Utility guideline and considerations for the novel Hugo™ RAS (robotic-assisted surgery) system in colorectal surgery: surgical outcomes and initial experience in a tertiary center.

PURPOSE: A novel robotic platform-Hugo™ RAS (robotic-assisted surgery) system-has been introduced with several innovations that may prove advantageous for surgeons, such as an open console and four interchangeable modular arms. Our study aims to evaluate this platform's safety, efficacy, and potential impact on the surgical treatment of colorectal pathology. METHODS: Patients underwent robotic-assisted colorectal procedures with the Hugo™ RAS system at the General University Hospital of Elche from October 2023 to July 2024. Patient characteristics, intraoperative and postoperative variables, and robotic technical issues were recorded. RESULTS: Forty consecutive patients were included (14 right, 13 left, and 8 rectum neoplasms; 4 left diverticulitis; and 1 ileocecal Crohn's disease). The patients' characteristics were as follows: median age, 69.5 years; 24 males and 16 females; 45% ASA III-IV; and Charlson Comorbidity Index > 5:42.5%. We recorded four medical (2 anemia, 1 phlebitis, and 1 admission to the intensive care unit) and three surgical (1 hematoma of the incision, 1 intestinal occlusion, and 1 dehiscence of the anastomosis) postoperative complications. We had no conversions neither open nor laparoscopic surgery. The average hospital stay was 3 days, with no mortality or readmission. CONCLUSIONS: The Hugo™ RAS system is safe and feasible for colorectal procedures. The modularity of the arms provides the versatility of configurations adjusted depending on the patient's body features and the surgeon's preferences and greater adaptability to operating rooms. The open console is highly comfortable and ergonomic for the surgeon, allowing communication with the operating room environment. TRIAL REGISTRATION: NCT06512480.

Assessment of contaminants of emerging concern and antibiotic resistance genes in the Mapocho River (Chile): A comprehensive study on water quality and municipal wastewater impact.

The primary objective of this study was to evaluate the persistence and elimination of Contaminants of Emerging Concern (CECs) in municipal wastewater treatment plants (MWWTPs) and their presence in the Mapocho River within the metropolitan area of Santiago, Chile. The use of advanced analytical techniques, based on liquid chromatography coupled to both low and high-resolution mass spectrometry, allowed a comprehensive overview on the presence of CECs in samples. Additionally, a preliminary assessment of the microbiological aspects aimed to determine the presence of indicator microorganisms of fecal contamination, such as Escherichia coli and total coliforms was conducted. Furthermore, a qualitative assessment of Antibiotic Resistant Genes (ARGs) was performed. No CECs were detected upstream to the MWWTPs. However, the results from various wastewater samples (influent, secondary, and tertiary effluents) revealed significant diversity, with 73 CECs detected alongside prevalent ARGs including sulI, sulfII, qnrB, and blaTEM. The presence of CECs and ARGs downstream of the MWWTP in the Mapocho River was mainly attributed to effluent discharge. On the other hand, typical values for a healthy river and a MWWTP with a final disinfection stage were found in terms of fecal contamination. Consequently, the imperative for developing tertiary or quaternary treatments capable of degrading CECs and ARGs to minimize environmental impact is underscored. These findings hold public health significance, offering insights into potential risks and influencing future legislative measures in Chile.

Population Pharmacokinetics and Exposure-Response Analysis of a Fixed-Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults.

Trichuris trichiura is a soil-transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co-administered with ivermectin. A fixed-dose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure-response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T. trichiura. Nonlinear mixed-effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure-response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two-compartmental model with first-order absorption and the pharmacokinetics of ivermectin was described using a two-compartmental model with zero-order followed by first-order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure-response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T. trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.

Transparent porous films with real refractive index close to unity for photonic applications.

Herein, we demonstrate mechanically stable large-area thin films with a purely real refractive index (n) close to 1 in the optical range. At specific wavelengths, it can reach values as small as n = 1.02, the lowest reported for thin solid slabs. These are made of a random network of interwoven spherical silica shells, created by chemical vapour deposition of a thin layer of silica on the surface of randomly packed monodisperse polymer nanoparticles that form a film. Thermal processing of the composites results in highly porous silica-based transparent thin films. We demonstrate the potential of this approach by making novel photonic materials such as strong optical diffusers, built by integrating scattering centers within the ultralow n transparent films, or highly efficient light-emitting slabs, in which losses by total internal reflection are practically absent as a result of the almost null optical impedance at the film-air interface.

