Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

Three-phase equilibria of hydrates from computer simulation. I. Finite-size effects in the methane hydrate.

Clathrate hydrates are vital in energy research and environmental applications. Understanding their stability is crucial for harnessing their potential. In this work, we employ direct coexistence simulations to study finite-size effects in the determination of the three-phase equilibrium temperature (T3) for methane hydrates. Two popular water models, TIP4P/Ice and TIP4P/2005, are employed, exploring various system sizes by varying the number of molecules in the hydrate, liquid, and gas phases. The results reveal that finite-size effects play a crucial role in determining T3. The study includes nine configurations with varying system sizes, demonstrating that smaller systems, particularly those leading to stoichiometric conditions and bubble formation, may yield inaccurate T3 values. The emergence of methane bubbles within the liquid phase, observed in smaller configurations, significantly influences the behavior of the system and can lead to erroneous temperature estimations. Our findings reveal finite-size effects on the calculation of T3 by direct coexistence simulations and clarify the system size convergence for both models, shedding light on discrepancies found in the literature. The results contribute to a deeper understanding of the phase equilibrium of gas hydrates and offer valuable information for future research in this field.

Three-phase equilibria of hydrates from computer simulation. II. Finite-size effects in the carbon dioxide hydrate.

In this work, the effects of finite size on the determination of the three-phase coexistence temperature (T3) of the carbon dioxide (CO2) hydrate have been studied by molecular dynamic simulations and using the direct coexistence technique. According to this technique, the three phases involved (hydrate-aqueous solution-liquid CO2) are placed together in the same simulation box. By varying the number of molecules of each phase, it is possible to analyze the effect of simulation size and stoichiometry on the T3 determination. In this work, we have determined the T3 value at 8 different pressures (from 100 to 6000 bar) and using 6 different simulation boxes with different numbers of molecules and sizes. In two of these configurations, the ratio of the number of water and CO2 molecules in the aqueous solution and the liquid CO2 phase is the same as in the hydrate (stoichiometric configuration). In both stoichiometric configurations, the formation of a liquid drop of CO2 in the aqueous phase is observed. This drop, which has a cylindrical geometry, increases the amount of CO2 available in the aqueous solution and can in some cases lead to the crystallization of the hydrate at temperatures above T3, overestimating the T3 value obtained from direct coexistence simulations. The simulation results obtained for the CO2 hydrate confirm the sensitivity of T3 depending on the size and composition of the system, explaining the discrepancies observed in the original work by Míguez et al. [J. Chem Phys. 142, 124505 (2015)]. Non-stoichiometric configurations with larger unit cells show a convergence of T3 values, suggesting that finite-size effects for these system sizes, regardless of drop formation, can be safely neglected. The results obtained in this work highlight that the choice of a correct initial configuration is essential to accurately estimate the three-phase coexistence temperature of hydrates by direct coexistence simulations.

Three-phase equilibria of hydrates from computer simulation. III. Effect of dispersive interactions in the methane and carbon dioxide hydrates.

In this work, the effect of the range of dispersive interactions in determining the three-phase coexistence line of the CO2 and CH4 hydrates has been studied. In particular, the temperature (T3) at which solid hydrate, water, and liquid CO2/gas CH4 coexist has been determined through molecular dynamics simulations using different cutoff values (from 0.9 to 1.6 nm) for dispersive interactions. The T3 of both hydrates has been determined using the direct coexistence simulation technique. Following this method, the three phases in equilibrium are put together in the same simulation box, the pressure is fixed, and simulations are performed at different temperatures T. If the hydrate melts, then T > T3. Conversely, if the hydrate grows, then T < T3. The effect of the cutoff distance on the dissociation temperature has been analyzed at three different pressures for CO2 hydrate: 100, 400, and 1000 bar. Then, we have changed the guest and studied the effect of the cutoff distance on the dissociation temperature of the CH4 hydrate at 400 bar. Moreover, the effect of long-range corrections for dispersive interactions has been analyzed by running simulations with homo- and inhomogeneous corrections and a cutoff value of 0.9 nm. The results obtained in this work highlight that the cutoff distance for the dispersive interactions affects the stability conditions of these hydrates. This effect is enhanced when the pressure is decreased, displacing the T3 about 2-4 K depending on the system and the pressure.

