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Background: The open-label, single-arm, multicenter ORZORA trial (NCT02476968) evaluated the efficacy and safety of maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) who had tumor BRCA mutations (BRCAm) of germline (g) or somatic (s) origin or non-BRCA homologous recombination repair mutations (HRRm) and were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment. Methods: Patients received maintenance olaparib capsules (400mg twice daily) until disease progression. Prospective central testing at screening determined tumor BRCAm status and subsequent testing determined gBRCAm or sBRCAm status. Patients with predefined non-BRCA HRRm were assigned to an exploratory cohort. The co-primary endpoints were investigator-assessed progression-free survival (PFS; modified Response Evaluation Criteria in Solid Tumors v1.1) in BRCAm and sBRCAm cohorts. Secondary endpoints included health-related quality of life (HRQoL) and tolerability. Results: 177 patients received olaparib. At the primary data cut-off (17 April 2020), the median follow-up for PFS in the BRCAm cohort was 22.3months. The median PFS (95% CI) in BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts was 18.0 (14.3-22.1), 16.6 (12.4-22.2), 19.3 (14.3-27.6) and 16.4 (10.9-19.3) months, respectively. Most patients with BRCAm reported improvements (21.8%) or no change (68.7%) in HRQoL and the safety profile was as expected. Conclusions: Maintenance olaparib had similar clinical activity in PSR OC patients with sBRCAm and those with any BRCAm. Activity was also observed in patients with a non-BRCA HRRm. ORZORA further supports use of maintenance olaparib in all patients with BRCA-mutated, including sBRCA-mutated, PSR OC.

Abstract: In the context of a balanced diet, wheat, mainly used as whole grains, is a good source of nutrients, including fibers and bioactive compounds. Cereals belong to the Poaceae family and are crucial for maintaining a healthy status, granted by their nutritional and chemical properties. Recent studies have demonstrated that the intake of whole grains and grain-based products may reduce the risk of oxidative stress, thus lowering chronic and age-related disorders, such as obesity, cardiovascular diseases, type II diabetes and cancer. Indeed, several studies report that regular whole grain consumption is associated with lower levels of total and LDL-cholesterol, triglycerides, fasting glucose, blood pressure and body mass index. Moreover, ancient wheat species have become increasingly interested in human health, containing several nutraceutical compounds, such as vitamins and minerals. The numerous phytochemicals present in ancient wheat (polyphenols, carotenoids, phytosterols and phenolic compounds) provide, in fact, antioxidant properties, which are essential in the prevention of various chronic and degenerative diseases. This review aims to report information on ancient wheat species, discussing their composition and nutraceutical properties compared with modern varieties and highlighting the beneficial impact on human health.

Strongyloidiasis develops from the infection with Strongyloides stercoralis (Family: Strongylidae) and was recently considered a neglected tropical disease by the World Health Organization due to its global distribution and high burden of infection. Here, we present the cases of two patients under corticosteroid therapy after neurosurgical surgery who developed septic shock-like hyperinfection syndrome due to disseminated strongyloidiasis. The first case is a 77-year-old man from Cape Verde who was diagnosed with an extra-axial right parietal brain mass. He was given dexamethasone and was submitted to a biparietal craniotomy. His condition deteriorated and he was admitted to the intensive care unit (ICU), where he was diagnosed with disseminated strongyloidiasis with hyperinfection. Anthelmintic treatment and corticosteroid therapy were rapidly tapered and stopped. Neurological dysfunction persisted and the patient was transferred to the ward. The patient had died after complications of hospital-acquired pneumonia. The second case is a 47-year-old man from Guinea-Bissau who was diagnosed with a space-occupying lesion in the right temporal region and started treatment with dexamethasone. He underwent a craniectomy with partial excision of the lesion (high-grade glioma). Later his neurologic state worsened, and he was diagnosed with septic shock and hospital-acquired pneumonia. He was admitted to the ICU, the diagnosis of disseminated strongyloidiasis and hyperinfection syndrome was made and he initiated treatment with ivermectin and albendazole. Corticosteroid therapy was tapered. The patient’s clinical status deteriorated, and multiple opportunistic infections were diagnosed during the ICU stay, which lead him to die. Clinicians should have a high index of suspicion when in the presence of corticosteroid-treated patients with sepsis. Preventive strategies and subsequent treatment should be considered in patients with a risk of acquisition or dissemination. Treating severe strongyloidiasis is still a clinical challenge and a delayed diagnosis can significantly worsen the outcomes of the patients affected, as seen in the presented cases.

The Defense Advanced Research Projects Agency (DARPA) Subterranean Challenge represented a multiyear (2018–2021), competition-based initiative to inspire and shape the future of field robotics, specifically in advancing integrated technologies for operating in complex underground environments. Bringing together robotics researchers and innovators from around the world to compete in physical and simulated contests, it spotlighted significant opportunities to incentivize and extract high-value technical results and insights to inform future advances. This article captures and quantifies these results, extracts relevant insights, and offers lessons learned and recommendations for further work.