Immunomodulatory markers and therapies for the management of infant respiratory syncytial virus infection.

INTRODUCTION: The human respiratory syncytial virus (hRSV) is one of childhood diseases' most common respiratory pathogens and is associated with lower respiratory tract infections. The peak in disease that this virus can elicit during outbreaks is often a significant burden for healthcare systems worldwide. Despite theapproval of treatments against hRSV, this pathogen remains one the most common causative agent of infant mortality around the world. AREAS COVERED: This review focuses on the key prognostic and immunomodulatory biomarkers associated with hRSV infection, as well as prophylactic monoclonal antibodies and vaccines. The goal is to catalyze a paradigm shift within the scientific community toward the discovery of novel targets to predict the clinical outcome of infected patients, as well as the development of novel antiviral agents targeting hRSV. The most pertinent research on this topic was systematically searched and analyzed using PubMed ISI Thomson Scientific databases. EXPERT OPINION: Despite advances in approved therapies against hRSV, it is crucial to continue researching to develop new therapies and to find specific biomarkers to predict the severity of infection. Along these lines, the use of multi-omics data, artificial intelligence and natural-derived compounds with antiviral activity could be evaluated to fight hRSV and develop methods for rapid diagnosis of severity.

Long-term benefit of ustekinumab in ulcerative colitis in clinical practice: ULISES study.

BACKGROUND: Ustekinumab is approved for ulcerative colitis (UC). AIMS: To assess the durability of ustekinumab in patients with UC and its short-term effectiveness, durability and tolerability in clinical practice. METHODS: Retrospective, multicentre study of patients who had received their first ustekinumab dose at least 16 weeks before inclusion. Patients were followed until treatment discontinuation or last visit. Only patients with active disease at the start of ustekinumab treatment were considered in the effectiveness analysis. Patients who stopped ustekinumab before their last visit were considered not to be in subsequent remission. RESULTS: We included 620 patients; 155 (25%) discontinued ustekinumab during follow-up (median 12 months). Rate of discontinuation was 20% per patient-year of follow-up. Anaemia at baseline (hazard ratio, HR 1.5; 95% confidence interval [CI] 1.1-2.1), steroids at baseline (HR 1.5; 95% CI 1.06-2.08) and more severe clinical activity at baseline (HR 1.5; 95% CI 1.09-2.06) were associated with higher risk of discontinuation. At the end of induction, 226 (40%) patients were in steroid-free clinical remission. Moderate-severe vs mild disease activity at baseline (odds ratio [OR] 0.3; 95% CI 0.2-0.5), male sex (OR 0.5; 95% CI 0.4-0.8), and increased number of previous biologics (OR 0.6; 95% CI 0.6-0.8) were associated with lower likelihood of steroid-free clinical remission at week 16. One hundred and seventy-six patients (28%) had at least one adverse event. We observed no negative impact of ustekinumab on extraintestinal manifestations and/or immune-mediated diseases. CONCLUSIONS: Ustekinumab durability in UC was relatively high, and treatment was effective in highly refractory patients. The safety profile was consistent with previous studies.

Baseline gut microbiota diversity and composition and albendazole efficacy in hookworm-infected individuals.

Soil-transmitted helminth (STH) infections account for a significant global health burden, necessitating mass drug administration with benzimidazole-class anthelmintics, such as albendazole (ALB), for morbidity control. However, ALB efficacy shows substantial variability, presenting challenges for achieving consistent treatment outcomes. We have explored the potential impact of the baseline gut microbiota on ALB efficacy in hookworm-infected individuals through microbiota profiling and machine learning (ML) techniques. Our investigation included 89 stool samples collected from hookworm-infected individuals that were analyzed by microscopy and quantitative PCR (qPCR). Of these, 44 were negative by microscopy for STH infection using the Kato-Katz method and qPCR 21 days after treatment, which entails a cure rate of 49.4%. Microbiota characterization was based on amplicon sequencing of the V3-V4 16S ribosomal RNA gene region. Alpha and beta diversity analyses revealed no significant differences between participants who were cured and those who were not cured, suggesting that baseline microbiota diversity does not influence ALB treatment outcomes. Furthermore, differential abundance analysis at the phylum, family and genus levels yielded no statistically significant associations between bacterial communities and ALB efficacy. Utilizing supervised ML models failed to predict treatment response accurately. Our investigation did not provide conclusive insights into the relationship between gut microbiota and ALB efficacy. However, the results highlight the need for future research to incorporate longitudinal studies that monitor changes in the gut microbiota related to the infection and the cure with ALB, as well as functional metagenomics to better understand the interaction of the microbiome with the drug, and its role, if there is any, in modulating anthelmintic treatment outcomes in STH infections. Interdisciplinary approaches integrating microbiology, pharmacology, genetics and data science will be pivotal in advancing our understanding of STH infections and optimizing treatment strategies globally.