Effect of substrate mismatch, orientation, and flexibility on heterogeneous ice nucleation.

Heterogeneous nucleation is the main path to ice formation on Earth. The ice nucleating ability of a certain substrate is mainly determined by both molecular interactions and the structural mismatch between the ice and the substrate lattices. We focus on the latter factor using molecular simulations of the mW model. Quantifying the effect of structural mismatch alone is challenging due to its coupling with molecular interactions. To disentangle both the factors, we use a substrate composed of water molecules in such a way that any variation on the nucleation temperature can be exclusively ascribed to the structural mismatch. We find that a 1% increase in structural mismatch leads to a decrease of ∼4 K in the nucleation temperature. We also analyze the effect of orientation of the substrate with respect to the liquid. The three main ice orientations (basal, primary prism, and secondary prism) have a similar ice nucleating ability. We finally assess the effect of lattice flexibility by comparing substrates where molecules are immobile to others where a certain freedom to fluctuate around the lattice positions is allowed. Interestingly, we find that the latter type of substrate is more efficient in nucleating ice because it can adapt its structure to that of ice.

[Comparison of quality of life in patients living with HIV infection through pharmaceutical care according to CMO methodology vs. conventional follow-up. MAS-VIH project]. / Comparación de la calidad de vida en personas que viven con infección por VIH en seguimiento mediante atención farmacéutica según metodología capacidad motivación-oportunidad vs. seguimiento convencional. Proyecto MAS-VIH.

OBJECTIVE: To compare quality of life, in patients living with HIV infection with pharmaceutical care according to the CMO methodology: capacity, motivation and opportunity versus conventional follow-up. METHODS: Longitudinal, prospective, multicenter, health intervention study, conducted between October 2019 and November 2021 in 14 centers throughout Spain. Patients over 18 years of age, receiving antiretroviral treatment and attending the consultations of the participating Pharmacy Services for 1 year were included. Patients who did not have the autonomy to complete the planned questionnaires were excluded. At baseline, participating centers were randomized to continue using the same systematics of work (traditional follow-up) or to implement the CMO model using patient stratification models, goal setting in relation to pharmacotherapy, use of motivational interviewing, as well as longitudinal follow-up enabled by new technologies. The main variable was the difference in the number of dimensions positively affected in each follow-up arm at 24 weeks of follow-up according to the MOS-HIV questionnaire. In the CMO group, the interventions performed the most frequently were recorded. RESULTS: 151 patients were included. The median age was 51.35 years. A significant improvement in quality of life was found at the end of follow-up in the CMO group, reducing the number of patients with negatively affected dimensions (2/11 vs 8/11). The most frequent interventions carried out in the CMO group, according to the taxonomy, were Motivation (51,7%) and review and validation (49,4%). CONCLUSIONS: The quality of life of patients is higher in those centers that develop Pharmaceutical Care based on the CMO methodology compared to traditional follow-up.

Evaluación de la filtración apical al utilizar dos selladores biocerámicos / Evaluation of apical leakage when using two bioceramic sealers

