In-depth comparison of the metabolic and pharmacokinetic behaviour of the structurally related synthetic cannabinoids AMB-FUBINACA and AMB-CHMICA in rats.

Synthetic cannabinoids receptor agonists (SCRAs) are often almost completely metabolised, and hence their pharmacokinetics should be carefully evaluated for determining the most adequate biomarker in toxicological analysis. Two structurally related SCRAs, AMB-FUBINACA and AMB-CHMICA, were selected to evaluate their in vivo metabolism and pharmacokinetics using male Sprague-Dawley rats. Brain, liver, kidney, blood (serum) and urine samples were collected at different times to assess the differences in metabolism, metabolic reactions, tissue distribution and excretion. Both compounds experimented O-demethyl reaction, which occurred more rapidly for AMB-FUBINACA. The parent compounds and O-demethyl metabolites were highly bioaccumulated in liver, and were still detected in this tissue 48 h after injection. The different indazole/indole N-functionalisation produced diverse metabolic reactions in this moiety and thus, different urinary metabolites were formed. Out of the two compounds, AMB-FUBINACA seemed to easily cross the blood-brain barrier, presenting higher brain/serum concentrations ratio than AMB-CHMICA.

Low birth weight as a potential risk factor for severe COVID-19 in adults.

The identification of factors predisposing to severe COVID-19 in young adults remains partially characterized. Low birth weight (LBW) alters cardiovascular and lung development and predisposes to adult disease. We hypothesized that LBW is a risk factor for severe COVID-19 in non-elderly subjects. We analyzed a prospective cohort of 397 patients (18-70 years) with laboratory-confirmed SARS-CoV-2 infection attended in a tertiary hospital, where 15% required admission to Intensive Care Unit (ICU). Perinatal and current potentially predictive variables were obtained from all patients and LBW was defined as birth weight ≤ 2.500 g. Age (adjusted OR (aOR) 1.04 [1-1.07], P = 0.012), male sex (aOR 3.39 [1.72-6.67], P < 0.001), hypertension (aOR 3.37 [1.69-6.72], P = 0.001), and LBW (aOR 3.61 [1.55-8.43], P = 0.003) independently predicted admission to ICU. The area under the receiver-operating characteristics curve (AUC) of this model was 0.79 [95% CI, 0.74-0.85], with positive and negative predictive values of 29.1% and 97.6% respectively. Results were reproduced in an independent cohort, from a web-based survey in 1822 subjects who self-reported laboratory-positive SARS-CoV-2 infection, where 46 patients (2.5%) needed ICU admission (AUC 0.74 [95% CI 0.68-0.81]). LBW seems to be an independent risk factor for severe COVID-19 in non-elderly adults and might improve the performance of risk stratification algorithms.

Understanding the pharmacokinetics of synthetic cathinones: Evaluation of the blood-brain barrier permeability of 13 related compounds in rats.

Synthetic cathinones are the second most commonly seized new psychoactive substance family in Europe. These compounds have been related to several intoxication cases, including fatalities. Although the pharmacological effects, metabolism, and pharmacokinetics of cathinones have been studied, there is little information about the permeability of these compounds through the blood-brain barrier (BBB). This is an important parameter to understand the behavior and potency of cathinones. In this work, 13 selected cathinones have been analyzed in telencephalon tissue from Sprague-Dawley rats intraperitoneally dosed at 3 mg/kg. Our results revealed a direct relationship between compound polarity and BBB permeability, with higher permeability for the more polar cathinones. The chemical moieties present in the cathinone had an important impact on the BBB permeability, with lengthening of the α-alkyl chain or functionalization of the aromatic ring with alkyl moieties resulting in lower concentration in telencephalon tissue. Our data suggest that transport of cathinones is a carrier-mediated process, similar to cocaine transport across the BBB.

Chaotic wave dynamics in weakly magnetized spherical Couette flows.

