Neural general circulation models for weather and climate.

General circulation models (GCMs) are the foundation of weather and climate prediction1,2. GCMs are physics-based simulators that combine a numerical solver for large-scale dynamics with tuned representations for small-scale processes such as cloud formation. Recently, machine-learning models trained on reanalysis data have achieved comparable or better skill than GCMs for deterministic weather forecasting3,4. However, these models have not demonstrated improved ensemble forecasts, or shown sufficient stability for long-term weather and climate simulations. Here we present a GCM that combines a differentiable solver for atmospheric dynamics with machine-learning components and show that it can generate forecasts of deterministic weather, ensemble weather and climate on par with the best machine-learning and physics-based methods. NeuralGCM is competitive with machine-learning models for one- to ten-day forecasts, and with the European Centre for Medium-Range Weather Forecasts ensemble prediction for one- to fifteen-day forecasts. With prescribed sea surface temperature, NeuralGCM can accurately track climate metrics for multiple decades, and climate forecasts with 140-kilometre resolution show emergent phenomena such as realistic frequency and trajectories of tropical cyclones. For both weather and climate, our approach offers orders of magnitude computational savings over conventional GCMs, although our model does not extrapolate to substantially different future climates. Our results show that end-to-end deep learning is compatible with tasks performed by conventional GCMs and can enhance the large-scale physical simulations that are essential for understanding and predicting the Earth system.

Learning skillful medium-range global weather forecasting.

Global medium-range weather forecasting is critical to decision-making across many social and economic domains. Traditional numerical weather prediction uses increased compute resources to improve forecast accuracy but does not directly use historical weather data to improve the underlying model. Here, we introduce GraphCast, a machine learning-based method trained directly from reanalysis data. It predicts hundreds of weather variables for the next 10 days at 0.25° resolution globally in under 1 minute. GraphCast significantly outperforms the most accurate operational deterministic systems on 90% of 1380 verification targets, and its forecasts support better severe event prediction, including tropical cyclone tracking, atmospheric rivers, and extreme temperatures. GraphCast is a key advance in accurate and efficient weather forecasting and helps realize the promise of machine learning for modeling complex dynamical systems.

Schwannoma of the seminal vesicle: Case report and review of the literature.

Seminal vesicles can be affected by tumours originating in other locations. However, primary tumours of the seminal vesicle are extremely rare, with less than 100 cases reported in literature. Seminal vesicle adenocarcinoma is the most common type, but there are also other malign lesions. Diagnosis is challenging due to the lack of early symptoms and well-defined criteria. These tumours are usually asymptomatic and discovered incidentally during imaging tests or pelvic surgery. Definitive diagnosis requires anatomopathological analysis. Case report of 58-years-old man with schwannoma of the seminal vesicle. We describe the main characteristics of these tumours as well as their therapeutic approach.

Long-term Recurrence and Progression Patterns in a Contemporary Series of Patients with Carcinoma In Situ of the Bladder With or Without Associated Ta/T1 Disease Treated with Bacillus Calmette-Guérin: Implications for Risk-adapted Follow-up.

BACKGROUND: Limited data are available on patients with carcinoma in situ (CIS) of the bladder managed according to current clinical practice guidelines. OBJECTIVE: To assess the patterns of recurrence, progression to muscle-invasive bladder cancer (MIBC), and upper tract urothelial carcinoma (UTUC) in patients with CIS, and to compare the effectiveness of adequate versus inadequate bacillus Calmette-Guérin (BCG) immunotherapy. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of 386 patients with CIS of the bladder with or without associated pTa/pT1 disease treated with BCG between 2008 and 2015. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier estimations and an inverse probability of treatment weighting (IPTW)-Cox regression were performed to compare recurrence-free survival (RFS) and progression-free survival (PFS) and UTUC incidence over time for patients who received adequate versus inadequate BCG treatment. RESULTS AND LIMITATIONS: The median follow-up was 70.5 mo. At 5 and 10 yr, RFS was 82% and 52%, PFS was 93.6% and 75.8%, and UTUC incidence was 1.7% and 2.9%, respectively. Most recurrence (73.6%) and progression (69.1%) events occurred in the first 3 yr of follow-up, while 38.7% of UTUC incident events were recorded after 5 yr of follow-up. IPTW-Cox regression revealed that patients who received BCG treatment had a lower risk of recurrence (hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.13-0.34), progression (HR 0.46, 95% CI 0.25-0.87), and UTUC incidence (HR 0.24, 95% CI 0.09-0.64). Limitations include the retrospective design and potential selection bias. CONCLUSIONS: Patients with CIS of the bladder show a high risk of recurrence, progression, and UTUC incidence. Most of these outcomes occur during the first 3 yr of follow-up, but a significant proportion of the events occur at long-term follow-up. Although receipt of adequate BCG treatment improves outcomes, intensive and long-term surveillance may be warranted. PATIENT SUMMARY: We investigated the long-term cancer control outcomes for patients with carcinoma in situ (CIS; cancerous cells that have not spread from where they first formed) of the bladder. Patients with CIS have a high risk of cancer recurrence and progression. Treatment with bacillus Calmette-Guérin (BCG) improves outcomes.

