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Purpose of Review: This review examines the long-term efficacy and safety of various nutritional and pharmacological strategies for managing obesity. The focus is on the Mediterranean diet (MedDiet), very low-energy ketogenic therapy (VLEKT), and pharmacological interventions such as naltrexone/bupropion and liraglutide. Given the chronic nature of obesity, understanding the sustainability and impact of these treatments over time is critical., Recent Findings: The MedDiet has shown significant benefits for cardiovascular health and moderate long-term weight loss, though it does not always outperform other diets in terms of weight reduction. VLEKT is highly effective for rapid weight loss, but concerns remain about its long-term sustainability. Pharmacological treatments, including naltrexone/bupropion and liraglutide, have shown promise in promoting significant weight loss and improving metabolic markers. However, issues related to long-term adherence and potential side effects need further exploration. Both nutritional and pharmacological strategies offer valuable tools in obesity management. While treatments like VLEKT and pharmacological options provide significant short-term benefits, the MedDiet remains a sustainable long-term approach. The long-term efficacy and safety of naltrexone/bupropion and liraglutide require more investigation to address challenges in weight maintenance and side effects. Further studies are needed to establish the optimal duration and combination of these therapies for sustained obesity management., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The challenge of addressing obesity persists in healthcare, necessitating nuanced approaches and personalized strategies. This study aims to evaluate the effects of diverse therapeutic interventions on anthropometric and biochemical parameters in individuals with overweight and obesity within a real-world clinical context., Methods: A retrospective analysis was conducted on 192 patients (141 females, 51 males) aged 18 to 75, with a BMI ranging from 25 to 30 (14.1%) and BMI ≥ 30 (85.9%), observed over a 12-month period at our Endocrinology Unit. Treatment cohorts comprised individuals following different regimens: Mediterranean Diet (MD), with an approximate daily intake of 1500 kcal for women and 1800 kcal for men (71% patients); Ketogenic Diet (KD), utilizing the VLCKD protocol characterized by a highly hypocaloric dietary regimen < 800 kcal/day (14% patients); metformin, administered using the oral formulation (5% patients); pharmacological intervention with GLP1-RA administered via subcutaneous injection with incremental dosage (10% patients). Supply constraints limited the efficacy of Liraglutide, whereas Semaglutide was excluded from comparisons due to its unavailability for obesity without diabetes. Blood tests were conducted to assess lipid profile, glycemic profile, and anthropometric parameters, including BMI, waist circumference, and waist-to-height ratio., Results: Significant BMI changes were observed from baseline to 6 months across MD, KD, and Liraglutide groups (p < 0.05). KD exhibited notable reductions in waist circumference and waist-to-height ratio within the initial quarter (p < 0.05), with a significant triglyceride decrease after 6 months (p < 0.05), indicating its efficacy over MD. Liraglutide demonstrated a substantial reduction in HbA1 c levels in the first quarter (p < 0.05). During the first three months, the ANOVA test on fasting blood glucose showed a statistically significant impact of the time variable (p < 0.05) rather than the specific treatments themselves (Liraglutide and KD), suggesting that adherence during the early stages of therapy may be more critical than treatment choice., Conclusions: Positive outcomes from targeted interventions, whether pharmacological or dietary should encourage the exploration of innovative, long-term strategies that include personalized treatment alternation. The absence of standardized protocols underscores the importance of careful and tailored planning in managing obesity as a chronic condition., (© 2024. The Author(s).)

