Three-year efficacy of switching to dolutegravir plus lamivudine: A real-world study.

BACKGROUND: Dolutegravir (DTG) plus lamivudine (3TC) has proven highly efficacious as a switching strategy in virologically suppressed people with HIV (PWH). As this strategy was introduced relatively recently, real-world, long-term durability studies are lacking. METHODS: We performed a retrospective review of treatment-experienced patients who started DTG + 3TC in a cohort of PWH. HIV-RNA <50 copies/mL was analysed at 144 weeks in an intention-to-treat (ITT) analysis (missing = failure) and a per-protocol (PP) analysis (patients with missing data or changes for reasons other than virological failure were excluded). RESULTS: The study population comprised 358 PWH (19% women). Median age and time with HIV infection were 51.7 and 13.4 years, respectively. The median number of previous antiretroviral combinations was three. Previous virological failure was reported in 27.1% of patients, and the M184V resistance mutation was detected in 17 patients. At 144 weeks, the percentage of individuals with HIV-RNA <50 copies/mL was 77.4% (277/358) in the ITT analysis and 95.5% (277/290) in the PP analysis. A total of 68 participants were excluded from the PP analysis (data missing, 25, discontinuation due to toxicity, 19; other, 16; death, 8). Two people with virological failure selected resistance-associated mutations (M184V and M184V + R263K). HIV-RNA remained undetectable in 17 patients with a previous history of the M184V mutation. CONCLUSION: Our results confirm the real-world, long-term efficacy, tolerability and high genetic barrier of DTG + 3TC in treatment-experienced PWH. Although scarce, mutations causing resistance to nucleosides and integrase can emerge.

Clearance, biodistribution, and neuromodulatory effects of aluminum-based adjuvants. Systematic review and meta-analysis: what do we learn from animal studies?

Aluminum (Al) salts are commonly used as adjuvants in human and veterinary vaccines for almost a century. Despite this long history of use and the very large number of exposed individuals, data in the literature concerning the fate of these molecules after injection and their potential effects on the nervous system is limited. In the context of (i) an increase of exposure to Al salts through vaccination; (ii) the absence of safety values determined by health regulators; (iii) the lack of robustness of the studies used as references to officially claim Al adjuvant innocuity; (iv) the publication of several animal studies investigating Al salts clearance/biopersistence and neurotoxicity; we have examined in this review all published studies performed on animals and assessing Al adjuvants kinetics, biodistribution, and neuromodulation since the first work of A. Glenny in the 1920s. The diversity of methodological approaches, results, and potential weaknesses of the 31 collected studies are exposed. A large range of protocols has been used, including a variety of exposure schedule and analyses methods, making comparisons between studies uneasy. Nevertheless, published data highlight that when biopersistence, translocation, or neuromodulation were assessed, they were documented whatever the different in vivo models and methods used. Moreover, the studies pointed out the crucial importance of the different Al adjuvant physicochemical properties and host genetic background on their kinetics, biodistribution, and neuromodulatory effects. Regarding the state of the art on this key public health topic, further studies are clearly needed to determine the exact safety level of Al salts.

Gibbs thermodynamics and surface properties at the nanoscale.

Gibbs's classical thermodynamic framework approximates systems as infinitely large phases separated by infinitely thin surfaces. The range of validity of this classical framework naturally comes under scrutiny as we become interested in the properties of ever smaller systems. This Communication clarifies that while Gibbs's original framework of bulk phase thermodynamics did require modifications to describe the properties of very small (i.e., non-additive) phases, his classical framework remains fundamentally valid to describe the thermodynamic properties of surfaces. We explain why classical surface laws are applicable at the nanoscale, as suggested by simulations and confirmed by experiments. We also show that a generalized Gibbs-Tolman-Koenig-Buff equation and the resulting Tolman's law for surface tension are obtained from a classical thermodynamic analysis in the Tolman region, a region of interaction between the system and the environment.

