Temporal Notch signaling regulates mucociliary cell fates through Hes-mediated competitive de-repression.

Tissue functions are determined by the types and ratios of cells present, but little is known about self-organizing principles establishing correct cell type compositions. Mucociliary airway clearance relies on the correct balance between secretory and ciliated cells, which is regulated by Notch signaling across mucociliary systems. Using the airway-like Xenopus epidermis, we investigate how cell fates depend on signaling, how signaling levels are controlled, and how Hes transcription factors regulate cell fates. We show that four mucociliary cell types each require different Notch levels and that their specification is initiated sequentially by a temporal Notch gradient. We describe a novel role for Foxi1 in the generation of Delta-expressing multipotent progenitors through Hes7.1. Hes7.1 is a weak repressor of mucociliary genes and overcomes maternal repression by the strong repressor Hes2 to initiate mucociliary development. Increasing Notch signaling then inhibits Hes7.1 and activates first Hes4, then Hes5.10, which selectively repress cell fates. We have uncovered a self-organizing mechanism of mucociliary cell type composition by competitive de-repression of cell fates by a set of differentially acting repressors. Furthermore, we present an in silico model of this process with predictive abilities.

[Forecasting models to guide intensive care COVID-19 capacities in Germany]. / Prognosemodelle zur Steuerung von intensivmedizinischen COVID-19-Kapazitäten in Deutschland.

BACKGROUND: Time-series forecasting models play a central role in guiding intensive care coronavirus disease 2019 (COVID-19) bed capacity in a pandemic. A key predictor of future intensive care unit (ICU) COVID-19 bed occupancy is the number of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the general population, which in turn is highly associated with week-to-week variability, reporting delays, regional differences, number of unknown cases, time-dependent infection rates, vaccinations, SARS-CoV­2 virus variants, and nonpharmaceutical containment measures. Furthermore, current and also future COVID ICU occupancy is significantly influenced by ICU discharge and mortality rates. METHODS: Both the number of new SARS-CoV­2 infections in the general population and intensive care COVID-19 bed occupancy rates are recorded in Germany. These data are statistically analyzed on a daily basis using epidemic SEIR (susceptible, exposed, infection, recovered) models using ordinary differential equations and multiple regression models. RESULTS: Forecast results of the immediate trend (20-day forecast) of ICU occupancy by COVID-19 patients are made available to decision makers at various levels throughout the country. CONCLUSION: The forecasts are compared with the development of available ICU bed capacities in order to identify capacity limitations at an early stage and to enable short-term solutions to be made, such as supraregional transfers.

Data-driven prediction of COVID-19 cases in Germany for decision making.

BACKGROUND: The COVID-19 pandemic has led to a high interest in mathematical models describing and predicting the diverse aspects and implications of the virus outbreak. Model results represent an important part of the information base for the decision process on different administrative levels. The Robert-Koch-Institute (RKI) initiated a project whose main goal is to predict COVID-19-specific occupation of beds in intensive care units: Steuerungs-Prognose von Intensivmedizinischen COVID-19 Kapazitäten (SPoCK). The incidence of COVID-19 cases is a crucial predictor for this occupation. METHODS: We developed a model based on ordinary differential equations for the COVID-19 spread with a time-dependent infection rate described by a spline. Furthermore, the model explicitly accounts for weekday-specific reporting and adjusts for reporting delay. The model is calibrated in a purely data-driven manner by a maximum likelihood approach. Uncertainties are evaluated using the profile likelihood method. The uncertainty about the appropriate modeling assumptions can be accounted for by including and merging results of different modelling approaches. The analysis uses data from Germany describing the COVID-19 spread from early 2020 until March 31st, 2021. RESULTS: The model is calibrated based on incident cases on a daily basis and provides daily predictions of incident COVID-19 cases for the upcoming three weeks including uncertainty estimates for Germany and its subregions. Derived quantities such as cumulative counts and 7-day incidences with corresponding uncertainties can be computed. The estimation of the time-dependent infection rate leads to an estimated reproduction factor that is oscillating around one. Data-driven estimation of the dark figure purely from incident cases is not feasible. CONCLUSIONS: We successfully implemented a procedure to forecast near future COVID-19 incidences for diverse subregions in Germany which are made available to various decision makers via an interactive web application. Results of the incidence modeling are also used as a predictor for forecasting the need of intensive care units.

[Review of the use of botulinum toxin in urology]. / Revisión del uso de la toxina botulínica en urología.

OBJECTIVE: There are several procedures for the management and treatment of the neurogenic bladder. These are adjusted individually according to the results of the clinical examination and complementary tests. This study evaluates the results of treatment with botulinum toxin and its place in current therapeutic armamentarium. METHODS: We reviewed the outstanding literature in the field of neurorology on the criteria, indications, side effects and applications of botulinum toxin. RESULTS: Most of the authors have reported botulinum toxin to be useful in the treatment of voiding disorders secondary to neurological and pelvic floor muscle disorders. CONCLUSIONS: Intramuscular injection of botulinum toxin in the detrusor or external sphincter of the bladder produces a paralyzing (relaxing), therapeutic and reversible effect. The latter is one of its most important characteristics. It has also been found to be effective for non-specific perineal-prostatic pain, for which few treatments are available.

[Prostaglandin treatment in neurological patients with erectile dysfunction]. / Tratamiento con prostaglandinas en pacientes neurológicos con disfunción eréctil.