Background: Severe and/or symptomatic hypocalcemia due to hypoparathyroidism is the main contraindication for discharge in patients who have undergone thyroid surgery. Hypomagnesemia may contribute to the onset of hypoparathyroidism and is frequently observed after thyroid surgery in hypocalcemic patients. The impact of prophylactic and postoperative Magnesium supplementation on postoperative hypocalcemia and hypomagnesemia was prospectively evaluated by comparing patients undergoing prophylactic supplementation to a control group of patients who had only received magnesium after evidence of postoperative hypomagnesemia., Methods: One hundred and twenty patients who underwent a total thyroidectomy participated in the study. Seventy-three patients were included in the study group, 47 in the control group. Prior to surgery, patients in the study group were given magnesium orally for 5 days; postoperatively, calcium and magnesium was administered to all patients who displayed hypocalcemia and hypomagnesemia., Results: Postoperative biochemical hypocalcemia (serum calcium <8.5 mg/dL, regardless of its clinical severity) was found in 60 patients (50%) on D1 and in 58 patients (48.4%) on D2. Among hypocalcemic patients, hypomagnesemia was recorded in 29 at D1 (48%), and in 46 at D2 (79%). A significant positive correlation was found between magnesium, calcium, and parathyroid hormone in the first two postoperative days, while a significant inverse correlation occurred for these same parameters and length of hospital stay (P<0.001). One hundred and five patients (87.5%) were discharged as expected on the second postoperative day (65 in the study group, 40 in the control group, P=0.724), whereas 15 patients (12.5%) required prolonged hospitalization (eight in the study group, seven in the control group, P=0.721). The Study group only showed significantly higher magnesium levels on the first postoperative day (P=0.03)., Conclusions: Although magnesium and calcium levels showed the same trend after thyroidectomy, neither Magnesium prophylaxis nor Magnesium treatment influenced the clinical course of postoperative hypocalcemia.

The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua , which means door . How many new doors will this old drug be able to open?, Competing Interests: The authors declare no conflicts of interest.

Pancreatic fluid collections (PFCs) are well-known complications of acute pancreatitis. The overinfection of these collections leads to a worsening of the prognosis with an increase in the morbidity and mortality rate. The primary strategy for managing infected pancreatic necrosis (IPN) or symptomatic PFCs is a minimally invasive step-up approach, with endosonography-guided (EUS-guided) transmural drainage and debridement as the preferred and less invasive method. Different stents are available to drain PFCs: self-expandable metal stents (SEMSs), double pigtail stents (DPPSs), or lumen-apposing metal stents (LAMSs). In particular, LAMSs are useful when direct endoscopic necrosectomy is needed, as they allow easy access to the necrotic cavity; however, the rate of adverse events is not negligible, and to date, the superiority over DPPSs is still debated. Moreover, the timing for necrosectomy, the drainage technique, and the concurrent medical management are still debated. In this review, we focus attention on indications, timing, techniques, complications, and particularly on aspects that remain under debate concerning the EUS-guided drainage of PFCs.

Background: Syndrome of inappropriate antidiuresis (SIAD) is one of the most frequent causes of euvolemic hyponatremia (serum sodium levels < 135 mEq/L) and it represents more than 35% of hyponatremia cases in hospitalized patients. It is characterized by an inappropriate vasopressin (AVP)/antidiuretic hormone (ADH) secretion, which occurs independently from effective serum osmolality or circulating volume, leading to water retention via its action on type 2 vasopressin receptor in the distal renal tubules. Corpus callosum agenesis (CCA) is one of the most common congenital brain defects, which can be associated to alterations in serum sodium levels. This report presents a rare case of chronic hyponatremia associated with SIAD in a woman with CCA, whose correction of serum sodium levels only occurred following twice-daily tolvaptan administration., Case Presentation: A 30-year-old female was admitted to our hospital for non-acute hyponatremia with dizziness, headache, distal tremors, and concentration deficits. She had profound hyponatremia (Na 121 mmol/L) with measured plasma hypo-osmolality (259 mOsm/Kg) and urinary osmolality greater than 100 mOsm/Kg (517 mOsm/Kg). She presented clinically as normovolemic. After the exclusion of other causes of normovolemic hyponatremia, such as hypothyroidism and adrenal insufficiency, a diagnosis of SIAD was established. We have ruled out paraneoplastic, inflammatory, and infectious causes, as well as ischemic events. Her medical history showed a CCA and frontal teratoma. We administered tolvaptan initially at a low dosage (15 mg once a day) with persistence of hyponatremia. Therefore, the dosage was first doubled (30 mg once a day) and then increased to 45 mg once a day with an initial improvement in serum sodium levels, although not long-lasting. We therefore tried dividing the 45 mg tolvaptan administration into two doses of 30 mg and 15 mg respectively, using an off-label treatment schedule, thus achieving long-lasting serum sodium levels in the low-normal range associated with a general clinical improvement., Conclusions: This report underlines the importance of the correct diagnosis, management and treatment of SIAD, as well as the need for further studies about the pharmacokinetics and pharmacodynamics of vasopressin receptor antagonists., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Arecco, Demontis, Della Sala, Musso, Gay, Boschetti, Ferone and Gatto.)