2019 update of the European AIDS Clinical Society Guidelines for treatment of people living with HIV version 10.0.

BACKGROUND: The European AIDS Clinical Society (EACS) Guidelines cover key aspects of HIV management with major updates every two years. GUIDELINE HIGHLIGHTS: The 2019 Guidelines were extended with a new section focusing on drug-drug interactions and other prescribing issues in people living with HIV (PLWH). The recommendations for treatment-naïve PLWH were updated with four preferred regimens favouring unboosted integrase inhibitors. A two-drug regimen with dolutegravir and lamivudine, and a three-drug regimen including doravirine were also added to the recommended initial regimens. Lower thresholds for hypertension were expanded to all PLWH and for cardiovascular disease prevention, the 10-year predicted risk threshold for consideration of antiretroviral therapy (ART) modification was lowered from 20% to 10%. Frailty and obesity were added as new topics. It was specified to use urine albumin to creatinine ratio to screen for glomerular disease and urine protein to creatinine ratio for tubular diseases, and thresholds were streamlined with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations. Hepatitis C virus (HCV) treatment recommendations were split into preferred and alternative treatment options. The algorithm for management of recently acquired HCV infection was updated and includes recommendations for early chronic infection management. Treatment of resistant tuberculosis (TB) was streamlined with the World Health Organization (WHO) recommendations, and new tables on immune reconstitution inflammatory syndrome, on when to start ART in the presence of opportunistic infections and on TB drug dosing were included. CONCLUSIONS: The EACS Guidelines underwent major revisions of all sections in 2019. They are available in four different formats including a new interactive web-based version and are translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish.

Epithelial-Mesenchymal Transition in a Case of Metastatic Thyroid Carcinoma in a Brown Bear (Ursus arctos).

A 20-year-old male brown bear (Ursus arctos) with a 20 × 25 cm necrotic mass adjacent to the trachea was diagnosed as having an anaplastic thyroid carcinoma. Metastases were observed in the lungs and one adrenal gland and, histologically, these had anaplastic and follicular carcinoma patterns, respectively. E-cadherin labelling was observed in the adrenal mass only, while N-cadherin immunolabelling was detected in the thyroid gland and lung masses. Thyroid-specific markers (thyroid transcription factor-1, thyroglobulin) were expressed in the adrenal gland metastasis. This case illustrates an example of a primary epithelial-mesenchymal transition (EMT) enabling metastasis to distant organ sites, followed by a mesenchymal-epithelial transition within the adrenal gland microenvironment, allowing invasion and reacquisition of thyroid epithelial cell features. EMTs help to understand the phenomenon of carcinoma cell plasticity in enabling colonization and growth of metastases.

Determinants of blood telomere length in antiretroviral treatment-naïve HIV-positive participants enrolled in the NEAT 001/ANRS 143 clinical trial.

OBJECTIVES: Our aim was to investigate factors associated with baseline blood telomere length in participants enrolled in NEAT 001/ANRS 143, a randomized, open-label trial comparing ritonavir-boosted darunavir (DRV/r) plus raltegravir (RAL) with DRV/r plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in antiretroviral therapy (ART)-naïve HIV-positive adults. METHODS: A cross-sectional study of 201 randomly selected participants who had stored samples available was carried out. We measured telomere length (i.e. the relative telomere length, calculated as the telomere to single copy gene ratio) at baseline with monochrome quantitative multiplex polymerase chain reaction (PCR). We used multivariable predictive linear regression to calculate mean differences and 95% confidence intervals (CIs) for the association between baseline telomere length and baseline characteristics. RESULTS: The baseline characteristics of the 201 participants did not differ from those of the 805 participants in the parent trial population: 89% were male, the mean age was 39 years, 83.6% were Caucasian, 93% acquired HIV infection via sexual transmission, the mean estimated time since HIV diagnosis was 2.1 years, the mean HIV-1 RNA load was 4.7 log10 HIV-1 RNA copies/mL, the mean nadir and baseline CD4 counts were 301 and 324 cells/µL, respectively, and the mean CD4:CD8 ratio was 0.4. In the univariate analysis, shorter telomere length was associated with older age (per 10 years) (P < 0.001), HIV-1 RNA ≥ 100 000 copies/mL (P = 0.001), CD4 count < 200 cells/µL (P = 0.037), lower CD4:CD8 ratio (P = 0.018), statin treatment (P = 0.004), and current alcohol consumption (P = 0.035). In the multivariable analysis, older age (P < 0.001) and HIV RNA ≥ 100 000 copies/mL (P = 0.054) were independently associated with shorter telomere length. CONCLUSIONS: Both age and HIV RNA viral load correlated with shorter blood telomere length in untreated persons living with HIV. These results suggest that HIV infection and age have synergistic and independent impacts upon immunosenescence.