A cirurgia robótica tem sido almejada por profissionais cirurgiões, visto que, é um procedimento considerado de alta eficácia, assim como, apresenta reduzidos níveis de riscos ao paciente, o que configura significativamente a qualidade elevada do procedimento médico. Logo, tem sido utilizada no tratamento cirúrgico de diversos tipos de câncer, o qual tem demonstrado melhores resultados quando comparados com procedimentos mais invasivas ou tradicionais O principal objetivo do é discutir por meio de uma revisão sistematizada da literatura acerca dos avanços da cirurgia robótica no tratamento dos demais tipos de cânceres. O presente estudo trata-se de uma revisão sistemática da literatura, de modo que, realizou-se buscas de na Scielo, Periódico Capes e na Biblioteca Virtual em Saúde (BVS), através de termos específicos do Decs, o qual resultou-se em: “Neoplasias” AND “Procedimentos Cirúrgicos Robóticos” AND “Terapêutica”. Foram elegíveis um total de 8 estudos na presente revisão sistemática. Este procedimento é devidamente realizado com menores danos de incisão possível no paciente, de modo que, possibilitou a diminuição de dores pós-operatórios, além da redução de sangramentos, traumas, respostas inflamatórias, tempo de internação e até mesmo melhores resultados estéticos nos pacientes, quando comparados com os métodos mais tradicionais e invasivos.

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/., The success of personalized medicine depends on the discovery of biomarkers that allow oncologists to identify patients that will benefit from a particular targeted drug. Molecular tests are mostly performed using tumor samples, which may not be representative of the tumor's temporal and spatial heterogeneity. Liquid biopsies, and particularly the analysis of circulating tumor DNA, are emerging as an interesting means for diagnosis, prognosis, and predictive biomarker discovery. In this study, the amplification refractory mutation system (ARMS) coupled with high-resolution melting analysis (HRMA) was developed for detecting two of the most relevant KRAS mutations in codon 12. After optimization with commercial cancer cell lines, KRAS mutation screening was validated in tumor and plasma samples collected from patients with pancreatic ductal adenocarcinoma (PDAC), and the results were compared to those obtained by Sanger sequencing (SS) and droplet digital polymerase chain reaction (ddPCR). The developed ARMS-HRMA methodology stands out for its simplicity and reduced time to result when compared to both SS and ddPCR but showing high sensitivity and specificity for the detection of mutations in tumor and plasma samples. In fact, ARMS-HRMA scored 3 more mutations compared to SS (tumor samples T6, T7, and T12) and one more compared to ddPCR (tumor sample T7) in DNA extracted from tumors. For ctDNA from plasma samples, insufficient genetic material prevented the screening of all samples. Still, ARMS-HRMA allowed for scoring more mutations in comparison to SS and 1 more mutation in comparison to ddPCR (plasma sample P7). We propose that ARMS-HRMA might be used as a sensitive, specific, and simple method for the screening of low-level mutations in liquid biopsies, suitable for improving diagnosis and prognosis schemes., This work is financed by national funds from FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB. FCT-MCTES is also acknowledged for 2020.07660.BD for BBO. Open access funding provided by FCT|FCCN (b-on).

Despite extensive search efforts, direct observations of the first [Population III (Pop III)] stars have not yet succeeded. Theoretical studies have suggested that late Pop III star formation is still possible in pristine clouds of high-mass galaxies, co-existing with Pop II stars, down to the epoch of reionization. Here, we re-assess this finding by exploring Pop III star formation in six 50 h−1 cMpc simulations performed with the hydrodynamical code dustyGadget. We find that Pop III star formation (∼10−3.4–10−3.2 M⊙ yr−1 cMpc−3) is still occurring down to z ∼ 6–8, i.e. well within the reach of deep JWST surveys. At these epochs, $\gtrsim\!{10}~{{\ \rm per\ cent}}$ of the rare massive galaxies with M⋆ ≳ 3 × 109 M⊙ are found to host Pop III stars, although with a Pop III/Pop II mass fraction $\lesssim\!0.1~{{\ \rm per\ cent}}$ . Regardless of their mass, Pop III-hosting galaxies are mainly found on the main sequence, at high star-formation rates, probably induced by accretion of pristine gas. This scenario is also supported by their increasing star-formation histories and their preferential location in high-density regions of the cosmic web. Pop III stars are found both in the outskirts of metal-enriched regions and in isolated, pristine clouds. In the latter case, their signal may be less contaminated by Pop IIs, although its detectability will strongly depend on the specific line of sight to the source, due to the complex morphology of the host galaxy and its highly inhomogeneous dust distribution.