Objetivo: Evaluar con técnica de diafanización el gra-do de filtración apical al utilizar dos selladores bio-cerámicos y la técnica de cono único con taper ex vivo. Materiales y métodos: Se utilizaron 60 premola-res inferiores humanos uniradiculares extraídos. La instrumentación se realizó con lima Primary 25/.07 (WaveOne Gold, Dentsply Maillefer), según protocolo del fabricante. Se irrigó con NaOCl 2,5% y EDTAC 17%. Para la obturación, la muestra se dividió aleatoria-mente en 4 grupos (n=15). Grupo 1: Cono único y Bio C Sealer. Grupo 2: Cono único y MTA Fillapex. Grupo control negativo: no se obturó. Grupo control positi-vo: Cono único y AH Plus. En todas las muestras se aplicaron dos capas de esmalte para uñas en toda la superficie dentaria con excepción del tercio apical y del grupo control positivo, que se esmaltó en su tota-lidad. Medio de filtración: tinta china negra por difu-sión pasiva. Se diafanizó con técnica de Robertson. Se usó programa AutoCad 2022, para medir filtración en milímetros lineales. Los datos se analizaron me-diante prueba de Kruskal-Wallis seguida por compa-raciones post hoc empleando el método de Conover (p<0,05, significativo). Resultados: La filtración con Bio C Sealer, MTA Fillapex, control negativo y control positivo tuvo una media (mínimo-máximo) de 0 (0-2), 1 (0-3), 6 (2-12) y 0 (0-0); sin diferencias significativas entre Bio C Sealer y MTA Fillapex (p>0,05), ni entre Bio C Sealer y control positivo (p>0,05); pero con di-ferencias significativas entre MTA Fillapex y control positivo (p<0,05), y entre control negativo y cual-quiera de los otros tres grupos (p<0,05). Conclusión: La obturación con Bio C Sealer lograría un nivel de sellado similar al que se obtiene con el control po-sitivo; mientras que la obturación con MTA Fillapex produciría un sellado ligeramente menos efectivo que el control positivo. Sin embargo, la filtración no variaría sustancialmente entre obturaciones con Bio C Sealer y MTA Fillapex (AU)

Objective: To evaluate the degree of apical filtration with diaphanization technique, using two bioceramic sealers and single cone technique with taper, ex vivo. Materials and methods: 60 extracted single-root human mandibular premolars were used. The instrumentation was carried out with primary file 25/.07 (WaveOne Gold, Dentsply Maillefer), according to the manufacturer's protocol. Irrigation was done with 2.5% NaOCl and 17% EDTAC. For obturation, the sample was randomly divided in 4 groups (n=15). Group 1: Single cone and Bio C Sealer. Group 2: Single cone and MTA Fillapex. Negative control group: it was not obturated. Positive control group: Single cone and AH Plus. In all samples, two layers of nail polish were applied to the entire tooth surface with exception of apical third and the positive control group, which was completely glazed. Filtration medium: black Chinese ink by passive diffusion. It was diaphanized with Robertson technique. AutoCad 2022 program was used to measure filtration in linear millimeters. Data were analyzed using Kruskal-Wallis test, followed by post hoc comparisons using Conover method (p < 0.05, significant). Results: Filtration with Bio C Sealer, MTA Fillapex, negative control and positive control had a mean (minimum-maximum) of 0 (0-2), 1 (0-3), 6 (2-12) and 0 (0-0); no significant differences between Bio C Sealer and MTA Fillapex (p > 0.05), nor between Bio C Sealer and positive control (p > 0.05); but with significant differences between MTA Fillapex and positive control (p < 0.05), and between negative control and any of the other three groups (p < 0.05). Conclusion: Obturation with Bio C Sealer would achieve a level of sealing similar to obtained with the positive control; while obturation with MTA Fillapex would produce a slightly less effective seal than the positive control. However, filtration would not vary substantially between fillings with Bio C Sealer and MTA Fillapex (AU)

Prevalencia e impacto del sangrado menstrual abundante en España: resultados de una encuesta nacional / Prevalence and impact of heavy menstrual bleeding in Spain: Results of a national survey