Direct numerical simulations of a liquid metal filling the gap between two concentric spheres are presented. The flow is governed by the interplay between the rotation of the inner sphere (measured by the Reynolds number Re) and a weak externally applied axial magnetic field (measured by the Hartmann number Ha). By varying the latter, a rich variety of flow features, both in terms of spatial symmetry and temporal dependence, is obtained. Flows with two or three independent frequencies describing their time evolution are found as a result of Hopf bifurcations. They are stable on a sufficiently large interval of Hartmann numbers where regions of multistability of two, three, and even four types of these different flows are detected. The temporal character of the solutions is analyzed by means of an accurate frequency analysis and Poincaré sections. An unstable branch of flows undergoing a period doubling cascade and frequency locking of three-frequency solutions is described as well.

Experiences and real life management of insulin pump therapy in adults with type 1 diabetes / Experiencias y gestión en la vida real del tratamiento con bomba de insulina de adultos con diabetes tipo 1

Objective: There is scarce information regarding the performance of a specific, structured education program addressed to patients with type 1 diabetes (T1D) using continuous subcutaneous insulin infusion (CSII) including both routine use of the therapy and patient experience evaluation. We aimed to assess the routine use of CSII and patient's experience and satisfaction regarding a specific structured patient self-management education and care program. Methods: A retrospective, observational, cross-sectional study collecting CSII routine use downloaded data. Patient experience and satisfaction were evaluated using an anonymous online survey covering different aspects of CSII self-management education and care program. Results: 380 T1D subjects were included (aged 45.3±12.17 years, 62.1% women, diabetes duration 27.8±10.3 years, 9.7±4.7 years on CSII, HbA1c 7.7+1.0%; 61.0±7.9mmol/mol). Participants with HbA1c≤7.5% (58mmol/mol, n=178) did more SMBGs per day (4.4±2.1 vs. 3.9±1.9); used more boluses (5.0±1.8 vs. 4.5±2.0); the percentage of insulin given as bolus was higher (50.1±12.8 vs. 44.9±13.2%); the night bolus wizard (BW) high glucose target was lower (125.9±4.4 vs. 130.5±12.8mg/dl) and time on CSII therapy was shorter (8.9±4.6 vs. 10.3±4.6 years. p<0.05 all comparisons). More SMBG/day, shorter duration of CSII treatment, a lower BW low glucose target at night, a lower BW high glucose target at night, total insulin dose per day and total number of carbohydrates per day were related with better HbA1c levels. 60% of 373 patients answered the questionnaire. The response to the different aspects of the educational program was homogeneously highly satisfactory. Seventy-seven percent of patients scored the program as very useful. Ninety-three percent of CSII users would not return to their previous insulin treatment. Conclusions: The analysis of routine clinical use of CSII by T1D patients demonstrates that glucose control may be associated with some pump usage and adherence parameters. The overall user experience and satisfaction with our CSII self-management education and care program was remarkably favorable

Objetivo: Hay poca información sobre la eficacia de un programa educativo estructurado específico dirigido a los pacientes con diabetes tipo 1 (DT1) que utilizan infusión subcutánea continua de insulina (ISCI) que incluye tanto el uso habitual del tratamiento como la evaluación de la experiencia de los pacientes. Nuestro objetivo era valorar el uso habitual de la ISCI, la experiencia y la satisfacción del paciente con un programa educativo y asistencial estructurado específico para autogestión de los pacientes. Métodos: Estudio transversal retrospectivo observacional en el que se recogieron datos descargados sobre el uso habitual de la ISCI. Se evaluaron la experiencia y la satisfacción de los pacientes mediante una encuesta en línea anónima que abarcaba distintos aspectos del programa educativo y asistencial para autogestión de la ISCI. Resultados: Se incluyó a 380 pacientes con DT1 (45,3±12,17 años de edad, 62,1% mujeres, duración de la diabetes 27,8±10,3 años, 9,7±4,7 años con ISCI, HbA1c 7,7+1,0%; 61,0±7,9mmol/mol). Los participantes con HbA1c<7,5% (58mmol/mol, n=178) practicaron más autocontroles al día (4,4±2,1 vs. 3,9±1,9); usaron más bolos (5,0±1,8 vs. 4,5±2,0); tuvieron un porcentaje de insulina administrada en bolo mayor (50,1±12,8 vs. 44,9±13,2%) y el objetivo de glucosa nocturna alta en el recomendador de bolo (bolus wizard, BW) era más bajo (125,9±4,4 vs. 130,5±12,8mg/dl), y su tiempo con ISCI era menor (8,9±4,6 vs. 10,3±4,6 años, p<0,05 para todas las comparaciones). Más autocontroles al día, la menor duración del tratamiento con ISCI, un objetivo de glucosa baja del BW menor por la noche, un objetivo de glucosa alta del BW por la noche menor, la dosis total diaria de insulina y el número total de hidratos de carbono diarios estaban relacionados con mejores valores de HbA1c. El 60% de 373 pacientes contestaron el cuestionario. La respuesta a los distintos aspectos del programa educativo fue muy satisfactoria en conjunto. El 77% de los pacientes valoraron el programa como muy útil. El 93% de los usuarios de ISCI no volverían el tratamiento de insulina previo. Conclusiones: El análisis del uso clínico sistemático de la ISCI por pacientes con DT1 demuestra que el control de la glucosa puede relacionarse con algunos parámetros de uso y cumplimiento de la bomba. La experiencia global del usuario y la satisfacción con nuestro programa educativo y asistencial de autogestión de la ISCI fueron notablemente favorables

