The Excitatory Neuronal Network of the C2 Barrel Column in Mouse Primary Somatosensory Cortex

Local microcircuits within neocortical columns form key determinants of sensory processing. Here, we investigate the excitatory synaptic neuronal network of an anatomically defined cortical column, the C2 barrel column of mouse primary somatosensory cortex. This cortical column is known to process tactile information related to the C2 whisker. Through multiple simultaneous whole-cell recordings, we quantify connectivity maps between individual excitatory neurons located across all cortical layers of the C2 barrel column. Synaptic connectivity depended strongly upon somatic laminar location of both presynaptic and postsynaptic neurons, providing definitive evidence for layer-specific signaling pathways. The strongest excitatory influence upon the cortical column was provided by presynaptic layer 4 neurons. In all layers we found rare large-amplitude synaptic connections, which are likely to contribute strongly to reliable information processing. Our data set provides the first functional description of the excitatory synaptic wiring diagram of a physiologically relevant and anatomically well-defined cortical column at single-cell resolution

A Rapid Gamma-Ray Glow Flux Reduction Observed From 20 km Altitude

Two gamma-ray glows were observed by a high-altitude NASA ER-2 aircraft flying at 20 km altitude over a thunderstorm in Colorado, USA. The flux of the first glow rapidly intensified and then abruptly decreased within a few tens of milliseconds. On a timescale of seconds, the flux decrease occurred simultaneously with a hybrid intra-cloud/cloud-to-ground lightning discharge beneath the aircraft. However, a more detailed analysis of the discharge dynamics indicated that the discharge activity was unusually calm during the actual period of the flux decrease. The lightning was observed with on-board antennas, optical sensor, and ground-based lightning mapping and location networks. Its closest activity was 12 km away from the aircraft, below and slightly ahead the course. The gamma-ray flux reduction happened roughly in the middle of the lightning development process. The glow spectral analysis for the periods of a weak and strong flux enhancement has been done. The spectra were found to be background-like and similar to each other.publishedVersio

Gamma Ray Glow Observations at 20-km Altitude

In the spring of 2017 an ER‐2 aircraft campaign was undertaken over continental United States to observe energetic radiation from thunderstorms and lightning. The payload consisted of a suite of instruments designed to detect optical signals, electric fields, and gamma rays from lightning. Starting from Georgia, USA, 16 flights were performed, for a total of about 70 flight hours at a cruise altitude of 20 km. Of these, 45 flight hours were over thunderstorm regions. An analysis of two gamma ray glow events that were observed over Colorado at 21:47 UT on 8 May 2017 is presented. We explore the charge structure of the cloud system, as well as possible mechanisms that can produce the gamma ray glows. The thundercloud system we passed during the gamma ray glow observation had strong convection in the core of the cloud system. Electric field measurements combined with radar and radio measurements suggest an inverted charge structure, with an upper negative charge layer and a lower positive charge layer. Based on modeling results, we were not able to unambiguously determine the production mechanism. Possible mechanisms are either an enhancement of cosmic background locally (above or below 20 km) by an electric field below the local threshold or an enhancement of the cosmic background inside the cloud but then with normal polarity and an electric field well above the Relativistic Runaway Electron Avalanche threshold.publishedVersio

Plan de negocios para una plataforma de atención médica virtual de baja complejidad

