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The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m 2 /d iv on days 1–3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H 0 50%, H 1 72%, β 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile. Immune checkpoint inhibitors have been incorporated as the standard of care for some high-grade neuroendocrine neoplasms (NEN), but their efficacy in digestive NEN is still unclear. Here the authors report the results of a phase II trial of nivolumab (anti-PD1) in combination with platinum-doublet chemotherapy (carboplatin-etoposide) as first-line treatment in patients with unresectable or metastatic advanced grade 3 NENs of gastro-enteropancreatic or unknown origin.

Agriculture uses 80% of global water resources, driving several water management challenges across the world. These challenges require the exchange of effective practices. We found that California’s Tulare Lake Basin (TLB) and Mexico’s Nazas–Aguanaval watershed share key features, leading us to propose the TLB as a model of climate resilience. After contrasting the policies for TLB with those for Nazas–Aguanaval, we found that no constrained pricing policy proposal exists for the Nazas–Aguanaval watershed. We apply a hydro-economic model using Positive Mathematical Programming to support an incentive structure for reducing water use in agriculture while maximizing profits. The optimal crop policy could reduce water demand by 20%, with a trade-off of an 11% reduction in profits. This would save 185.4 hm3/year, which represents 90% of the volume required for an ongoing infrastructure project for urban water supply in the watershed. Additionally, implementing a price of 14 USD/dam3 could increase the irrigation district’s revenue, boosting farmers’ profits by up to 16% and district revenue by up to 134%. Our results demonstrate the benefits of applying Positive Mathematical Programming in a semiarid watershed to support water and agriculture policy. This research is a starting point for increasing the climate resilience of watersheds under water and financial stress.

For patients with metastatic colorectal cancer (mCRC) that have failed a first-line oxaliplatin-based regimen, the preferred treatment option is an irinotecan-based regimen. This prospective, observational, noncomparative, post-authorization safety study (OZONE) evaluated the safety and effectiveness of aflibercept plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) in patients with mCRC treated in daily practice after failure of an oxaliplatin-based regimen. Patients were grouped by age, renal impairment, hepatic impairment, race, number, and type of prior anticancer therapy. Of 766 treated patients enrolled, 59.5% were male, 94.8% had an Eastern Cooperative Oncology Group performance status of 0–1, all received previous chemotherapy (97.8% including oxaliplatin), and 58.6% had prior exposure to bevacizumab. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 68.3% of patients. Neutropenia, hypertension, diarrhea, and asthenia were the most frequently occurring grade ≥ 3 TEAEs. Antivascular endothelial growth factor class events were infrequent. Subgroup analyses did not reveal major differences in the safety profile according to age, renal and hepatic status, race, or prior anticancer therapy. For the total population, median overall survival was 12.5 months, median progression-free survival was 6.1 months, and overall response rate was 16.3%. Aflibercept in combination with FOLFIRI is a safe and efficacious regimen administered in current clinical practice to patients with mCRC previously treated with oxaliplatin. The study results, conducted in real-world clinical practice with a less selected patient population, are aligned with the VELOUR (NCT00561470) trial and no new safety issues were identified.

Groundwater is critical for society's adaptation to climate variability and change but simultaneously, is threatened by them. This paper reviews the linkages between climate oscillations and groundwater, focusing on studies reported in the Scopus database that use wavelet analysis. A total of 27 records published since 2009, covering North America, Europe, and Asia, have been analysed. El Nino Southern Oscillation (ENSO), the North Atlantic Oscillation (NAO), Arctic Oscillation, and the Pacific Decadal Oscillation (PDO) show important effects on groundwater levels in North America. In Europe, NAO is the most dominant, while in Asia, distinct climate indices impact groundwater levels at different periodicities. The hydrogeological features of the aquifers condition the magnitude of the response of groundwater to the climate signal and there is conflicting evidence concerning the effects of land-use change and human activities on detecting climate signals in aquifers. Further research must focus on understanding the effect of human activities in the climate signal perception in aquifers, unravelling the physical mechanisms underlying the propagation of climate signals through aquifers, developing predictive models to support water management decisions, and finding alternative methods to assess this influence in regions with limited observational data. The interaction between the atmosphere and groundwater is of critical relevance for the achievement of water security and this review contributes to synthesizing our current understanding of this relationship.

