HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the primary treatment for non-muscle-invasive bladder cancer (NMIBC), known to stimulate inflammatory cytokines, notably interferon (IFN)-γ. We observed that prolonged IFN-γ exposure fosters adaptive resistance in recurrent tumors, aiding immune evasion and tumor proliferation. We identify HLA-E and NKG2A, part of a novel NK and T cell checkpoint pathway, as key mediators of resistance in BCG-unresponsive NMIBC. IFN-γ enhances HLA-E and PD-L1 expression in recurrent tumors, with an enrichment of intra-tumoral NKG2A-expressing NK and CD8 T cells. CXCL9+ macrophages and dendritic cells and CXCL12-expressing stromal cells likely recruit CXCR3/CXCR4-expressing NK and T cells and CXCR7+ HLA-EHIGH tumor cells. NK and CD8 T cells remain functional within BCG-unresponsive tumors but are inhibited by HLA-E and PD-L1, providing a framework for combined NKG2A and PD-L1 blockade strategy for bladder-sparing treatment of BCG-unresponsive NMIBC.

Forest disturbance regimes and trends in continental Spain (1985-2023) using dense landsat time series.

Forest disturbance regimes across biomes are being altered by interactive effects of global change. Establishing baselines for assessing change requires detailed quantitative data on past disturbance events, but such data are scarce and difficult to obtain over large spatial and temporal scales. The integration of remote sensing with dense time series analysis and cloud computing platforms is enhancing the ability to monitor historical disturbances, and especially non-stand replacing events along climatic gradients. Since the integration of such tools is still scarce in Mediterranean regions, here, we combine dense Landsat time series and the Continuous Change Detection and Classification - Spectral Mixture Analysis (CCDC-SMA) method to monitor forest disturbance in continental Spain from 1985 to 2023. We adapted the CCDC-SMA method for improved disturbance detection creating new spectral libraries representative of the study region, and quantified the year, month, severity, return interval, and type of disturbance (stand replacing, non-stand replacing) at a 30 m resolution. In addition, we characterised forest disturbance regimes and trends (patch size and severity, and frequency of events) of events larger than 0.5 ha at the national scale by biome (Mediterranean and temperate) and forest type (broadleaf, needleleaf and mixed). We quantified more than 2.9 million patches of disturbed forest, covering 4.6 Mha over the region and period studied. Forest disturbances were on average larger but less severe in the Mediterranean than in the temperate biome, and significantly larger and more severe in needleleaf than in mixed and broadleaf forests. Since the late 1980s, forest disturbances have decreased in size and severity while increasing in frequency across all biomes and forest types. These results have important implications as they confirm that disturbance regimes in continental Spain are changing and should therefore be considered in forest strategic planning for policy development and implementation.

Scalable stable comb-to-tone integrated RF photonic drive for superconducting qubits.

The recent advent of quantum computing has the potential to overhaul security, communications, and scientific modeling. Superconducting qubits are a leading platform that is advancing noise-tolerant intermediate-scale quantum processors. The implementation requires scaling to large numbers of superconducting qubits, circuit depths, and gate speeds, wherein high-purity RF signal generation and effective cabling transport are desirable. Fiber photonic-enhanced RF signal generation has demonstrated the principle of addressing both signal generation and transport requirements, supporting intermediate qubit numbers and robust packaging efforts; however, fiber-based approaches to RF signal distribution are often bounded by their phase instability. Here, we present a silicon photonic integrated circuit-based version of a photonic-enhanced RF signal generator that demonstrates the requisite stability, as well as a path towards the necessary signal fidelity.

Predictive factors of osteoporotic hip fracture in octogenarians.

