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The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation^{1,2}. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole^3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of 8.4_{-1.1}^{+0.5} Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow., 50 pages, 18 figures, 3 tables, author's version of the paper published in Nature

Limited data are available on patients with carcinoma in situ (CIS) of the bladder managed according to current clinical practice guidelines.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.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.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.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.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.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.

To monitor the early emergence of genetic mutations related to reduced susceptibility to monoclonal anti-body (mAb)-based treatment in immunocompromised patients with long-term viral excretion using whole-genome sequencing at a tertiary university hospital in Barcelona, Spain.Serial severe acute respiratory syndrome coronavirus 2-positive samples (mid-December 2021-mid-March 2022) from eight immunosuppressed, fully vaccinated patients (for solid-organ transplantation or haematologic malignancies) with long-term viral excretion despite undergoing mAb therapy (sotrovimab) for coronavirus disease 2019 were selected. Whole-genome sequencing was performed following the ARTIC, version 4.1, protocol on the MiSeq platform. Mutations in the coding sequence of the spike protein with a frequency of ≥5% were studied.A total of 37 samples from the studied cases were analysed. All the cases, except one, were confirmed to have the Omicron variant BA.1; one had Delta (AY.100). Thirty-four different mutations were detected within the receptor-binding domain of the spike protein in 62.5% of patients, eight of which were not lineage related and located in the sotrovimab target epitope (P337L, E340D, E340R, E340K, E340V, E340Q, R346T and K356T). Except for P337L, all changes showed a significant increase in frequency or fixation after the administration of sotrovimab. Some of them have been associated with either reduced susceptibility to mAb therapy, such as those at position 340, or the acquisition of a new glycosylation site (346 and 356 positions).This study highlights the importance of monitoring for early in vivo selection of mutations associated with reduced susceptibility to mAb therapy, especially in immunocompromised patients receiving anti-viral drugs, whose immune response is not able to control viral replication, resulting in long-term viral shedding, and those receiving selective evolution pressure. Virologic surveillance of genetically resistant viruses to available anti-viral therapies is considered a priority for both patients and the community.

Hypothesis: Carbon dioxide hydrates are ice-like nonstoichiometric inclusion solid compounds with importance to global climate change, and gas transportation and storage. The thermodynamic and kinetic mechanisms that control carbon dioxide nucleation critically depend on hydrate-water interfacial free energy. Only two independent indirect experiments are available in the literature. Interfacial energies show large uncertainties due to the conditions at which experiments are performed. Under these circumstances, we hypothesize that accurate molecular models for water and carbon dioxide combined with computer simulation tools can offer an alternative but complementary way to estimate interfacial energies at coexistence conditions from a molecular perspective. Calculations: We have evaluated the interfacial free energy of carbon dioxide hydrates at coexistence conditions (three-phase equilibrium or dissociation line) implementing advanced computational methodologies, including the novel Mold Integration methodology. Our calculations are based on the definition of the interfacial free energy, standard statistical thermodynamic techniques, and the use of the most reliable and used molecular models for water (TIP4P/Ice) and carbon dioxide (TraPPE) available in the literature. Findings: We find that simulations provide an interfacial energy value, at coexistence conditions, consistent with the experiments from its thermodynamic definition. Our calculations are reliable since are based on the use of two molecular models that accurately predict: (1) The ice-water interfacial free energy; and (2) the dissociation line of carbon dioxide hydrates. Computer simulation predictions provide alternative but reliable estimates of the carbon dioxide interfacial energy. Our pioneering work demonstrates that is possible to predict interfacial energies of hydrates from a truly computational molecular perspective and opens a new door to the determination of free energies of hydrates., We thank Pedro J. Pérez for the critical reading of the manuscript. We also acknowledge Centro de Supercomputación de Galicia (CESGA, Santiago de Compostela, Spain) and MCIA (Mésocentre de Calcul Intensif Aquitain) of the Universités de Bordeaux and Pau et Pays de l’Adour (France) for providing access to computing facilities. We thank financial support from the Ministerio de Economía, Industria y Competitividad (FIS2017- 89361-C3-1-P), Junta de Andalucía (P20-00363), and Universidad de Huelva (P.O. FEDER UHU-1255522), all three cofinanced by EU FEDER funds. J.A. acknowledges Contrato Predoctoral de Investigación from XIX Plan Propio de Investigación de la Universidad de Huelva and a FPU Grant (Ref. FPU15/03754) from Ministerio de Educación, Cultura y Deporte. J. A., J. M. M., and F. J. B. thankfully acknowledge the computer resources at Magerit and the technical support provided by the Spanish Supercomputing Network (RES) (Project QCM- 2018–2- 0042). Funding for open access charge: Universidad de Huelva / CBUA