Demographic, co-intoxicants and other characteristics of citalopram-involved overdose deaths.

Selective serotonin reuptake inhibitors (SSRIs) including citalopram are commonly used antidepressants that can be involved in drug-related deaths along with opioids and other substances. This study characterized citalopram involvement in West Virginia (WV) drug-related deaths compared to other SSRI and non-SSRI-related deaths. All 2005-2021 WV drug-related deaths were analyzed in this retrospective study. Demographics, other substances involved, and comorbidities in cases in which citalopram was listed on the death certificate were compared to other SSRI-related and total non-SSRI deaths. Citalopram concentrations and the association between citalopram presence with predicted fentanyl concentrations were determined. Citalopram was the most common antidepressant present in the deaths (4.5% of 14,363 total), with most (81%) unintentional. Male: female ratios in citalopram cases (0.9:1) were significantly lower than in non-SSRI deaths (2.3:1). Almost two-thirds of citalopram deaths had ≥ 4 substances involved compared to 26% of non-SSRI deaths. Overall, oxycodone was most frequently identified in citalopram deaths (fentanyl more commonly in recent years), followed by alprazolam and diazepam. Cardiovascular comorbidity was significantly more common in citalopram than non-SSRI deaths. No association was found between citalopram presence and predicted fentanyl concentrations. Most citalopram-related deaths were unintentional and involved proportionately more females, with larger numbers of concurrent substances present and more cardiovascular comorbidity compared to non-SSRI deaths. Citalopram is widely used and less toxic than many antidepressants. The extent to which it contributed to overdose deaths can be difficult to ascertain given the multiple substances usually present.

PIK3CA mutational status in tissue and plasma as a prognostic biomarker in HR+/HER2- breast cancer.

INTRODUCTION: Hotspots (HS) mutations in the PIK3CA gene may lead to poorer oncological outcomes and endocrine resistance in advanced breast cancer (BC), but their prognostic role in early-stage disease remains controversial. The overall agreement within plasma and tissue methods has not been well explored. Our aim was to correlate tissue and plasma approaches and to analyze the prognostic impact of PIK3CA mutations (PIK3CAm) in HR+/HER2- BC. METHODS: A retrospective and unicentric analysis of PIK3CA mutational status in tissue and plasma samples by Cobas®PIK3CA Mutation Kit in patients with HR+/HER2- BC. RESULTS: We analyzed 225 samples from 161 patients with luminal BC. PIK3CA mutations were identified in 62 patients (38.5%), of which 39.6% were found in tissue and 11.8% in plasma. In advanced disease, plasma and tissue correlation rate was performed in 64 cases, with an overall agreement of 70.3%. Eighty patients were treated with CDK4/6 inhibitors + endocrine therapy. We observed a moderately worse progression-free survival (PFS) in PIK3CAm versus wild-type (WT) (24 m vs. 30 m; HR = 1.39, p = 0.26). A subanalysis was carried out based on exons 9 and 20, which showed a statistically poorer PFS in PIK3CAm exon 9 versus 20 population (9.7 m vs. 30.3 m; HR = 2.84; p = 0.024). Furthermore, detection of PIK3CAm in plasma was linked to a worse PFS vs PIK3CAm detection just in tissue (12.4 vs. 29.3; HR = 2.4; p = 0.08). CONCLUSIONS: Our findings suggest the PIK3CA evaluation in tissue as the diagnostic method of choice, however, additional investigations are required to improve the role of liquid biopsy in the PIK3CA assessment. PIK3CAm show worse outcomes in advanced luminal BC, especially in exon 9 mutation carriers, despite visceral involvement, prior exposure to endocrine therapy or detection of PIK3CAm in plasma, with an unclear prognosis in early-stage disease. Nonetheless, this should be validated in a prospective cohort study.

Differences in the ventilatory thresholds in treadmill according to training status in 971 males and 301 females: a cross-sectional study.