Experiences and real life management of insulin pump therapy in adults with type 1 diabetes.

OBJECTIVE: There is scarce information regarding the performance of a specific, structured education program addressed to patients with type 1 diabetes (T1D) using continuous subcutaneous insulin infusion (CSII) including both routine use of the therapy and patient experience evaluation. We aimed to assess the routine use of CSII and patient's experience and satisfaction regarding a specific structured patient self-management education and care program. METHODS: A retrospective, observational, cross-sectional study collecting CSII routine use downloaded data. Patient experience and satisfaction were evaluated using an anonymous online survey covering different aspects of CSII self-management education and care program. RESULTS: 380 T1D subjects were included (aged 45.3±12.17 years, 62.1% women, diabetes duration 27.8±10.3 years, 9.7±4.7 years on CSII, HbA1c 7.7+1.0%; 61.0±7.9mmol/mol). Participants with HbA1c≤7.5% (58mmol/mol, n=178) did more SMBGs per day (4.4±2.1 vs. 3.9±1.9); used more boluses (5.0±1.8 vs. 4.5±2.0); the percentage of insulin given as bolus was higher (50.1±12.8 vs. 44.9±13.2%); the night bolus wizard (BW) high glucose target was lower (125.9±4.4 vs. 130.5±12.8mg/dl) and time on CSII therapy was shorter (8.9±4.6 vs. 10.3±4.6 years. p<0.05 all comparisons). More SMBG/day, shorter duration of CSII treatment, a lower BW low glucose target at night, a lower BW high glucose target at night, total insulin dose per day and total number of carbohydrates per day were related with better HbA1c levels. 60% of 373 patients answered the questionnaire. The response to the different aspects of the educational program was homogeneously highly satisfactory. Seventy-seven percent of patients scored the program as very useful. Ninety-three percent of CSII users would not return to their previous insulin treatment. CONCLUSIONS: The analysis of routine clinical use of CSII by T1D patients demonstrates that glucose control may be associated with some pump usage and adherence parameters. The overall user experience and satisfaction with our CSII self-management education and care program was remarkably favorable.

[Continuous use of PDE5 inhibitors in the treatment of erectile dysfunction: New insights and opportunities]. / Uso continuado de inhibidores de la PDE5 en el tratamiento de la disfunción eréctil: nuevas perspectivas y oportunidades.

At present, there is debate regarding the continuous use of phosphodiesterase 5 inhibitors in the treatment of erectile dysfunction. Cumulative evidence supports the benefit, even at low doses, thatcontinuous treatment has on erectile function -even in difficult-to-treat patients-, and on the spontaneity and naturalness of sexual relationships. Safety and tolerability have also proven to be good. Beyond phosphodiesterase 5 inhibition, the effect of continuous treatment of erectile function appears to be based on improvement of endothelial function and oxygenation of the penile vascular bed as a result of the increased number of erections, hence playing down the importance of pharmacokinetics. Although evidence is still limited, this new scenario opens new paths for the treatment of erectile dysfunction patients in whom on-demand treatments are not effective or deemed appropriate, and would benefit the spontaneity of sexual life.

