High-resolution image dataset for the automatic classification of phenological stage and identification of racemes in Urochloa spp. hybrids.

Urochloa grasses are widely used forages in the Neotropics and are gaining importance in other regions due to their role in meeting the increasing global demand for sustainable agricultural practices. High-throughput phenotyping (HTP) is important for accelerating Urochloa breeding programs focused on improving forage and seed yield. While RGB imaging has been used for HTP of vegetative traits, the assessment of phenological stages and seed yield using image analysis remains unexplored in this genus. This work presents a dataset of 2,400 high-resolution RGB images of 200 Urochloa hybrid genotypes, captured over seven months and covering both vegetative and reproductive stages. Images were manually labelled as vegetative or reproductive, and a subset of 255 reproductive stage images were annotated to identify 22,340 individual racemes. This dataset enables the development of machine learning and deep learning models for automated phenological stage classification and raceme identification, facilitating HTP and accelerated breeding of Urochloa spp. hybrids with high seed yield potential.

Substrate Interference and Strain in the Second-Harmonic Generation from MoSe2 Monolayers.

Nonlinear optical materials of atomic thickness, such as non-centrosymmetric 2H transition metal dichalcogenide monolayers, have a second-order nonlinear susceptibility (χ(2)) whose intensity can be tuned by strain. However, whether χ(2) is enhanced or reduced by tensile strain is a subject of conflicting reports. Here, we grow high-quality MoSe2 monolayers under controlled biaxial strain created by two different substrates and study their linear and nonlinear optical responses with a combination of experimental and theoretical approaches. Up to a 15-fold overall enhancement in second-harmonic generation (SHG) intensity is observed from MoSe2 monolayers grown on SiO2 when compared to its value on a Si3N4 substrate. By considering an interference contribution from different dielectrics and their thicknesses, a factor of 2 enhancement of χ(2) was attributed to the biaxial strain: substrate interference and strain are independent handles to engineer the SHG strength of non-centrosymmetric 2D materials.

GLABRA2 transcription factor integrates arsenic tolerance with epidermal cell fate determination.

Arsenic poses a global threat to living organisms, compromising crop security and yield. Limited understanding of the transcriptional network integrating arsenic-tolerance mechanisms with plant developmental responses hinders the development of strategies against this toxic metalloid. Here, we conducted a high-throughput yeast one-hybrid assay using as baits the promoter region from the arsenic-inducible genes ARQ1 and ASK18 from Arabidopsis thaliana, coupled with a transcriptomic analysis, to uncover novel transcriptional regulators of the arsenic response. We identified the GLABRA2 (GL2) transcription factor as a novel regulator of arsenic tolerance, revealing a wider regulatory role beyond its established function as a repressor of root hair formation. Furthermore, we found that ANTHOCYANINLESS2 (ANL2), a GL2 subfamily member, acts redundantly with this transcription factor in the regulation of arsenic signaling. Both transcription factors act as repressors of arsenic response. gl2 and anl2 mutants exhibit enhanced tolerance and reduced arsenic accumulation. Transcriptional analysis in the gl2 mutant unveils potential regulators of arsenic tolerance. These findings highlight GL2 and ANL2 as novel integrators of the arsenic response with developmental outcomes, offering insights for developing safer crops with reduced arsenic content and increased tolerance to this hazardous metalloid.

Single-dose 1cp-LSD administration for canine anxiety: a pilot study.

Anxiety affects 14-20% of dogs. Pharmacological treatments often fail. Psychedelics have shown to be useful for anxiety and depression in humans, but their veterinary use remains unexplored. We aimed to determine the effects of low-dose 1-cyclopropionyl-d-lysergic acid diethylamide (1cp-LSD) administered in a single dose to a dog, to observe the effect and establish the safety of the substance. The patient was a 13-year-old female dog, weighing 13 kg, mixed breed, and spayed. A total of 5 µg was administered orally, equivalent to 0.38 µg/kg. The animal has had a history of separation related behavioral problems throughout her life. To objectively assess the degree of anxiety in the dog, a validated scale was utilized. The trial was scheduled at the house where the animal lives. The owner was present throughout the experience. Informed consent was obtained prior to the assay. The trial began at 12:15 p.m. on January 10, 2024, lasting for 5 and a half hours. The response to anxiety-inducing stimuli was equally anxious during the first two hours. From that point onwards, a significant change in the animal's behavior was observed, with no signs/mild signs of anxiety. The trial concluded without any adverse effects on the animal. The patient did not show signs of having a psychedelic experience. This is the first time that a study of this nature has been conducted and reported in the canine species. 1cp-LSD proved to be safe and exerted the desired effect on the animal's behavior, significantly reducing the patient's anxiety.

