3D printed PEDOT:PSS-based conducting and patternable eutectogel electrodes for machine learning on textiles.

The proliferation of medical wearables necessitates the development of novel electrodes for cutaneous electrophysiology. In this work, poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) is combined with a deep eutectic solvent (DES) and polyethylene glycol diacrylate (PEGDA) to develop printable and biocompatible electrodes for long-term cutaneous electrophysiology recordings. The impact of printing parameters on the conducting properties, morphological characteristics, mechanical stability and biocompatibility of the material were investigated. The optimised eutectogel formulations were fabricated in four different patterns -flat, pyramidal, striped and wavy- to explore the influence of electrode geometry on skin conformability and mechanical contact. These electrodes were employed for impedance and forearm EMG measurements. Furthermore, arrays of twenty electrodes were embedded into a textile and used to generate body surface potential maps (BSPMs) of the forearm, where different finger movements were recorded and analysed. Finally, BSPMs for three different letters (B, I, O) in sign-language were recorded and used to train a logistic regressor classifier able to reliably identify each letter. This novel cutaneous electrode fabrication approach offers new opportunities for long-term electrophysiological recordings, online sign-language translation and brain-machine interfaces.

Light-Based 3D Multi-Material Printing of Micro-Structured Bio-Shaped, Conducting and Dry Adhesive Electrodes for Bioelectronics.

In this work, a new method of multi-material printing in one-go using a commercially available 3D printer is presented. The approach is simple and versatile, allowing the manufacturing of multi-material layered or multi-material printing in the same layer. To the best of the knowledge, it is the first time that 3D printed Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) micro-patterns combining different materials are reported, overcoming mechanical stability issues. Moreover, the conducting ink is engineered to obtain stable in-time materials while retaining sub-100 µm resolution. Micro-structured bio-shaped protuberances are designed and 3D printed as electrodes for electrophysiology. Moreover, these microstructures are combined with polymerizable deep eutectic solvents (polyDES) as functional additives, gaining adhesion and ionic conductivity. As a result of the novel electrodes, low skin impedance values showed suitable performance for electromyography recording on the forearm. Finally, this concluded that the use of polyDES conferred stability over time, allowing the usability of the electrode 90 days after fabrication without losing its performance. All in all, this demonstrated a very easy-to-make procedure that allows printing PEDOT:PSS on soft, hard, and/or flexible functional substrates, opening up a new paradigm in the manufacturing of conducting multi-functional materials for the field of bioelectronics and wearables.

Hydrophobic Eutectogels as Electrodes for Underwater Electromyography Recording.

Underwater recording remains a critical challenge in bioelectronics because traditional flexible electrodes can not fulfill essential requirements such as stability and steady conductivity in aquatic environments. Herein, we show the use of elastic gels made of hydrophobic natural eutectic solvents as water-resistant electrodes. These eutectogels are designed with tailorable mechanical properties via one-step photopolymerization of acrylic monomers in different eutectic mixtures composed of fatty acids and menthol. The low viscosity of the eutectics turns the formulations into suitable inks for 3D printing, allowing fast manufacturing of complex objects. Furthermore, the hydrophobic nature of the building blocks endows the eutectogels with excellent stability and low water uptake. The obtained flexible eutectogel electrodes can record real-time electromyography (EMG) signals with low interference in the air and underwater.

High Density Body Surface Potential Mapping with Conducting Polymer-Eutectogel Electrode Arrays for ECG imaging.

Electrocardiography imaging (ECGi) is a non-invasive inverse reconstruction procedure which employs body surface potential maps (BSPM) obtained from surface electrode array measurements to improve the spatial resolution and interpretability of conventional electrocardiography (ECG) for the diagnosis of cardiac dysfunction. ECGi currently lacks precision, which has prevented its adoption in clinical setups. The introduction of high-density electrode arrays could increase ECGi reconstruction accuracy but is not attempted before due to manufacturing and processing limitations. Advances in multiple fields have now enabled the implementation of such arrays which poses questions on optimal array design parameters for ECGi. In this work, a novel conducting polymer electrode manufacturing process on flexible substrates is proposed to achieve high-density, mm-sized, conformable, long-term, and easily attachable electrode arrays for BSPM with parameters optimally selected for ECGi applications. Temporal, spectral, and correlation analysis are performed on a prototype array demonstrating the validity of the chosen parameters and the feasibility of high-density BSPM, paving the way for ECGi devices fit for clinical application.