Clinical Profile and Prognosis of a Real-World Cohort of Patients With Moderate or Severe Cancer Therapy-Induced Cardiac Dysfunction.

Introduction and Objectives: Cancer therapy-related cardiac dysfunction (CTRCD) is a common cause of cancer treatment withdrawal, related to the poor outcomes. The cardiac-specific treatment could recover the left ventricular ejection fraction (LVEF). We analyzed the clinical profile and prognosis of patients with CTRCD in a real-world scenario. Methods: A retrospective study that include all the cancer patients diagnosed with CTRCD, defined as LVEF < 50%. We analyzed the cardiac and oncologic treatments, the predictors of mortality and LVEF recovery, hospital admission, and the causes of mortality (cardiovascular (CV), non-CV, and cancer-related). Results: We included 113 patients (82.3% women, age 49.2 ± 12.1 years). Breast cancer (72.6%) and anthracyclines (72.6%) were the most frequent cancer and treatment. Meantime to CTRCD was 8 months, with mean LVEF of 39.4 ± 9.2%. At diagnosis, 27.4% of the patients were asymptomatic. Cardiac-specific treatment was started in 66.4% of patients, with LVEF recovery-rate of 54.8%. Higher LVEF at the time of CTRCD, shorter time from cancer treatment to diagnosis of CTRCD, and younger age were the predictors of LVEF recovery. The hospitalization rate was 20.4% (8.8% linked to heart failure). Treatment with trastuzumab and lower LVEF at diagnosis of CTRCD were the predictors of mortality. Thirty point nine percent of patients died during the 26 months follow-up. The non-CV causes and cancer-related were more frequent than CV ones. Conclusions: Cardiac-specific treatment achieves LVEF recovery in more than half of the patients. LVEF at the diagnosis of CTRCD, age, and time from the cancer treatment initiation to CTRCD were the predictors of LVEF recovery. The CV-related deaths were less frequent than the non-CV ones. Trastuzumab treatment and LVEF at the time of CTRCD were the predictors of mortality.

What Should Be Known by a Urologist About the Medical Management of COVID-19's Patients?

PURPOSE OF REVIEW: The alarming number of confirmed COVID-19 cases put a strain on the healthcare systems, which had to reallocate human and technical resources to respond to the emergency. Many urologists became integrated into multidisciplinary teams, dealing with this respiratory illness and its unknown management. It aims to summarize the epidemiological, clinical, diagnostical, and therapeutical characteristics of COVID-19, from a practical perspective, to ease COVID-19 management to non-physician staff. RECENT FINDINGS: We performed a narrative review of the literature regarding COVID-19, updated to May 8th, 2020, at PubMed and COVID resource platforms of the main scientific editorials. COVID-19, characterized by fever, myalgias, dyspnea, and dry cough, varies widely from asymptomatic infection to death. Arrhythmias and thrombotic events are prevalent. Lymphopenia and inflammatory reactant elevation on laboratory, as well as bilateral and peripheral ground-glass opacities or consolidations on X-Ray, are usually found in its assessment. Little is known about SARS-CoV-2 immunology. To date, no therapy has demonstrated efficacy in COVID-19. Of-level or compassionate-use therapies are prescribed in the context of clinical trials. We should become familiar with specific adverse events and pharmacological interactions. The COVID-19 pandemic has paralyzed the urological activity, and its long-term consequences are unpredictable. Despite not being used to deal with respiratory diseases, the urologists become easily qualified to manage COVID-19 by following protocols and being integrated into multidisciplinary teams, helping to overcome the pandemic.