OBJECTIVE: This study aims to identify the risk factors associated with osteoporotic hip fractures in octogenarians and seeks to refine primary prevention strategies for these fractures. MATERIAL AND METHODS: We conducted a case-control study involving individuals aged 79 years and older with hip fractures, comparing them to age- and sex-matched controls without a history of hip fractures. We collected epidemiological, clinical, anthropometric, and analytical factors. We evaluated the presence of osteoporosis using bone densitometry. We defined sarcopenia according the European Working Group on Sarcopenia in Older People criteria (EWGSOP2). RESULTS: Ninety-five patients per group were analyzed, with a mean age of 82 years, of which 74% were women. The multivariate analysis included statistically significant factors found in the univariate analysis (p < 0.05). These factors included the Barthel Index, nutritional assessment using the CONUT tool, folic acid, vitamin D deficiency, presence of previous fractures, loss of visual acuity, bicipital circumference, sarcopenia, and osteoporosis (densitometry in the neck of the femur). The Nutritional state (OR: 0.08 [0.01-0.61]), the folic acid levels (OR 0.32 [0.1-1]), and a loss of visual acuity (OR 33.16 [2.91-377.87]) were the independent risk factors associated with hip fracture. CONCLUSIONS: The assessment of nutritional status in elderly patients, coupled with a comprehensive geriatric assessment, represents easily reproducible and cost-effective tools. These tools can effectively aid in identifying individuals at risk of hip fractures, thereby contributing to more targeted and efficient preventive measures.

Perioperative stress and anxiety in parents of children operated on for congenital heart disease.

INTRODUCTION: Levels of stress and anxiety suffered by parents of children with congenital heart disease (PCUCS) during their children's admission for cardiac surgery may be higher than those suffered by other parents who go through the same experience. OBJECTIVE: General objective of this study was to measure the stress and anxiety suffered by PCUCS and parents of children undergoing renal surgery (PCURS) in relation to the intervention of their children. The specific objective of the quantitative study was to compare global stress and anxiety according to sex, time of the perioperative period, and cohort. The general objective of the qualitative section is to explore the experience that PCUCS and PCURS have during their hospital stay and to identify the specific factors that influence the genesis of stress and anxiety. METHOD: A cohort study was carried out in which PCURS and PCUCS were included. The quantitative part was performed by comparing the scores of three questionnaires that measure stress levels (PSS-14), state anxiety (STAIE) and trait anxiety (STAIR) throughout three perioperative moments. At the same time, a qualitative study was carried out with semi-structured interviews and collection of diaries on which a descriptive phenomenological analysis was carried out, according to Munhall. The analysis of the text was carried out according to Colaizzi. RESULTS: Stress and anxiety levels were significantly higher in PCUCS compared to PCURS. Mothers in the cardiac cohort were those with the highest scores on all scales. In the qualitative study, four themes emerged: "stress and anxiety from the moment of diagnosis", "surgical intervention as a critical moment", "harshness of the postoperative period in the Intensive Care Unit" and "joy and gratitude versus dependence and fear for the future". CONCLUSIONS: PCUCS suffer higher levels of stress and anxiety than PCURS, being the mothers of the cardiac cohort those who suffer these disorders with greater intensity. This study can constitute a starting point to develop strategies that cover these parental needs.

Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer.

BACKGROUND: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. PATIENTS AND METHODS: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. RESULTS: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. CONCLUSIONS: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

Pembrolizumab in combination with gemcitabine for patients with HER2-negative advanced breast cancer: GEICAM/2015-04 (PANGEA-Breast) study.

BACKGROUND: We evaluated a new chemoimmunotherapy combination based on the anti-PD1 monoclonal antibody pembrolizumab and the pyrimidine antimetabolite gemcitabine in HER2- advanced breast cancer (ABC) patients previously treated in the advanced setting, in order to explore a potential synergism that could eventually obtain long term benefit in these patients. METHODS: HER2-negative ABC patients received 21-day cycles of pembrolizumab 200 mg (day 1) and gemcitabine (days 1 and 8). A run-in-phase (6 + 6 design) was planned with two dose levels (DL) of gemcitabine (1,250 mg/m2 [DL0]; 1,000 mg/m2 [DL1]) to determine the recommended phase II dose (RP2D). The primary objective was objective response rate (ORR). Tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumors and myeloid-derived suppressor cells (MDSCs) levels in peripheral blood were analyzed. RESULTS: Fourteen patients were treated with DL0, resulting in RP2D. Thirty-six patients were evaluated during the first stage of Simon's design. Recruitment was stopped as statistical assumptions were not met. The median age was 52; 21 (58%) patients had triple-negative disease, 28 (78%) visceral involvement, and 27 (75%) ≥ 2 metastatic locations. Progression disease was observed in 29 patients. ORR was 15% (95% CI, 5-32). Eight patients were treated ≥ 6 months before progression. Fourteen patients reported grade ≥ 3 treatment-related adverse events. Due to the small sample size, we did not find any clear association between immune tumor biomarkers and treatment efficacy that could identify a subgroup with higher probability of response or better survival. However, patients that experienced a clinical benefit showed decreased MDSCs levels in peripheral blood along the treatment. CONCLUSION: Pembrolizumab 200 mg and gemcitabine 1,250 mg/m2 were considered as RP2D. The objective of ORR was not met; however, 22% patients were on treatment for ≥ 6 months. ABC patients that could benefit of chemoimmunotherapy strategies must be carefully selected by robust and validated biomarkers. In our heavily pretreated population, TILs, PD-L1 expression and MDSCs levels could not identify a subgroup of patients for whom the combination of gemcitabine and pembrolizumab would induce long term benefit. TRIAL REGISTRATION: ClinicalTrials.gov and EudraCT (NCT03025880 and 2016-001,779-54, respectively). Registration dates: 20/01/2017 and 18/11/2016, respectively.