Purpose: The correct risk categorization and staging of upper tract urothelial cancer (UTUC) is key for disease management. Computerized tomography urography and urinary cytology have limited accuracy for risk stratification of UTUC. Ureteroscopy may increase the risk of bladder cancer recurrence. Recently, Bladder EpiCheckTM (EpiCheck) showed a high accuracy in the detection of bladder cancer. The aim of the study is to investigate the diagnostic accuracy of EpiCheck in the clinical management of UTUC and to compare it with urinary cytology. Materials and Methods: In this single-arm, blinded, prospective, single-center study (February 2019eDecember 2020), all patients who were candidates for ureteroscopy for suspicion of UTUC were included. Bladder and upper urinary tract (UUT) samples were collected before ureteroscopy to test for cytology and Epicheck. EpiCheck accuracy was calculated in bladder and UUT samples and compared to cytology. Results: EpiCheck resulted diagnostic in 83/86 (97%) and 73/75 (97%) of UUT and bladder samples. Histology was positive in 47/83 (57%) and 42/73 (58%) cases, respectively. In UUT samples, EpiCheck yielded a sensitivity/specificity/negative predictive value (NPV)/positive predictive value of 83%/79%/77%/84% vs 59%/88%/61%/87% of cytology. The sensitivity/NPV for high-grade tumors was 96%/97% for EpiCheck vs 71%/86% for cytology. EpiCheck indicated ureteroscopy in 45/80 (56%) patients, missing 17%/4% of all/high-grade UTUC with 9% of unnecessary ureteroscopy. In bladder samples, the sensitivity/NPV for high-grade tumors was 71%/88% for EpiCheck and 59%/87% for cytology. Conclusions: Epicheck may be an important tool to decrease the number of unnecessary ureteroscopy. The clinical implementation of EpiCheck in UTUC warrants further investigation in multicentric prospective randomized trials.

Recently, different therapeutic lines have been tried in the initial stage of the disease of COVID-19, including remdesivir and molnupiravir. There is scarce evidence on the efficacy and safety of molnupiravir in kidney transplant recipients (KTRs).ingle-center prospective cohort study' all adult KTRs diagnosed with COVID-19 and treated with molnupiravir or remdesivir from January to April 2022 were included.Nine KTRs with SARS-CoV-2 (Omicron variant) infection and mild symptoms received molnupiravir in an outpatient basis and were compared with a cohort of similar patients treated with remdesivir (n = 7). Three patients in the molnupiravir cohort were in the early posttransplant period and received a basiliximab (n = 2) or antithymocite globulin-based induction (n = 1). One of the patients had been treated with methylprednisolone bolus and antithymocite globulin for an episode of acute rejection in the previous months. They were all vaccinated with mRNA vaccines' and all but 1 had serological response. Only one of the patients experienced clinical worsening despite molnupiravir treatment and developed pneumonia requiring hospital admission. None of the patients suffered adverse effects attributed to molnupiravir' and no adjustment of tacrolimus dose was needed. None of the patients treated with remdesivir progressed in COVID-19 severity.Our study suggests that KTRs with SARS-CoV-2 infection under treatment with molnupiravir have a good clinical evolution with a probable lower risk for hospitalization and no adverse effects. At the renal level, molnupiravir was well tolerated, with no evidence of nephrotoxicity secondary to the drug nor interactions with the immunosuppressive therapy.