Implementación y evaluación de un programa de gestión de calidad para el monitoreo de glucómetros en un hospital universitario / Implementation and evaluation of a management program quality for monitoring glucometers in a hospital academic

Introducción: El uso de dispositivos portátiles para controlar la glucemia se ha extendido en los últimos años a las entidades hospitalarias, porque proporcionan un resultado rápido al realizarse al lado de la cama del paciente (point-of-care testing). Objetivo: Describir el proceso y los resultados de la implementación de un programa de gestión de calidad para el control de glucómetros hospitalarios. Materiales y Métodos: Se presenta la implementación de un programa de gestión de calidad para evaluar 50 glucómetros pertenecientes a siete áreas críticas del Hospital Italiano de Buenos Aires (Unidad Coronaria, Terapia Intensiva de Adultos y Pediátrica, Terapia Intermedia, Central de Emergencias de Adultos y Pediátrica, Unidad de Cuidados Intensivos Neonatológicos), desde el 1 de enero de 2014 hasta la actualidad, basado en tres estrategias: control diario, análisis mensual (precisión y exactitud) y control de muestras paralelas. Resultados: Luego de instaurar este programa y analizar los datos de los primeros 17 meses, se requirió un recambio total de 292 glucómetros: 150 debido al control de calidad diario, 119 por el análisis mensual y 23 por el control de muestras paralelas. Esto implicó retirar 17/50 glucómetros por mes. Conclusiones: Si bien estos dispositivos son útiles por su rápida respuesta, el 34,6% debió ser reemplazado por no haber superado alguno de los requisitos planteados en las estrategias de evaluación. La peor performance fue en los niveles de hipoglucemia, situación de interés para la rápida toma de decisiones. Es importante destacar la necesidad de aplicación de un plan de calidad para glucómetros sobre la base de un diseño propio y a medida de la institución para garantizar la seguridad del paciente.(AU)

Introduction: The use of portable devices for glycemic control has been extended in recent years to hospital entities, because they provide a rapid result when they are performed at or near the patient's bedside (point of care testing). Objective: To describe the process and results of the implementation of a quality management program to control of hospital glucometers. Materials and Methods: We present the implementation of a quality management program to evaluate 50 glucometers belonging to seven critical areas of Hospital Italiano de Buenos Aires (Coronary Unit, Adult and Pediatric Intensive Care Unit, Intermediate Therapy, Adult and Pediatric Emergency Center, Unit of Neonatal Intensive Care), from January 1, 2014 to the present, based on three strategies: Daily Control, Monthly Analysis and Control of Parallel Samples. Results: After implementing this program and analyzing the first 17 months, the substitution of 292 glucometers was required: 150 due to daily quality control, 119 per monthly analysis and 23 due to control parallel samples. This involved withdrawing 17/50 glucometers monthly. Conclusions: Although these devices are useful because of their rapid response, 34.6% had to be replaced because they exceeded the requirements presented in the evaluation strategies. The worst performance was in levels of hypoglycemia, a situation of interest for rapid decision-making. It is important to emphasize the need to apply a quality plan for glucometers based on an own design and suitable for the institution to guarantee the safety of the patient.(AU)

Arteriovenous malformations: a diagnostic and therapeutic challenge.