Hyper-Reflective Outer Nuclear Layer (HONL) in Vogt-Koyanagi-Harada Disease and Sympathetic Ophthalmia.

PURPOSE: To describe the optical coherence tomography (OCT) findings of hyper-reflective outer nuclear layer (HONL) in two cases of stromal choroiditis (Vogt-Koyanagi-Harada disease - VKH, and sympathetic ophthalmia - SO). METHODS: Case report. RESULTS: Clinical and imaging findings of two patients (37-year-old female with VKH and 34-year-old male with SO) have been described. Both patients showed typical features of the disease with subretinal fluid accumulation and choroidal thickening on OCT. However, OCT of both patients at the initial visit revealed HONL, which was unusual in these conditions. During follow-up, OCT scans revealed thinning and atrophy of the outer retinal layers, irregular thickening of the retinal pigment epithelium, and irregular autofluorescence pattern on autofluorescence imaging. CONCLUSIONS: The presence of HONL may serve as a poor prognostic factor in VKH and SO, resulting in thinning and atrophy of the outer retinal layers.

Modified videoendoscopic inguinal lymphadenectomy through suprafascial approach: Technical description and preliminary surgical outcomes.

INTRODUCTION: The videoendoscopic approach to inguinal lymph node dissection (VEIL) has been suggested as an excellent alternative carrying lower morbidity but equivalent oncological control. One of its most difficult steps is the development of an appropriate plane of dissection. A suprafascial approach would allow for better exposure. The objective of this study is to determine the feasibility, in terms of safety and oncological control, of a technical modification to the classical VEIL technique using a suprafascial plane of dissection in an initial series of patients. PATIENTS AND METHODS: A single institution retrospective review of patients undergoing VEIL technique using our modified suprafascial approach was conducted. A step-by-step surgical description is provided. Data collected included demographics; comorbid conditions; disease characteristics; intraoperative factors; and postoperative factors. RESULTS: A total of 7 patients (12 procedures) were included. Average age was 64.42 years old, and 71.42% of the patients were male. The procedure was performed bilaterally in 71.4% of the cases. Median estimated blood loss was 10 mL (range 10-25). Mean operative time was 185 min (range 120-170). Median number of nodes removed was 10.25 nodes (range 7-11). Only one of the patients (8.3%) experienced a Clavien-Dindo grade IIIa complication requiring delayed percutaneous drainage replacement. Median time until drainage removal was 13 days (range 10-16). Median length of stay was 48 hours but ranged from 24-96 hours within the series. CONCLUSIONS: The modified VEIL technique using a suprafascial plane of the dissection, allows a bilateral ILND in highly competitive operative times and with limited morbidity, without compromising its oncological efficacy.

Tau Appearance from High-Energy Neutrino Interactions.

High-energy muon and electron neutrinos yield a non-negligible flux of tau neutrinos as they propagate through Earth. In this Letter, we address the impact of this additional component in the PeV and EeV energy regimes for the first time. Above 300 TeV, this contribution is predicted to be significantly larger than the atmospheric background, and it alters current and future neutrino telescopes' capabilities to discover a cosmic tau-neutrino flux. Further, we demonstrate that Earth-skimming neutrino experiments, designed to observe tau neutrinos, will be sensitive to cosmogenic neutrinos even in extreme scenarios without a primary tau-neutrino component.

Non-metastatic castration-resistant prostate cancer: management recommendations.