The relentless contribution of women’s studies and feminist theory has shaped current academic and cultural perceptions of such a controversial subject as rape, which up to this day has received a fair share of attention but which will never cease to stimulate research, nor satisfy our enquiries. This paper aims to provide an analysis of literary and legal responses to this issue in two near contemporary tragedies: Titus Andronicus by William Shakespeare and Appius and Virginia by John Webster and Thomas Heywood, a work awaiting critical consideration. The plays present diegetic and mimetic similarities and are bound by a strong intertextuality which refers to their common sources. The paper also investigates those issues relating to the visual representation and the verbal transmission of rape, problems which feature in earlier and contemporary legal statutes.

We investigate a degenerating elliptic problem in a multi-structure $\Omega_\varepsilon$ of $ \mathbb{R}^3$, in the framework of the thermal stationary conduction with highly contrasting diffusivity. Precisely, $\Omega_\varepsilon$ consists of a fixed basis $\Omega^-$ surmounted by a thin cylinder $\Omega_\varepsilon^+$ with height $1$ and cross-section with a small diameter of order $\varepsilon$. Moreover, $\Omega^+_\varepsilon$ contains a cylindrical core, always with height $1$ and cross-section with diameter of order $\varepsilon$, with conductivity of order $1$, surrounded by a ring with conductivity of order $\varepsilon^2$. Also $\Omega^-$ has conductivity of order $\varepsilon^2$. By assuming that the temperature is zero on the top and on the bottom of the boundary of $\Omega_\varepsilon$, while the flux is zero on the remaining part of the boundary, under a suitable choice of the source term we prove that the limit problem, as $\varepsilon$ vanishes, boils down to two uncoupled problems: one in $\Omega^-$ and one in $\Omega^+_1$, and the problem in $\Omega^+_1$ is nonlocal. Moreover, a corrector result is obtained.

PURPOSE Appendiceal adenocarcinomas (ACs) are rare, histologically diverse malignancies treated as colorectal cancers despite having distinct biology and clinical behavior. To guide clinical decision making, we defined molecular subtypes of AC associated with patient survival, metastatic burden, and chemotherapy response. PATIENTS AND METHODS A comprehensive molecular analysis was performed in patients with AC to define molecular subtypes. Associations between molecular subtype and overall survival, intraoperative peritoneal cancer index, and first-line chemotherapy response were assessed adjusting for histopathologic and clinical variables using multivariable Cox proportional hazards, linear regression, and logistic regression models. RESULTS We defined distinct molecular lineages of mucinous appendiceal adenocarcinoma (MAAP) from co-occurring mutations in GNAS, RAS, and TP53. Of 164 MAAP tumors, 24 were RAS-mutant (mut) predominant ( RAS-mut/ GNAS-wild-type [wt]/ TP53-wt) with significantly decreased mutations and chromosomal alterations compared with tumors with GNAS mutations (GNAS-mut predominant) or TP53 mutations (TP53-mut predominant). No patient with RAS-mut predominant subtype metastatic MAAP died of cancer, and overall survival in this subgroup was significantly improved compared with patients with GNAS-mut ( P = .05) and TP53-mut ( P = .004) predominant subtypes. TP53-mut predominant subtypes were highly aneuploid; increased tumor aneuploidy was independently ( P = .001) associated with poor prognosis. The findings retained significance in patients with any metastatic AC. RAS-mut predominant metastases exhibited reduced peritoneal tumor bulk ( P = .04) and stromal invasion ( P < .001) compared with GNAS-mut or TP53-mut predominant tumors, respectively. Patients with RAS-mut predominant MAAP responded more to first-line chemotherapy (50%) compared with patients with GNAS-mut predominant tumors (6%, P = .03). CONCLUSION AC molecular patterns identify distinct molecular subtypes: a clinically indolent RAS-mut/GNAS-wt/TP53-wt subtype; a chemotherapy-resistant GNAS-mut predominant subtype; and an aggressive, highly aneuploid TP53-mut predominant subtype. Each subtype exhibits conserved clinical behavior irrespective of histopathology.