PURPOSE: To analyze the influence of training status on the percentage of maximum oxygen consumption, heart rate and velocity (%VO2max, %HRmax and %Vmax) at which ventilatory threshold 1 and ventilatory threshold 2 occur (VT1 and VT2, respectively), in males and females separately considering age, during a ramp incremental treadmill test. METHODS: 791 males (36.8 ± 9.9 years) and 301 females (33.9 ± 11.0 years) performed a ramp incremental exercise test until fatigue where VT1 and VT2 were determined. Participants were classified as low, medium or high training status combining the oxygen consumption at VT1, VT2 and VO2max by clustering analysis. RESULTS: VO2max is poorly correlated with the %VO2max, %HRmax and %Vmax at which VT1 and VT2 occur (r < 0.3), in contrast, there is a positive correlation between oxygen consumption at VT1 and VT2 with the %VO2max, %HRmax and %Vmax at which VT1 and VT2, respectively, occur in males and females (r = 0.203-0.615). Furthermore, we observed the %VO2max, %HRmax and %Vmax at which thresholds occur were greater the higher the training status (all p < 0.003). CONCLUSION: The physiological determinants of the percentage of maximum at which VT1 and VT2 occur are more related to oxygen consumption at VT1 and VT2, respectively, than to VO2max. Moreover, due to the higher percentage of maximum at which VT1 and VT2 occur in individuals with a higher training status, the common strategy consisting of establishing exercise intensity as a fixed percentage of maximum might not be effective to match intensity across individuals with different training status. CLINICAL TRIAL REGISTRATION: NCT06246760.

Rare mediastinal small round cell melanoma with synovial sarcoma-like immunophenotype: A potential diagnostic pitfall.

Melanoma can pose a significant diagnostic challenge due to the high variability in histological morphology and expression of non-melanocytic immunomarkers. We present a case of a 47-year-old male with an aggressive mediastinal neoplasm and disseminated disease posing several diagnostic challenges. Multiple biopsies were submitted from different anatomic locations and during multiple time points showing an undifferentiated round cell tumor (URCT) with synovial sarcoma-like immunophenotype. SS18::SSX fusion was sought through NGS study for diagnostic confirmation. NGS results revealed NRAS and CDKN2A mutations and absence of fusions, resulting in a new review of the histologic material with a broader immunohistochemical panel, finding strong positivity to melanic antibodies. This case is an illustrative example of a malignant melanoma with small round cell morphology showing aberrant expression of CD99, BCL2, TLE1 and SS18-SSX antibodies exposing a potentially hazardous pitfall highlighting the importance of a wide differential diagnosis and the role of confirmational studies with molecular tests.

Correlation between systemic allergen desensitisation and long-term asthma protection in mice following intravenous administration of the live tuberculosis vaccine MTBVAC.

BACKGROUND: MTBVAC is a live attenuated tuberculosis vaccine, currently undergoing phase III evaluation for tuberculosis prevention. In previous preclinical studies, we found that local pulmonary administration of MTBVAC via the intranasal route had a strong therapeutic effect against asthma. This effect correlated with the abrogation of allergen-specific Th2 response in the lungs. METHODS: Using different mouse models of asthma, we investigated the effect of MTBVAC administered by intravenous (IV) route and its potential as immunotherapeutic agent to induce desensitisation of allergen-specific responses at a systemic level. We explored the effects of this process in the efficacy against airway hyperresponsiveness (AHR) induced by exposure to different allergens. FINDINGS: IV MTBVAC was highly efficient at reducing AHR induced by different allergens. Additionally, IV MTBVAC was found to be well-tolerated, being progressively eliminated from the different organs analysed. From a mechanistic standpoint, we observed that MTBVAC intravenous, but not intranasal, impaired allergen-specific Th2 response in both lungs and spleen. This reduction at a systemic level correlated with long-term therapeutic protection against allergen exposure. Our results also revealed differential immunological mechanisms governing systemic and local pulmonary allergen desensitisation processes. Notably, in a cohort of patients with asthma sensitive to house dust mite (HDM), in vitro incubation of peripheral blood mononuclear cells (PBMCs) with MTBVAC prevented allergen-specific production of Th2 cytokines IL-4 and IL-5. INTERPRETATION: Altogether, our results suggest that intravenous MTBVAC could be a plausible allergen desensitising approach for treatment of asthma, and could provide long-term protection against allergen exposure. FUNDING: MCIN/AEI/10.13039/501100011033 [grants number RTI2018-097625-B-I00 and PID2022-138624OB-I00]; Consorcio Centro de Investigación Biomédica en Red- (Groups CB06/06/0020 and CB06/06/0013), Instituto de Salud Carlos III.