Expression of miR-100 and miR-138 as prognostic biomarkers in non-muscle-invasive bladder cancer.

microRNA alterations are involved in bladder cancer tumorigenesis. The aim of the current study was to evaluate the potential role of miR-100 and miR-138 as prognostic biomarkers in Ta/T1 non-muscle-invasive bladder cancer (NMIBC). We assessed a quantitative RT-PCR analysis of miR-100 and miR-138 in 50 bladder tumor samples (stage Ta/T1) and four healthy adjacent tissues. Western blot analysis was used to measure protein expression of FGFR3 and cyclin D3 in order to know whether these targets can be regulated by miR-100 and miR-138, respectively. The statistical analysis included non-parametric tests (Mann-Whitney U and Kruskal-Wallis) and univariate survival analysis by Kaplan-Meier method and the log-rank test. Low expression of miR-138 characterized recurrent tumors (p = 0.043), and higher expression levels were associated with longer recurrence-free survival (p = 0.012). However, low miR-100 expression correlated with longer progression-free survival (marginal significance; p = 0.053) and cancer-specific overall survival (p = 0.006). Additionally, higher levels of miR-100 were associated with negative FGFR3 protein expression (p = 0.032) and higher levels of miR-138 were associated with positive cyclin D3 protein expression (p = 0.037). Our results support miR-138 and miR-100 as prognostic biomarkers in patients with NMIBC.

[BCG and bladder cancer: Past, present and future.] / BCG y cáncer de vejiga: pasado, presente y futuro.

BCG has been used in the treatment of NMIBC for more than 40 years. Nevertheless, its exact working mechanisms have not been completely discovered. Clinical and basic research done over all these years has generated much information but it could be summarized in a few simple statements. It has been demonstrated the best route of administration is intravesical, BCG is superior than intracavitary chemotherapy to prevent recurrence but its adverse events are worse. Recently, it has been demonstrated that BCG could delay or prevent progression to infiltrative cancer. Nevertheless, to achieve this, maintenance therapy is necessary. Therefore, the recommendation is to treat middle and high risk cases with BCG. No significant differences in efficacy have been found between the various strains but differences in recurrence have been found between standard and reduced doses.Furthermore, the presence or absence of side effects does not seem to be a prognostic factor for the efficacy of BCG and, maintenance therapy is not associated with a significant increase in toxicity. In the future, the optimal schedule and doses must be defined, and it probably will be different for each individual. BCG shortage has led to try alternative therapies through chemo hyperthermia or electrical gradient application the efficacy of which should be evaluated. New strains and immunological treatments are also under research.

Inmunoterapia con BCG BCG y cáncer de vejiga: pasado, presente y futuro / BCG and bladder cancer: Past, present and future

Hace más de 40 años que se utiliza la BCG en el tratamiento del CVNMI. Sin embargo, los mecanismos de trabajo exactos de su funcionamiento aún no han sido totalmente descubiertos. La investigación clínica y básica realizada durante todos estos años ha generado mucha información pero que podría resumirse en unas pocas afirmaciones sencillas. Se ha demostrado que la mejor vía de administración de BCG es la vía intravesical, que la BCG es superior a la quimioterapia intracavitaria para prevenir la recurrencia pero que sus efectos adversos son peores. Recientemente se ha demostrado que BCG podría prevenir o retrasar la progresión a cáncer infiltrante. Sin embargo, para lograr esto, la terapia de mantenimiento es necesaria. Por ello, se recomienda que los tumores de riesgo intermedio y alto se traten con BCG. No se han encontrado diferencias significativas en la eficacia entre las diferentes cepas, pero si diferencia de recurrencia en la utilización de una dosis estándar frente a una reducida. Además, la presencia o ausencia de efectos secundarios no parece ser un factor pronóstico para la eficacia de BCG y la terapia de mantenimiento no se asocia con un aumento significativo de la toxicidad. En el futuro, se debe definir el esquema y la dosis óptimos, y esto probablemente sea diferente para cada individuo. La falta de suministros de BCG ha hecho que se prueben terapias alternativas mediante quimiohipertermia o aplicación de un gradiente eléctrico cuya efectividad debe ser evaluada. Nuevas cepas y tratamientos inmunológicos están también siendo investigados

BCG has been used in the treatment of NMIBC for more than 40 years. Nevertheless, its exact working mechanisms have not been completely discovered. Clinical and basic research done over all these years has generated much information but it could be summarized in a few simple statements. It has been demonstrated the best route of administration is intravesical, BCG is superior than intracavitary chemotherapy to prevent recurrence but its adverse events are worse. Recently, it has been demonstrated that BCG could delay or prevent progression to infiltrative cancer. Nevertheless, to achieve this, maintenance therapy is necessary. Therefore, the recommendation is to treat middle and high risk cases with BCG. No significant differences in efficacy have been found between the various strains but differences in recurrence have been found between standard and reduced doses. Furthermore, the presence or absence of side effects does not seem to be a prognostic factor for the efficacy of BCG and, maintenance therapy is not associated with a significant increase in toxicity. In the future, the optimal schedule and doses must be defined, and it probably will be different for each individual. BCG shortage has led to try alternative therapies through chemo hyperthermia or electrical gradient application the efficacy of which should be evaluated. New strains and immunological treatments are also under research

X-ray Free Electron Laser Determination of Crystal Structures of Dark and Light States of a Reversibly Photoswitching Fluorescent Protein at Room Temperature.