Background: In order to determine the optimal treatment strategy for oligometastatic breast cancer (OMBC), effective and safe treatments for metastatic sites and sensitive and specific imaging techniques are needed. But it is also essential to know the incidence of oligometastatic breast cancer and its clinical and biological characteristics [1]. Efficient imaging techniques and therapeutic tools exist, but knowledge of incidence, clinical and biological characteristics of OMBC is scarce. This is partly due to the lack of publications describing these data on recent, consecutive, and unselected series of OMBC. Methods: we retrospectively collected data from 998 patients diagnosed with synchronous or metachronous metastatic breast cancer (MBC) between January 2014 and December 2018 at our institution. The only criterion used to define OMBC was the presence of one to five metastases at diagnosis. Hormone receptor (HR) and HER2 receptor status, histology, SBR grade, number of metastases and organs affected were collected. Results: Of 998 MBC, 15.8% were OMBC (158/998). Among the series, 88% (139/158) of OMBC had 1 to 3 metastases and 86.7% (137/158) had only one organ involved. Among 158 patients, 52.5% (n=83) had bone metastases, 20.9% (n=33) had lymph node metastases, 14.6% (n=23) had liver metastases, 13.3% (n=21) had brain metastases, 8.2% (n=13) had lung metastases, and 3.8% (n=6) had others (skin, pancreas, adrenal). Among these 158 patients, 83.4% (n=131) had ductal breast carcinoma, 55.7% (n=88) had HR+/HER2- OMBC, 25.3% (n=40) had HER2+ OMBC and 19% (n=30) had HR-/HER2- OMBC. HR+/HER2- subtype was statistically associated with bone and bone only metastases (p=0.001), HER2+ subtype with brain metastases (p=0.001) and HR-/HER2- subtype with lymph node metastases (p=0.008). Visceral metastases (lung or liver) are not statistically associated with any biological subtypes. The proportion of OMBC with SBR grade III was statistically higher than in a series of 22,109 patients with MBC [2] (49.4% vs 35.2%; p< 0.001). Conclusion: OMBC is a heterogeneous entity. OMBC incidence is certainly much higher than the commonly used values. OMBC is not an indolent disease, and each subgroup, according to its biological and anatomical characteristics, may deserve a specific management. [1] Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol Off J Am Soc Clin Oncol 1995;13:8–10. https://doi.org/10.1200/JCO.1995.13.1.8. [2] Deluche E, Antoine A, Bachelot T, Lardy-Cleaud A, Dieras V, Brain E, et al. Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008–2016. Eur J Cancer 2020;129:60–70. https://doi.org/10.1016/j.ejca.2020.01.016. Citation Format: Jean Louis LACAZE, Clémence Brac de la Perrière, Mony Ung, Florence Dalenc, Vincent Nicolai, Eleonore De Maio, Marion Montastruc, Bastien Cabarrou, Nils Monselet, Ciprian Chira, Gauthier Glemarec, Thibaut Cassou-Mounat. Clinical and biological features of 158 consecutive and unselected oligometastatic breast cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-25.

Background: Deaths can occur after a patient has survived treatment for a serious illness in an intensive care unit (ICU). Mortality rates after leaving the ICU can be considered indicators of health care quality. This study aims to describe risk factors and mortality of surviving patients discharged from an ICU in a university hospital.Methods: Retrospective cohort study carried out from January 2017 to December 2018. Data on age, sex, length of hospital stay, diagnosis on admission to the ICU, hospital discharge outcome, presence of infection, and Simplified Acute Physiology Score III (SAPS 3) prognostic score were collected. Infected patients were considered as those being treated for an infection on discharge from the ICU. Patients were divided into survivors and non-survivors on leaving the hospital. The association between the studied variables was performed using the logistic regression model. Results: A total of 1,025 patients who survived hospitalization in the ICU were analyzed, of which 212 (20.7%) died after leaving the ICU. When separating the groups of survivors and non-survivors according to hospital outcome, the median age was higher among non-survivors. Longer hospital stays and higher SAPS 3 score values were observed among non-survivors. In the logistic regression, the variables age, length of hospital stay, SAPS 3, presence of infection, and readmission to the ICU were associated with hospital mortality.Conclusions: Infection on ICU discharge, ICU readmission, age, length of hospital stay, and SAPS 3 score increased risk of death in ICU survivors.

Purpose: Data about incidence, biological and clinical characteristics of oligometastatic breast cancer (OMBC) are scarce. However, these data are essential in determining optimal treatment strategy. Gaining knowledge of these elements means observing and describing large, recent, and consecutive series of OMBC in their natural history. Methods: We collected data retrospectively at our institution from 998 consecutive patients diagnosed and treated with synchronous or metachronous metastatic breast cancer (MBC) between January 2014 and December 2018. The only criterion used to define OMBC was the presence of one to five metastases at diagnosis. Results: Of 998 MBC, 15.8% were classified OMBC. Among these, 88% had one to three metastases, and 86.7% had only one organ involved. Bone metastases were present in 52.5% of cases, 20.9% had progression to lymph nodes, 14.6% to the liver, 13.3% to the brain, 8.2% to the lungs, and 3.8% had other metastases. 55.7% had HR+/HER2- OMBC, 25.3% had HER2+ OMBC, and 19% HR-/HER2- OMBC. The HR+/HER2- subtype statistically correlated with bone metastases (p=0.001), the HER2+ subtype with brain lesions (p=0.001), and the HR-/HER2- subtype with lymph node metastases (p=0.008). Visceral metastases were not statistically associated with any OMBC subtypes (p=0.186). OMBC-SBR grade III was proportionally higher than in the ESME series of 22,109 MBC (49.4% vs. 35.2%, p< 0.001). Conclusion: OMBC is a heterogeneous entity whose incidence is higher than has commonly been published. Not an indolent disease, each subgroup, with its biological and anatomical characteristics, merits specific management.