Antecedentes: El sangrado menstrual abundante (SMA) es un problema ginecológico frecuente. Los datos sobre su prevalencia en España y su impacto son limitados. Material y métodos: Encuesta realizada en España en mujeres de 23-49 años incluidas en un panel en línea voluntario. La encuesta abordó varios aspectos, incluidos las características y el impacto de la menstruación. La información se recogió mediante un cuestionario semiestructurado enviado por correo electrónico. Los resultados se ponderaron por edad y distribución geográfica. Resultados: Se obtuvieron datos de 1.206 mujeres de las 4.478 invitadas (26,9%), de las que 1.169 (96,9%) tenían la menstruación. El 32,7% (n=373) expresó tener «sangrado menstrual excesivo» (SME), lo que se asoció con una mayor frecuencia e intensidad de síntomas menstruales. También con un porcentaje superior de mujeres a las que la menstruación limita «bastante o mucho» (29,1% frente a 15,7% con sangrado normal/leve). Las relaciones sexuales fueron el ámbito más afectado (al 59% les limitaba «bastante o mucho»). El porcentaje de mujeres con afectación de los ámbitos analizados fue significativamente superior entre aquellas con SME, excepto para la vida familiar. El 67,5% de las mujeres con SME había acudido al médico por este motivo; el 19,8% seguía algún tratamiento específico. Conclusiones: En nuestra muestra de 1.206 mujeres de edad fértil, el 6,2% presentaba SMA (SME+limitación «bastante o mucho» de la vida diaria). El SME tiene un impacto importante en la vida diaria de la mujer. Dos de cada 3consultan al médico por este motivo.(AU)

Background: Heavy menstrual bleeding (HMB) is a common gynecological complaint. Data on its prevalence and impact in Spain are limited. Material and methods: A voluntary web-based survey was conducted in Spain among women aged 23–49. The survey covered several aspects of menstruation, including the characteristics and impact. The information was gathered using a semi-structured questionnaire sent by email. Results were weighted by age and geographic distribution. Results: Of the 4478 women invited to participate, 1206 (26.9%) responded, of whom 1169 (96.9%) were menstruating. 32.7% (n=373) said they experienced “excessive menstrual bleeding” (EMB), which was associated with increased frequency and intensity of menstrual symptoms as well as a higher percentage of women whose menstruation limited them “a lot or quite a lot” (29.1% vs. 15.7% with normal/light bleeding). Sexual intercourse was the domain most affected (59% were limited “a lot or quite a lot”). Except for family life, the impact on the domains analyzed was significantly higher among women with EMB. 67.5% of women with EMB had seen a doctor for this reason; 19.8% were receiving some type of treatment. Conclusions: In our sample of 1206 women of childbearing age, 6.2% had HMB (EMB+“a lot or quite a lot” of limitations of daily activities). Excessive menstrual bleeding has a major impact on the daily lives of women. Two out of 3see a doctor for this reason.(AU)

Growth rate of CO2 and CH4 hydrates by means of molecular dynamics simulations.

CO2 and CH4 hydrates are of great importance both from an energetic and from an environmental point of view. It is therefore highly relevant to quantify and understand the rate with which they grow. We use molecular dynamics simulations to shed light on the growth rate of these hydrates. We put the solid hydrate phase in contact with a guest aqueous solution in equilibrium with the pure guest phase and study the growth of both hydrates at 400 bars with temperature. We compare our results with previous calculations of the ice growth rate. We find a growth rate maximum as a function of the supercooling in all cases. The incorporation of guest molecules into the solid structure strongly decelerates hydrate growth. Consistently, ice grows faster than either hydrate and the CO2 hydrate grows faster than the CH4 one because of the higher solubility of CO2. We also quantify the molecular motion required to build the solids under study and find that the distance traveled by liquid molecules exceeds by orders of magnitude that advanced by any solid. Less molecular motion is needed in order for ice to grow as compared to the hydrates. Moreover, when temperature increases, more motion is needed for solid growth. Finally, we find a good agreement between our growth rate calculations and experiments of hydrate growth along the guest-solution interface. However, more work is needed to reconcile experiments of hydrate growth toward the solution among each other and with simulations.

α-Synuclein Attenuates Maneb Neurotoxicity through the Modulation of Redox-Sensitive Transcription Factors.