Tolerance to spittlebugs (Aeneolamia varia) in Urochloa spp. and Megathyrsus maximus grasses: A dataset for plant damage phenotyping.

This dataset results from controlled experiments that assess the tolerance of Urochloa spp. and Megathyrsus maximus grasses to nymphal and adult spittlebug damage, particularly from Aeneolamia varia, which significantly impacts forage production in Neotropical regions. Data were collected under standardized conditions using high-throughput phenotyping methods, integrating image-capture techniques and analyses to ensure precise and consistent data acquisition. The dataset serves as a foundational resource for developing and validating computer vision models aimed at automated phenotyping, enabling accurate and high-throughput assessment of plant tolerance to spittlebug damage. Researchers can use the dataset to benchmark and compare different methodologies for plant damage assessment, fostering standardization and reproducibility in phenotyping studies.

Using an organizational change model to improve lung cancer surgery services over five years.

Background: Lung cancer is the most common cause of cancer death in the UK resulting in 21% of all cancer deaths. In 2016, local lung cancer surgery services required improvement due to under-representation in cancer resections and resource scarcity during the pandemic, which affected critical care bed availability and extended postoperative stays. The aim of this service improvement was to increase the number of lung cancer resection; develop minimally invasive techniques and reduce the use of Critical Care Unit beds by 35% (a subsequent goal). Methods: A five-year plan, guided by Kotter's 8-step change model, was initiated to address these issues. This model promotes sustainable change by setting clear goals, effective communication, and stakeholder involvement. Initial changes included hiring a thoracic surgeon experienced in uniportal video assisted thoracoscopy and enhanced recovery protocols. The team grew to three thoracic surgeons by 2020. The service increased operating theatre days and adopted new postoperative practices to reduce complications and hospital stays. Lung Cancer Multidisciplinary Team Meetings were consistently covered by thoracic surgeons, ensuring comprehensive care. Data on surgical activity were collected from departmental databases and national audits, with internal audits conducted regularly. Statistical significance was tested using chi-square tests with P values <0.05. Results: The number of surgical procedures more than doubled, with primary lung cancer resections increasing nearly three-fold from 12.8% to 29.8% over six years. Postoperative complications and mortality rates remained low. Critical care bed usage dropped significantly during the pandemic, with new protocols enabling safe recovery in general surgical areas. Conclusions: The successful expansion of thoracic surgical services was attributed to the dedicated minimally invasive surgeons, enhanced recovery measures, and skilled staff. The change model facilitated efficient and dynamic progress. With the introduction of lung cancer screening programs, the demand for surgical services is expected to rise. The effective change model will be re-applied to meet this demand. The organizational change model, focused on patients and staff, achieved sustained quality improvement in lung cancer care despite challenging conditions like the coronavirus disease 2019 pandemic.

Exploring Quinazoline Nitro-Derivatives as Potential Antichagasic Agents: Synthesis and In Vitro Evaluation.

Trypanosoma cruzi is a protozoan parasite that causes Chagas disease in humans. The current antichagasic drugs nifurtimox and benznidazole have inconveniences of toxicity; therefore, the search for alternative therapeutic strategies is necessary. The present study reports the synthesis, drug-likeness predictions, and in vitro anti-trypanosome activity of a series of 14 quinazoline 2,4,6-triamine derivatives. All compounds were tested against T. cruzi (epimastigotes and trypomastigotes) and in HFF1 human foreskin fibroblasts. The bioassays showed that compounds 2-4 containing nitrobenzoyl substituents at 6-position of the quinazoline 2,4,6-triamine nucleus were the most potent on its antiprotozoal activity. The effect was observed at 24 h and it was preserved for at least 5 days. Also, compounds 2-4 were not toxic to the human control cells, showing high selectivity index. The quinazoline nitro derivatives have potential use as antichagasic agents.