Many dermatologists are largely unfamiliar with arteriovenous malformations (AVMs). This is partly due to the low prevalence of these lesions and to the fact that they are generally managed by other specialists, in particular, interventional radiologists and pediatric, maxillofacial, and plastic surgeons. In this article, we review the recommended nomenclature for AVMs and look at their clinical manifestations and diagnosis, as well as the ideal type and time of treatment. AVMs should be managed from a multidisciplinary approach, and the dermatologist's primary goal should be to make a proper diagnosis and thereby avoid unnecessary treatments.

An efficient method for enzyme immobilization evidenced by atomic force microscopy.

Immobilization of proteins in a functionally active form and proper orientation is fundamental for effective surface-based protein analysis. A new method is presented for the controlled and oriented immobilization of ordered monolayers of enzymes whose interaction site had been protected using the protein ligand. The utility of this method was demonstrated by analyzing the interactions between the enzyme ferredoxin-NADP+ reductase (FNR) and its redox partner ferredoxin (Fd). The quality of the procedure was deeply evaluated through enzymatic assays and atomic force microscopy. Single-molecule force spectroscopy revealed that site-specifically targeted FNR samples increased the ratio of recognition events 4-fold with regard to the standard randomly modified FNR samples. The results were corroborated using the cytochrome c reductase activity that gave an increase on surface between 6 and 12 times for the site-specifically targeted FNR samples. The activity in solution for the enzyme labeled from the complex was similar to that exhibited by wild-type FNR while FNR randomly tagged showed a 3-fold decrease. This indicates that random targeting protocols affect not only the efficiency of immobilized proteins to recognize their ligands but also their general functionality. The present methodology is expected to find wide applications in surface-based protein-protein interactions biosensors, single-molecule analysis, bioelectronics or drug screening.

Size-dependent properties of magnetoferritin.

We report a detailed experimental study of maghemite nanoparticles, with sizes ranging from 1.6 to 6 nm, synthesized inside a biological mould of apoferritin. The structural characterization of the inorganic cores, using TEM and x-ray diffraction, reveals a low degree of crystalline order, possibly arising from the nucleation and growth of multiple domains inside each molecule. We have also investigated the molecular structure by means of atomic force microscopy in liquid. We find that the synthesis of nanoparticles inside apoferritin leads to a small, but measurable, decrease in the external diameter of the protein, probably associated with conformational changes. The magnetic response of the maghemite cores has been studied by a combination of techniques, including ac susceptibility, dc magnetization and Mössbauer spectroscopy. From the equilibrium magnetic response, we have determined the distribution of magnetic moments per molecule. The results show highly reduced magnetic moments. This effect cannot be ascribed solely to the canting of spins located at the particle surface but, instead, it suggests that magnetoferritin cores have a highly disordered magnetic structure in which the contributions of different domains compensate each other. Finally, we have also determined, for each sample, the distribution of the activation energies required for the magnetization reversal and, from this, the size-dependent magnetic anisotropy constant K. We find that K is enormously enhanced with respect to the maghemite bulk value and that it increases with decreasing size. The Mössbauer spectra suggest that low-symmetry atomic sites, probably located at the particle surface and at the interfaces between different crystalline domains, are the likely source of the enhanced magnetic anisotropy.

On the occurrence of Anaecypris hispanica, an extremely endangered Iberian endemism, in the Guadalquivir River basin.

The jarabugo Anaecypris hispanica, considered endemic to the Guadiana River basin, has been found in the Guadalquivir River. First genetic data showed a high degree of similarity to those of the Guadiana River populations. The genetic study recovered five different groups of haplotypes, the Guadalquivir River specimens belong to the largest and most widely extended group.