Signal strength of STING activation determines cytokine plasticity and cell death in human monocytes.

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway is a cytosolic sensor of microbial and host-derived DNA and plays a key role in innate immunity. Activation of STING by cyclic dinucleotide (CDN) ligands in human monocytes induces a type I interferon response and production of pro-inflammatory cytokines associated with the induction of massive cell death. In this study we have re-evaluated the effect of signal strength of STING activation on the cytokine plasticity of human monocytes. CDN (2'3'c-GAMP) and non-CDN (diABZI, MSA-2) STING ligands in the range of EC50 concentrations (15 µM 2'3'c-GAMP, 100 nM diABZI, 25 µM MSA-2) induced IFN-ß, IP-10, and large amounts of IL-1ß and TNF-α, but no IL-10 or IL-19. Interestingly, LPS-induced production of IL-10 and IL-19 was abolished in the presence of diABZI or MSA-2, whereas IL-1ß and TNF-α were not inhibited. Surprisingly, we observed that tenfold lower (MSA-2, i.e. 2.5 µM) or 100-fold lower (diABZI, i.e. 1 nM) concentrations strongly stimulated secretion of anti-inflammatory IL-10 and IL-19, but little of IL-1ß and TNF-α. Induction of IL-10 was associated with up-regulation of PRDM1 (Blimp-1). While cytokine secretion stimulated by the higher concentrations was accompanied by apoptosis as shown by cleavage of caspase-3 and PARP-1, the low concentrations did not trigger overt cell death yet induced cleavage of gasdermin-D. Our results reveal a previously unrecognized plasticity of human monocytes in their signal strength-dependent production of pro- versus anti-inflammatory cytokines upon STING activation.

Analysis of the Seasonal Fluctuation of γδ T Cells and Its Potential Relation with Vitamin D3.

In addition to its role in bone metabolism, vitamin D3 exerts immunomodulatory effects and has been proposed to contribute to seasonal variation of immune cells. This might be linked to higher vitamin D3 levels in summer than in winter due to differential sun exposure. γδ T cells comprise a numerically small subset of T cells in the blood, which contribute to anti-infective and antitumor immunity. We studied the seasonal fluctuation of γδ T cells, the possible influence of vitamin D3, and the effect of the active metabolite 1α,25(OH)2D3 on the in vitro activation of human γδ T cells. In a retrospective analysis with 2625 samples of random blood donors, we observed higher proportions of γδ T cells in winter when compared with summer. In a prospective study over one year with a small cohort of healthy adults who did or did not take oral vitamin D3 supplementation, higher proportions of γδ T cells were present in donors without oral vitamin D3 uptake, particularly in spring. However, γδ T cell frequency in blood did not directly correlate with serum levels of 25(OH)D3. The active metabolite 1α,25(OH)2D3 inhibited the in vitro activation of γδ T cells at the level of proliferation, cytotoxicity, and interferon-γ production. Our study reveals novel insights into the seasonal fluctuation of γδ T cells and the immunomodulatory effects of vitamin D3.

Stimulatory and inhibitory activity of STING ligands on tumor-reactive human gamma/delta T cells.

Ligands for Stimulator of Interferon Genes (STING) receptor are under investigation as adjuvants in cancer therapy. Multiple effects have been described, including induction of immunogenic cell death and enhancement of CD8 T-cell mediated anti-tumor immunity. However, the potential effects of STING ligands on activation and effector functions of tumor-reactive human γδ T cells have not yet been investigated. We observed that cyclic dinucleotide as well as novel non-dinucleotide STING ligands diABZI and MSA-2 co-stimulated cytokine induction in Vδ2 T cells within peripheral blood mononuclear cells but simultaneously inhibited their proliferative expansion in response to the aminobisphosphonate Zoledronate and to γδ T-cell specific phosphoantigen. In purified γδ T cells, STING ligands co-stimulated cytokine induction but required the presence of monocytes. STING ligands strongly stimulated IL-1ß and TNF-α secretion in monocytes and co-stimulated cytokine induction in short-term expanded Vδ2 γδ T-cell lines. Simultaneously, massive cell death was triggered in both cell populations. Activation of STING as revealed by TBK1/IRF3 phosphorylation and IP-10 secretion varied among STING-expressing tumor cells. STING ligands modulated tumor cell killing by Vδ2 T cells as analyzed in Real-Time Cell Analyzer to variable degree, depending on the tumor target and time course kinetics. Our study reveals complex regulatory effects of STING ligands on human γδ T cells in vitro. These results help to define conditions where STING ligands might boost the efficacy of γδ T cell immunotherapy in vivo.