Background: The role of vitamin D (25(OH)D) in the pathogenesis and outcome of several conditions, including autoimmune diseases, diabetes and cancers is largely described in the literature. The aims of this study were to evaluate the prevalence of 25(OH)D deficit in a cohort of patients with neuroendocrine neoplasms (NENs) in comparison to a matched healthy control group and to analyze the possible role of 25(OH)D as a prognostic factor for NENs in terms of biological aggressiveness, tumor progression and survival. Methods: From 2009 to 2023, 172 patients with NENs (99 females; median age, 63 years) were included in the study. Serum 25(OH)D levels were defined as deficient if ≤20 ng/mL. The possible associations between 25(OH)D levels and disease grading, staging, ki67%, overall survival (OS), and progression-free survival (PFS) were considered. Results: NEN patients had significantly lower 25(OH)D levels compared to controls ( p < 0.001) regardless of the primary origin. Patients with 25(OH)D < 20 ng/mL had a significantly higher ki67 index ( p = 0.02) compared to the ones with 25(OH)D levels above 20 ng/mL. Patients with disease progression were found to have a significantly lower 25(OH)D at baseline ( p = 0.02), whereas PFS and OS were not significantly influenced by 25(OH)D. Conclusions: Vitamin D deficiency is highly prevalent among NENs and is associated with higher ki67 and disease progression. Our study highlights the importance of monitoring 25(OH)D levels in patients with NENs, as its deficiency appeared to be linked to the worst biological tumor aggressiveness.

Background: We present an intriguing case of primary adrenal lymphoma, with associated primary adrenal insufficiency (PAI), in a patient presenting a transitory partial 21-hydroxylase deficiency during the active phase of the adrenal disease., Case Presentation: An 85-years old woman was referred because of worsening asthenia, lumbar pain, generalized myalgia and arthralgia. During investigations a computed tomography (CT) scan evidenced two large bilateral adrenal masses, highly suspicious for primary adrenal tumor. The hormonal assessment revealed very low levels of morning plasma cortisol and 24-h urinary cortisol, elevated ACTH levels with low plasma concentration of aldosterone, pointing to the diagnosis of PAI. After diagnosis of PAI our patient started glucocorticoid and mineralcorticoid replacement therapy with clinical benefit. In order to further characterize the adrenal lesions, adrenal biopsy, was performed. The histology revealed a high grade non-Hodgkin lymphoma with an immunophenotype consistent with intermediate aspects between diffuse large B-cell and Burkitt lymphoma, with a high proliferation index (KI-67 > 90%). The patient received chemotherapy with epirubicin, vincristine, cyclophosphamide, and rituximab, associated with methylprednisolone that resulted in a complete clinical and radiological remission within one year. After 2 years from the diagnosis and a total of 6 cycles of rituximab, the patient was in good clinical condition and was taking only the replacement therapy for PAI. The patient initially presented also a slight increase of 17-hydroxyprogesterone (17-OHP) for age that normalize after resolution of lymphoproliferative disease., Conclusions: In the presence of bilateral adrenal disease and/or in the presence of signs and symptoms of PAI clinicians must exclude the presence of PAL. The evidence of elevated ACTH-stimulated 17-OHP levels also in patients with other adrenal masses, together with the detection of elevated basal 17-OHP levels in our patient make it more plausible, in our view, an effect of the lesion on the "healthy" adrenal tissue residue than a direct secretory activity by the adrenal tumor., (© 2023. The Author(s).)