Differential exposure to second-generation anticoagulant rodenticides in raptors from continental and insular regions of the Iberian Peninsula.

The global impact of anticoagulant rodenticides (ARs) on non-target species is well-recognized. Birds of prey, as apex predators, are highly vulnerable to AR exposure and are widely used as biomonitors for priority pollutants in Europe. This study investigates differential SGAR exposure in raptors from insular versus continental regions, hypothesizing greater exposure in insular areas due to ecological factors like reduced prey diversity, intensive rodenticide use, and resistant rodent populations. We analyzed the livers of 190 common kestrels (Falco tinnunculus) and 104 common buzzards (Buteo buteo) across the Iberian Peninsula and its archipelagos using LC-MS/MS to assess their role as AR sentinels and the differences between insular and continental areas. Results revealed a high prevalence (>80%) of second-generation anticoagulant rodenticides (SGARs), with brodifacoum and bromadiolone, being the most frequent. Multiple SGAR detections were also common (≈50%). A binomial logistic regression showed that species and region significantly influence the likelihood of SGAR exposure. Kestrels had a greater probability of exceeding 100 ng/g wet weight (ww) compared to buzzards. Raptors from insular territories were ten times more likely to have higher SGAR concentrations than those from continental areas. However, the legal restriction on SGAR bait concentrations that came into effect in 2018 did not significantly impact exposure levels. This study highlights the need for targeted conservation efforts to mitigate AR exposure risk in vulnerable island ecosystems.

Successfully Nonsurgical Epidermoid Cyst Management with Recombinant Hydrolytic Enzymes: A Case Report.

Introduction: Epidermoid cysts (E.C.s), also known as sebaceous cysts, are benign asymptomatic subepidermal nodules filled with keratin material. These cysts originate from the follicular infundibulum, which when obstructed by keratin, results in cyst formation. Conventionally, E.C.s have been managed surgically with a high success rate and minimal complications. In this report, we present the successful resolution of an E.C. using a minimally invasive technique involving the intralesional injection of recombinant hydrolytic enzymes like hyaluronidase, collagenase, and lipase. Case Presentation: A 44-year-old woman with no significant medical history presented to the clinic with a mass on her right cheek that had been evolving for over 10 years. Skin and soft tissue ultrasound confirmed the presence of an E.C. of 9.3×6.6 × 9.3 mm. Owing to the size and location of the cyst, a decision was made to infiltrate the lesion with recombinant enzymes. Remarkably, significant clinical improvement was observed on Day 21, and complete dissolution of the E.C. occurred 40 days after the initial intervention. Importantly, no recurrences were observed during the 4-year follow-up period. Conclusion: Intralesional administration of hydrolytic enzymes represents an innovative technique in the management of E.C.s. However, further controlled studies are required to determine the efficacy and safety of this procedure.

A stacked autoencoder-based aid system for severity degree classification of knee ligament rupture.

BACKGROUND: Knee ligament rupture is one of the most common injuries, but the diagnosis of its severity tends to require the use of complex methods and analyses that are not always available to patients. AIM: The objective of this research is the investigation and development of a diagnostic aid system to analyze and determine patterns that characterize the presence of the injury and its degree of severity. METHODS: Implement a novel proposal of a framework based on stacked auto-encoder (SAE) for ground reaction force (GRF) signals analysis, coming from the GaitRec database. Analysis of the raw data is used to determine the main features that allow us to diagnose the presence of a knee ligament rupture and classify its severity as high, mid or mild. RESULTS: The process is divided into two stages to determine the presence of the lesion and, if necessary, evaluate variations in features to classify the degree of severity as high, mid, and mild. The framework presents an accuracy of 87 % and a F1-Score of 90 % for detecting ligament rupture and an accuracy of 86.5 % and a F1-Score of 87 % for classifying severity. CONCLUSION: This new methodology aims to demonstrate the potential of SAE in physiotherapy applications as an evaluation and diagnostic tool, identifying irregularities associated with ligament rupture and its degree of severity, thus providing updated information to the specialist during the rehabilitation process.

Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity.

Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity.

Targeting spinal mechanistic target of rapamycin complex 2 alleviates inflammatory and neuropathic pain.

The development and maintenance of chronic pain involves the reorganization of spinal nociceptive circuits. The mechanistic target of rapamycin complex 2 (mTORC2), a central signaling hub that modulates both actin-dependent structural changes and mTORC1-dependent mRNA translation, plays key roles in hippocampal synaptic plasticity and memory formation. However, its function in spinal plasticity and chronic pain is poorly understood. Here we show that pharmacological activation of spinal mTORC2 induces pain hypersensitivity, whereas its inhibition, using downregulation of the mTORC2-defining component Rictor, alleviates both inflammatory and neuropathic pain. Cell-type-specific deletion of Rictor showed that the selective inhibition of mTORC2 in a subset of excitatory neurons impairs spinal synaptic potentiation and alleviates inflammation-induced mechanical and thermal hypersensitivity, and nerve injury-induced heat hyperalgesia. The ablation of mTORC2 in inhibitory interneurons strongly alleviated nerve injury-induced mechanical hypersensitivity. Our findings reveal the role of mTORC2 in chronic pain and highlight its cell-type-specific functions in mediating pain hypersensitivity in response to peripheral inflammation and nerve injury.

Triiodide Formation Governs Oxidation Mechanism of Tin-Lead Perovskite Solar Cells via A-Site Choice.

Mixed tin-lead (Sn-Pb) halide perovskites stand out as promising materials for next-generation photovoltaics and near-infrared optoelectronics. However, their sensitivity to oxidative degradation remains a major hurdle toward their widespread deployment. A holistic understanding of their oxidation processes considering all their constituent ions is therefore essential to stabilize these materials. Herein, we reveal that A-site cation choice plays an inconspicuous yet crucial role in determining Sn-Pb perovskite stability toward oxidation. Comparing typical A-site compositions, we show that thin films and solar cells containing cesium are more resistant to oxidative stress relative to their methylammonium analogs. We identify degradation in these compositions to be closely linked to the presence of triiodide, a harmful species evolving from native I2 oxidants. We find that hydrogen bonding between methylammonium and I2 promotes triiodide formation, while the strong polarizing character of cesium limits this process by capturing I2. Inspired from these findings, we design two strategies to boost stability of sensitive methylammonium-based Sn-Pb perovskite films and devices against oxidation. Specifically, we modulate the polarizing character of surface A-sites in perovskite via CsI and RbI coatings, and we incorporate Na2S2O3 as an I2 scavenging additive. These crucial mechanistic insights will pave the way for the design of highly efficient and stable Sn-Pb perovskite optoelectronics.

Effect of bariatric surgery in the body burden of persistent and non-persistent pollutants: longitudinal study in a cohort of morbidly obese patients.

Introduction: Obesity is a pathological state that involves the dysregulation of different metabolic pathways and adipose tissue cells, constituting a risk factor for the development of other diseases. Bariatric surgery is the most effective treatment. The study of the behavior of pollutants in situations of extreme weight loss can provide biomonitoring information and tools to manage diseases of environmental etiology. Aim: To determine the prevalence of serum persistent and non-persistent pollutants in obese patients subjected to bariatric surgery and analyze the impact of sociodemographic variables on these changes. Methods: GC-MS/MS and UHPLC-MS/MS were utilized to determine the detection rates and concentrations of 353 compounds, including persistent organic pollutants (POPs), pesticides, pharmaceuticals, and rodenticide, in serum samples of 59 obese patients before and after undergoing bariatric surgery. Results: Detection rates of p,p'-DDE, HCB, ß-HCH, naphthalene, phenanthrene and PCB congeners 138, 153 and 180 significantly increased due to surgery-induced weight loss. Serum levels of p,p'-DDE, PCB-138, PCB-153 and PCB-180 also increased after surgery. Correlations between naphthalene levels, weight loss, variation of total lipids and time after surgery were found. Additionally, correlations were observed between concentrations of PCB-138 and weight loss, and between phenanthrene levels and reduction of total lipids. No statistically significant differences were observed for other groups of contaminants, pharmaceuticals and other chemicals included in the quantification methods. Conclusions: Increment of POPs was observed after bariatric surgery. Serum concentrations of POPs after surgery were influenced by adiposity-related variables. Although biomonitoring studies show a decreasing tendency of exposure, rapid weight loss leads to an increase of circulating POPs. Further research on the interplay between adipose tissue, POPs and peripheral organs is required.