The accumulation and aggregation of α-synuclein is a pathognomonic sign of Parkinson's disease (PD). Maneb (MB) exposure has also been reported as one environmental triggering factor of this multifactorial neurodegenerative disease. In our laboratory, we have previously reported that mild overexpression of α-synuclein (200% increase with respect to endogenous neuronal levels) can confer neuroprotection against several insults. Here, we tested the hypothesis that α-synuclein can modulate the neuronal response against MB-induced neurotoxicity. When exposed to MB, cells with endogenous α-synuclein expression displayed increased reactive oxygen species (ROS) associated with diminished glutamate-cysteine ligase catalytic subunit (GCLc) and hemeoxygenase-1 (HO-1) mRNA expressions and upregulation of the nuclear factor erythroid 2-related factor 2 (NRF2) repressor, BTB domain and CNC homolog 1 (BACH1). We found that α-synuclein overexpression (wt α-syn cells) attenuated MB-induced neuronal damage by reducing oxidative stress. Decreased ROS found in MB-treated wt α-syn cells was associated with unaltered GCLc and HO-1 mRNA expressions and decreased BACH1 expression. In addition, the increased SOD2 expression and catalase activity were associated with forkhead box O 3a (FOXO3a) nuclear compartmentalization. Cytoprotective effects observed in wt α-syn cells were also associated with the upregulation of silent information regulator 1 (SIRT1). In control cells, MB-treatment downregulated glutathione peroxidase 4 mRNA levels, which was coincident with increased ROS content, lipid peroxidation, and mitochondrial alterations. These deleterious effects were prevented by ferrostatin-1, an inhibitor of ferroptosis, under conditions of endogenous α-synuclein expression. The overexpression of α-synuclein attenuated MB toxicity by the activation of the same mechanisms as ferrostatin-1. Overall, our findings suggest that mild overexpression of α-synuclein attenuates MB-induced neurotoxicity through the modulation of NRF2 and FOXO3a transcription factors and prevents cell death probably by intervening in mechanisms associated with ferroptosis. Thus, we postulate that early stages of α-synuclein overexpression could be potentially neuroprotective against MB neurotoxicity.

Functional phenotypic plasticity mediated by water stress and [CO2] explains differences in drought tolerance of two phylogenetically close conifers.

Forests are threatened globally by increased recurrence and intensity of hot droughts. Functionally close coexisting species may exhibit differences in drought vulnerability large enough to cause niche differentiation and affect forest dynamics. The effect of rising atmospheric [CO2], which could partly alleviate the negative effects of drought, may also differ between species. We analysed functional plasticity in seedlings of two taxonomically close pine species (Pinus pinaster Ait., Pinus pinea L.) under different [CO2] and water stress levels. The multidimensional functional trait variability was more influenced by water stress (preferentially xylem traits) and [CO2] (mostly leaf traits) than by differences between species. However, we observed differences between species in the strategies followed to coordinate their hydraulic and structural traits under stress. Leaf 13C discrimination decreased with water stress and increased under elevated [CO2]. Under water stress both species increased their sapwood area to leaf area ratios, tracheid density and xylem cavitation, whereas they reduced tracheid lumen area and xylem conductivity. Pinus pinea was more anisohydric than P. pinaster. Pinus pinaster produced larger conduits under well-watered conditions than P. pinea. Pinus pinea was more tolerant to water stress and more resistant to xylem cavitation under low water potentials. The higher xylem plasticity in P. pinea, particularly in tracheid lumen area, expressed a higher capacity of acclimation to water stress than P. pinaster. In contrast, P. pinaster coped with water stress comparatively more by increasing plasticity of leaf hydraulic traits. Despite the small differences observed in the functional response to water stress and drought tolerance between species, these interspecific differences agreed with ongoing substitution of P. pinaster by P. pinea in forests where both species co-occur. Increased [CO2] had little effect on the species-specific relative performance. Thus, a competitive advantage under moderate water stress of P. pinea compared with P. pinaster is expected to continue in the future.