Over the past few years, several applications have been extensively exploiting the advantages of deep learning, in particular when using convolutional neural networks (CNNs). The intrinsic flexibility of such models makes them widely adopted in a variety of practical applications, from medical to industrial. In this latter scenario, however, using consumer Personal Computer (PC) hardware is not always suitable for the potential harsh conditions of the working environment and the strict timing that industrial applications typically have. Therefore, the design of custom FPGA (Field Programmable Gate Array) solutions for network inference is gaining massive attention from researchers and companies as well. In this paper, we propose a family of network architectures composed of three kinds of custom layers working with integer arithmetic with a customizable precision (down to just two bits). Such layers are designed to be effectively trained on classical GPUs (Graphics Processing Units) and then synthesized to FPGA hardware for real-time inference. The idea is to provide a trainable quantization layer, called Requantizer , acting both as a non-linear activation for neurons and a value rescaler to match the desired bit precision. This way, the training is not only quantization-aware , but also capable of estimating the optimal scaling coefficients to accommodate both the non-linear nature of the activations and the constraints imposed by the limited precision. In the experimental section, we test the performance of this kind of model while working both on classical PC hardware and a case-study implementation of a signal peak detection device running on a real FPGA. We employ TensorFlow Lite for training and comparison, and use Xilinx FPGAs and Vivado for synthesis and implementation. The results show an accuracy of the quantized networks close to the floating point version, without the need for representative data for calibration as in other approaches, and performance that is better than dedicated peak detection algorithms. The FPGA implementation is able to run in real time at a rate of four gigapixels per second with moderate hardware resources, while achieving a sustained efficiency of 0.5 TOPS/W (tera operations per second per watt), in line with custom integrated hardware accelerators.

Background: The vanishing testis syndrome (VTS), is a 46, XY disorder of sex development (46, XY DSD) and is characterized by the absence of testis in a 46, XY subject with male genitalia, gonadal dysgenesis and consequent hypergonadotropic hypogonadism., Case Presentation: A young man affected by VTS has been followed up for more than 15-year in our center. The patient received different testosterone formulations, which modulated his IGF-1 levels and height velocity, depending on different stimulatory effects, mimicking pubertal spurt until achieving a final height in line with his genetic target. Exogenous testosterone, activating GH/IGF-1 system, can directly influence growth pattern. With this particular case report we demonstrate that an accurate monitoring of patients with VTS, as well as a perfect reproduction of testosterone secretion during pubertal spurt, can guarantee a normal growth and development and, consequently, a high level of quality of life in adulthood., Conclusion: Testosterone levels act an important role during pubertal spurt in modulating the GH/IGF-1 axis, besides its well-known impact in sexual development. Very little amount of exogenous testosterone can stimulate IGF-1 secretion and provide to growth velocity the drive that characterizes the initial phases of the growth spurt., (© 2023. The Author(s).)

Although GH and IGF-1 excess has a controversial impact on bone mineral density (BMD), acromegalic patients display variable degrees of bone structure impairment. In this study, we aim to investigate the usefulness of trabecular bone score (TBS), compared to BMD, in identifying acromegalic patients with impaired lumbar spine trabecular microarchitecture. Forty-four acromegalic patients were investigated for disease control, metabolic and gonadal status, bone metabolism parameters, and the presence of vertebral fractures (VFs). Patients and matched healthy controls underwent BMD and TBS examination. Mean TBS values were lower in patients than in controls (p < 0.001), without significant differences in mean lumbar and femoral BMD. TBS values were significantly higher in controlled patients compared to the uncontrolled ones (p = 0.012). No significant differences were found in bone markers with respect to disease control. Mean TBS or lumbar BMD did not significantly differ in patients with or without VFs (prevalence 11.4%). TBS and BMD levels were lower in hypogonadal patients compared to the eugonadal ones (p = 0.030 and p < 0.001, respectively). In conclusion, TBS values are significantly lower in patients than in controls, confirming the presence of impaired lumbar spine trabecular bone in acromegaly. Both uncontrolled disease and hypogonadism contribute to TBS deterioration in acromegaly.