Background A minority of phase III trials in gastrointestinal oncology are positive. We assessed the association between their outcome and the level and characteristics of preexisting evidence. Methods EMBASE, PubMed, and proceedings from international meetings were searched for phase III gastrointestinal cancer trials (gastroesophageal, hepatocellular, biliary tract, pancreatic, small bowel, colorectal, anal, stromal, and neuroendocrine) between January 2000 and June 2020. Trials investigating anticancer drugs for advanced disease, with superiority design and standard treatments as control were eligible. The highest level of preexisting evidence was retrieved from the main study report. Results A total of 193 phase III trials were included, and 69 (35.8%) met their primary endpoint. Positivity rates were as follows: gastroesophageal 37%, colorectal 48%, pancreatic 17.1%, hepatocellular 20%, neuroendocrine 75%, and both biliary tract and GIST 60%. No information about preexisting evidence was found for 44 trials (22.8%). For the remaining 149, preexisting evidence consisted of phase II studies in 123 cases (82.6%) and phase I studies in 26 cases (17.4%). The probability of success was 34.1%, 35.8%, and 35.7%, respectively (P = .934). No parameter from prior studies predicted the outcome of phase III trials except β < .2 (P = .048). A numerically increased success rate was observed for phase III trials preceded by positive phase II studies (41.9% vs 18.5%, P = .2). Conclusions There does not appear to be an association between level of prior evidence and success of phase III gastrointestinal cancer trials. These data, along with the high phase III failure rate, highlight the need to improve the drug development process in this setting.

Background We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. Methods Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests. Results Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P Conclusions Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.

Diante da realidade na qual temos vivido, marcada por negacionismos e discursos de ódio, propomos neste estudo refletir direcionadas/o com o questionamento: a construção de estereótipos ocasiona a exclusão nos espaços escolares de pessoas entendidas neste estudo como (des)viadas por meio da deportação feita a seus corpos, direitos e vidas? Para tanto, consideramos utilizar a abordagem qualitativa, com coleta de dados por meio de entrevistas semiestruturadas e a técnica Snowball para selecionar as pessoas participantes, compondo 3 colaboradores. Para análise e referencial teórico, utilizamos Foucault e pessoas que se alinham com seus estudos. Todo o percurso reflexivo que o texto propõe leva o questionamento nas posturas ao que tange a escola, a formação docente, currículo e as políticas públicas. Um investimento que se alinhe na busca de possibilitar o espaço escolar como um local que legitima as diferenças e não naturaliza a exclusão.

First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced NSCLC. We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival.Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). OS, PFS, ORR, DOR, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor-burden reduction in responders to nivolumab plus ipilimumab were also assessed.In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). ORR was 36%; median DOR was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor PD-L11%, ≥1%, 1-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor-burden reduction ≥80%, 50-80%, or 30-50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population.Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC.

La Industria 4.0 o 4ta. Revolución Industrial es el dominio de los procesos industriales por medios cibernéticos [1]. Esta cibercultura requiere ingenieros competentes técnicamente, creativos, innovadores y capaces de comunicarse de manera compleja [2,3]. Tal formación implica un enfoque de enseñanza acorde. Investigamos: cuáles son los factores que promueven la creatividad y la innovación de los estudiantes de Ingeniería Industrial e impulsan el rol del docente hacia un enfoque curricular promotor de ellos. Se trabajó sobre los docentes, titular y ayudante, y 40 alumnos de la materia Organización Industrial A (80% trabaja) de Ingeniería Industrial de la Universidad de Morón, turno noche, en los períodos lectivos 2018 y 2019. Se aplicó la investigación-acción donde dos observadoras registraron el desarrollo de las clases y a posteriori analizaron con los docentes, elaborando categorías conceptuales: postura del docente frente al alumnado, participación de los alumnos, estrategias, recursos didácticos y evaluación. Dieron lugar a postular un nuevo enfoque para los cursos que se implementó durante 2018 y 2019, pasando de la práctica conductista al modelo ecológico [4]. Los alumnos respondieron positivamente al nuevo enfoque. El nivel de aprobación de trabajos prácticos fue 92,3 % en 2019; lo que dio un incremento de 26 % entre 2017 y 2019.