INTRODUCTION AND OBJECTIVE: Survival and quality of life (QoL) of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) deteriorate significantly when they develop metastases. New generation antiandrogens (apalutamide, enzalutamide and darolutamide) can prolong metastasis-free survival (MFS) and overall survival (OS) in these patients, maintaining their QoL. MATERIAL AND METHODS: After the performance of a systematic review of the literature, a scientific committee reached a consensus on simple and practical recommendations to consolidate and improve the management of patients with nmCRPC in urology consultations. RESULTS: Recommendations are made on the frequency of PSA determination and imaging tests in patients with nmCRPC. The importance of co-morbidities in patients with nmCRPC is also highlighted, and recommendations are also made on functional and QoL assessment that can be carried out during urology consultations. The efficacy, safety, and effects on QoL of new generation antiandrogens are reviewed. CONCLUSIONS: To evaluate treatment of patients with nmCRPC, it is necessary to consider co-morbidities and QoL, in addition to age. New generation antiandrogens are a safe and effective treatment option for patients with nmCRPC. The recommendations of this review can be helpful in optimizing the management of nmCRPC patients in urology consultations.

[Prevalence and incidence of ictus in Europe: systematic review and meta-analysis].

BACKGROUND: Stroke is the second cause of death and the first cause of disability in Europe. The number of stroke patients shows a rapidly increasing due to the increase in the elderly population. The aim of this meta-analysis is to evaluate the prevalence and incidence of stroke in Europe. METHOD: We conducted a literature search in MEDLINE, SCOPUS, CINAHL Complete and EMBASE, using the keywords "stroke", "cerebrovascular accident", "epidemiology", "prevalence", "incidence" and "Europe". In order to evaluate the quality and risk of bias, we used the Hoy's modified scale for prevalence studies and the Newcastle Ottawa Scale for incidence studies. A random effects model with 95% confidence intervals (95%CI) was used for the meta-analysis. The I2 statistic was applied to assess heterogeneity. RESULTS: The prevalence of stroke in Europe adjusted for sex was estimated at 9.2% (95%CI: 4.4-14.0). The prevalence was 9.1% (95%CI: 4.7-13.6) in men and 9.2% (95%CI: 4.1-14.4) in women, and increased with age. The incidence of stroke in Europe adjusted for sex was 191.9 per 100,000 person-years (95%CI: 156.4-227.3); it was 195.7 per 100,000 person-years (95%CI: 142.4-249.0) in men and 188.1 per 100,000 person-years (95%CI: 138.6-237.7) in women. Again, these rates increased with age. CONCLUSION: The prevalence of stroke in Europe is 9.2%. The incidence of stroke in Europe is 191.9 per 100,000 person-years. The prevalence of stroke has increased, whereas the incidence of stroke is stable in comparison with studies conducted at the beginning of the 21st century.

The interaction of deep convection with the general circulation in Titan's atmosphere. Part 1: Cloud Resolving Simulations.

The deep convective cloud-environment feedback loop is likely important to Titan's global methane, energy, and momentum cycles, just as it is for Earth's global water, energy, and momentum budgets. General circulation models of Titan's atmosphere are unable to explicitly simulate deep convection and must instead parameterize the impact of this important subgrid-scale phenomenon on the model-resolved atmospheric state. The goal of this study is to better quantify through cloud resolving modeling the effects of deep convective methane storms on their environment and to feed that information forward to improve parameterizations in global models. Dozens of atmospheric profiles unstable with respect to deep moist convection are extracted from the global Titan Atmospheric Model (TAM) and used to initialize the cloud-resolving Titan Regional Atmospheric Modeling System (TRAMS). Mean profiles of heating/cooling and moistening/drying of the large-scale environment in TRAMS indicate that Titan's deep convection forces the environment in a manner analogous to Earth: Large-scale subsidence of the environmental air warms and dries the environment, but clouds can also moisten the environment through the detrainment and evaporation of condensate near cloud top. Relative humidity profiles and characteristic convective time scales are derived to guide the tuning of the deep convective parameterization implemented in TAM, as described in a companion paper. The triggering of convection, the dry convective mixing of the planetary boundary layer, and the entrainment of environmental air into rising air parcels are found to be critical to determining whether a deep convective cloud will form. Only profiles with relatively large convective available potential energy (CAPE) and well mixed planetary boundary layers with high relative humidity were found to produce storms. Environments with low level thermal inversions and planetary boundary layers with low relative humidity or rapidly decreasing moisture with height failed to generate deep convection in TRAMS despite positive CAPE.