Budget impact analysis of introducing fruquintinib for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and biologics in the United States from the payer perspective.

AIMS: Fruquintinib is a selective small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 recently approved in the United States (US) for the treatment of adult patients with metastatic colorectal cancer (CRC) who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, anti-epidermal growth factor receptor therapy. This study aimed to estimate the 5-year budget impact of fruquintinib from a US payer perspective (commercial and Medicare). MATERIALS AND METHODS: A budget impact model was developed to compare two scenarios: a reference scenario in which patients received regorafenib, trifluridine/tipiracil, or trifluridine/tipiracil with bevacizumab and an alternative scenario in which patients received reference scenario treatments or fruquintinib. Market shares were evenly divided across available options. A 5-year time horizon and a hypothetical health plan of 1 million members was assumed. The model included epidemiological inputs to estimate the eligible population; clinical inputs for treatment duration, progression-free survival, overall survival, and adverse event (AE) frequency; and cost inputs for treatment, AEs, disease management, subsequent therapy, and terminal care costs. Budget impact was reported as total, per member per year (PMPY), and per member per month (PMPM). RESULTS: The model estimated an eligible population of 194 patients (39 per year) over 5 years. In the base case, the estimated 5-year budget impact of fruquintinib was $4,077,073 ($0.82 PMPY and 0.07 PMPM) for a commercial health plan. During the first year, the estimated budget impact was $627,570 ($0.63 PMPY and 0.05 PMPM). Results were robust across sensitivity analyses. PMPM costs from the Medicare perspective were greater than the base-case (commercial) ($0.17 vs. $0.07) due to higher incidence of CRC in that population. CONCLUSIONS: Fruquintinib is associated with a low budget impact for payers based on proposed thresholds in the US.

Fruquintinib is a treatment for metastatic colorectal cancer that has progressed after or not responded to multiple guideline-recommended therapies. This budget impact analysis was conducted to estimate the added costs a health plan would incur over a 5-year period if it chose to cover this therapy. The analysis found that the per plan member per month cost of covering fruquintinib was $0.07 for a United States commercial health plan and $0.17 for Medicare.

Improving wine fermentation efficiency of Torulaspora delbrueckii by increasing the ploidy of yeast inocula.

The life cycle of most non-conventional yeasts, such as Torulaspora delbrueckii (Td), is not as well-understood as that of Saccharomyces cerevisiae (Sc). Td is generally assumed to be haploid, which detracts from some biotechnological properties compared to diploid Sc strains. We analyzed the life cycle of several Td wine strains and found that they were mainly diploid during exponential growth in rich medium. However, most cells became haploid in stationary phase, as observed for Sc haploid heterothallic strains. When transferred and incubated in nutrient-deficient media, these haploid cells became polymorphic, enlarged, and transitioned to diploid or polyploid states. The increased ploidy, that mainly results from supernumerary mitosis without cytokinesis, was followed by sporulation. A similar response was observed in yeasts that remained alive during the second fermentation of base wine for sparkling wine making, or during growth in ethanol-supplemented medium. This response was not observed in the Sc yeast populations under any of the experimental conditions assayed, which suggests that it is a specific adaptation of Td to the stressful fermentation conditions. This response allows Td yeasts to remain alive and metabolically active longer during wine fermentation. Consequently, we designed procedures to increase the cell size and ploidy of haploid Td strains. Td inocula with increased ploidy showed enhanced fermentation efficiency compared to haploid inocula of the same strains.