Background: Diabetic striatopathy is defined as a state of hyperglycemia associated with chorea/ballism, striatal hyperdensity at CT, or hyperintensity at T1-weighted MRI. It is considered a rare complication of uncontrolled diabetes but prevalence data are scarce., Objectives: Characterize diabetic striatopathy prevalence in the population afferent to the largest teaching hospital in Genova (Liguria, Italy) and investigate the role of glycated hemoglobin level in predicting the risk., Methods: Data were retrospectively obtained from general population undergoing blood sampling for glycated hemoglobin and resulting with HbA1c values ≥ 8%, from January 2014 to June 2017. Brain neuroimaging of those who underwent at least a brain CT or MRI was examined in search of findings compatible with diabetic striatopathy and clinical information was collected. Logistic regression was used to predict the risk of diabetic striatopathy based on age and HbA1c values., Results: Subjects with uncontrolled diabetes were 4603. Brain neuroimaging was available in 1806 subjects and three patients with diabetic striatopathy were identified, all of them reporting choreic movements. The prevalence of hemichorea due to diabetic striatopathy was therefore 3 cases out of 1806 (0.16%) in our population. Hepatic and hypoxic encephalopathies were the conditions most frequently mimicking diabetic striatopathy. Odds ratio of diabetic striatopathy and HbA1c level was significantly correlated (p = 0.0009)., Conclusions: To the best of our knowledge, this study is the first to evaluate the prevalence of diabetic striatopathy in Italy. High HbA1c values may have a role in predicting diabetic striatopathy., (© 2022. The Author(s).)

The spaceborne imaging spectroscopy mission PRecursore IperSpettrale della Missione Applicativa (PRISMA), launched on 22 March 2019 by the Italian Space Agency, opens new opportunities in many scientific domains, including precision farming and sustainable agriculture. This new Earth Observation (EO) data stream requires new-generation approaches for the estimation of important biophysical crop variables (BVs). In this framework, this study evaluated a hybrid approach, combining the radiative transfer model PROSAIL-PRO and several machine learning (ML) regression algorithms, for the retrieval of canopy chlorophyll content (CCC) and canopy nitrogen content (CNC) from synthetic PRISMA data. PRISMA-like data were simulated from two images acquired by the airborne sensor HyPlant, during a campaign performed in Grosseto (Italy) in 2018. CCC and CNC estimations, assessed from the best performing ML algorithms, were used to define two relations with plant nitrogen uptake (PNU). CNC proved to be slightly more correlated to PNU than CCC ( R 2 = 0.82 and R 2 = 0.80, respectively). The CNC-PNU model was then applied to actual PRISMA images acquired in 2020. The results showed that the estimated PNU values are within the expected ranges, and the temporal trends are compatible with plant phenology stages., Competing Interests: Disclosure statement No potential conflict of interest was reported by the authors.

Background: To investigate the effects of the COVID-19 lockdowns on the vasculopathic population. Methods: The Divisions of Vascular Surgery of the southern Italian peninsula joined this multicenter retrospective study. Each received a 13-point questionnaire investigating the hospitalization rate of vascular patients in the first 11 months of the COVID-19 pandemic and in the preceding 11 months. Results: 27 out of 29 Centers were enrolled. April-December 2020 (7092 patients) vs. 2019 (9161 patients): post-EVAR surveillance, hospitalization for Rutherford category 3 peripheral arterial disease, and asymptomatic carotid stenosis revascularization significantly decreased (1484 (16.2%) vs. 1014 (14.3%), p = 0.0009; 1401 (15.29%) vs. 959 (13.52%), p = 0.0006; and 1558 (17.01%) vs. 934 (13.17%), p < 0.0001, respectively), while admissions for revascularization or major amputations for chronic limb-threatening ischemia and urgent revascularization for symptomatic carotid stenosis significantly increased (1204 (16.98%) vs. 1245 (13.59%), p < 0.0001; 355 (5.01%) vs. 358 (3.91%), p = 0.0007; and 153 (2.16%) vs. 140 (1.53%), p = 0.0009, respectively). Conclusions: The suspension of elective procedures during the COVID-19 pandemic caused a significant reduction in post-EVAR surveillance, and in the hospitalization of asymptomatic carotid stenosis revascularization and Rutherford 3 peripheral arterial disease. Consequentially, we observed a significant increase in admissions for urgent revascularization for symptomatic carotid stenosis, as well as for revascularization or major amputations for chronic limb-threatening ischemia.