Contains fulltext : 294430.pdf (Publisher’s version ) (Open Access) BACKGROUND: Ta grade 3 (G3) non-muscle-invasive bladder cancer (NMIBC) is a relatively rare diagnosis with an ambiguous character owing to the presence of an aggressive G3 component together with the lower malignant potential of the Ta component. The European Association of Urology (EAU) NMIBC guidelines recently changed the risk stratification for Ta G3 from high risk to intermediate, high, or very high risk. However, prognostic studies on Ta G3 carcinomas are limited and inconclusive. OBJECTIVE: To evaluate the prognostic value of categorizing Ta G3 compared to Ta G2 and T1 G3 carcinomas. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data for 5170 primary Ta-T1 bladder tumors from 17 hospitals were analyzed. Transurethral resection of the tumor was performed between 1990 and 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to recurrence and time to progression were analyzed using cumulative incidence functions, log-rank tests, and multivariable Cox-regression models with interaction terms stratified by institution. RESULTS AND LIMITATIONS: Ta G3 represented 7.5% (387/5170) of Ta-T1 carcinomas of which 42% were classified as intermediate risk. Time to recurrence did not differ between Ta G3 and Ta G2 (p = 0.9) or T1 G3 (p = 0.4). Progression at 5 yr occurred for 3.6% (95% confidence interval [CI] 2.7-4.8%) of Ta G2, 13% (95% CI 9.3-17%) of Ta G3, and 20% (95% CI 17-23%) of T1 G3 carcinomas. Time to progression for Ta G3 was shorter than for Ta G2 (p

In this paper, the solubility of carbon dioxide (CO2) in water along the isobar of 400 bar is determined by computer simulations using the well-known TIP4P/Ice force field for water and the TraPPE model for CO2. In particular, the solubility of CO2 in water when in contact with the CO2 liquid phase and the solubility of CO2 in water when in contact with the hydrate have been determined. The solubility of CO2 in a liquid–liquid system decreases as the temperature increases. The solubility of CO2 in a hydrate–liquid system increases with temperature. The two curves intersect at a certain temperature that determines the dissociation temperature of the hydrate at 400 bar (T3). We compare the predictions with T3 obtained using the direct coexistence technique in a previous work. The results of both methods agree, and we suggest 290(2) K as the value of T3 for this system using the same cutoff distance for dispersive interactions. We also propose a novel and alternative route to evaluate the change in chemical potential for the formation of hydrates along the isobar. The new approach is based on the use of the solubility curve of CO2 when the aqueous solution is in contact with the hydrate phase. It considers rigorously the non-ideality of the aqueous solution of CO2, providing reliable values for the driving force for nucleation of hydrates in good agreement with other thermodynamic routes used. It is shown that the driving force for hydrate nucleation at 400 bar is larger for the methane hydrate than for the carbon dioxide hydrate when compared at the same supercooling. We have also analyzed and discussed the effect of the cutoff distance of dispersive interactions and the occupancy of CO2 on the driving force for nucleation of the hydrate.

Book Review

Bacterial prostatitis, acute or chronic, is one of the most prevalent urogenital infections in men. Its diagnosis requires the application of a careful methodology. Gram-negative bacilli are the most frequent causative agents, and in recent years, an increase in the frequency of multiresistant bacteria has been detected. The choice of the optimal antimicrobial treatment requires the selection of drugs with proven in vitro activity associated with good penetration into the prostatic tissue, especially in chronic forms of infection.The aim of this article is to summarize the current evidence regarding the pathogenesis, etiology, empirical and definitive antimicrobial therapy, and new pharmacotherapeutic interventions to improve the prognosis of bacterial acute or chronic prostatitis.Bacterial prostatitis requires the application of an accurate diagnostic protocol to identify the causative agent and establish the optimal antimicrobial treatment. The structural and biochemical characteristics of prostatic tissue result in poor penetration of antimicrobials; therefore, in the choice of treatment, it is essential to select agents with proven antimicrobial activity and pharmacokinetic characteristics that ensure good and sustained concentrations in this area. Patients with chronic forms of infection require prolonged treatment, and relapses of the infectious process are frequent.