Uso continuado de inhibidores de la PDE5 en el tratamiento de la disfunción eréctil: nuevas perspectivas y oportunidades / Continuous use of PDE5 inhibitors in the treatment of erectile dysfunction: New insights and opportunities

Actualmente existe un debate acerca del uso continuado de los inhibidores de la fosfodiesterasa 5 en el tratamiento de la disfunción eréctil. Varios estudios apoyan el beneficio que, incluso a bajas dosis, esta estrategia terapéutica tiene sobre la función eréctil -incluso en pacientes considerados difíciles de tratar-, y sobre la espontaneidad y naturalidad de las relaciones sexuales. También ha demostrado además ser bien tolerados y seguros. Más allá de la inhibición de la fosfodiesterasa 5, el efecto sobre la función eréctil parece basarse en la mejora de la función endotelial y de la oxigenación del área vascular peneana resultado del incremento del número de erecciones, restando así importancia a la farmacocinética. Aunque la evidencia es limitada, este nuevo escenario abre nuevas oportunidades en el tratamiento de pacientes para los que el tratamiento a demanda no es efectivo o apropiado, y podría favorecer la espontaneidad de la vida sexual (AU)

At present, there is debate regarding the continuous use of phosphodiesterase 5 inhibitors in the treatment of erectile dysfunction. Cumulative evidence supports the benefit, even at low doses, thatcontinuous treatment has on erectile function -even in difficult-to-treat patients-, and on the spontaneity and naturalness of sexual relationships. Safety and tolerability have also proven to be good. Beyond phosphodiesterase 5 inhibition, the effect of continuous treatment of erectile function appears to be based on improvement of endothelial function and oxygenation of the penile vascular bed as a result of the increased number of erections, hence playing down the importance of pharmacokinetics. Although evidence is still limited, this new scenario opens new paths for the treatment of erectile dysfunction patients in whom on-demand treatments are not effective or deemed appropriate, and would benefit the spontaneity of sexual life (AU)

Continuation and stability of rotating waves in the magnetized spherical Couette system: secondary transitions and multistability.

Rotating waves (RW) bifurcating from the axisymmetric basic magnetized spherical Couette (MSC) flow are computed by means of Newton-Krylov continuation techniques for periodic orbits. In addition, their stability is analysed in the framework of Floquet theory. The inner sphere rotates while the outer is kept at rest and the fluid is subjected to an axial magnetic field. For a moderate Reynolds number Re = 103 (measuring inner rotation), the effect of increasing the magnetic field strength (measured by the Hartmann number Ha) is addressed in the range Ha∈(0, 80) corresponding to the working conditions of the HEDGEHOG experiment at Helmholtz-Zentrum Dresden-Rossendorf. The study reveals several regions of multistability of waves with azimuthal wavenumber m = 2, 3, 4, and several transitions to quasi-periodic flows, i.e modulated rotating waves. These nonlinear flows can be classified as the three different instabilities of the radial jet, the return flow and the shear layer, as found in the previous studies. These two flows are continuously linked, and part of the same branch, as the magnetic forcing is increased. Midway between the two instabilities, at a certain critical Ha, the non-axisymmetric component of the flow is maximum.

Diagnóstico, tratamiento y seguimiento de la eyaculación precoz: recomendaciones de experto / Diagnosis, treatment and follow-up of premature ejaculation: expert's recommendations

