stable domain in the pressure-temperature phase diagram. With a combination of new experimental results and literature data, this case of crystalline dimorphism has finally been solved and it is shown that form II possesses a stable domain at high pressure and high temperature, even though its density is lower than that of form I, the stable form under ordinary pressure and temperature conditions. The phase diagram of benzophenone is a clear demonstration of the fact that to understand the phase behaviour of a chemical substance both the exchange of heat (due to the change in intermolecular interactions) and work (due to the change of volume at a given pressure) need to be taken into account.

Dynamic heterogeneity in the glass-like monoclinic phases of CBr(n)Cl(4-n), n = 0,1,2.

Glassy dynamics of rigid molecules is still a matter of controversy: the physics behind the relaxation process at time scales faster than that ruled by the viscosity, the so called Johari-Goldstein process, is not known. In this work we unravel the mechanism of such a process by using a simple molecular model in which the centers of mass of the molecules are forming an ordered lattice, and molecular reorientation is performed by jumps between equilibrium orientations. We have studied the dynamics of simple quasi-tetrahedral molecules CBr(n)Cl(4-n), n = 0, 1, 2, in their monoclinic phases by means of dielectric spectroscopy and nuclear quadrupole resonance: the first technique allows to measure in a broad time scale but it is insensitive to molecular particularities, while the second has a restricted time window but senses the movement of each chlorine atom separately. The dynamic picture emerging from these techniques is that the secondary relaxation process is related to the different molecular surroundings around each nonequivalent atom of the molecule. Dynamical heterogeneities thus seem to be the cause of the secondary relaxation in this simple model of glass.

Differences in first neighbor orientation behind the anomalies in the low and high density trans-1,2-dichloroethene liquid.

Trans-1,2-dichloroethene (HClC=CClH) has several structural and dynamic anomalies between its low- and high-density liquid, previously found through neutron scattering experiments. To explain the microscopic origin of the differences found in those experiments, a series of molecular dynamics simulations were performed. The analysis of molecular short-range order shows that the number of molecules in the first neighbor shell is 12 for the high-density liquid and 11 for the low-density one. It also shows that the angular position of the center of mass of the first neighbor is roughly the same although the molecular orientation is not. In both liquids the first neighbor and its reference molecule arrange mainly in two configurations, each being the most probable in one of the liquids. First neighbors in the configuration that predominates in the high-density liquid tend to locate themselves closer to the reference molecule, an evidence that they are more strongly bonded. This arrangement facilitates a better packing of the rest of molecules in the first neighbor shell so that on average an additional molecule can be included, and is proposed to be the key in the explanation of all the observed anomalies in the characteristics of both liquids.

[Ischaemic stroke due to basilar artery occlusion in a puerperal patient with SARS-CoV-2 infection]. / Ictus isquémico por oclusión de la arteria basilar en una paciente puérpera con infección por SARS-CoV-2.

INTRODUCTION: Infection by coronavirus type 2, which is the cause of severe acute respiratory syndrome (SARS-CoV-2), gives rise to thromboembolic complications, including acute cerebrovascular disease. Due to the hypercoagulable state that accompanies pregnancy, the thrombotic risk in these patients may be particularly significant. CASE REPORT: We report the case of a 41-year-old woman, 34+1 weeks pregnant, diagnosed with bilateral interstitial pneumonia, caused by coronavirus disease 2019 (COVID-19). The patient presented with severe respiratory failure, and so the decision was made to perform an emergency caesarean section and she was transferred to the intensive care unit. During her stay in hospital, the patient suffered a sudden episode of decreased level of consciousness, and magnetic resonance angiography revealed thrombosis in the left vertebral artery and in the basilar artery, with the presence of acute ischaemic infarction in both cerebellar hemispheres and bilateral involvement of the brainstem. CONCLUSION: Severe SARS-CoV-2 disease results in a prothrombotic state that correlates with the prognosis of the disease. The last trimester of pregnancy and the puerperium are known prothrombotic risk factors. Recommendations for anticoagulation management in pregnant patients with COVID-19 are based on limited evidence. This is the first case to be published in Spain involving cerebral arterial thrombosis in a pregnant patient with SARS-CoV-2 infection.

TITLE: Ictus isquémico por oclusión de la arteria basilar en una paciente puérpera con infección por SARS-CoV-2.Introducción. La infección por coronavirus de tipo 2 (SARS-CoV-2), causante del síndrome respiratorio agudo grave (COVID-19), produce complicaciones tromboembólicas, incluyendo casos de enfermedad cerebrovascular aguda. Debido al estado de hipercoagulabilidad que acompaña al embarazo, el riesgo trombótico en estas pacientes puede ser especialmente relevante. Caso clínico. Presentamos el caso de una mujer de 41 años, gestante de 34 + 1 semanas, diagnosticada de neumonía intersticial bilateral, SARS-CoV-2. La paciente presentó insuficiencia respiratoria grave, por lo que se decidió la realización de una cesárea urgente y se trasladó a la unidad de cuidados intensivos. Durante su estancia en ésta, la paciente presentó un episodio brusco de disminución del nivel de consciencia, y se evidenció por angiorresonancia magnética una trombosis en la arteria vertebral izquierda y en la arteria basilar, con presencia de infarto isquémico agudo en ambos hemisferios cerebelosos y afectación bilateral del tronco del encéfalo. Conclusión. La enfermedad grave por el SARS-CoV-2 produce un estado protrombótico que se correlaciona con el pronóstico de la enfermedad. El último trimestre del embarazo y el puerperio son factores de riesgo protrombóticos conocidos. Las recomendaciones del manejo de anticoagulación en pacientes embarazadas con COVID-19 se basan en una evidencia limitada. Éste es el primer caso publicado en España de trombosis arterial cerebral en una paciente embarazada con infección por el SARS-CoV-2.