The maze of real-world evidence frameworks: from a desert to a jungle! An environmental scan and comparison across regulatory and health technology assessment agencies.

Aim: Regulatory and health technology assessment (HTA) agencies have increasingly published frameworks, guidelines, and recommendations for the use of real-world evidence (RWE) in healthcare decision-making. Variations in the scope and content of these documents, with updates running in parallel, may create challenges for their implementation especially during the market authorization and reimbursement phases of a medicine's life cycle. This environmental scan aimed to comprehensively identify and summarize the guidance documents for RWE developed by most well-established regulatory and reimbursement agencies, as well as other organizations focused on healthcare decision-making, and present their similarities and differences. Methods: RWE guidance documents, including white papers from regulatory and HTA agencies, were reviewed in March 2024. Data on scope and recommendations from each body were extracted by two reviewers and similarities and differences were summarized across four topics: study planning, choosing fit-for-purpose data, study conduct, and reporting. Post-authorization or non-pharmacological guidance was excluded. Results: Forty-six documents were identified across multiple agencies; US FDA produced the most RWE-related guidance. All agencies addressed specific and often similar methodological issues related to study design, data fitness-for-purpose, reliability, and reproducibility, although inconsistency in terminologies on these topics was noted. Two HTA bodies (National Institute for Health and Care Excellence [NICE] and Canada's Drug Agency) each centralized all related RWE guidance under a unified framework. RWE quality tools and checklists were not consistently named and some differences in preferences were noted. European Medicines Agency, NICE, Haute Autorité de Santé, and the Institute for Quality and Efficiency in Health Care included specific recommendations on the use of analytical approaches to address RWE complexities and increase trust in its findings. Conclusion: Similarities in agencies' expectations on RWE studies design, quality elements, and reporting will facilitate evidence generation strategy and activities for manufacturers facing multiple, including global, regulatory and reimbursement submissions and re-submissions. A strong preference by decision-making bodies for local real-world data generation may hinder opportunities for data sharing and outputs from international federated data networks. Closer collaboration between decision-making agencies towards a harmonized RWE roadmap, which can be centrally preserved in a living mode, will provide manufacturers and researchers clarity on minimum acceptance requirements and expectations, especially as novel methodologies for RWE generation are rapidly emerging.

Responses of Dunaliella sp. AL-1 to chromium and copper: Biochemical and physiological studies.

Microalgae have gained recognition as versatile candidates for the remediation of heavy metals (HMs). This study investigated the biosorption potential of Dunaliella sp. AL1 for copper (Cu(II)) and hexavalent chromium (Cr(VI)) in aqueous solutions. The marine microalga Dunaliella sp. AL1 was exposed to half-sublethal concentrations of both metals in single and bimetallic systems, and responses in algal growth, oxidative stress, photosynthetic pigment production, and photosynthetic performance were evaluated. Cu and/or Cr exposure increased the generation of reactive oxygen species (ROS) in microalgae cells but did not impact algal growth. In terms of photosynthesis, there was a decrease in chlorophylls and carotenoids production in the microalgae culture treated with Cr, either alone or in combination with Cu. The study recorded promising metal removal efficiencies: 26.67%-20.11% for Cu and 94.99%-95.51% for Cr, in single and bimetallic systems, respectively. FTIR analysis revealed an affinity of Cu and Cr ions towards aliphatic/aldehyde C-H, N-H bending, and phosphate groups, suggesting the formation of complex bonds. Biochemical analysis of microalgae biomass collected after the removal of Cr alone or in combination with Cu showed a significant decrease in total carbohydrate content and soluble protein levels. Meanwhile, higher lipid accumulation was recorded and evidenced by BODIPY 505/515 staining. Fatty acid composition analysis by GC revealed a modulation in lipid composition, with a decrease in the ratio of unsaturated fatty acids (UFA) to saturated fatty acids (SFA), in response to Cu, Cr, and Cu-Cr exposure, indicating the suitability of the biomass for sustainable biofuel production.

Adverse event costs of systemic therapies for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy and biologics in the US.