Morbilidad en mujeres postmenopáusicas pobres / Morbidity in postmenopausal women with poverty

Background: Less favored social classes usually have more unhealthy life-styles and a more difficult access to Health Resources. Aim: To study the possible association between poverty and some common diseases, in a population of postmenopausal women. Material and Methods: Four hundred and forty nine poor women aged 56 ± 12 years and 776 consecutive women aged 53 ± 12 years, answered a personal interview about their lifestyles and medications used. Their medical records were reviewed and they were subjected to a complete physical examination, including weight and height measurement. A fasting blood sample was also obtained. Poverty was defined according to criteria of the Spanish National Institute of Statistics that is based on the income in Euros and the number of family members that share such income. Results: A higher proportion of poor women live in rural areas. They were shorter, had a higher weight and thus a higher body mass index, smoked less and drank less alcohol than their non-poor counterparts drink. The consumption of caffeine, the actual calcium intake and the physical activity during leisure time was similar in both groups. Compared with their counterparts, poor women had a higher prevalence of diabetes mellitus (15.9 and 10.1 percent respectively, p = < 0.01), obesity (44.2 and 24.3 percent respectively, p < 0.01) hypertension (24.3 and 16.4 percento respectively, p<0.01) and autoimmune rheumatic diseases (7.8 and 4.8 percent> respectively, p = 0.03). A multiple logistic regression model showed that obesity, hypertension, diabetes mellitus, smoking, alcohol consumption and living in rural areas, were independently associated to poverty. Conclusions: Poor postmenopausal women have a higher prevalence of diabetes mellitus, obesity, autoimmune rheumatic diseases and hypertension and lower frequency of smoking and alcohol consumption than their affluent counterparts do.

[Macronutrients intake in school teenagers in Soria capital]. / Ingesta de macronutrientes en adolescentes escolarizados en Soria capital.

OBJECTIVES: To study the macronutrients intake in Soria teenagers from 10 to 19 years, as well as their body mass index (BMI). METHODS: A seven-day diet questionnaire filled in by an accidental sample of teenagers (54 boys and 56 girls) from public schools in the capital. Working out the average daily intake of energy, carbohydrates, lipids and proteins by the software of "Alimentación y Salud" which also gives values of individual recommended dietary allowances (RDAs) related to each individual's particular characteristics. Use of Student's t-test to compare the average values of the estimated intakes of different nutrients and their RDAs. RESULTS: In general, the intakes of energy, proteins and lipids are statistically significant over the RDAs, while the carbohydrates intake is under the recommendations. With reference to the type of lipids, the intake is over the RDAs for cholesterol, monounsaturated fatty acids, and saturated fatty acids, but not for polyunsaturated fatty acids. Among girls from 13 years of age more than 12% have a higher BMI than 26 kg/m2, but between 10 and 12 years of age more than 20% of the students have this parameter under 16 kg/m2. CONCLUSIONS: According to the results, it would be useful to implement some nutritional intervention among the adolescents in Soria capital to promote a healthy feeding in order to avoid possible disorders (obesity, anorexia, etc.).

Effects on development.

This chapter will review the effects produced on neural development by maternal consumption of cannabinoids during gestation and lactation, with emphasis in the maturation of several neurotransmitter systems (dopamine, serotonin, opioids, cannabinoids, etc.) and possible modifications in their functional expression at the behavioral or neuroendocrine levels. In addition, we have analyzed the possible existence of a sexual dimorphism in these ontogenic effects of cannabinoids, as well as the possible molecular mechanism underlying such effects. In general, the results discussed support the view that exposure to cannabinoids during critical periods of development produces marked modifications in the functional expression of diverse neuronal systems in adulthood. Furthermore, the functions of endocannabinoids in the brain are large not only in adulthood, but also in the period of prenatal and postnatal development. Thus, endocannabinoids have been reported to be present in early ages and to play a role in the process of brain development: neural proliferation and migration, axonal elongation, synaptogenesis and/or myelogenesis.

Plasma erythropoietin levels in the oldest old.