El presente plan de negocio tiene como objetivo principal determinar la viabilidad y la puesta en marcha de una empresa que brinda el servicio de atención médica virtual para patologías de baja complejidad a través de una plataforma digital de fácil acceso y navegación, llamada Doctor 24, la cual estará dirigida a personas del nivel socioeconómico (NSE) C de Lima Metropolitana. La oportunidad de negocio surge gracias a que existe un limitado acceso al sistema de salud público y privado, a la escasa oferta de un servicio privado eficiente y accesible económicamente, y al grave problema de automedicación existente en la mayoría de la población de Lima Metropolitana. Bajo este contexto, en el mercado local existen servicios de telesalud dirigidos a los sectores socioeconómicos A y B; sin embargo, ninguno cubre correctamente en oportunidad, eficiencia y pertinencia las necesidades del NSE C. La validación de este modelo se realizó mediante una investigación de mercado con sondeos cualitativos y cuantitativos, cuyas principales conclusiones destacan la necesidad de rapidez en el acceso a los servicios de salud, los altos costos que se derivan de la salud privada y el error en el diagnóstico médico por no tener la posibilidad de acceder a servicios de mayor calidad. Por ello, el 71 % de los entrevistados se mostraron dispuestos a contratar algún servicio de teleconsulta para la atención de dolencias agudas y un 81 %, a pagar entre S/ 21 y S/ 40 por el servicio. La oferta de Doctor 24 estará enfocada en tres pilares: (i) atención inmediata 24/7, (ii) efectividad en el diagnóstico y en el tratamiento médico, y (iii) brindar un precio accesible al servicio por suscripción o atención inmediata. Los clientes de Doctor 24 tendrán a su disposición el canal digital para solicitar el servicio médico, el cual incluirá una web y una aplicación compatible con IOS y Android. El servicio será brindado por un staff médico propio enfocado en el cliente, y se dispondrá de una división digital, responsable del UX/UI de la plataforma, advanced analytic y marketing digital, y una división de operaciones, responsable de la gestión de recursos humanos, de finanzas, legal y del servicio posventa. Para llevar a cabo la operatividad de la idea de negocio se han definido tres objetivos: calidad, disponibilidad y entrega de servicio. Asimismo, se han estructurado los procesos operativos en dos grupos: front y back office, con la finalidad de brindar un servicio oportuno y de calidad que supere las expectativas de los clientes. Por otro lado, se ha elaborado un plan de estrategias de recursos humanos enfocado en el reclutamiento, el desarrollo y la fidelización del personal con el objetivo de contar con un equipo identificado con la organización y comprometidos a brindar un servicio de excelencia con un enfoque centrado en el cliente. Finalmente, se realizaron proyecciones económicas y financieras del proyecto Doctor 24. Asumiendo aun un nivel conservador de penetración en el segmento objetivo, el nivel de consultas proyectados al año 5 es de 1,152,054, lo que permite un volumen de ventas netas de S/ 27,698,240, con un EBITDA de S/ 6,422,307 (23 % sobre las ventas). La inversión inicial y capital de trabajo para los primeros dos años ascenderá a S/ 3,728,219. Esta se financiará totalmente con aporte de capital de los socios. Doctor 24 alcanzará una TIR de 35 % con un VAN de S/ 1,680,307 en las proyecciones a cinco años. A partir del año 5, se estima que el resultado del EBITDA estará cercano al 25 % sobre las ventas y el crecimiento de ventas se estabilizará en entre +5 y 10 % anualmente

Multicentric assessment of safety and efficacy of combinatorial adjuvant brain metastasis treatment by intraoperative radiotherapy and immunotherapy

Purpose Following surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy (EBRT) by enabling superior organ at risk preservation, reduction of in-hospital times and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs). Methods In a multicentric approach incorporating individual patient data from six international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis (RN), leptomeningeal spread (LMS), local control (LC), distant brain progression (DBP) and estimated overall survival (OS). Results A total of 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow up was 13.2 (1.2-102.4) months and the median IORT dose was 25 (18-30) Gy prescribed to the applicator surface. There was one grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative RN rate was observed. The 1-year LCR was 98.0% and the 1-year DBP-free rate 60.0%. Median time to DBP was 5.5 (1.0-18.5) months in the subgroup of patients experiencing DBP and the cumulative LMS rate was 4.9%. The median estimated OS was 26 (1.2-not reached) months with a 1-year survival rate of 74.0%. Early initiation of IT/TT was associated with a non-significant trend towards improved DBP rate and OS. Conclusion The combination of ICIs/TT with IORT for resected BMs does not seem to increase toxicity, while yielding encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial

Effect of pre-contraction on β-adrenoceptor-mediated relaxation of rat urinary bladder

Purpose The human physiological bladder contraction is largely mediated by acetylcholine acting on muscarinic receptors, but in pathophysiological settings the relative role of non-cholinergic stimuli gains importance. beta-Adrenoceptor agonists are currently in clinical development as treatments for the overactive bladder syndrome. Therefore, we have explored the ability of the beta-adrenoceptor agonist isoprenaline to induce rat isolated bladder strip relaxation on pre-contraction with the muscarinic agonist carbachol as compared to bladder tone induced by several non-cholinergic stimuli. Methods Bladder tone was induced by passive tension, receptor independently by KCl, carbachol, bradykinin or serotonin. Concentration-response curves were generated for relaxation by isoprenaline, and a single concentration of the receptor-independent relaxant forskolin was also tested. Results The various contractile stimuli induced different degrees of bladder tone, but the ability of isoprenaline or forskolin to relax rat bladder was not correlated with the degree of tone. Isoprenaline was significantly less potent and effective in causing relaxation against carbachol-induced tone than against any other stimulus, whereas no such relationship was observed for forskolin. Conclusions We conclude that beta-adrenoceptor agonists can induce rat bladder relaxation against a wide range of contractile stimuli and are more potent and/or effective against non-cholinergic stimuli than against muscarinic agonism. This profile appears desirable for agents intended for the treatment of overactive bladde