We deal with analytic three-dimensional symmetric systems whose origin is a Hopf-zero singularity. Once it is not completely analytically integrable, we provide criteria on the existence of at least one functionally independent analytic first integral. In the generic case, we characterize the analytic partially integrable systems by using orbitally equivalent normal forms. We also solve the problem through the existence of a class of formal inverse Jacobi multiplier of the system., This work has been partially supported by Ministerio de Economía y Competitividad, Plan Nacional I+D+I co-financed with FEDER funds, in the frame of the project PGC2018-096265-B-I00, and by Consejería de Educación y Ciencia de la Junta de Andalucía (FQM-276, P12-FQM-1658 and UHU126150).

Context Grading is the mainstay for treatment decisions for patients with non–muscle-invasive bladder cancer (NMIBC). Objective To determine the requirements for an optimal grading system for NMIBC via expert opinion. Evidence acquisition A multidisciplinary working group established by the International Society of Urological Pathology reviewed available clinical, histopathological, and molecular evidence for an optimal grading system for bladder cancer. Evidence synthesis Bladder cancer grading is a continuum and five different grading systems based on historical grounds could be envisaged. Splitting of the World Health Organization (WHO) 2004 low-grade class for NMIBC lacks diagnostic reproducibility and molecular-genetic support, while showing little difference in progression rate. Subdividing the clinically heterogeneous WHO 2004 high-grade class for NMIBC into intermediate and high risk categories using the WHO 1973 grading is supported by both clinical and molecular-genetic findings. Grading criteria for the WHO 1973 scheme were detailed on the basis of literature findings and expert opinion. Conclusions Splitting of the WHO 2004 high-grade category into WHO 1973 grade 2 and 3 subsets is recommended. Provision of more detailed histological criteria for the WHO 1973 grading might facilitate the general acceptance of a hybrid four-tiered grading system or—as a preferred option—a more reproducible three-tiered system distinguishing low-, intermediate (high)-, and high-grade NMIBC. Patient summary Improvement of the current systems for grading bladder cancer may result in better informed treatment decisions for patients with bladder cancer.

We report a case of a liver transplant performed in a patient with a history of SARS-CoV-2 infection who presented with a positive polymerase chain reaction test for SARS-CoV-2 on the day of transplant. The transplant procedure was performed without complications, and the patient did not develop symptoms after the initiation of immunosuppression. We also reviewed the literature for similar cases. The emergence of SARS-CoV-2 has forced the medical community to continuously adapt protocols to the current situation. Prudence is needed in immuno- compromised patients, and clinical experience is being built day by day. Thus, a positive polymerase chain reaction test for SARS-CoV-2 in a recipient should not always prevent a liver transplant.

Supplementary figure S7. Progression-free survival curve in patients with all EAU low risk tumors and EAU high risk patients with a good class tumor (good class: hypomethylated GATA2 and mutated FGFR3). Progressive disease is defined as progression to stage T2 or higher stage disease.

Supplementary figure S5. Progression-free survival curves in all patients for (A) EAU risk category, (B) FGFR3, (C) GATA2 and (D) TBX3. Progressive disease is defined as progression to stage T2 or higher stage disease. P-values (log-rank test) are indicated in each figure.

Supplementary figure S8. Progression-free survival curve in patients with EAU high risk tumors of a combination of FGFR3 and GATA2 status. Blue: good status (hypomethylated GATA2 and mutated FGFR3), green; moderate status (either hypermethylated GATA2 and mutated FGFR3 or hypomethylated GATA2 and wild type FGFR3) or red: poor status (hypermethylated GATA2 and wild type FGFR3) compared to a progression free survival curse in all EAU high risk patients. Progressive disease is defined as progression to stage T2 or higher stage disease.