Monocyte-dependent co-stimulation of cytokine induction in human γδ T cells by TLR8 RNA ligands.

Human Vγ9Vδ2 T cells recognize pyrophosphates produced by microbes and transformed cells and play a role in anti-infective immunity and tumor surveillance. Toll-like receptors (TLR) are pattern recognition receptors in innate immune cells which sense microbial structures including nucleic acids. Given that γδ T cells are in clinical development for application in cellular cancer immunotherapy and TLR ligands have potent adjuvant activity, we investigated the co-stimulatory role of selected TLR ligands in γδ T-cell activation. Here we have used recently described RNA ligands for TLR7 and TLR8 together with Vγ9Vδ2 T-cell specific pyrophosphate antigens to analyze the rapid cytokine induction in Vδ2 T cells as well as the accessory cell requirements. While TLR8- as well as TLR7/8-specific RNA did not induce IFN-γ in Vδ2 T cells on their own, they provided strong co-stimulation for Vδ2 T cells within peripheral blood mononuclear cells in the presence of additional T-cell receptor activation. In contrast, TLR7 ligands were ineffective. Purified γδ T cells did not directly respond to TLR8 co-stimulation but required the presence of monocytes. Further experiments revealed a critical role of IL-1ß and IL-18, and to a slightly lesser extent of IL-12p70, in the co-stimulation of Vδ2 T cells by TLR8 and TLR7/8 RNA ligands. Results of intracellular cytokine expression were validated by ELISA analysis of cytokines in cell culture supernatants. The cell context-dependent adjuvant activity of TLR8 and TLR7/8 RNA ligands described here might be important for the future optimization of γδ T-cell based cancer immunotherapy.

Correction to: Cancer immunotherapy with γδ T cells: many paths ahead of us.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Correction: Serrano, R.; Wesch, D.; Kabelitz, D. Activation of Human γδ T Cells: Modulation by Toll-Like Receptor 8 Ligands and Role of Monocytes. Cells 2020, 9, 713.

The authors wish to make the following changes to their paper [...].

Cancer immunotherapy with γδ T cells: many paths ahead of us.

γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αß T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.

Activation of Human γδ T Cells: Modulation by Toll-Like Receptor 8 Ligands and Role of Monocytes.

BACKGROUND: Human Vγ9Vδ2 γδ T cells can kill a variety of cancer cells and have attracted substantial interest for cancer immunotherapy. Toll-like receptor (TLR) ligands are promising adjuvants for cancer immunotherapy, but TLR7/8 ligand Resiquimod has been shown to inhibit CD4 T-cell activation in a monocyte-dependent manner. Therefore, we studied the modulation of human γδ T-cell activation by TLR7/8 ligands. METHODS: Peripheral blood mononuclear cells (PBMC) or purified γδ T cells together with purified monocytes were stimulated with zoledronic acid or phosphoantigens in the absence or presence of various imidazoquinoline TLR7 or TLR8 agonists. Read-out systems included interferon-γ induction and cellular expansion of γδ T cells, as well as viability, cell surface antigen modulation, and IL-1ß and TNF-α production of monocytes. RESULTS: TLR8 ligand TL8-506 and TLR7/8 ligand Resiquimod (but not TLR7 ligands) rapidly induced IFN-γ expression in γδ T cells within PBMC, and co-stimulated phosphoantigen-induced IFN-γ expression in γδ T cells. On the other hand, TLR8 ligands potently suppressed γδ T-cell expansion in response to zoledronic acid and phosphoantigen. Purified monocytes secreted large amounts of IL-1ß and TNF-α when stimulated with TLR8 ligands but simultaneously underwent substantial cell death after 24 h. CONCLUSIONS: TLR8 ligand-activated monocytes potently co-stimulate early γδ T-cell activation but failed to provide accessory cell function for in vitro expansion of γδ T cells.