Professional narratives on continued training in the laboral landscape of social education.

Introduction: Labor consolidation is not a sufficient criterion to abandon the need for the qualification and requalification of professionals, especially in the field of education, which must respond to the uncertainties of society in the light of trends and advances incorporated in pedagogical research. Methods: The present qualitative study analyzes the training demands of social education professionals from their own perspective, using their own stories in a semi-structured interview format conducted with), key informants from governmental and non-governmental organizations in southeastern Spain, specifically from the autonomous community of the region of Murcia. Results: According to the results, the most frequent and significant formative limitations are those referred to in the field of social policies, legislative training, administrative processing, specialized work in specific sectors or collectives, and mediation. Similarly, the results reveal fashion themes (mental health, gender) and reiteration of non-exclusive conditioners of social education. These are extrapolable to other areas, such as the increasing bureaucracy and complexity in the proceedings as common places in the reflection of professionals with their own initiative and commitment to their own updating that is associated with a reflective criticism of their own professionalization. Discussion: The diverse range of responses and subjects, as indicated by the numerous descriptors needed for the categorization and their respective percentages, leads us to conclude that ongoing professional training does not encourage excessive specialization. Instead, it necessitates offering a broad range of training adjusted to the versatility of situations.

A brief research report of suicide rates in the Brazilian elderly over a 12-year period: the lack of association of the "Setembro Amarelo" campaign for suicide prevention.

Objectives: Aiming to disseminate information related to suicide prevention in Brazil, the "Setembro Amarelo" campaign has been conducted since 2015. The objective of this study is to assess the association between this campaign and elderly suicide rates over a 12-year period. Methods: Data were gathered from the Mortality Information System and the Notifiable Diseases Information System, established by public institutions in Brazil. An interrupted time-series framework was applied to assess the association between the "Setembro Amarelo" campaign and suicide mortality rates in the elderly population (60 et plus) in the southeastern region of Brazil. We consider three monthly outcomes: all suicides, suicides in males and suicide in females. We operationalize the campaign assuming three effects: short-term, declining and sustained. The period of analysis was from 2011-2022. Results: The suicide-mortality rate over time has remained stable; the average rate in the pre-campaign period was 0.028 and increased slightly to 0.035. Regardless of the campaign's operationalization and the outcome used, results show no significant associations between the campaign and elderly suicide rates. The campaign was associated with non-significant decreased effects of 15% (P=0.532) in the short term, and 16% (P=0.446) assuming the campaign was sustained. Conclusions: There is a lack of association between the campaign and suicide rates, among the elderly in Brazil's southeastern region. As suicide is complex and multifactorial, more research is needed. The campaign, while raising awareness and reducing stigma, may not reduce suicides. To reduce the suicide rate in the elderly requires addressing social, economic and cultural factors, multisectoral interventions, and upholding basic human rights.

Effects of ß-Alanine Supplementation on Subjects Performing High-Intensity Functional Training.

BACKGROUND: ß-alanine, a non-essential amino acid found in the diet and produced through nucleotide catabolism, is significant for muscle performance due to its role in carnosine synthesis. This study aims to assess the impact of a 4-week ß-alanine supplementation on neuromuscular fatigue in individuals engaging in High-Intensity Functional Training (HIFT) and its subsequent effect on sports performance, distinguishing between central fatigue from the CNS and peripheral fatigue from the muscular system. MATERIALS AND METHODS: This study (a randomized controlled trial) comprised a total of 27 subjects, who were divided into two groups. Group A (the control group) was administered sucrose powder, while Group B (the experimental group) was given ß-alanine powder. The subjects were randomly assigned to either the experimental or control groups. This study lasted four weeks, during which both groups participated in high-intensity interval training (HIFT) on the first day to induce fatigue and work close to their VO2 max. RESULTS: Statistically significant changes were in the sports performance variables, specifically vertical jump and jumping power (p = 0.027). These changes were observed only in the group that had been supplemented with ß-alanine. Nevertheless, no alterations were observed in any other variables, including fatigue, metabolic intensity of exercise, or perceived intensity (p > 0.05). CONCLUSIONS: A four-week ß-alanine intake program demonstrated an improvement in the capacity of subjects, as evidenced by enhanced vertical jump and power performance. Nevertheless, it does result in discernible alterations in performance.

Not all severe malaria cases are severe: Is it time to redefine severity criteria for malaria in non-endemic regions?