Supplementary Table S2. Cut-offs for dichotomization of the methylation marker results were chosen based on the desired sensitivity-specificity trade-off for progression to MIBC as visualized by the receiver-operating characteristic curve (ROC curve); the point on the curve closest to the upper left corner.

Supplementary Table S3. Distribution of the EAU category and administration of intravesical instillations per country. Between brackets the percentage (%) within each country is given.

Supplementary Data from Identification of PMF1 Methylation in Association with Bladder Cancer Progression

Purpose: Polyamines are important regulators of cell growth and death. The polyamine modulated factor-1 (PMF-1) is involved in polyamine homeostasis. After identifying an enriched CpG island encompassing the PMF1 promoter, we aimed at evaluating the clinical relevance of PMF1 methylation in bladder cancer.Experimental Design: The epigenetic silencing of PMF1 by hypermethylation was tested in bladder cancer cells (n = 11) after azacytidine treatment. PMF1 methylation status was evaluated in 507 bladder tumors and 118 urinary specimens of bladder cancer patients and controls. PMF1 protein expression was analyzed by immunohistochemistry on tissue arrays containing bladder tumors for which PMF1 methylation was assessed (n = 218).Results: PMF1 hypermethylation was associated with gene expression loss, being restored in vitro by a demethylating agent. An initial set of 101 primary frozen bladder tumors served to identify PMF1 hypermethylation in 88.1% of the cases. An independent set of 406 paraffin-embedded tumors also revealed a high PMF1 methylation rate (77.6%). PMF1 methylation was significantly associated with increasing stage (P = 0.025). Immunohistochemical analyses revealed that PMF1 methylation was associated with cytoplasmic PMF1 expression loss (P = 0.032). PMF1 protein expression patterns were significantly associated with stage (P < 0.001), grade (P < 0.001), and poor overall survival using univariate (P < 0.001) and multivariate (P = 0.011) analyses. Moreover, PMF1 methylation in urinary specimens distinguished bladder cancer patients from controls (area under the curve = 0.800).Conclusion: PMF1 was identified to be epigenetically modified in bladder cancer. The association of PMF1 methylation with tumor progression and its diagnostic ability using urinary specimens support including PMF1 assessment for the clinical management of bladder cancer patients.

Purpose: The European Association of Urology (EAU) guidelines for non–muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC.Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups.Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%).Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. Clin Cancer Res; 24(7); 1586–93. ©2018 AACR.

Supplementary figure S6. Progression-free survival curves in EAU high risk patients for (A) Intravesical instillations, (B) Grade, (C) FGFR3 and (D) GATA2. Progressive disease is defined as progression to stage T2 or higher stage disease. P-values (log-rank test) are indicated in each figure.

Supplementary Table S4. Number of patients progressing to MIBC and person-time per risk group. Suggested risk groups are based on a combination of GATA2 methylation and FGFR3 mutation status for EAU high risk tumors.

Supplementary Table S1. Sequences of the primers and probes used in the methylation analyses for the different CpGs in the GATA2, TBX2, TBX3 and ZIC4 genes. All sequences are noted from 5'' to 3''.