Trastornos Hipertensivos del embarazo: clínica y epidemiología, Hospital regional Santa Teresa 2015 / Hypertensive disorders of pregnancy: clinical and epidemiological Regional Hospital Santa Teresa 2015

Antecedentes: El Hospital Santa Teresa (HRST) es un hospital regional de segundo nivel con capacidad de brindar un mayor nivel de resolución a procesos mórbidos, pese a que está limitado por sus características de infraestructura, equipamiento, personal y en la capacidad para el manejo de complicaciones en las gestantes. Es necesario determinar las características de las paci - entes con trastornos hipertensivos del embarazo para fortalecer su capacidad de atención. Objetivo: Describir las características clíni - cas y epidemiológicas de los trastornos hipertensivos del embarazo de la sala de labor y partos del Hospital Regional Santa Teresa, Comayagua, durante el año 2015. Métodos: Estudio observacional descriptivo. En este período ingresaron 6,090 gestantes, de las cuales 361 (5.9%) presentaron enfermedad hipertensiva del embarazo. Se estimó un tamaño de muestra de 186 (51.5%, IC95%). Las variables incluyeron datos sociodemográicos, antecedentes gineco-obstétricos, manifestaciones clínico-laboratoriales, diagnóstico, manejo terapéutico y complicaciones. La información recolectada fue ingresada en base de datos Epiinfo versión 7.1.5 (CDC, Atlanta). Los resultados se presentan como frecuencias, porcentajes, rangos y promedios. La información personal de los casos se manejó conidencialmente. Resultados: El 58.6%(109) tenían entre 19 a 35 años, 65.1% (121) con ≥ 5 controles prenatales. El signo clínico más frecuente edema 37.1%(69), laboratorialmente lactato deshidrogenasa 69.9%(130). La vía de parto más frecuente fue vaginal 63.4%(118), 45.1%(84) ameritó uso de antihipertensivos, 25.8%(48) anticonvulsivantes. El trastorno hipertensivo más frecuente fue la preeclampsia-eclampsia con un 65.1%(121) y la complicación más frecuente síndrome HELLP 3.7%(7). Discusión: La prevalencia de los trastornos hipertensivos fue de 5.9% respectivamente...(AU)

[Ocular infestation by plerocercoid of Spirometra mansonoides: first case report in Peru]. / Infestación ocular por plerocercoide de Spirometra mansonoides: primer reporte en el Perú.

Plerocercoidosis is a parasitic zoonosis caused by plerocercoid larvae of the genus Spirometra. The larvae migrate through the intestinal wall tissue, by subcutaneous route and can reach different areas of the body like the head, the brain and the eye socket. A case is reported of a 45 year-old man from the Peruvian Amazon with burning sensation associated with conjunctival edema and hemorrhage in the outer eye border of the right eye for eleven months. A localized worm in the right orbital cavity was observed, which was extracted. Morphological and histopathological studies identified it as Spirometra mansonoides localized in the eye, which is the first case reported in Peru.

Infestación ocular por plerocercoide de Spirometra mansonoides: primer reporte en el Perú / Ocular infestation by plerocercoid of Spirometra mansonoides: first case report in Perú

La plerocercoidiosis es una zoonosis parasitaria producida por la larva plerocercoide de Spirometra. Esta larva migra por el tejido de la pared intestinal, mediante la ruta subcutánea y puede llegar a diferentes áreas del cuerpo humano como la cabeza, el cerebro y la órbita ocular. Se reporta el caso de un varón de 45 años procedente de la Amazonía peruana, quien presentó ardor asociado con edema y hemorragia conjuntival en el borde ocular externo del ojo derecho, durante once meses. Se observó un helminto localizado en la cavidad orbitaria derecha, el cual se extrajo y por estudios morfológicos e histopatológicos se identificó como Spirometra mansonoides de localización ocular el que se reporta por primera vez en el Perú.