First 10 Months of TGF Observations by ASIM

The Atmosphere‐Space Interactions Monitor (ASIM) was launched to the International Space Station on 2 April 2018. The ASIM payload consists of two main instruments, the Modular X‐ray and Gamma‐ray Sensor (MXGS) for imaging and spectral analysis of Terrestrial Gamma‐ray Flashes (TGFs) and the Modular Multi‐spectral Imaging Array for detection, imaging, and spectral analysis of Transient Luminous Events and lightning. ASIM is the first space mission designed for simultaneous observations of Transient Luminous Events, TGFs, and optical lightning. During the first 10 months of operation (2 June 2018 to 1 April 2019) the MXGS has observed 217 TGFs. In this paper we report several unprecedented measurements and new scientific results obtained by ASIM during this period: (1) simultaneous TGF observations by Fermi Gamma‐ray Burst Monitor and ASIM MXGS revealing the very good detection capability of ASIM MXGS and showing substructures in the TGF, (2) TGFs and Elves produced during the same lightning flash and even simultaneously have been observed, (3) first imaging of TGFs giving a unique source location, (4) strong statistical support for TGFs being produced during the upward propagation of a leader just before a large current pulse heats up the channel and emits a strong optical pulse, and (5) the t 50 duration of TGFs observed from space is shorter than previously reported.publishedVersio

Opportunities and Alternatives of Modern Radiation Oncology and Surgery for the Management of Resectable Brain Metastases.

Postsurgical radiotherapy (RT) has been early proven to prevent local tumor recurrence, initially performed with whole brain RT (WBRT). Subsequent to disadvantageous cognitive sequalae for the patient and the broad distribution of modern linear accelerators, focal irradiation of the tumor has omitted WBRT in most cases. In many studies, the effectiveness of local RT of the resection cavity, either as single-fraction stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic RT (hFSRT), has been demonstrated to be effective and safe. However, whereas prospective high-level incidence is still lacking on which dose and fractionation scheme is the best choice for the patient, further ablative techniques have come into play. Neoadjuvant SRS (N-SRS) prior to resection combines straightforward target delineation with an accelerated post-surgical phase, allowing an earlier start of systemic treatment or rehabilitation as indicated. In addition, low-energy intraoperative RT (IORT) on the surgical bed has been introduced as another alternative to external beam RT, offering sterilization of the cavity surface with steep dose gradients towards the healthy brain. This consensus paper summarizes current local treatment strategies for resectable brain metastases regarding available data and patient-centered decision-making

Biomarkers of Nutrition for Development (BOND)—Iron Review

This is the fifth in the series of reviews developed as part of the Biomarkers of Nutrition for Development (BOND) program. The BOND Iron Expert Panel (I-EP) reviewed the extant knowledge regarding iron biology, public health implications, and the relative usefulness of currently available biomarkers of iron status from deficiency to overload. Approaches to assessing intake, including bioavailability, are also covered. The report also covers technical and laboratory considerations for the use of available biomarkers of iron status, and concludes with a description of research priorities along with a brief discussion of new biomarkers with potential for use across the spectrum of activities related to the study of iron in human health. The I-EP concluded that current iron biomarkers are reliable for accurately assessing many aspects of iron nutrition. However, a clear distinction is made between the relative strengths of biomarkers to assess hematological consequences of iron deficiency versus other putative functional outcomes, particularly the relationship between maternal and fetal iron status during pregnancy, birth outcomes, and infant cognitive, motor and emotional development. The I-EP also highlighted the importance of considering the confounding effects of inflammation and infection on the interpretation of iron biomarker results, as well as the impact of life stage. Finally, alternative approaches to the evaluation of the risk for nutritional iron overload at the population level are presented, because the currently designated upper limits for the biomarker generally employed (serum ferritin) may not differentiate between true iron overload and the effects of subclinical inflammation