On the dimorphism of prednisolone: The topological pressure-temperature phase diagram involving forms I and II.

The dimorphism of the corticosteroid anti-inflammatory drug prednisolone has been investigated by the construction of a topological pressure-temperature phase diagram, using crystallographic and calorimetric data. The system is enantiotropic, because the temperature of the I-II equilibrium under atmospheric conditions (400-463 K) is lower than that of the two melting equilibria (518.7 K for form II and 526.3 K for form I). The slope of the I-II equilibrium in the pressure-temperature phase diagram is negative and relatively steep; therefore, form II, which is the stable form at room temperature, will not easily encounter conditions where form I will become stable even under industrial processing conditions. On the other hand, extreme small amounts of form I have been observed to spontaneously transform into form II in a time interval of about six years at room temperature and it can be concluded that although form I is very persistent under ambient conditions, it does slowly convert into form II. Moreover, the system does not obey the density rule.

Enthalpy space analysis of the evolution of the primary relaxation time in ultraslowing systems.

For decades the Vogel-Fulcher-Tammann equation has dominated the description of dynamics of the non-Arrhenius behavior in glass forming systems. Recently, this dominance has been questioned. Hecksher et al. [Nat. Phys. 4, 737 (2008)], Elmatad et al. [J. Phys. Chem. B 113, 5563 (2009)], and Mauro et al. [Proc. Natl. Acad. Sci. U.S.A. 106, 19780 (2009)] indicated superiority of several equations showing no divergence at a finite (nonzero) temperature. This paper shows distortion-sensitive and derivative based empirical analysis of the validity of leading equations for portraying the previtreous evolution of primary relaxation time.

Prevalence for the universal distribution of relaxation times near the glass transitions in experimental model systems: rodlike liquid crystals and orientationally disordered crystals.

Recently, Nielsen et al. [J. Chem. Phys. 130, 154508 (2009); Philos. Mag. 88, 4101 (2008)] demonstrated a universal pattern for the high frequency wing of the loss curve for primary relaxation time on approaching the glass transition for organic liquids. In this contribution it is presented that a similar universality occurs for glass-forming liquid crystals and orientationally disordered crystals (plastic crystals). Empirical correlations of the found behavior are also briefly discussed.

Low-Temperature Heat Capacity Anomalies in Ordered and Disordered Phases of Normal and Deuterated Thiophene.

We measured the specific heat Cp of normal (C4H4S) and deuterated (C4D4S) thiophene in the temperature interval of 1 ≤ T, K ≤ 25. C4H4S exhibits a metastable phase II2 and a stable phase V, both with frozen orientational disorder (OD), whereas C4D4S exhibits a metastable phase II2, which is analogous to the OD phase II2 of C4H4S and a fully ordered stable phase V. Our measurements demonstrate the existence of a large bump in the heat capacity of both stable and metastable C4D4S and C4H4S phases at temperatures of ∼10 K, which significantly departs from the expected Debye temperature behavior of Cp ≈ T3. This case study demonstrates that the identified low-temperature Cp anomaly, typically referred to as a "Boson-peak" in the context of glassy crystals, is not exclusive of disordered materials.

Alpha-relaxation dynamics of orientanionally disordered mixed crystals composed of Cl-adamantane and CN-adamantane.

The alpha-relaxation dynamics of 1-cyano-adamantane (CNA) and its mixtures with 1-chloro-adamantane (ClA) has been studied by means of broadband dielectric spectroscopy. The existence of orientationally disordered (OD) face centered cubic mixed crystals (ClA(1-X)CNA(X)) for 0.5 < or = X < or = 1 has been put in evidence by thermodynamics and structural analyses. In addition to the OD phase of CNA, mixed crystals with compositions higher than the equimolar one exhibit a freezing of the orientational degrees of freedom into a glassy state, which involves also a strong increase of the antiferroelectric order at temperatures higher than the dielectric glass transition temperature. This experimental evidence is revealed by a stairlike effect in the variation of the Kirkwood factor with the temperature as a consequence of a twin effect in the dielectric strength without any anomaly in the temperature-density curves. The characteristic relaxation times are analyzed as a function of temperature and mole fraction. By setting a common temporal origin ("isochronal origin") at tau(T(g)) = 100 s for each mole fraction, it emerges that the substitution of ClA molecules by those of CNA (diminution of X) gives rise to a slow down in the dynamics, despite that the molecular volume of ClA molecules are smaller than those of CNA. This fact goes along and is accompanied by a diminution of the lattice packing with the decrease of composition. It is also shown that the heterogeneities produced by the concentration fluctuations due to the chemical disorder are the main contribution to the non-exponential character of the alpha-relaxation peaks.