Scaled charges for ions: An improvement but not the final word for modeling electrolytes in water.

In this work, we discuss the use of scaled charges when developing force fields for NaCl in water. We shall develop force fields for Na+ and Cl- using the following values for the scaled charge (in electron units): ±0.75, ±0.80, ±0.85, and ±0.92 along with the TIP4P/2005 model of water (for which previous force fields were proposed for q = ±0.85 and q = ±1). The properties considered in this work are densities, structural properties, transport properties, surface tension, freezing point depression, and maximum in density. All the developed models were able to describe quite well the experimental values of the densities. Structural properties were well described by models with charges equal to or larger than ±0.85, surface tension by the charge ±0.92, maximum in density by the charge ±0.85, and transport properties by the charge ±0.75. The use of a scaled charge of ±0.75 is able to reproduce with high accuracy the viscosities and diffusion coefficients of NaCl solutions for the first time. We have also considered the case of KCl in water, and the results obtained were fully consistent with those of NaCl. There is no value of the scaled charge able to reproduce all the properties considered in this work. Although certainly scaled charges are not the final word in the development of force fields for electrolytes in water, its use may have some practical advantages. Certain values of the scaled charge could be the best option when the interest is to describe certain experimental properties.

Profil hématologique des patients VIH/SIDA à l'hôpital régional de Nzérékoré / Hematological profi le of HIV/AIDS patients at the Nzérékoré Regional Hospital

Introduction. Le VIH/SIDA est à l'origine d'un grand nombre de manifestations biologiques à titre de troubles hématologiques graves pouvant atteindre toutes les lignées sanguines. L'objectif de cette étude était de mettre en évidence les anomalies de l'hémogramme chez les PVVIH à Nzérékoré afi n de contribuer à une meilleure prise en charge. Méthodes. Il s'agissait d'une étude prospective de type descriptif à visée analytique d'une durée de 6 mois allant du 25 février au 25 août 2021 sur les PVVIH dans le service de médecine générale de l'Hôpital régional de Nzérékoré. Résultats. Durant notre étude, la prévalence hospitalière du VIH au service de médecine générale de l'hôpital régional de Nzérékoré était de 20,34%. L'âge moyen était de 36,98 ans, le sexe féminin prédominait avec un sex-ratio de 0,74 ; majoritairement mariés (53,33%) et ménagères (41,66%). Les anomalies hématologiques les plus représentées étaient l'anémie (95%) et la lymphopénie (77,5) dont la majorité était au stade III et IV. Conclusion. Le VIH/SIDA reste un problème de santé publique. Son évolution est liée à des anomalies aussi cliniques que biologique imposant un suivi régulier et adéquat

Introduction. HIV/AIDS is the cause of a large number of biological manifestations as serious hematological disorders that can affect all blood lines. The objective of this study was to highlight blood count abnormalities in PLWHA in Nzérékoré in order to contribute to better management. Methods. This was a prospective descriptive study with an analytical aim, lasting 6 months from February 25 to August 25, 2021, on PLHIV in the general medicine department of the Nzérékoré regional hospital.. Results. During our study, the hospital prevalence of HIV in the general medicine department of the regional hospital of Nzérékoré was 20.34%. The average age was 36.98 years, the female sex predominated with a sex ratio of 0.74; the majority were married (53.33%) and housewives (41.66%). The most common hematological abnormalities were anemia (95%) and lymphopenia (77.5), the majority of which were stage III and IV. Conclusion. HIV/AIDS remains a public health problem. Its evolution is linked to both clinical and biological abnormalities requiring regular and adequate follow-up.

Lack of sex-related analysis and reporting in Cochrane Reviews: a cross-sectional study.