The new 2019 coronavirus 19 disease (CoVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to health systems. As a global health problem, this pandemic poses a huge threat to people and is responsible for significant morbidity and mortality worldwide. On the other hand, obesity has also reached epidemic proportions and poses another challenge to the healthcare system. There is increasing evidence of a strong association between obesity and CoVID-19 disease, but the mechanisms underlying the link between the two remain unclear and the role of obesity also remains to be elucidated. In particular obesity-related low-grade inflammation has been hypothesized as the Achille's heel that could predispose subjects with obesity to a more severe CoVID-19 compared to subjects with normal weight. Hence, we summarized recent evidence on the role of low-grade inflammation in clinical aspects of CoVID-19 in subjects with obesity in both childhood and adulthood. Further, we provide molecular insights to explain this link., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The recently launched and upcoming hyperspectral satellite missions, featuring contiguous visible-to-shortwave infrared spectral information, are opening unprecedented opportunities for the retrieval of a broad set of vegetation traits with enhanced accuracy through novel retrieval schemes. In this framework, we exploited hyperspectral data cubes collected by the new-generation PRecursore IperSpettrale della Missione Applicativa (PRISMA) satellite of the Italian Space Agency to develop and test a hybrid retrieval workflow for crop trait mapping. Crop traits were mapped over an agricultural area in north-east Italy (Jolanda di Savoia, FE) using PRISMA images collected during the 2020 and 2021 vegetative seasons. Leaf chlorophyll content, leaf nitrogen content, leaf water content and the corresponding canopy level traits scaled through leaf area index were estimated using a hybrid retrieval scheme based on PROSAIL-PRO radiative transfer simulations coupled with a Gaussian processes regression algorithm. Active learning algorithms were used to optimise the initial set of simulated data by extracting only the most informative samples. The accuracy of the proposed retrieval scheme was evaluated against a broad ground dataset collected in 2020 in correspondence of three PRISMA overpasses. The results obtained were positive for all the investigated variables. At the leaf level, the highest accuracy was obtained for leaf nitrogen content (LNC: r 2 =0.87, nRMSE=7.5%), while slightly worse results were achieved for leaf chlorophyll content (LCC: r 2 =0.67, nRMSE=11.7%) and leaf water content (LWC: r 2 =0.63, nRMSE=17.1%). At the canopy level, a significantly higher accuracy was observed for nitrogen content (CNC: r 2 =0.92, nRMSE=5.5%) and chlorophyll content (CCC: r 2 =0.82, nRMSE=10.2%), whereas comparable results were obtained for water content (CWC: r 2 =0.61, nRMSE=16%). The developed models were additionally tested against an independent dataset collected in 2021 to evaluate their robustness and exportability. The results obtained (i. e., LCC: r 2 =0.62, nRMSE=27.9%; LNC: r 2 =0.35, nRMSE=28.4%; LWC: r 2 =0.74, nRMSE=20.4%; LAI: r 2 =0.84, nRMSE=14.5%; CCC: r 2 =0.79, nRMSE=18.5%; CNC: r 2 =0.62, nRMSE=23.7%; CWC: r 2 =0.92, nRMSE=16.6%) evidence the transferability of the hybrid approach optimised through active learning for most of the investigated traits. The developed models were then used to map the spatial and temporal variability of the crop traits from the PRISMA images. The high accuracy and consistency of the results demonstrates the potential of spaceborne imaging spectroscopy for crop monitoring, paving the path towards routine retrievals of multiple crop traits over large areas that could drive more effective and sustainable agricultural practices worldwide., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