A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment.

Brucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

Osteoporotic vertebral fractures: A diagnostic challenge in the 21st century.

Vertebral fractures are the most prevalent osteoporotic fractures and are paradoxically the most underdiagnosed. While only one-third of patients have acute pain, they can present other associated chronic complications. Vertrebal fractures are associated with the onset of new fractures, both vertebral and nonvertebral. Radiography of the dorsal-lumbar spine is a useful tool for detecting them but depends on the subjective interpretation of the physician conducting the assessment. New techniques, such as vertebral morphometry, have recently demonstrated greater efficacy in detecting v vertebral fractures and are performed concomitantly with bone densitometry. Knowing how to identify vertebral fractures is essential for the secondary prevention of new fractures and improving our patients' quality of life.

Clinical drivers for imaging testing in non-metastatic castration-resistant prostate cancer in clinical practice: Results of the IDENTIFICA study. / Factores clínicos determinantes para la realización de pruebas de imagen en cáncer de próstata resistente a la castración no metastásico en la práctica clínica: resultados del estudio IDENTIFICA.

INTRODUCTION: The aim of the study was to describe the clinical drivers that lead physicians to perform imaging tests in search of metastasis in non-metastasic castration prostate resistant cancer (nmCRPC) patients. METHODS: Observational, cross-sectional study conducted at the Departments of Urology of 38 Spanish hospitals. The study included 188 patients diagnosed with nmCRPC who underwent an imaging test for the assessment of metástasis. In one study visit, physicians were requested to specify the clinical factors that led them to perform these tests. The results of the imaging tests and the clinical characteristics of the patients since the time of prostate cancer (PC) diagnosis, were reported. Regression analyses were used to determine predictors of imaging test results. RESULTS: Prostate-specific antigen (PSA) level was the most important driver to order imaging tests (57.1%), followed by regular follow-up (16.5%) and PSA doubling time (PSADT) (12.0%). Although these drivers were not associated to detection of metastasis, patients with PSA levels ≥20 ng/mL had a greater risk of metastasis than patients with PSA levels <4ng/mL (P=.004) and CRPC patients diagnosed with metastasis (mCRPC) had higher median PSA levels (20.9; interquartile range [IQR]: 6.7-38.6) than nmCRPC (9.1; IQR: 5.0-18.0) (P=.005). Sixty-six percent of the patients did not undergo any imaging test after CRPC diagnosis until the study visit (10.6, IQR: 4.0-19.5 months). Curative-intent treatment at PC diagnosis and Gleason score predicted longer time from PC to CRPC diagnosis. CONCLUSIONS: Physicians based their decisions to order imaging tests for metastasis detection in nmCRPC patients mainly on PSA and PSA kinetics, including the regular follow-up stated by guideline recommendations.

Trends in mortality from stroke in the European Union, 1996-2015.

BACKGROUND AND PURPOSE: Stroke is the second largest single cause of death in Europe, responsible for 9% and 13% of all deaths in men and women, respectively. There have been large overall declines in stroke mortality rates in the majority of European countries in recent decades. The aim of this study was to analyse trends in mortality caused by stroke in the 28 member countries of the European Union (EU) over the last two decades. METHODS: We extracted data for age-standardized stroke mortality rates per 100 000 in the EU for the period 1996-2015 from the World Health Organization database. Joinpoint regression analysis was used to analyse the trends and compute the annual percent change (APC) in the EU as a whole and by country. Analyses were conducted by gender and by European region. RESULTS: Mortality from stroke has decreased in the EU over the study period by an average APC of 4.2%. All countries showed downward trends, with the sharpest decreases in Estonia, Portugal and Austria. We recorded statistically significant decreases of 4.2% and 4.3% in mortality rates in men and women, respectively, in the whole EU. Southern and western countries showed the steepest decreases, whereas mortality has increased in northern countries in recent years. CONCLUSIONS: Stroke mortality has decreased in the EU, in both sexes, especially in southern and western European countries. Our results could be a reference for the development of primary prevention and acute management of stroke policies focused on countries with higher mortality.