BACKGROUND: Sex-specific analysis and reporting may allow a better understanding of intervention effects and can support the decision-making process. Well-conducted systematic reviews (SRs), like those carried out by the Cochrane Collaboration, provide clinical responses transparently and stress gaps of knowledge. This study aimed to describe the extent to which sex is analysed and reported in a cross-section of Cochrane SRs of interventions, and assess the association with the gender of main authorships. METHODS: We searched SRs published during 2018 within the Cochrane Database of Systematic Reviews. An investigator appraised the sex-related analysis and reporting across sections of SRs and collected data on gender and country of affiliation of the review first and last authors, and a second checked for accuracy. We conducted descriptive statistics and bivariate logistic regression to explore the association between the gender of the authors and sex-related analysis and reporting. RESULTS: Six hundred and ten Cochrane SRs were identified. After removing those that met no eligibility criteria, 516 reviews of interventions were included. Fifty-six reviews included sex-related reporting in the abstract, 90 considered sex in their design, 380 provided sex-disaggregated descriptive data, 142 reported main outcomes or performed subgroup analyses by sex, and 76 discussed the potential impact of sex or the lack of such on the interpretations of findings. Women represented 53.1 and 42.2% of first and last authorships, respectively. Women authors (in first and last position) had a higher possibility to report sex in at least one of the review sections (OR 2.05; CI 95% 1.12-3.75, P=0.020) than having none. CONCLUSIONS: Sex consideration amongst Cochrane SRs was frequently missing. Structured guidance to sex-related analysis and reporting is needed to enhance the external validity of findings. Likewise, including gender diversity within the research workforce and relevant authorship positions may foster equity in the evidence generated.

Genetic variants associated with steatohepatitis and liver fibrosis in HIV-infected patients with NAFLD.

Background and aims: Nonalcoholic fatty liver disease (NAFLD) is a common cause of liver damage in people living with HIV (PLWHIV). Several studies have investigated candidate genes for susceptibility to NAFLD and to steatohepatitis. PNPLA3, TM6SF2, and MBOAT7-TMC4 have been reported to be associated with elevated ALT levels and the histologic parameters of nonalcoholic steatohepatitis and severity of fibrosis. Our objective was to analyze the relationship between PNPLA3, TM6SF2, and MBOAT7-TMC4 and steatosis, steatohepatitis, and liver fibrosis in PLWHIV with NAFLD. Method: A cohort of PLWHIV with persistently elevated aminotransferase levels and suspected NAFLD who underwent liver biopsy and determination of genetic variants was assessed at two large centers in Spain. All participants included in the current study were genotyped for rs738409 (PNPLA3), rs58542926 (TM6SF2), and rs641738 (MBOAT7-TMC4). Results: The study population comprised PLWHIV who were on stable antiretroviral therapy [7.7% women; median age, 49.3 years (44-53.4)]. The median CD4 count was 829 (650-980), 60% had metabolic syndrome, and 18.5% were diabetic. The median BMI was 28.9 (25.5-30.8). Patients with liver steatosis (any grade) vs. nonsteatosis tended to harbor the PNPLA3 G allele variant [57.6% vs. 16.7% (p = 0.09)], but not TM6SF2 or MBOAT7-TMC4 variants. However, those with steatohepatitis vs. nonsteatohepatitis significantly more frequently had the PNPLA3 G allele variant [69.4% vs. 39.1% (p < 0.05)] and the MBOAT7-TMC4 A allele variant [75% vs. 42% (p < 0.05)]. In our cohort, the TM6SF2 gene variant was not associated with steatosis or steatohepatitis. The PNPLA3 G allele variant was associated with steatohepatitis [OR 4.9 (1.3-18); p 0.02] and liver fibrosis [OR 4.3 (1.1-17.4); p 0.04], and the MBOAT7-TMC4 A allele variant was associated with steatohepatitis [OR 6.6 (1.6-27.6); p 0.01]. Conclusion: The PNPLA3 G allele variant and MBOAT7-TMC4 A allele variant were associated with steatohepatitis and liver fibrosis in PLWHIV with persistently elevated aminotransferases and NAFLD. We recommend routine genotyping for PNPLA3 and MBOAT7-TMC4 in PLWHIV with NAFLD to identify those at higher risk of progression.