Integrated Water Resources Management (IWRM) of the city of Seville, Spain, located in the southern Guadalquivir River Basin is assessed applying the city blueprint approach (CBA). The trends and pressures framework identifies five major indicators reflecting ‘concern’ for Seville’s urban water management: heat island effect, urban drainage flooding, river peak discharges, unemployment rate and economic pressure. The results indicate increased daytime and night-time temperatures and increased urban flooding due to sealed soil, and river rise from regional precipitation under climate change. The financial pressures are driven by the high unemployment rate and the low per capita income compared to other cities assessed. The city blueprint framework identifies three categories reflecting ‘poor’ performance for the urban water management of Seville: water infrastructure, solid waste and climate adaptation. An aging sewer network, low operational cost recovery and combined-sewer overflow systems dominate. Solid waste management is characterized by high waste generation, low recycling rate and minimal energy recovery. The percentage of green space is low, but growing. The Governance Capacity Framework identifies five conditions reflecting ‘limited’ governance of water scarcity: awareness, useful knowledge, continuous learning, agents of change and financial viability. The assessment of water governance reflects a low citizens’ sense of urgency. Integrating citizens and stakeholders in a more participative governance will result in increased awareness of economic efforts required to face water scarcity, renewal of water infrastructure and climate adaptation. The blue city index (BCI) of Seville is 5.8/10, placing it highly among other Mediterranean cities, and in the top 20% of 125 cities assessed worldwide. Application of the CBA to the urban water resources of cities allows clear definition of water and resource management challenges and is the first step to becoming a ‘water smart’ city.

Powerful relativistic jets in active galactic nuclei (AGN) are believed to be originated from the accretion of material onto the supermassive black hole (SMBH)1. The nearby radio galaxy M87 is one of the best examples of this phenomenon, and the recent detection of a black-hole shadow with the Event Horizon Telescope provided compelling evidence for this paradigm2. However, whether the central SMBH in M87 has a spin or not, a fundamental parameter of a BH along with the mass, remains unconstrained by observations since the appearance of the photon ring is rather insensitive to the spin2-4. A clue to this challenge is to trace the long-term evolution of the innermost jet base where the central BH and accretion disk tightly regulate its flow dynamics. Here we report an extensive analysis of the morphological evolution of the M87 jet nozzle based on 170 high-resolution radio images spanning more than two decades. The ensemble of the data reveals a periodic (a period of 11 years) variation of the jet direction with a peak-to-peak amplitude of ~10 deg on the sky. A successful fit of a precession model to the data as well as general-relativistic magnetohydrodynamic simulations strongly supports the presence of a spinning BH in M87, inducing a Lense-Thirring precession of a misaligned accretion disk by the frame-dragging effect5. Our results suggest that jet precession with a spinning BH can commonly exist in other more distant AGN but had evaded detection due to the small magnitude and long period of position angle variation.

To analyze the impact of the foot health and health behavior and the characteristics of outdoor footwear among minority ethnic groups.A cross-sectional study design using the Foot Health Status Questionnaire: foot pain, foot function, shoe, general foot health, general health, physical activity, social capacity, and vigor. Outcomes included the self-reported type of outdoor footwear and clinical characteristics by sex were collected in 2019-2020.A total of 78 Roma participants self-identified as members of this ethnic minority and 72 participants non-Roma were assessed (n = 150).The lower score values was recorded in the footwear and general foot health domains in Roma population. General population obtained higher scores in general health domains. The most common outdoor footwear types were running shoes and walking shoes in non-Roma population, versus flip flops and slippers in Roma population. Clinical characteristics did not show any statistically significant differences (p .05).Roma people wear flip flops and slippers and non-Roma people running shoes and walking shoes. These findings reveal cultural differences that make it easier for the Roma population to experience a greater burden of foot health problems. General foot health and foot pain dimensions show statistically significant differences among ethnicity.