BACKGROUND: The current definition of severe malaria in non-endemic areas follows WHO criteria, which mainly target children in malaria-endemic areas, potentially misclassifying cases in non-endemic regions. We assessed the performance of a modified severe malaria classification criteria within our patient cohort. METHODS: A cohort study of patients managed for malaria in a non-endemic setting (2005-2023) was analyzed. We classified patients into severe malaria (SM) using WHO 2013 criteria except for hyperparasitemia, where 2 % threshold was applied. Patients with SM were distinguished as very severe malaria (VSM) when presenting at least one of the following conditions: parasitemia >10 %, pulmonary edema, impaired consciousness, seizures, renal failure, metabolic acidosis or hyperlactatemia, shock or hypoglycemia. In patients with SM and no criteria for VSM, less severe malaria (LSM) was defined by: 2-10 % parasitemia, hyperbilirubinemia, prostration, anemia or minor bleeding. The primary composite outcome was death or the need for a life-saving intervention, as analyzed in the three comparative groups. Secondary outcome was the prevalence of co-infections. RESULTS: Among 506 patients with malaria, 176 (34.8 %) presented with SM. A total of 37 (7.3 %) patients developed a life-threatening condition, namely death (n = 4) and/or the need for life-saving interventions (n = 34). All fatalities and 33 out of the 34 life-saving interventions occurred in the VSM group. Patients in LSM group did not develop any life-threatening conditions. As to co-infections, 28 (5.5 %) patients had a community-acquired co-infection, with no differences between groups (p = 0.763). CONCLUSIONS: Severity criteria definitions would benefit from a review when assessing patients with malaria in non-endemic areas. Within the spectrum of SM, patients reclassified as LSM have a low risk of developing a life-threatening condition and present low co-infection incidence and could benefit from management out of intensive care units and a restrictive use of empirical antibiotics.

Local weather phenomenon Galerna influences daily radon concentrations in northern Iberian Peninsula.

One of the main factors that affect urban air quality is meteorology. The objective of this study is to understand and characterise the influence that "Galerna" (GL) (an abrupt westerly change over the northern coast of Spain) has on the daily variability of the air quality over Bilbao city (northern Spain). A total of 46 one-day periods from 2009 to 2019 during which GL have been analysed. Radon observations at the Bilbao city radiological station were used because radon is a suitable atmospheric tracer by which to assess and characterise air quality dynamics. The cluster analysis of these periods revealed that increases in radon concentrations, mainly in the afternoon, are associated with the occurrence of GL, but that, this increase in the daily variability of radon concentrations in Bilbao is not reflected in all these GL periods. This variability in the impact of the GL scenario on radon concentrations is associated with the location of Bilbao: along the Nervion valley and 16 km from the coast. The analysis of three GL periods using 10-min surface meteorological and radon data showed an anomalous increase in radon with the arrival of maritime winds, which is associated with the process of a progressive accumulation of radon concentrations over the coastal area in the previous days, and the displacement of these air masses inland owing to the development of the GL event. Our results consequently identify the impact of GL on urban air quality in the afternoon, along with the fact that the complex layout of this coastal area, with the presence of valleys and mountains, favours the formation of reservoir layers above the coastal and valley areas, thus influencing on daily variability of air pollution concentrations. These increases in radon concentrations do not present a significant impact on human health.

Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.

Circulating tumor DNA (ctDNA) is emerging as a potential biomarker in early-stage urothelial cancer, but its utility in metastatic disease remains unknown. In the phase 3 KEYNOTE-361 study, pembrolizumab with and without chemotherapy was compared with chemotherapy alone in patients with metastatic urothelial cancer. The study did not meet prespecified efficacy thresholds for statistical significance. To identify potential biomarkers of response, we retrospectively evaluated the association of pre- and posttreatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA was associated with best overall response (BOR; P = 0.009), progression-free survival (P < 0.001) and overall survival (OS; P < 0.001) for pembrolizumab but not for chemotherapy (all; P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) was more associated with BOR (P = 4.39 × 10-5) and OS (P = 7.07 × 10-5) than chemotherapy (n = 102; BOR: P = 1.01 × 10-4; OS: P = 0.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show a statistically significant independent value for explaining OS beyond radiographic change by RECIST v.1.1 when jointly modeled (pembrolizumab P = 0.364; chemotherapy P = 0.823). These results suggest distinct patterns in early ctDNA changes with immunotherapy and chemotherapy and differences in their association with long-term outcomes, which provide preliminary insights into the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: NCT02853305 .