OBJECTIVE: To evaluate the efficacy of prostaglandin E1 in the treatment of erectile dysfunction in patients with spinal cord or head injury. METHODS: The study comprised 41 patients; 5 head and 36 spinal cord injury. Of these 36 patients, 20 had a lesion in the dorsal and 26 in the lumbosacral spine; 11 were complete and 25 incomplete. Mean age was 38.5 years. Therapy was started at a minimum dose of 5 mg up to maximum of 20 mg in each patient. All patients were taught the correct use of intracavernous self injection of prostaglandin E1. The analyses, ECG and penile echo Doppler evaluations of all patients showed no significant findings that contraindicated treatment. The overall response and the response according to the site of lesion, type of lesion and age were evaluated. RESULTS: The overall response rate was 78.8%. Erection was not achieved in 9 patients even with the 20 mg maximum dose. The response rate was 100% in the group of patients with head injury. In the spinal cord injured patients, the response rate was 83.3% in patients < 30 years and 57.2% in patients > 30 years old. The 2 mg dose was effective in 1 patient, the 10 mg in 17 and the 20 mg dose in 14 patients. A positive response was achieved in 55.5% of the patients with complete and 72.7% of the patients with incomplete spinal lesions. No complications of intracavernous injection of prostaglandin were found. Prostaglandin self injection therapy achieved satisfactory results in all patients. CONCLUSIONS: Prostaglandin injection is very effective in the treatment of erectile dysfunction in patients with spinal cord or head injury. A higher percentage of efficacy was found in the younger patients, in those with incomplete lesions and those with head injury. The dose required is usually lower than in the non neurological patients.

Revisión del uso de la toxina botulínica en urología / Review of the use botulinum-A toxin in urology

OBJETIVOS: El manejo y tratamiento de la vejiga neurógena ofrece una serie de procedimientos que se ajustan individualmente dependiendo del resultado de la exploración clínica y las pruebas complementarias. Con este trabajo hemos pretendido valorar los resultados con el tratamiento mediante toxina botulínica con la finalidad de incorporarla al arsenal terapéutico existente. MÉTODO: Hemos realizado una búsqueda y revisión bibliográfica exhaustiva para unificar criterios e indicaciones así como efectos secundarios y aplicaciones recogiendo los autores y las publicaciones que gozan de mayor prestigio en neurourología. RESULTADOS: La mayoría de los autores coincide en que estamos ante un preparado útil en el tratamiento de las alteraciones miccionales secundarias a procesos neurológicos así como para la musculatura del suelo pélvico. CONCLUSIONES: Las instilaciones intramusculares de Tox.B sobre el detrusor o el esfínter externo vesicales produce un efecto paralizante (relajante), terapéutico y reversible que le hacen una de sus características más ventajosas. A nivel de los dolores inespecíficos perinéprostáticos donde existen pocos tratamientos resolutivos, también se ha mostrado eficaz (AU)

Tratamiento con prostaglandinas en pacientes neurológicos con disfunción eréctil / Prostaglandins in the treatment of spinal cord injured patients with erectile dysfunction

OBJETIVO: Valoramos la eficacia de la prostaglandina E1 en una serie de 41 pacientes con lesiones traumáticas medulares o traumatismo craneoencefálico que condicionan una disfunción eréctil.MÉTODOS: Sobre una serie de 41 pacientes se trataba en 5 casos de traumatismos craneoencefálico, en 36 casos de lesiones medulares con 20 casos de lesión medular dorsal, 16 casos de lesión medular lumbosacra, 11 casos de lesión medular completa y 25 casos de lesión medular incompleta. La edad media fue de 38`5 años. Se inició a dosis mínimas- 5- en cada paciente hasta un máximo de 20, siendo instruidos en el manejo correcto de la inyección intracavernosa de prostaglandina-E1. En todos los pacientes se realizó analítica general, E.C.G. y ECO Doppler peneano sin hallazgos significativos que contraindicaran el tratamiento. Se valoró la respuesta global y la respuesta en función del nivel de la lesión, grado de la misma y edad del paciente.RESULTADOS: La tasa global de respuesta satisfactoria en nuestra serie fue del 78,8 por ciento. En 9 pacientes no se presentó erección satisfactoria con dosis máximas de 20 microgramos. En los traumatismos craneoencefálicos la tasa de respuesta fue del 100 por ciento, en los pacientes menores de 30 años del 83,3 por ciento, en los mayores de 30 años del 57,2 por ciento, en las lesiones medulares. Se constató dosis eficaz de 2 microgramos en 1 paciente, de 10 microgramos en 17 pacientes y 20 microgramos en 14 pacientes. La respuesta fue positiva de las completas del 55,5 por ciento y en las incompletas del 72,7 por ciento. Ningún paciente presentó complicaciones con la inyección intracavernosa de prostaglandina. La autoinyección domiciliaria resultó satisfactoria en todos los pacientes.CONCLUSIONES: La prostaglandina-E1 es una opción terapéutica muy eficaz en el tratamiento de la disfunción eréctil de los pacientes afectos de lesiones traumáticas medulares o craneoencefálicas. Se observa un porcentaje mayor de eficacia en los pacientes jóvenes, en lesiones medulares incompletas o con traumatismo cráneo-encefálico. Las dosis requeridas suelen ser menores que en el resto de la población no neurológica (AU)