The photochromic fluorescent protein Skylan-NS (Nonlinear Structured illumination variant mEos3.1H62L) is a reversibly photoswitchable fluorescent protein which has an unilluminated/ground state with an anionic and cis chromophore conformation and high fluorescence quantum yield. Photo-conversion with illumination at 515 nm generates a meta-stable intermediate with neutral trans-chromophore structure that has a 4 h lifetime. We present X-ray crystal structures of the cis (on) state at 1.9 Angstrom resolution and the trans (off) state at a limiting resolution of 1.55 Angstrom from serial femtosecond crystallography experiments conducted at SPring-8 Angstrom Compact Free Electron Laser (SACLA) at 7.0 keV and 10.5 keV, and at Linac Coherent Light Source (LCLS) at 9.5 keV. We present a comparison of the data reduction and structure determination statistics for the two facilities which differ in flux, beam characteristics and detector technologies. Furthermore, a comparison of droplet on demand, grease injection and Gas Dynamic Virtual Nozzle (GDVN) injection shows no significant differences in limiting resolution. The photoconversion of the on- to the off-state includes both internal and surface exposed protein structural changes, occurring in regions that lack crystal contacts in the orthorhombic crystal form.

Stimulated X-ray Raman scattering - a critical assessment of the building block of nonlinear X-ray spectroscopy.

With the invention of femtosecond X-ray free-electron lasers (XFELs), studies of light-induced chemical reaction dynamics and structural dynamics reach a new era, allowing for time-resolved X-ray diffraction and spectroscopy. To ultimately probe coherent electron and nuclear dynamics on their natural time and length scales, coherent nonlinear X-ray spectroscopy schemes have been proposed. In this contribution, we want to critically assess the experimental realisation of nonlinear X-ray spectroscopy at current-day XFEL sources, by presenting first experimental attempts to demonstrate stimulated resonant X-ray Raman scattering in molecular gas targets.

Ultrafast isomerization initiated by X-ray core ionization.

Rapid proton migration is a key process in hydrocarbon photochemistry. Charge migration and subsequent proton motion can mitigate radiation damage when heavier atoms absorb X-rays. If rapid enough, this can improve the fidelity of diffract-before-destroy measurements of biomolecular structure at X-ray-free electron lasers. Here we study X-ray-initiated isomerization of acetylene, a model for proton dynamics in hydrocarbons. Our time-resolved measurements capture the transient motion of protons following X-ray ionization of carbon K-shell electrons. We Coulomb-explode the molecule with a second precisely delayed X-ray pulse and then record all the fragment momenta. These snapshots at different delays are combined into a 'molecular movie' of the evolving molecule, which shows substantial proton redistribution within the first 12 fs. We conclude that significant proton motion occurs on a timescale comparable to the Auger relaxation that refills the K-shell vacancy.

Experimental simulation of simultaneous vision.

PURPOSE: To present and validate a prototype of an optical instrument that allows experimental simulation of pure bifocal vision. To evaluate the influence of different power additions on image contrast and visual acuity. METHODS: The instrument provides the eye with two superimposed images, aligned and with the same magnification, but with different defocus states. Subjects looking through the instrument are able to experience pure simultaneous vision, with adjustable refractive correction and addition power. The instrument is used to investigate the impact of the amount of addition of an ideal bifocal simultaneous vision correction, both on image contrast and on visual performance. the instrument is validated through computer simulations of the letter contrast and by equivalent optical experiments with an artificial eye (camera). Visual acuity (VA) was measured in four subjects (AGE: 34.3 ± 3.4 years; spherical error: -2.1 ± 2.7 diopters [D]) for low and high contrast letters and different amounts of addition. RESULTS: The largest degradation in contrast and visual acuity (∼25%) occurred for additions around ±2 D, while additions of ±4 D produced lower degradation (14%). Low additions (1-2 D) result in lower VA than high additions (3-4 D). CONCLUSIONS: A simultaneous vision instrument is an excellent tool to simulate bifocal vision and to gain understanding of multifocal solutions for presbyopia. Simultaneous vision induces a pattern of visual performance degradation, which is well predicted by the degradation found in image quality. Neural effects, claimed to be crucial in the patients' tolerance of simultaneous vision, can be therefore compared with pure optical effects.