Objetivos. Elaborar recomendaciones sobre el diagnóstico, tratamiento y seguimiento de la eyaculación precoz (EP). Material y método. Un grupo multidisciplinar de expertos planteó las preguntas clínicas. En base a una revisión sistemática no exhaustiva y la experiencia clínica, se elaboraron recomendaciones que fueron validadas en una ronda Delphi y, posteriormente, en una reunión presencial. Resultados. El interrogatorio es básico para el diagnóstico de la EP, que se complementará con una exploración física y con el uso de cuestionarios específicos. El tratamiento psicológico de la EP con terapia sexual y técnicas conductuales es eficaz, siendo más eficaz combinado con tratamiento farmacológico. No se recomienda el uso de agentes anestésicos ni las intervenciones quirúrgicas. Los inhibidores selectivos de la recaptación de serotonina (ISRS) son eficaces y seguros, siendo la dapoxetina el único fármaco con indicación. Los inhibidores de la fosfodiesterasa tipo5 no tienen suficiente evidencia que avale su uso. No existen estrategias estandarizadas de seguimiento de esta patología, si bien se pueden utilizar herramientas como escalas, cuestionarios o la autoestimación del tiempo de latencia intravaginal para la evaluación de la respuesta, y un seguimiento específico de visitas en caso de la toma de ISRS. Conclusiones. El presente consenso propone diversas recomendaciones referidas al manejo de la EP fundamentadas en la evidencia y en la experiencia clínica y que pretende ser un instrumento útil al clínico implicado en el manejo de estos pacientes (AU)

Objectives. To develop recommendations on the diagnosis, treatment and monitoring of premature ejaculation (PE). Material and method. A multidisciplinary group of experts created clinical questions. Based on a non-exhaustive systematic review and their clinical experience, recommendations were developed and validated in a Delphi round and, after that, in a meeting. Results. Interviews are essential for the diagnosis of PE, which has to be complemented with a physical examination and the use of specific questionnaires. Psychological treatment of PE with sex therapy and behavioral techniques is effective, and it is more effective when combined with drug treatment. The use of anesthetic agents or surgical interventions is not recommended. Selective serotonin reuptake inhibitors (SSRIs) are effective and safe, being dapoxetine the only drug with specific indication for PE. Inhibitors of phosphodiesterase type5 have not enough evidence to support their use. There are no standardized monitoring strategies for this disease, although tools such as scales, questionnaires or self-esteem intravaginal latency time for response assessment can be used, in addition to specific follow-up visits if the patient is taking SSRIs. Conclusions. This consensus proposes several recommendations regarding the management of PE according to evidence and clinical experience and aims at being a useful clinical instrument for the management of these patients (AU)

Telomere homeostasis is compromised in spermatocytes from patients with idiopathic infertility.

OBJECTIVE: To study whether the telomere structure of germ cells from idiopathic infertile men is altered and if this impairment is influenced by meiotic recombination and telomere length. DESIGN: We performed a detailed analysis of both telomeric repeat-containing RNA (TERRA) and telomerase distribution in testis cell spreads by combining immunofluorescence and RNA fluorescent in situ hybridization. In addition we analyzed meiotic recombination between homologous chromosomes by immunofluorescence and telomere length by quantitative fluorescent in situ hybridization. SETTING: University. PATIENT(S): Men consulting for fertility problems. INTERVENTION(S): Unilateral testicular biopsies. MAIN OUTCOME MEASURE(S): We observed that TERRA levels and its nuclear distribution were compromised in infertile patients. In addition, the presence of the protein component of telomerase at telomeres decreased in the affected patients. However, neither telomerase-TERRA association nor telomere length was altered in spermatocytes I of infertile samples compared with control individuals. In addition, we observed that meiotic recombination was reduced in infertile individuals. RESULT(S): Telomere homeostasis is impaired in infertile patients, and this was translated into a decrease in TERRA levels together with an alteration of the TERRA-protein component of telomerase telomeric association in primary spermatocytes. CONCLUSION(S): This study demonstrates for the first time that telomere structure and homeostasis in germ cells is compromised in infertile individuals. In the light of our results we propose that the analysis of telomeric structure (i.e., TERRA levels and telomere association with TERRA and telomerase) would provide new tools for our understanding of the origin of human infertility.

Antisymmetric polar modes of thermal convection in rotating spherical fluid shells at high taylor numbers.

The onset of thermal convection in a rotating spherical shell of intermediate radius ratio eta=0.4 is studied numerically for Taylor numbers Ta > or = 10(11) and the Prandtl number of the liquid sodium (sigma=0.01). For the first time, it is shown that at very high Taylor numbers the first unstable mode can be antisymmetric with respect to the equator and confined inside a cylinder tangent to the inner sphere at the equator (polar mode). The exponent of the power law determined from the asymptotic dependence of the critical Rayleigh number for very high Ta is 0.57, lower than 2/3, given theoretically for the spiraling columnar modes, and than 0.63, found numerically for the outer equatorially attached modes.