Part of this study was presented at the 27th European Congress of Clinical Microbiology and Infectious Diseases, Vienna, Austria 2017., [Introduction] Immune response stimulation may be an adjuvant to antimicrobial treatment. Here, we evaluated the impact of immune response modification by lysophosphatidylcholine (LPC), combined with imipenem or ceftazidime, in murine models of peritoneal sepsis (PS) and pneumonia induced by Pseudomonas aeruginosa., [Methods] The imipenem and ceftazidime-susceptible strain (Pa39) and imipenem and ceftazidime-resistant strain (Pa238) were used. Ceftazidime pharmacokinetic and pharmacodynamic parameters were determined. The therapeutic efficacy and TNF-α and IL-10 levels were determined in murine models of PS and pneumonia induced by Pa39 and Pa238 and treated with LPC, imipenem or ceftazidime, alone or in combination., [Results] In the PS model, LPC+ceftazidime reduced spleen and lung Pa238 concentrations (−3.45 and −3.56 log10 CFU/g; P < 0.05) to a greater extent than ceftazidime monotherapy, while LPC + imipenem maintained the imipenem efficacy (−1.66 and −1.45 log10 CFU/g; P > 0.05). In the pneumonia model, LPC + ceftazidime or LPC + imipenem reduced the lung Pa238 concentrations (−2.37 log10 CFU/g, P = 0.1, or −1.35 log10 CFU/g, P = 0.75). For Pa39, no statistically significant difference was observed in the PS and pneumonia models between combined therapy and monotherapy. Moreover, LPC + imipenem and LPC+ceftazidime significantly decreased and increased the TNF-α and IL-10 levels, respectively, in comparison with the untreated controls and monotherapies., [Conclusions] These results demonstrate the impact of immune response modification by LPC plus antibiotics on the prognosis of infections induced by ceftazidime-resistant P. aeruginosa., [Introducción] La estimulación de la respuesta inmunitaria podría ser adyuvante al tratamiento antimicrobiano. En este estudio, hemos evaluado el impacto de la modificación de la respuesta inmunitaria por la lisofosfatidilcolina (LPC), combinada con imipenem ó ceftazidima, en modelos murinos de sepsis peritoneal (SP) y de neumonía por Pseudomonas aeruginosa (P. aeruginosa)., [Métodos] La cepa sensible a imipenem y ceftazidima (Pa39) y la cepa resistente a ambos antibióticos (Pa238) fueron usadas. Los parámetros farmacocinéticos/farmacodinámicos de ceftazidima fueron determinados. La eficacia terapéutica y los niveles de TNF-α and IL-10 fueron determinados en los modelos murinos de SP y de neumonía por Pa39 y Pa238 y tratados con LPC, imipenem o ceftazidima, en monoterapia ó en combinación., [Resultados] En el modelo de SP, LPC + ceftazidima redujo la concentración de Pa238 en el bazo y el pulmón (–3,45 y –3,56 log10 UFC/g; p < 0,05) en comparación con ceftazidima, mientras LPC + impenem mantuvo la eficacia de imipenem (–1,66 y –1,45 log10 UFC/g; p > 0,05). En el modelo de neumonía, LPC + ceftazidima o LPC + imipenem redujo la concentración de Pa238 en pulmón (–2,37 log10 UFC/g, p = 0,1 o –1,35 log10 UFC/g, p = 0,75). Para Pa39, no se observó diferencia estadística significativa entre la terapia combinada y la monoterapia en los modelos de SP y de neumonía. Además, LPC + imipenem y LPC + ceftazidime redujeron y aumentaron los niveles de TNF-α y IL-10, respectivamente, en comparación con los controles no tratados y las monoterapias., [Conclusiones] Estos resultados demuestran el impacto de la modificación de la respuesta inmunitaria por LPC en combinación con antibióticos en el pronóstico de las infecciones por P. aeruginosa ceftazidima-resistente., This study was supported by the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (grant PI13/01744, PI16/01306), and by Consejería de Innovación, Ciencia y Empresa (P11-CTS-6317). Younes Smani is supported by the Subprograma Miguel Servet Tipo I from the Ministerio de Economía y Competitividad of Spain (CP15/01358). The MEDINA authors disclosed the receipt of financial support from Fundación MEDINA, a public-private partnership of Merck Sharp & Dohme de España S.A./Universidad de Granada/Junta de Andalucía.