In the next few years, the new Copernicus Hyperspectral Imaging Mission (CHIME) is foreseen to be launched by the European Space Agency (ESA). This missions will provide an unprecedented amount of hyperspectral data, enabling new research possibilities within several fields of natural resources, including the "agriculture and food security" domain. In order to efficiently exploit this upcoming hyperspectral data stream, new processing methods and techniques need to be studied and implemented. In this work, the hybrid approach (HYB) and its variant, featuring sampling dimensionality reduction through active learning heuristics (HAL), were applied to CHIME-like data to evaluate the retrieval of crop traits, such as chlorophyll and nitrogen content at both leaf (LCC and LNC) and canopy level (CCC and CNC). The results showed that HYB was able to provide reliable estimations at canopy level (R 2 = 0.79, RMSE = 0.38 g m -2 for CCC and R 2 = 0.84, RMSE = 1.10 g m -2 for CNC) but failed at leaf level. The HAL approach improved retrieval accuracy at canopy level (best metric: R 2 = 0.88 and RMSE = 0.21 g m -2 for CCC; R 2 = 0.93 and RMSE = 0.71 g m -2 for CNC), providing good results also at leaf level (best metrics: R 2 = 0.72 and RMSE = 3.31 μg cm -2 for LCC; R 2 = 0.56 and RMSE = 0.02 mg cm -2 for LNC). The promising results obtained through the hybrid approach support the feasibility of an operational retrieval of chlorophyll and nitrogen content, e.g., in the framework of the future CHIME mission. However, further efforts are required to investigate the approach across different years, sites and crop types in order to improve its transferability to other contexts., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The unprecedented availability of optical satellite data in cloud-based computing platforms, such as Google Earth Engine (GEE), opens new possibilities to develop crop trait retrieval models from the local to the planetary scale. Hybrid retrieval models are of interest to run in these platforms as they combine the advantages of physically- based radiative transfer models (RTM) with the flexibility of machine learning regression algorithms. Previous research with GEE primarily relied on processing bottom-of-atmosphere (BOA) reflectance data, which requires atmospheric correction. In the present study, we implemented hybrid models directly into GEE for processing Sentinel-2 (S2) Level-1C (L1C) top-of-atmosphere (TOA) reflectance data into crop traits. To achieve this, a training dataset was generated using the leaf-canopy RTM PROSAIL in combination with the atmospheric model 6SV. Gaussian process regression (GPR) retrieval models were then established for eight essential crop traits namely leaf chlorophyll content, leaf water content, leaf dry matter content, fractional vegetation cover, leaf area index (LAI), and upscaled leaf variables (i.e., canopy chlorophyll content, canopy water content and canopy dry matter content). An important pre-requisite for implementation into GEE is that the models are sufficiently light in order to facilitate efficient and fast processing. Successful reduction of the training dataset by 78% was achieved using the active learning technique Euclidean distance-based diversity (EBD). With the EBD-GPR models, highly accurate validation results of LAI and upscaled leaf variables were obtained against in situ field data from the validation study site Munich-North-Isar (MNI), with normalized root mean square errors (NRMSE) from 6% to 13%. Using an independent validation dataset of similar crop types (Italian Grosseto test site), the retrieval models showed moderate to good performances for canopy-level variables, with NRMSE ranging from 14% to 50%, but failed for the leaf-level estimates. Obtained maps over the MNI site were further compared against Sentinel-2 Level 2 Prototype Processor (SL2P) vegetation estimates generated from the ESA Sentinels' Application Platform (SNAP) Biophysical Processor, proving high consistency of both retrievals ( R from 0.80 to 0.94). Finally, thanks to the seamless GEE processing capability, the TOA-based mapping was applied over the entirety of Germany at 20 m spatial resolution including information about prediction uncertainty. The obtained maps provided confidence of the developed EBD-GPR retrieval models for integration in the GEE framework and national scale mapping from S2-L1C imagery. In summary, the proposed retrieval workflow demonstrates the possibility of routine processing of S2 TOA data into crop traits maps at any place on Earth as required for operational agricultural applications.2 from 0.80 to 0.94). Finally, thanks to the seamless GEE processing capability, the TOA-based mapping was applied over the entirety of Germany at 20 m spatial resolution including information about prediction uncertainty. The obtained maps provided confidence of the developed EBD-GPR retrieval models for integration in the GEE framework and national scale mapping from S2-L1C imagery. In summary, the proposed retrieval workflow demonstrates the possibility of routine processing of S2 TOA data into crop traits maps at any place on Earth as required for operational agricultural applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.