Synapsis and meiotic recombination analyses: MLH1 focus in the XY pair as an indicator.

BACKGROUND: Anomalies in meiotic prophase I have been related to partial or total meiotic arrest. These anomalies include an abnormal synaptic process, resulting in disorders in meiotic recombination. METHODS: In the present study, we analyse primary spermatocytes from 12 infertile men (four with non-obstructive azoospermia, six with oligoastenoteratozoospermia, one with astenoteratozoospermia and one normozoospermic) and five control fertile donors using immunocytological techniques for synaptonemal complex, meiotic recombination and centromeric proteins. RESULTS: Mean numbers of MLH1 foci per cell, frequencies of cells presenting an MLH1 focus in the XY pair and percentages of cells affected by abnormal synaptic patterns (gaps and splits) are reported for each of the infertile patients and control men. A positive correlation between the frequency of cells showing a recombination focus in the XY pair and the number of autosomal recombination foci per cell is found. CONCLUSIONS: Reduced recombination in the XY pair and an increased number of cells affected by gaps may explain some idiopathic male infertility cases. The results suggest that recombination in the XY pair could be an indicator for general recombination frequency and for a successful meiotic process.

Outcome of intracytoplasmic sperm injection in relation to the meiotic pattern in patients with severe oligoasthenozoospermia.

OBJECTIVE: The aim of the study was to evaluate the intracytoplasmic sperm injection outcome in a selected group of patients with oligoasthenozoospermia in relation to the results obtained from their meiotic analysis. DESIGN: Retrospective clinical study. SETTING: An assisted reproduction service and a university department. PATIENT(S): One hundred thirty-seven men with oligoasthenozoospermia grouped in relation to their meiotic pattern. INTERVENTION(S): Two hundred twenty-four intracytoplasmic sperm injection cycles from 137 men with oligoasthenozoospermia in whom diagnostic meiotic analyses had been performed. MAIN OUTCOME MEASURE(S): Fertilization, pregnancy, implantation, and abortion rates. RESULT(S): There were no significant statistical differences in fertilization, pregnancy, implantation, or abortion rates among the three groups studied. CONCLUSION(S): No statistically significant differences in fertilization, pregnancy, implantation, or abortion rates were found in patients with oligoasthenozoospermia in relation to the meiotic pattern.

Spermatogenic patterns and early embryo development after intracytoplasmic sperm injection in severe oligoasthenozoospermia.

PURPOSE: Evaluate the influence of different baseline spermatogenic patterns [meiotic pattern (normal or abnormal), sperm concentration (> 1 x 10(6)/mL or < or = 1 x 10(6)/mL), and the combined meiosis-sperm concentration pattern] on early embryo development in severe oligoasthenozoospermia. METHODS: Embryo outcomes (fertilization rate, cleavage rate, and 4-cell stage embryo division rate on day 2) after IVF-ICSI in 75 oligoasthenozoospermia and 79 normozoospermic males. RESULTS: The embryo division rate was significantly lower in oligoasthenozoospermia compared to normozoospermia (50.43% vs. 58.72%, p < 0.01) and in the oligoasthenozoospermia group for meiotic anomalies (43.40%), sperm concentration < or = 1 x 10(6)/mL (44.35%), and the combined pattern < or = 1 x 10(6)/mL with meiotic anomalies (37.17%). Logistic regression analysis showed a synergic effect (OR = 2.00; 95% CI = 1.28-3.12) when the two spermatogenic patterns predictive of slow embryo development [meiotic anomalies (OR = 1.49; 95% CI = 1.03-2.15) and sperm concentration < or = 1 x 10(6)/mL (OR = 1.53; 95% CI = 1.09-2.13)] were present. CONCLUSIONS: The data suggest that the early embryonic developmental capacity is inversely related to the severity of spermatogenic impairment (meiotic anomalies and/or sperm concentration < or = 1 x 10(6)/mL).