In this work, the liquid-liquid phase equilibria and interfacial properties of methyl ester + water binary mixtures are determined at atmospheric pressure and from 278 to 358 K combining the direct coexistence technique and molecular dynamics simulations. Methyl esters are modelled using new parametrizations based on the united atom TraPPE model force field proposed recently by us [E. Feria, J. Algaba, J. M. Míguez, A. Mejía, P. Gómez-Álvarez and F. J. Blas

In this paper, we introduce a novel model of multi-issue bankruptcy problem inspired from a real problem of abatement of emissions of different pollutants in which pollutants can have more than one effect on atmosphere. In our model, therefore, several perfectly divisible goods (estates) have to be allocated among certain set of agents (claimants) that have exactly one claim which is used in all estates simultaneously. In other words, unlike of the multi-issue bankruptcy problems already existent in the literature, this model study situations with multi- dimensional states, one for each issue and where each agent claims the same to the different issues in which participates. In this context, we present an allocation rule that generalizes the well-known constrained equal awards rule from a procedure derived from analyzing this rule for classical bankruptcy problems as the solution to a sucession of linear programming problems. Next, we carry out an study of its main properties, and we characterize it using the well-known property of consistency.

Interpretation of resolved polarized images of black holes by the Event Horizon Telescope (EHT) requires predictions of the polarized emission observable by an Earth-based instrument for a particular model of the black hole accretion system. Such predictions are generated by general relativistic radiative transfer (GRRT) codes, which integrate the equations of polarized radiative transfer in curved spacetime. A selection of ray-tracing GRRT codes used within the EHT collaboration is evaluated for accuracy and consistency in producing a selection of test images, demonstrating that the various methods and implementations of radiative transfer calculations are highly consistent. When imaging an analytic accretion model, we find that all codes produce images similar within a pixel-wise normalized mean squared error (NMSE) of 0.012 in the worst case. When imaging a snapshot from a cell-based magnetohydrodynamic simulation, we find all test images to be similar within NMSEs of 0.02, 0.04, 0.04, and 0.12 in Stokes I, Q, U , and V respectively. We additionally find the values of several image metrics relevant to published EHT results to be in agreement to much better precision than measurement uncertainties., Comment: Accepted for publication in ApJ

We show how to efficiently decompose a parameterized multi-qubit Pauli (PMQP) gate into native parameterized two-qubit Pauli (P2QP) gates minimizing both the circuit depth and the number of P2QP gates. Given a realistic quantum computational model, we argue that the technique is optimal in terms of the number of hardware native gates and the overall depth of the decomposition. Starting from PMQP gate decompositions for the path and star hardware graph, we generalize the procedure to any generic hardware graph and provide exact expressions for the depth and number of P2QP gates of the decomposition. Furthermore, we show how to efficiently combine the decomposition of multiple PMQP gates to further reduce the depth as well as the number of P2QP gates for a combinatorial optimization problem using the Lechner-Hauke-Zoller (LHZ) mapping., Comment: 17 pages, 4 figures

Digital-Analog Quantum Computation (DAQC) has recently been proposed as an alternative to the standard paradigm of digital quantum computation. DAQC creates entanglement through a continuous or analog evolution of the whole device, rather than by applying two-qubit gates. This manuscript describes an in-depth analysis of DAQC by extending its implementation to arbitrary connectivities and by performing the first systematic study of its scaling properties. We specify the analysis for three examples of quantum algorithms, showing that except for a few specific cases, DAQC is in fact disadvantageous with respect to the digital case., Comment: 16+5 pages, 11 figures

We present a general strategy for mapping fermionic systems to quantum hardware with square qubit connectivity which yields low-depth quantum circuits, counted in the number of native two-qubit fSIM gates. We achieve this by leveraging novel operator decomposition and circuit compression techniques paired with specifically chosen fermion-to-qubit mappings that allow for a high degree of gate cancellations and parallelism. Our mappings retain the flexibility to simultaneously optimize for qubit counts or qubit operator weights and can be used to investigate arbitrary fermionic lattice geometries. We showcase our approach by investigating the tight-binding model, the Fermi-Hubbard model as well as the multi-orbital Hubbard-Kanamori model. We report unprecedentedly low circuit depths per single Trotter layer with up to a factor 3.2 improvement upon previous state-of-the-art. Additionally, we show that our decomposition and compression formalism produces favourable circuits even when no native parameterized two-qubit gates are available.