Assessment of Noninvasive Markers of Steatosis and Liver Fibrosis in Human Immunodeficiency Virus-Monoinfected Patients on Stable Antiretroviral Regimens.

Background: Nonalcoholic fatty liver disease (NAFLD) is a major nonacquired immune deficiency syndrome-defining condition for persons with human immunodeficiency virus (PWH). We aimed to validate noninvasive tests for the diagnosis of NAFLD in PWH. Methods: This is a cross-sectional study of PWH on stable antiretroviral therapy with persistently elevated transaminases and no known liver disease. The area under the receiver operating characteristic curve (AUROC) was calculated to compare the diagnostic accuracy of liver biopsy with abdominal ultrasound, transient elastography (TE) (including controlled attenuation parameter [CAP]), and noninvasive markers of steatosis (triglyceride and glucose index [TyG], hepatic steatosis index [HSI], fatty liver index [FLI]) and fibrosis ([FIB]-4, aminotransferase-to-platelet ratio index [APRI], NAFLD fibrosis score). We developed a diagnostic algorithm with serial combinations of markers. Results: Of 146 patients with increased transaminase levels, 69 underwent liver biopsy (90% steatosis, 61% steatohepatitis, and 4% F ≥3). The AUROC for steatosis was as follows: ultrasound, 0.90 (0.75-1); CAP, 0.94 (0.88-1); FLI, 0.81 (0.58-1); HSI, 0.74 (0.62-0.87); and TyG, 0.75 (0.49-1). For liver fibrosis ≥F3, the AUROC for TE, APRI, FIB-4, and NAFLD fibrosis score was 0.92 (0.82-1), 0.96 (0.90-1), 0.97 (0.93-1), and 0.85 (0.68-1). Optimal diagnostic performance for liver steatosis was for 2 noninvasive combined models of tests with TyG and FLI/HSI as the first tests and ultrasound or CAP as the second tests: AUROC = 0.99 (0.97-1, P < .001) and 0.92 (0.77-1, P < .001). Conclusions: Ultrasound and CAP performed best in diagnosing liver steatosis, and FLI, TyG, and HSI performed well. We propose an easy-to-implement algorithm with TyG or FLI as the first test and ultrasound or CAP as the second test to accurately diagnose or exclude NAFLD.

Prevalence of Intracranial Aneurysms in Hereditary Hemorrhagic Telangiectasia: Report from a Single Reference Center.

BACKGROUND AND PURPOSE: Neurologic manifestations in hereditary hemorrhagic telangiectasia include an increased incidence of brain abscesses and ischemic strokes due to paradoxic embolization in addition to a wide spectrum of symptoms and complications due to typical brain vascular malformations. Intracranial aneurysms are not part of this brain vascular malformation spectrum. The aim of this study was to determine their prevalence in patients with hereditary hemorrhagic telangiectasia. MATERIALS AND METHODS: This was a single-center, retrospective study. Adult patients from the institutional Hereditary Hemorrhagic Telangiectasia registry with a definitive diagnosis of hereditary hemorrhagic telangiectasia and an available report or angiographic imaging study were included and reviewed to determine the intracranial aneurysm prevalence. In addition, the morphologic characteristics of intracranial aneurysms and possible associated risk factors were collected. RESULTS: Two hundred twenty-eight patients were analyzed. Thirty-seven aneurysms in 33 patients (14.5%; 95% CI, 9.9%-19%) were found. The median diameter of intracranial aneurysms was 3.2 mm (interquartile range, 2.6-4.4 mm). No association between intracranial aneurysm and sex, age, or genetic background was noted. There were no subarachnoid hemorrhagic events due to intracranial aneurysm rupture. CONCLUSIONS: Due to the high prevalence of intracranial aneurysms in adult patients with hereditary hemorrhagic telangiectasia, further studies regarding bleeding risks and monitoring should be addressed.