Background: Dysfunction of dopaminergic pathways has been considered to play a pivotal role in Parkinson’s disease (PD), affecting the processing of emotional and rewarding information, and potentially leading to symptoms of depression or apathy. However, some aspects of motivation in PD might be affected by non-dopaminergic mechanisms. Aim and method: The objective of this experimental medicine study was to investigate the contribution of serotonergic modulation via administration of citalopram (20 mg) for 7 days on motivated decision-making in twenty PD patients, measured using several different computerised tasks and clinical questionnaires that probe different aspects of decision-making. Twenty healthy controls were additionally tested without medication to assess any baseline differences between the two groups. Results: Results indicated that PD patients were overall less motivated than controls on an effort- and reward-based decision-making task. Citalopram increased or decreased willingness to exert effort for reward, depending on whether baseline motivation was high or low, respectively. A task assessing decision-making under risk revealed higher levels of risk aversion for potential losses in PD patients, which neither serotonin nor the patient’s regular dopaminergic medication seemed to restore. However, citalopram in PD was associated with more risk-seeking choices for gains, although patients and controls did not differ on this at baseline. Conclusion: The results provide evidence for a role of the serotonergic system in influencing some aspects of motivated decision-making in PD processes.

Nanoparticles (NPs) and other engineered nanomaterials have great potential as nanodrugs or nanomedical devices for biomedical applications. However, the adsorption of proteins in blood circulation or similar physiological fluids can significantly alter the surface properties and therapeutic response induced by most nanomaterials. For example, interaction with proteins can change the bloodstream circulation time and availability of therapeutic NPs or hinder the accumulation in their desired target organs. Proteins can also trigger or prevent agglomeration. By combining experimental and computational approaches, we have developed NPs carrying polyethylene glycol (PEG) polymeric coatings that mimic the surface charge distribution of proteins typically found in blood, which are known to show low aggregation under normal blood conditions. Here, we show that NPs with coatings based on apoferritin or human serum albumin display better antifouling properties and weaker protein interaction compared to similar NPs carrying conventional PEG polymeric coatings.

The need to address the impact of air pollution on health is reinforced by recent scientific evidence and the 2021 WHO Air Quality Guidelines (AQG). Air pollution is an avoidable risk factor causing a high burden for society with elevated deaths, health disorders, disabilities and huge socio-economic costs, especially in low- and middle-income countries. We have evaluated recent evidence from international reports, systematic reviews and official websites of international agencies. Growing evidence shows a causal relationship between air pollution exposure and acute lower respiratory infections, chronic obstructive pulmonary disease, asthma and lung cancer. Exposure to air pollution in both the short- and long-term has a serious impact on respiratory health. Harmful effects occur even at very low pollutant concentration levels, and there are no detectable thresholds below which exposure may be considered safe. The adverse respiratory health effects of air pollutants, even at low levels, are confirmed by recent epidemiological studies. Scientific respiratory societies and patient associations, along with other stakeholders in the health sector, should increase their engagement and advocacy to raise awareness of clean air policies and the latest WHO AQG.

Several electrocardiogram (ECG) criteria have been proposed to predict the location of the culprit occlusion in specific subsets of patients presenting with ST-segment elevation myocardial infarction (STEMI). The aim of this study was to develop, through an independent validation of currently available criteria, a comprehensive and easy-to-use ECG algorithm, and to test its diagnostic performance in real-world clinical practice.We analyzed ECG and angiographic data from 419 consecutive STEMI patients submitted to primary percutaneous coronary intervention over a one-year period, dividing the overall population into derivation (314 patients) and validation (105 patients) cohorts. In the derivation cohort, we tested60 previously published ECG criteria, using the decision-tree analysis to develop the algorithm that would best predict the infarct-related artery (IRA) and its occlusion level. We further assessed the new algorithm diagnostic performance in the validation cohort.In the derivation cohort, the algorithm correctly predicted the IRA in 88% of cases and both the IRA and its occlusion level (proximal vs mid-distal) in 71% of cases. When applied to the validation cohort, the algorithm resulted in 88% and 67% diagnostic accuracies, respectively. In a real-world comparative test, the algorithm performed significantly better than expert physicians in identifying the site of the culprit occlusion (P = .026 vs best cardiologist and P.001 vs best emergency medicine doctor).Derived from an extensive literature review, this comprehensive and easy-to-use ECG algorithm can accurately predict the IRA and its occlusion level in all-comers STEMI patients.

Silica nanoparticles decorated with aminocarboxylate ligands are novel vehicles to deliver antibiotics which are otherwise not able to penetrate the bacteria membrane and can also include agents for tracking and imaging.