Background: Therapy using lutetium-177 dotatate (177LU) was approved in Europe for the treatment of advanced neuroendocrine tumors (NETs) in 2017. Since then, it has become part of the strategies in the treatment of NETs, making it now possible to evaluate real-life results. Research Design and Methods: Single-arm, retrospective, multicenter, cohort study of all the patients with metastatic NETs treated with 177LU (four cycles of 200 mCi every 8 weeks) in the two medical centers dedicated to the treatment of NETs from the region of Aragón, Spain, from 2017 to 2024. Descriptive analysis of demographic characteristics, efficacy, and survival analysis were performed using the statistics software Jamovi 2.6.14. Results: Sixty-eight patients were included. The majority were male, and the most frequent primary location was the pancreas. The ORR was 30.9%. The DCR was 88%. The median OS was 47.4 months [95% CI, 25.6–NE]. The median PFS was 26.1 months [95% CI, 18.5–68.3]. High-grade tumors, multiple previous treatments, and pancreatic location presented worse OS. In total, 42.6% presented any grade adverse event (17.2% hematologic, 30.9% GI symptoms). Conclusions: The efficacy of 177LU in our study is like that observed in similar studies. Acceptable tolerance has been shown. Pancreatic tumors, previous treatments, and higher grades demonstrated worse outcomes. The new research line must consider the use of treatment with 177LU in earlier lines for metastatic disease as well as its possible use in local or locally advanced disease.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of approximately 13% for advanced stages. While the majority of PDAC cases are sporadic, a significant subset is attributable to hereditary and familial predispositions, accounting for approximately 25% of cases. This article synthesizes recent advancements in the understanding, detection, and management of hereditary pancreatic cancer (PC). Results: Our review highlights the critical role of genetic testing (GT) in identifying high-risk individuals (HRIs), with germline pathogenic variants (PVs) found in up to 20% of hereditary PDAC cases. Since the implementation of next-generation sequencing (NGS) panels in 2014, detection capabilities have been significantly enhanced. HRIs can be included in screening programs that facilitate the early detection of PDAC. Early detection strategies, including the use of microribonucleic acid (miRNAs) signatures and novel imaging techniques like hyperpolarized 13C-magnetic resonance spectroscopy (MRS) have shown promising results. The identification of germline pathogenic variants (PVs) or mutations in homologous recombination (HR) genes plays a predictive role in the response to various treatments, prolonging patient survival. Discussion: Universal germline testing for PDAC, as recommended by the National Comprehensive Cancer Network (NCCN), is now a standard practice, facilitating the identification of at-risk individuals and enabling targeted surveillance and intervention. Multidisciplinary management, integrating genetic counseling, imaging, and gastrointestinal services, is essential for optimizing outcomes. Conclusions: Advances in genetic testing and biomarker research are transforming the landscape of hereditary PC management. Early detection and personalized treatment strategies are pivotal in improving survival rates. Ongoing multi-institutional research efforts are crucial for validating biomarkers and developing preventive measures, ultimately aiming to reduce the burden of this aggressive cancer.

PurposeThe aim of this paper is to share the details of a multidisciplinary approach, which includes occupational therapy, and to review the factors that should be considered in the evaluation and treatment of children with autism spectrum disorders (ASD) who are excessively selective in their food choices. Issues in this area are complex and often related to several complementary domains (medical, nutritional, psychosocial, sensorimotor, etc.). However, feeding disorders are frequently assessed and treated from a single discipline and important issues are missed or confounded.Design/methodology/approachA team of experienced clinicians in the field of paediatric feeding disorders gathered the knowledge and experience they acquired from working with individuals with ASD as well as with individuals with other neurodevelopmental diagnosis. A review of current literature in paediatric feeding disorders was used to document and explicate the multifactorial nature of feeding disorders in children with ASD and justify the need for a multidisciplinary approach to issues in this area.FindingsFeeding disorders in children with ASD are linked to multiple sensory, motor, behavioural, nutritional and gastrointestinal comorbidities. A multidisciplinary approach is needed and increasingly recommended. However, multidisciplinary teams, specialised in the care of children with ASD and feeding issues, continue to be difficult to locate and access for families. The authors sought to highlight the signs of feeding problems in children with ASD from different domains and share a model of a multidisciplinary approach that can lead to more successful interventions.Originality/valueThe detailed description of the domains linked to feeding issues and the clinical descriptions provided throughout the paper create a roadmap for other clinicians aiming to set up similar teams.

This study aimed to analyze the psychological affectation of health professionals (HPs) of Spanish Emergency Medical Services (EMSs) according to the cumulative incidence (CI) of COVID-19 cases in the regions in which they worked. A cross-sectional descriptive study was designed, including all HPs working in any EMS of the Spanish geography between 1 February 2021 and 30 April 2021. Their level of stress, anxiety and depression (DASS-21) and the perception of self-efficacy (G-SES) were the study’s main results. A 2-factor analysis of covariance was used to determine if the CI regions of COVID-19 cases determined the psychological impact on each of the studied variables. A total of 1710 HPs were included. A third presented psychological impairment classified as severe. The interaction of CI regions with the studied variables did not influence their levels of stress, anxiety, depression or self-efficacy. Women, younger HPs or those with less EMS work experience, emergency medical technicians (EMT), workers who had to modify their working conditions or those who lived with minors or dependents suffered a greater impact from the COVID-19 pandemic in certain regions. These HPs have shown high levels of stress, anxiety, depression and medium levels of self-efficacy, with similar data in the different geographical areas. Psychological support is essential to mitigate their suffering and teach them to react to adverse events.

We estimate the effect of unemployment on cultural expenditure and income, and the income elasticity of cultural demand. When a household member enters an unemployment spell, households reduce cultural expenditure and their income falls. Unemployment does not affect participation in cultural markets, and participating households exhibit larger income elasticity. The reduction in cultural expenditure and income is larger for men, and individuals who hold a tertiary education degree tend to experience a larger income fall and a smaller cultural expenditure reduction. We find that the reduction in cultural expenditure is larger during a recession, while the effect of unemployment on household income does not fluctuate much over the business cycle.