UNLABELLED: Erythropoietin (EPO) regulates erythrocytes production and is synthesized mainly by the kidney. Its production is reduced during chronic renal failure but is not altered by the senescence process in spite of the morphological changes that occur in the kidney. However, there is no information regarding what happens to erythropoietin synthesis during advanced ageing. Thus, we carried out an investigation to determine whether there was any significant difference in plasma erythropoietin between adults, old and very old people. MATERIAL AND METHODS: We studied 74 healthy volunteers: 22 adults, 30 old, and 22 very old. None of them were smokers or were suffering from any disease that may intefere with hemoglobin (Hb) levels or with EPO production. Hematocrit, Hb, plasma creatinine and plasma erythropoietin were measured, and creatinine clearance was calculated from serum creatinine using two different formulae. Statistical analysis was performed using ANOVA and Bonferroni tests. RESULTS AND CONCLUSION: Among the three groups we found a significant difference in creatinine clearance (p < 0.001), but not in plasma erythropoietin levels; we conclude that normal senescence does not alter plasma erythropoietin levels, even during advanced ageing.

The endocannabinoid system and Huntington's disease.

The research in Huntington's disease (HD) has been growing exponentially during the last decade, since the discovery of the genetic basis that leads to neurodegeneration. HD is one of several progressive neurodegenerative disorders, in which the underlying mutation is a CAG expansion encoding a polyglutamine tract in a specific protein, which in the case of HD, is called huntingtin. The first clinical symptoms of HD are generally psychiatric abnormalities, most commonly depression and mood disturbances. Involuntary choreiform movements and dementia develop over the next 15-20 years, and death generally results from complications derived from immobility. There is currently no cure, or even an effective therapy to offset the decline in mental and motor capabilities suffered by those affected by HD, but recent studies have started to examine the usefulness of different classes of new compounds. Among these, plant-derived, synthetic or endogenous cannabinoids have been proposed to have therapeutic value for the treatment of HD, since they act on cannabinoid CB(1) receptors located in the basal ganglia circuitry, that is affected by the striatal atrophy typical of HD. Recent studies have characterized the changes in these receptors, as well as their endogenous ligands, in the basal ganglia in a variety of animal models of HD. The results are indicative that the endocannabinoid system becomes hypofunctional in this disease, which could be related to the hyperkinesia typical of the earliest phases of this disease. In addition, it has been proposed that the loss of these receptors might be involved in the process of pathogenesis itself. This, together with the well-known protective properties of cannabinoid-related compounds, suggest that, in addition to a symptomatic usefulness, cannabinoids might also serve to delay or to arrest the development of this disease. The present article will review all recent data dealing with the biochemical, pharmacological and therapeutic bases that support a potential role of cannabinoids in the pathogenesis and/or therapeutic treatment of this motor disorder.

Cannabinoid effects on anxiety-related behaviours and hypothalamic neurotransmitters.

The aim of the present study was to examine the effects of the cannabinoid agonist CP 55,940 and the antagonist SR 141716A, alone and in combination, on rat exploratory and anxiety-like behaviour in the holeboard and elevated plus-maze tests. A further aim was to evaluate the effects of these treatments on hypothalamic neurotransmitters. Animals treated with CP 55,940 doses of 0.125 and 0.1 mg/kg exhibited less exploration and an increase in anxiety-like behaviour accompanied by great motor inhibition. No hypoactivity was seen at 0.075 mg/kg dosage, but anxiety and neophobic responses persisted, indicating independent and specific effects. Motor activity effects induced by CP 55,940 were reversed by pretreatment with SR 141716A (3 mg/kg). Surprisingly, when administered on its own, the antagonist also induced a reduction in exploratory parameters and an increase in anxiety-like responses. These apparently similar effects might be caused by different neural mechanisms. Finally, CP 55,940 increased hypothalamic dopamine and serotonin levels. These increases might be involved in the activation of the hypothalamic-pituitary-adrenal axis described for cannabinoids.