The reservoir of molecular gas (H$_{\rm 2}$) represents the fuel for the star formation (SF) of a galaxy. Connecting the star formation rate (SFR) to the available H$_{\rm 2}$ is key to accurately model SF in cosmological simulations of galaxy formation. We investigate how modifying the underlying modelling of H$_{\rm 2}$ and the description of stellar feedback in low-metallicity environments (LMF, i.e. low-metallicity stellar feedback) in cosmological, zoomed-in simulations of a Milky Way-size halo influences the formation history of the forming, spiral galaxy and its final properties. We exploit two different models to compute the molecular fraction of cold gas (f$_{\rm H_{\rm 2}}$): $i)$ the theoretical model by Krumholz et al. (2009b) and $ii)$ the phenomenological prescription by Blitz & Rosolowsky (2006). We find that the model adopted to estimate f$_{\rm H_{\rm 2}}$ plays a key role in determining final properties and in shaping the morphology of the galaxy. The clumpier interstellar medium (ISM) and the more complex H$_{\rm 2}$ distribution that the Krumholz et al. (2009b) model predicts result in better agreement with observations of nearby disc galaxies. This shows how crucial it is to link the SFR to the physical properties of the star-forming, molecular ISM. The additional source of energy that LMF supplies in a metal-poor ISM is key in controlling SF at high redshift and in regulating the reservoir of SF across cosmic time. Not only is LMF able to regulate cooling properties of the ISM, but it also reduces the stellar mass of the galaxy bulge. These findings can foster the improvement of the numerical modelling of SF in cosmological simulations., accepted for publication in MNRAS

ImportanceCurrent third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors for RAS wild-type (WT) MCRC may be valuable for these patients.ObjectiveTo compare the anti-EGFR monoclonal antibody panitumumab plus standard-of-care trifluridine-tipiracil with trifluridine-tipiracil alone as third-line therapy for RAS WT MCRC.Design, Setting, and ParticipantsThis phase 2 randomized clinical trial (RCT) was conducted in 7 Italian centers from June 2019 to April 2022. Patients with refractory RAS WT MCRC who had a partial or complete response to first-line chemotherapy plus an anti-EGFR monoclonal antibody and an anti-EGFR drug–free interval of 4 or more months during second-line therapy were included.InterventionsPatients were randomized 1:1 to receive panitumumab plus trifluridine-tipiracil or trifluridine-tipiracil alone.Main Outcomes and MeasuresThe primary end point was progression-free survival (PFS). Circulating tumor DNA (ctDNA) extended sequence variation analysis was performed in a subgroup of patients.ResultsOf 62 included patients, 31 received panitumumab plus trifluridine-tipiracil (19 [61.3%] male; median age, 65 years [range, 39-81 years]) and 31 received trifluridine-tipiracil alone (17 [54.8%] male; median age, 66 years [range, 32-82 years]). The primary end point was met. Median PFS was 4.0 months (95% CI, 2.8-5.3 months) in the panitumumab plus trifluridine-tipiracil arm vs 2.5 months (95% CI, 1.4-3.6 months) in the trifluridine-tipiracil only (hazard ratio [HR], 0.48; 95% CI, 0.28-0.82; P = .007). Pretreatment plasma RAS/BRAF WT ctDNA identified patients obtaining prolonged clinical benefit with panitumumab plus trifluridine-tipiracil compared with trifluridine-tipiracil, with PFS rates at 6 months of 38.5% vs 13.0% and at 12 months of 15.4% vs 0%. A ctDNA liquid-biopsy extended mutation analysis by FoundationOne Liquid CDx (profiling 324 genes) was performed in a subgroup of patients with baseline plasma RAS/BRAF WT ctDNA; in 15 of 23 patients (65.2%) whose tumors were WT for KRAS, NRAS, BRAFV600E, EGFR, ERBB2, MAP2K1, and PIK3CA, median PFS was 6.4 months (95% CI, 3.7-9.2 months). Within this group of 15 patients, 2 (13.3%) had partial response, 11 (73.3%) had stable disease, and 2 (13.3%) had disease progression as best response.Conclusions and RelevanceIn this RCT, third-line treatment with the anti-EGFR monoclonal antibody panitumumab plus the standard-of-care trifluridine-tipiracil resulted in improved PFS compared with treatment with trifluridine-tipiracil alone among patients with refractory RAS WT MCRC. The findings support the clinical utility of liquid biopsy–guided anti-EGFR rechallenge therapy for refractory RAS WT MCRC.Trial RegistrationClinicalTrials.gov Identifier: NCT05468892

IntroductionMost Mediterranean fish stocks are overexploited owing to high fishing efforts and poor exploitation patterns. Demersal trawl fisheries are considered the most impactful fishery type because of the high quantities of unwanted catch that is then routinely discarded at sea.MethodsIn the present study, two types of by-catch reduction devices (BRDs), that is a sorting grid (Grid-T45 40 mm) and a T90 50 mm codend, were compared to a typical commercial bottom trawl net (control) in terms of size structures and catch per unit effort to assess the effect of gear modification on the selectivity of crustacean fisheries in the central Mediterranean Sea. In particular, three randomly selected trawlers were involved in a paired hauls experiment fishing at the same time in the same fishing ground. Each trawler carried out four hauls per day during a 3-day campaign for a total of 36 hauls. The target species of the fishery is Parapenaeus longirostris (herein DPS), and the main commercial by-catch is Merluccius merluccius (herein HKE).ResultsThe results showed that the landing per unit effort (LPUE) of DPS was higher for Grid-T45 40 mm net, although it did not differ significantly from that of the control net. Conversely, the discard per unit effort (DPUE) of the control net was significantly higher than of both BRD configurations. For HKE, a slightly higher LPUE was recorded using the T90 50 mm codend compared to that of the control, but this result was not statistically significant. The lowest DPUE was found for the T90 50 mm codend, with significant differences compared to that of the control and Grid-T45 40 mm net. The catch comparison of the size structures analysed through generalised linear mixed models highlighted that the Grid-T45 40 mm net was more effective in catching adult DPS, whereas the T90 50 mm codend was more selective for adult HKE.DiscussionIn conclusion, although further studies should be carried out in future to test the performance of the BRDs in different areas and seasons, the investigated gear seems to be promising for reducing the catch of undersized individuals and contributing to mitigating the current overfishing of DPS and HKE.