Aim: The objective of this study was to compare adverse event (AE) management costs for fruquintinib, regorafenib, trifluridine/tipiracil (T/T) and trifluridine/tipiracil+bevacizumab (T/T+bev) for patients with metastatic colorectal cancer (mCRC) previously treated with at least two prior lines of therapy from the US commercial and Medicare payer perspectives. Materials & methods: A cost-consequence model was developed to calculate the per-patient and per-patient-per-month (PPPM) AE costs using rates of grade 3/4 AEs with incidence ≥5% in clinical trials, event-specific management costs and duration treatment. Anchored comparisons of AE costs were calculated using a difference-in-differences approach with best supportive care (BSC) as a common reference. AE rates and treatment duration were obtained from clinical trials: FRESCO and FRESCO-2 (fruquintinib), RECOURSE (T/T), CORRECT (regorafenib) and SUNLIGHT (T/T, T/T+bev). AE management costs for the commercial and Medicare perspectives were obtained from publicly available sources. Results: From the commercial perspective, the AE costs (presented as per-patient, PPPM) were: $4015, $1091 for fruquintinib (FRESCO); $4253, $1390 for fruquintinib (FRESCO-2); $17,110, $11,104 for T/T (RECOURSE); $9851, $4691 for T/T (SUNLIGHT); $8199, $4823 for regorafenib; and $11,620, $2324 for T/T+bev. These results were consistent in anchored comparisons: the difference-in-difference for fruquintinib based on FRESCO was -$1929 versus regorafenib and -$11,427 versus T/T; for fruquintinib based on FRESCO-2 was -$2257 versus regorafenib and -$11,756 versus T/T. Across all analyses, results were consistent from the Medicare perspective. Conclusion: Fruquintinib was associated with lower AE management costs compared with regorafenib, T/T and T/T+bev for patients with previously treated mCRC. This evidence has direct implications for treatment, formulary and pathways decision-making in this patient population.

A multidisciplinary approach using hydrogeochemistry, δ15NNO3 isotopes, land use, and statistical tools in evaluating nitrate pollution sources and biochemical processes in Costa Rican volcanic aquifers.

Nitrate pollution threatens the Barva and Colima multi-aquifer system, the primary drinking water source in the Greater Metropolitan Area of Costa Rica. In addressing nitrate contamination dynamics, this study proposes an integrated approach by combining multivariate statistical analyses, hydrochemical parameters, sewage discharge, and regional land-use and land-cover patterns to assess the extent and degree of contamination, dominant biogeochemical processes, and refine the interpretation of nitrate sources previously derived solely from δ15NNO3 information. Over seven years (2015-2022), 714 groundwater samples from 43 sites were analyzed for nitrate and major ions, including two sampling campaigns for dissolved organic and inorganic carbon, nitrite, ammonium, FeTotal, MnTotal, and δ15NNO3 analyses. The findings presented elevated nitrate concentrations in urban and agricultural/urban areas, surpassing the Maximum Concentration Levels on several occasions, and oxidizing conditions favoring mineralization and nitrification processes in unconfined Barva and locally confined Upper Colima/Lower Colima aquifers. Similar nitrate contents and spatial patterns in agricultural and urban zones in the shallow Barva aquifer suggest comparable contributions from nitrogen fertilizers and urban wastewaters despite the gradual increase in urban land cover and the reduction of agricultural areas. Isotopic analyses and dissolved organic carbon (DOC) indicate a shift in nitrate sources from agricultural to urban areas in both Barva and Colima aquifers. Principal Component and Hierarchical Cluster Analyses link land use, nitrate sources, and water quality. Three distinct sample clusters aligned with forest/grassland, agricultural/urban, and urban land use, emphasizing the impact of anthropogenic activities on groundwater quality, even in the deeper Colima aquifers. The study challenges nitrate isotope mixing models, enhancing accuracy in identifying pollution sources and assessing the spatial extent of contamination by incorporating DOC and other hydrochemical parameters. Similar outcomes, with and without the use of nitrate isotopes, reinforce the usefulness of the integrated approach, providing a practical and cost-effective alternative.