Plerocercoidosis is a parasitic zoonosis caused by plerocercoid larvae of the genus Spirometra. The larvae migrate through the intestinal wall tissue, by subcutaneous route and can reach different areas of the body like the head, the brain and the eye socket. A case is reported of a 45 year-old man from the Peruvian Amazon with burning sensation associated with conjunctival edema and hemorrhage in the outer eye border of the right eye for eleven months. A localized worm in the right orbital cavity was observed, which was extracted. Morphological and histopathological studies identified it as Spirometra mansonoides localized in the eye, which is the first case reported in Perú.

Timing of dose relative to sexual intercourse attempt in previous sildenafil citrate users treated with tadalafil: a geographical comparison from a single arm, open-label study.

INTRODUCTION: Previous research has demonstrated that sildenafil citrate users alter dosing-sexual attempt behavior when switched to tadalafil. The impact of geography and culture on sexual behavior with phosphodiesterase type 5 (PDE5) inhibitor treatment has not been fully investigated. AIM: To describe and compare the changes in dosing-sexual attempt behavior with sildenafil citrate vs. tadalafil treatment across four distinct geographies: Asia, Australia/New Zealand (ANZ), Central Eastern Europe/Middle East (CEE/ME), and Latin America (LA). METHODS: Data from a single-arm, open-label clinical trial conducted in 21 countries from November 2002 to May 2004 were used in this analysis. Men with erectile dysfunction and a history of > or =6-week prior sildenafil citrate use continued sildenafil citrate treatment for 4 weeks then switched to tadalafil for 8 weeks. Dosing instructions were provided. MAIN OUTCOMES MEASURES: Timing of dose and sexual intercourse was assessed through patient diaries for the final 4 weeks of each treatment period. RESULTS: A total of 2,760 men were enrolled: Asia 15.8%; ANZ 29.4%; CEE/ME 19.7%; LA 35.1%. The median time from dosing to intercourse was significantly increased during tadalafil treatment across all geographical regions; however, the magnitude of increase differed significantly by geography (P < 0.0001). The Asian cohort demonstrated the shortest duration between dosing and sexual intercourse attempts (irrespective of drug), and altered sexual behavior the least upon switching to tadalafil. The ANZ cohort demonstrated the longest duration between dosing and sexual intercourse attempts (irrespective of drug), and altered sexual behavior the most upon switching to tadalafil. CONCLUSION: Men with a history of established sildenafil citrate use alter their dose-attempt behavior when treated with tadalafil irrespective of geography. However, the extent to which sexual behavior alters is not uniform across geographical regions, suggesting that dosing instructions and duration of drug effectiveness, in combination with personal and cultural preferences, may determine sexual behavior with PDE5 inhibitor use.

Parafilias / Paraphilias

El campo de las parafilias ha estado presente en la literatura científica desde finales del siglo XIX (Kraft-Ebing). Paradójicamente, allí nació la sexología científica como tal. Comenzó tratando lo que para la época eran las perversiones sexuales, luego las desviaciones sexuales y ahora desde 1981 lo que Jhon Money bautizó como parafilias (APA-DSM-4)(OMS-CIE-10). Cada vez más se describen o se hacen aparentes nuevas formas de comportamientos sexuales, En el presente trabajo, se actualiza el conocimiento de la materia en referencia, haciendo énfasis en la clasificación fenomenológica propuesta por el autor en el Programa de Salud Sexual de la Asociación Mundial de Psiquiatría (WPA) 2004

Manipulación uretral: una parafilia inusual:reporte de caso clínico / Manipulation uretral: an unusual paraphilias:report case clinical

Nosotros reportamos un caso de auto-introducción de cuerpo extraño en uretra con motivos eróticos y buscando mejor control eyaculatorio, en un paciente con trastorno psiquiátricos y consumo frecuente de drogas. El dignóstico, tratamiento endoscópico y sus complicaciones desde el punto de vista urológico son descrito, dentro de un enfoque multidisciplinario

Violencia e inseguridad / Violence and insegurity

La violencia es una de las patologías sociales más frecuentes que afecta a la población mundial, principalmente en los países desarrollados. La violencia es el resultado de un comportamiento desviado, de origen multicausal en donde se identifican dos dimensiones: individual y social. El presente trabajo pretende mostrar 40 factores que tienen una reconocida relación con la conducta agresiva, la inseguridad y la criminalidad. Se plantean también algunos elementos de intervención, de acuerdo con los aspectos socioculturales venezolanos