This short research note was contributed to the paper (The Coming Decade of Digital brain.... Amunds et al) : The collision of increasingly powerful and AI driven digital technologies and vast amounts of brain data, which are growing exponentially at increasing levels of granularity is creating unprecedented opportunities and challenges for neuroscience. \ The rate of acquisition of new knowledge from research data is higher than the ability of the research community to process and act upon new findings. The adoption of informatics is necessary but in turn, it brings increasing layers of complexity and codification. To ensure trustworthiness and reliability, the convergence of digital technologies and brain data must be supported by shared knowledge representation models, so that the data structures and their encodings become universally accessible to researchers with diverse backgrounds and specializations. To some extent, these shared models are being developed and harmonized, although they are limited in scope. ; The evolution of neuromorphic computing comes with enormous complexities and risks thus increasing the need for accurate transparent and reliable knowledge models to ensure the accountability of computational models and infrastructures relying on powerful new technologies and architectures, yet devising such models is non-trivial, especially taking into account the dynamics of emergent knowledge in the context of shifting scientific paradigms. System level approaches that enable whole brain science need to be supported by system level knowledge representation to serve as the basis for adequate computational environments, while reducing the computational load. Systemic approaches must not only include function and structure models, but also requires the alignment of behavior, a characterization of behavioral aspects has been provided as a contribution to the ebrains/HBP project. Experiments must evaluate the different combinations of interactions between structure function and behaviors and scale free computation must be achieved to support the dynamic evolution of capabilities New Understanding of higher order cognitive functions such as meta cognition must drive the research agenda. Neurosymboilc integration using model cards can be leveraged to facilitate this convergence, Presented to Ebrains Colab as a contribution to paper under the same title

Context Endothelial progenitor cells (EPCs), which are involved in the mechanisms of vascular repair and sexual function, are decreased in diabetic women compared with general population. Objective This work aimed to investigate the circulating levels of EPCs and the change in sexual function during the menstrual cycle in women with type 1 diabetes (T1DM) compared with healthy women. Methods This case-control observational study was conducted at the Unit of Endocrinology and Metabolic Diseases at University Hospital “Luigi Vanvitelli’’ of Naples. Participants included 36 women with T1DM and 64 age-matched healthy controls. EPCs were quantified by flow cytometry and sexual function was assessed using the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale. All assessments were made at the follicular, ovulatory, and luteal phases of the same menstrual cycle. Main outcome measures included differences in EPCs levels and sexual function between patients and controls. Results Compared with controls, women with T1DM showed significantly lower levels of both CD34 + (P Conclusion Women with T1DM show lower levels of EPCs during the menstrual cycle compared with controls. EPCs count predicts sexual function in this selected population.

Although Tao brush has become one of the most studied and used endometrial cytological samplers, concerns remain about the adequacy of the cytological sample compared with definitive histology. We aimed to assess accuracy of cytological examination from Tao brush sampling in diagnosing endometrial premalignancy and malignancy through a systematic review and meta-analysis. Seven electronic databases were searched from January 2000 to July 2021 for all studies which allowed assessment of accuracy of Tao brush in diagnosing endometrial premalignancy and malignancy. We calculated sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), diagnostic odds ratio (DOR) and area under the curve (AUC) on summary receiver operating characteristic (SROC) curve. Five studies with 774 patients were included. In diagnosing endometrial premalignancy and malignancy, cytological examination from Tao brush endometrial sampling showed pooled sensitivity of 0.95 (95% CI, 0.90-0.98), specificity of 0.92 (95% CI, 0.90-0.94), LR+ of 12.73 (95% CI, 3.94-41.18), LR- of 0.09 (95% CI, 0.05-0.18), DOR of 184.84 (95% CI, 24.37-1401.79), AUC of 0.9757 (standard error: 0.013). In conclusion, cytological examination from Tao brush seems to have a high diagnostic accuracy and might be proposed as both screening and diagnostic tool. However, further studies are necessary to confirm these findings.